ArticleLiterature Review

How does blood glucose control with insulin save lives in intensive care?

December 2004
The Journal of clinical investigation 114(9):1187-95

December 2004
114(9):1187-95

Source
PubMed

Authors:

Patients requiring prolonged intensive care are at high risk for multiple organ failure and death. Insulin resistance and hyperglycemia accompany critical illness, and the severity of this "diabetes of stress" reflects the risk of death. Recently it was shown that preventing hyperglycemia with insulin substantially improves outcome of critical illness. This article examines some potential mechanisms underlying prevention of glucose toxicity as well as the effects of insulin independent of glucose control. Unraveling the molecular mechanisms will provide new insights into the pathogenesis of multiple organ failure and open avenues for novel therapeutic strategies.

DIFFERENCES IN BLOOD SUGAR LEVELS BEFORE AND AFTER MORNING AND AFTERNOON WALK IN TYPE II DIABETES MELITUS PATIENTS AT BABAKANSARI PUSKESMAS

Article

Full-text available

Apr 2023

Diabetes Mellitus (DM) is a non-communicable disease which causes an increase in blood sugar levels and is at risk of causing disease complications. Walking is done to increase the sensitivity of insulin receptors. Blood vessels in the afternoon are more vasodilated than in the morning due to the effects of circadian rhythms which affect hormone action. This study aims to determine the difference in the average value of blood sugar levels before and after walking in the morning and afternoon in patients with type II DM. The research design used was a preexperiment with a pretest-posttest two group design approach. The sample of 20 respondents who are divided into 2 groups, namely the morning group of 10 people and the afternoon group of 10 people, with purposive sampling. The results of this study showed that the amount of decrease in blood sugar levels in the morning group was 31.6 mg/dL and the amount of decrease in blood sugar levels in the afternoon group was 43.5 mg/dL. The results of statistical tests in the morning group obtained a value of p = 0.007 (p <0.05) and in the afternoon group obtained a value of p = 0.005 (p <0.05). The results showed that the afternoon group was more effective in reducing average blood glucose levels as a result of vasodilatation of blood vessels which is influenced by circadian rhythms compared to the morning group, so it can be concluded that there are differences in blood sugar levels before and after walking in the morning and in the afternoon in patients with type II DM. Therefore it is advisable to walk, especially in the afternoon which can lower blood sugar levels more for type II DM sufferers in an effort to control blood sugar levels.

GUIDELINES ON DIABETES, PRE-DIABETES, AND CARDIOVASCULAR DISEASES

Article

Full-text available

Jan 2007

The Task Force on Diabetes and Cardiovascular diseases of the European Society of Cardiology and of the European Association for the Study of Diabetes.

An insight to the incidence of acute pancreatitis, and co-morbidity of diabetes in SARS-COV2 infection

Article

Full-text available

Apr 2022

Since the emergence of SARS-COV2 infection, accumulating reports as well as evidences have been reported to the complex disease-disease interactions between this viral infection and the pre-existing diabetes co-morbidity. Hyperglycemia accompanied the onset of infection is repeatedly reported to be associated with the disease severity, prognosis and mortality rate elevation. Various mechanism has been speculated to lay behind the reported hyperglycemia including direct pancreatic tissues tropism besides the indirect cytokine storm overwhelming inflammatory immune response. In another perspective, other collection of studies has reported and emphasized the involvement of SARS-COV2 infection in the development of acute pancreatitis as one of this infection complications during the onset of infection, hence increasing the morbidity of such infection including the admission of the patients to the intensive care unit. Some have related the diagnosis of acute pancreatitis to the serum amylase and lipase levels manifested with the experienced GI symptoms, while, others consider CT scan images to confirm diagnosis. Finally, some reporters has hypothesized that SARS-COV2 infection may develop autoantibodies that probably precipitate type I diabetes mellitus long after infection. Therefore, due to significance of hyperglycemia/ diabetes to fate / severity of the infection as well as long term complications of SARS-COV2 this survey have covered aspects related to these issues.

Physiology in Medicine: Pathophysiology and management of critical illness polyneuropathy and myopathy

Article

Full-text available

Mar 2021

Critical illness associated weakness (CIAW) is an umbrella term used to describe a group of neuromuscular disorders caused by severe illness. It can be subdivided into three major classifications based on the component of the neuromuscular system (i.e. peripheral nerves or skeletal muscle or both) that are affected. This includes critical illness polyneuropathy (CIP), critical illness myopathy (CIM) and an overlap syndrome, critical illness polyneuromyopathy (CIPNM). It is a common complication observed in people with critical illness requiring intensive care unit (ICU) admission. Given CIAW is found in individuals experiencing grave illness, it can be challenging to study from a practical standpoint. However, over the past two decades, many insights into the pathophysiology of this condition have been made. Results from studies in both humans and animal models have found that a profound systemic inflammatory response and factors related to bioenergetic failure as well as microvascular, metabolic, and electrophysiological alterations underlie the development of CIAW. Current management strategies focus on early mobilization, achieving euglycemia, and nutritional optimization. Other interventions lack sufficient evidence, mainly due to a dearth of large trials. The goal of this Physiology in Medicine article is to highlight important aspects of the pathophysiology of these enigmatic conditions. It is hoped that improved understanding of the mechanisms underlying these disorders will lead to further study and new investigations for novel pharmacologic, nutritional, and exercise-based interventions to optimize patient outcomes.

Clinical Management of Diabetes Mellitus in the Era of COVID-19: Practical Issues, Peculiarities and Concerns

Article

Full-text available

Jul 2020

The management of patients with diabetes mellitus (DM) in the era of the COVID-19 pandemic can be challenging. Even if they are not infected, they are at risk of dysregulated glycemic control due to the restrictive measures which compromise and disrupt healthcare delivery. In the case of infection, people with DM have an increased risk of developing severe complications. The major principles of optimal care for mild outpatient cases include a patient-tailored therapeutic approach, regular glucose monitoring and adherence to medical recommendations regarding lifestyle measures and drug treatment. For critically ill hospitalized patients, tight monitoring of glucose, fluids, electrolytes, pH and blood ketones is of paramount importance to optimize outcomes. All patients with DM do not have an equally increased risk for severity and mortality due to COVID-19. Certain clinical and biological characteristics determine high-risk phenotypes within the DM population and such prognostic markers need to be characterized in future studies. Further research is needed to examine which subgroups of DM patients are expected to benefit the most from specific antiviral, immunomodulatory and other treatment strategies in the context of patient-tailored precision medicine, which emerges as an urgent priority in the era of COVID-19.

Elevated prehospital point-of-care glucose is associated with worse neurologic outcome after out-of-hospital cardiac arrest

Article

Full-text available

Mar 2022

Objectives Hyperglycemia is associated with poor outcomes in critically-ill patients. This has implications for prognostication of patients with out-of-hospital cardiac arrest (OHCA) and for post-resuscitation care. We assessed the association of hyperglycemia, on field point-of-care (POC) testing, with survival and neurologic outcome in patients with return of spontaneous circulation (ROSC) after OHCA. Methods This was a retrospective analysis of data in a regional cardiac care system from April 2011 through December 2017 of adult patients with OHCA and ROSC who had a field POC glucose. Patients were excluded if they were hypoglycemic (glucose <60 mg/dl) or received empiric dextrose. We compared hyperglycemic (glucose >250 mg/dL) with euglycemic (glucose 60–250 mg/dL) patients. Primary outcome was survival to hospital discharge (SHD). Secondary outcome was survival with good neurologic outcome (cerebral performance category 1 or 2 at discharge). We determined the adjusted odds ratios (AORs) for SHD and survival with good neurologic outcome. Results Of 9008 patients with OHCA and ROSC, 6995 patients were included; 1941 (28%) were hyperglycemic and 5054 (72%) were euglycemic. Hyperglycemic patients were more likely to be female, of non-White race, and have an initial non-shockable rhythm compared to euglycemic patients (p < 0.0001 for all). Hyperglycemic patients were less likely to have SHD compared to euglycemic survivors, 24.4% vs 32.9%, risk difference (RD) −8.5% (95 %CI −10.8%, −6.2%), p < 0.0001. Hyperglycemic survivors were also less likely to have good neurologic outcome compared to euglycemic survivors, 57.0% vs 64.6%, RD −7.6% (95 %CI −12.9%, −2.4%), p = 0.004. The AOR for SHD was 0.72 (95 %CI 0.62, 0.85), p < 0.0001 and for good neurologic outcome, 0.70 (95 %CI 0.57, 0.86), p = 0.0005. Conclusion In patients with OHCA, hyperglycemia on field POC glucose was associated with lower survival and worse neurologic outcome.

Glycemic Control in Neurological Intensive Care Unit Patients

Article

Full-text available

Aug 2021

Critically ill patients often develop hyperglycemia because of the metabolic response to trauma and stress. In response to any form of damage to the organism, it reacts by increasing its own glucose production which subsequently causes hyperglycemia. This adaptive reaction of the organism is directed to aid in the rapid restoration after the damage. Therefore, glucose is an indispensable substrate in the critically ill which aids the reparation process. Severe and persistent hyperglycemia is associated with unfavorable outcomes and is considered to be an independent predictor of in-hospital mortality. The discussion remains on whether hyperglycemia is just a marker of increased stress which makes it a surrogate indicator of disease severity or if it is the reason for the unfavorable outcome. A few years ago, several published articles suggested that a tight glycemic control within the normal range improves treatment outcome. Over time, researchers have changed their point of view and currently there is a discussion on this matter in the scientific literatures. At the same time, the question of what glycemic level should be maintained for patients in the Neurological Intensive Care Unit is a matter of discussion. In this review, the authors analyzed the latest guidelines on treatment of critical patients with neurosurgical and neurological pathologies, specifically the glycemic control in this category of patients.

Genome-wide association studies of Ca and Mn in the seeds of the common bean (Phaseolus vulgaris L.)

Article

Aug 2020

SNP markers linked to genes controlling Ca and Mn uptake were identified in the common bean seeds using DArT-based association mapping (AM). The Ca concentration in the seeds varied between 475 and 3100 mg kg⁻¹ with an average of 1280.9 mg kg⁻¹ and the Mn concentration ranged from 4.87 to 27.54 mg kg⁻¹ with a mean of 11.76 mg kg⁻¹. A total of 19,204 SNP markers were distributed across 11 chromosomes that correspond to the haploid genome number of the common bean. The highest value of ΔK was determined as K = 2, and 173 common bean genotypes were split into two main subclusters as POP1 (Mesoamerican) and POP2 (Andean). The results of the UPGMA dendrogram and PCA confirmed those of STRUCTURE analysis. MLM based on the Q + K model identified a large number of markers-trait associations. Of the 19,204 SNPs, five (on Pv2, 3, 8, 10 and 11) and four (on Pv2, 3, 8 and 11) SNPs were detected to be significantly related to the Ca content of the beans grown in Bornova and Menemen, respectively in 2015. In 2016, six SNPs (on Pv1–4, 8 and 10) were identified to be significantly associated with the Ca content of the seeds obtained from Bornova and six SNPs (on Pv1–4, 8 and 10) from Menemen. Eight (on Pv3, 5 and 11) and four (on Pv2, 5 and 11) SNPs had a significant association with Mn content in Bornova in 2015 and 2016, respectively. In Menemen, eight (on Pv3, 5, 8 and 11) and 11 (on Pv1, 2, 5, 10 and 11) SNPs had a significant correlation with Mn content in 2015 and 2016, respectively.

Impact of Initial Hyperglycaemia on Mortality in Reanimation

Article

Full-text available

Aug 2023

The relationship between hyperglycaemia on admission and patient outcome is modified by hyperlactatemia and diabetic status: a retrospective analysis of the eICU collaborative research database

Preprint

Full-text available

May 2023

Both blood glucose and lactate are well-known predictors of organ dysfunction and mortality in critically ill patients. Previous research has shown that concurrent adjustment for glucose and lactate modifies the relationship between these variables and patient outcomes, including blunting of the association between blood glucose and patient outcome. We aim to investigate the relationship between ICU admission blood glucose and hospital mortality while accounting for lactate and diabetic status. Across 43,250 ICU admissions, weighted to account for missing data, we assessed the predictive ability of several logistic regression and generalised additive models that included blood glucose, blood lactate and diabetic status. We found that inclusion of blood glucose marginally improved predictive performance in all patients: AUC-ROC 0.665 vs 0.659, with a greater degree of improvement seen in non- diabetics: AUC-ROC 0.675 vs 0.663. Inspection of the estimated risk profiles revealed the standard U-shaped risk profile for blood glucose was only present in non-diabetic patients after controlling for blood lactate levels. Future research should aim to utilise observational data to estimate whether interventions such as insulin further modify this effect, with the goal of informing future RCTs of interventions targeting glycaemic control in the ICU.

Extracellular vesicles regulate the transmission of insulin resistance and redefine noncommunicable diseases

Article

Full-text available

Jan 2023

Noncommunicable diseases (NCDs), such as diabetes and related neurological disorders, are considered to not be directly transmissible from one person to another. However, NCDs may be transmissible in vivo through extracellular vesicles (EVs). A long-term high-fat diet (HFD) can induce a series of health issues like hyperlipidemia, type 2 diabetes mellitus (T2DM), and diabetic peripheral neuropathy (DPN) due to insulin resistance. Multiple molecular signaling changes can stimulate insulin resistance, especially blocking insulin signaling by increased insulin resistance inducer (phosphorylation of negative regulatory sites of insulin receptor substrate (IRS) proteins) and decreased tyrosine phosphorylation of insulin receptor substrate (phosphorylation of positive regulatory sites of IRS), thus leading to reduced phosphorylation of AKT enzymes. Current efforts to treat T2DM and prevent its complications mainly focus on improving insulin sensitivity, enhancing insulin secretion, or supplementing exogenous insulin based on a common assumption that insulin resistance is noncommunicable. However, insulin resistance is transmissible within multiple tissues or organs throughout the body. Exploring the regulatory roles of EVs in developing insulin resistance may provide novel and effective preventive and therapeutic strategies.

Expert consensus on the glycemic management of critically ill patients

Article

Full-text available

Jul 2022

Causes of Hypoglycemia

Chapter

Full-text available

May 2022

Blood glucose levels may vary during the day, when this variation goes below a specific limit, hypoglycemia occurs. Hypoglycemia is often associated with reductions in quality of life and even the risk of death. Moreover, hypoglycemia is correlated with physical and/or psychological morbidity. It is usually a result of the complex interaction between hyperinsulinemia and the compromised physiological and behavioral responses attempting to reduce glucose levels. Nevertheless, several conditions can cause hypoglycemia, both in diabetic and non-diabetic patients. Mutually, diabetic and non-diabetic hypoglycemia is common in terms of several medications, alcohol ingestion, critical illnesses, and non-B cell tumors.

Resorcinol Derivatives as Novel Aldose Reductase Inhibitors: In Silico and In Vitro Evaluation

Article

Apr 2022
LETT DRUG DES DISCOV

Namık Kılınç

Background The polyol pathway, an alternative way of carbohydrate metabolism, is activated by hyperglycemia. Aldose reductase (AR), the first and rate-limiting enzyme of the polyol pathway, is responsible for the reduction of glucose to sorbitol. Inhibiting the aldose reductase enzyme and reducing the polyol pathway is considered an effective method to prevent and postpone the onset of diabetic complications. Objective Therefore, in this work, we investigate the inhibition effects of certain resorcinol derivatives and the positive control compound quercetin on the AR enzyme in vitro and in silico. These phenolic compounds, whose inhibitory effects on the AR enzyme were investigated, were also compared with known drugs in terms of their drug-like characteristics. Methods Three methods were used to determine the inhibitory effects of resorcinol derivatives on recombinant human AR enzyme. After the in vitro inhibition effects were determined spectrophotometrically, the binding energy and binding modes were determined by molecular docking method. Finally, the MM-GBSA method was used to determine the free binding energies of the inhibitors for the AR enzyme. Results 5-pentylresorcinol compound showed the strongest inhibition effect on recombinant human AR enzyme with an IC50 value of 9.90 µM. The IC50 values of resorcinol, 5-methylresorcinol, 4- ethylresorcinol, 4-hexylresorcinol, 2-methylresorcinol, and 2,5-dimethylresorcinol compounds were determined as 49.50 µM, 43.31 µM, 19.25 µM, 17.32 µM, 28.87 µM, 57.75 µM, respectively. Conclusion The results of this research showed that resorcinol compounds are effective AR inhibitors. These findings are supported by molecular docking, molecular mechanics, and ADME investigations undertaken to corroborate the experimental in vitro results.

Effect of hyperglycemia treatment on complications rate after pediatric cardiac surgery

Article

Full-text available

Mar 2022

Introduction: The goal of this study was to elucidate harmful complications of intraoperative hyperglycemia following children cardiac surgery and benefits of insulin administration for accurate blood sugar controlling. Methods: this study is a Randomized clinical trial. We conducted this study in the operating room of shahid madani hospital. Fifty patients who were children under 12 years old undergone cardiac surgery using cardiopulmonary bypass (CPB). Intraoperative insulin infusion was administered intravenously targeting blood sugar levels of 110-140 mg/dL. Blood sugar and arterial blood gas (ABG) were measured every 30 min during operation. Results: Inotropes were used less in the study than the placebo group during surgery. The means of hospitalization and extubation time were more in the placebo group than the study group(P =0.03) and (P =0.005), respectively. However, the mean time of hospitalization in the ICU ward did not differ significantly between the two groups. Conclusion: Hyperglycemia has a relation with long time of intubation and hospitalization in ICU. These findings suggest the positive effect of accurate blood sugar control on reducing complication and hospitalization time in children undergoing cardiac surgery.

The stress hyperglycemia ratio, a novel index of relative hyperglycemia, predicts short-term mortality in critically ill patients after esophagectomy

Article

Full-text available

Feb 2022
J Gastrointest Oncol

Background: Postoperative mortality and severe complications are associated with both long-term blood glucose management and the severity of stress hyperglycemia. The purpose of this study was to assess the predictive value of a novel index, the stress hyperglycemia ratio (SHR), for short-term mortality in critically ill patients following esophagectomy. Methods: A total of 356 patients who underwent esophagectomy for esophageal squamous cell carcinoma (ESCC) and were admitted to the intensive care unit (ICU) were included in this retrospective study. Based on the SHR values, patients were divided into low (SHR <1.14) or high (SHR ≥1.14) groups in the overall and diabetic populations. The major outcomes of this study were the 30- and 90-day all-cause mortalities. We used Cox proportional hazard regression, Kaplan-Meier survival analysis, and competing risk regression models to analyze the relationships between risk factors and outcomes. Results: The 30- and 90-day mortality in the high-SHR group were significantly higher compared to the low-SHR group in the total population (30-day: 1.3% vs. 10.5%, P<0.001; 90-day: 5.8% vs. 20.0%, P<0.001) and the diabetic population (30-day: 2.6% vs. 17.3%, P=0.026; 90-day: 5.1% vs. 36.5%, P<0.001). After adjusting for covariables, the risk of the 30-day mortality [1.770 (1.442, 3.170)] and 90-day mortality [1.869 (1.289, 3.409)] remained significant (P=0.035, P=0.045) in the total population. A similar result was observed in patients with diabetes [30-day: 1.642 (1.131, 2.710), P=0.015; 90-day: 2.136 (1.254, 3.946), P=0.005]. The Kaplan-Meier survival estimates for the 30-/90-day mortality also showed comparable results. The multivariable logistic regression analysis, including all glucose-related indices and the Acute Physiology and Chronic Health Evaluation (APACHE) II score, showed that SHR was independently correlated with the 30- and 90-day mortality; each 0.1-increase was related to a 3-4% elevation in the 30-/90-day mortality [odds ratio (OR), 1.044; 95% confidence interval (CI), 1.036-1.069; OR, 1.036; 95% CI, 1.021-1.051]. Conclusions: In this study, we found that a relative increase in blood glucose, as quantified by the SHR ≥1.14, was independently related to the higher 30-/90-day mortality in patients admitted to the ICU with severe complications following esophagectomy, while absolute hyperglycemia was not.

Routine laboratory test to assess the need of respiratory support in acute bronchiolitis

Article

Feb 2022

Background and objectives: Accurate and readily available biomarkers to predict the clinical course of bronchiolitis would enable enhanced decision-making in this setting. We explored the relationship of several biochemical parameters available at the pediatric emergency care setting with the need of advanced respiratory support (ARS): continuous positive airway pressure (CPAP), biphasic positive airway pressure (BiPAP) or invasive mechanical ventilation (MV) in bronchiolitis. Methods: Single-centre, prospective, observational, including infants aged less than 12 months diagnosed with acute bronchiolitis at the Pediatric Emergency Department. Determination of plasmatic values of several laboratory tests was performed at the time of hospital admission. Multivariate logistic analysis identified independent predictors for need of ARS. Results: From October 1, 2018, to May 1, 2020, we recruited 149 infants (58% male; median age of 1 (0.5-2.5) month). Thirty-seven (25%) cases required ARS. After adjusting by age, bacterial superinfection and comorbidities in the multivariate analysis, only higher levels of glycemia (p=0.001), CRP (p=0.028), CRP/albumin ratio (p=0.032) and NT-proBNP (p=0.001) remained independently associated with ARS. These biomarkers reached moderate prediction accuracy with AUC of ROC curves ranging from 0.701 to 0.830 (p=0.001). All they presented relatively high specificity (0.75-0.84) and negative predictive values (0.77-0.89) with low sensitivity and positive predictive values. They also correlated significantly with length of stay hospitalization (p=0.001). Conclusion: Increased plasmatic levels of CRP, CRP/albumin ratio, glycemia and NT-proBNP at hospital admission are associated with the need for ARS in infants with acute bronchiolitis. This article is protected by copyright. All rights reserved.

Hyperglycemia and Angiotensin-Converting Enzyme 2 in Pulmonary Function in the Context of SARS-CoV-2 Infection

Article

Full-text available

Jan 2022

Since the appearance of the severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003 in China, diabetes mellitus (DM) and hyperglycemia in patients infected with SARS-CoV, represent independent predictors of mortality. Therefore, metabolic control has played a major role in the prognosis of these patients. In the current pandemic of coronavirus disease 19 (COVID-19), multiple studies have shown that DM is one of the main comorbidities associated with COVID-19 and higher risk of complications and death. The incidence and prevalence of COVID-19 complications and death related with hyperglycemia in patients with or without DM are high. There are many hypotheses related with worse prognosis and death related to COVID-19 and/or hyperglycemia. However, the information about the interplay between hyperglycemia and angiotensin-converting enzyme 2 (ACE2), the critical receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in the context of SARS-CoV-2 infection, is almost null, but there is enough information to consider the possible participation of hyperglycemia in the glycation of this protein, unleashing a pool of reactions leading to acute respiratory distress syndrome and death in patients with COVID-19. In this document we investigated the current evidence related with ACE2 as a key element within the pathophysiological mechanism related with hyperglycemia extrapolating it to context of SARS-CoV-2 infection and its relationship with worse prognosis and death for COVID-19.

Cardiotoxicity with antihypertensive drugs (literature review) Part 1. Calcium channel blockers and beta-blockers

Article

Oct 2021

The effect of hypotensive drugs overdose on cardiovascular system is poorly studied; it should undergo clinical, experimental pharmacology and toxicology together with cardiology. There is too little information about cardiotoxicity of beta-blockers (β-blockers) and calcium channel blockers (CCB) in existing research literature. Intoxication from these groups of drugs causes similar severe hemodynamic abnormalities and myocardial insufficiency, however pathophysiological mechanisms of these abnormalities are not thoroughly studied. The review highlights how difficult it is to identify toxic level and distinctive features of clinical evidence of intoxication. Methods of diagnosis as well as β-blockers and CCB overdose treatment are discussed.

Hemorrhagic and thrombotic manifestations in the central nervous system in COVID-19: A large observational study in the Brazilian Amazon with a complete autopsy series

Article

Full-text available

Sep 2021
PLOS ONE

SARS-CoV-2 affects mainly the lungs, however, other manifestations, including neurological manifestations, have also been described during the disease. Some of the neurological findings have involved intracerebral or subarachnoid hemorrhage, strokes, and other thrombotic/hemorrhagic conditions. Nevertheless, the gross pathology of hemorrhagic lesions in the central nervous system has not been previously described in Brazilian autopsy cases. This study aimed to describe gross and microscopic central nervous system (CNS) pathology findings from the autopsies and correlate them with the clinical and laboratory characteristics of forty-five patients with COVID-19 from Manaus, Amazonas, Brazil. Forty-four patients were autopsied of which thirty-eight of these (86.36%) were positive by RT-PCR for COVID-19, and six (13.3%) were positive by the serological rapid test. Clinical and radiological findings were compatible with the infection. The patients were classified in two groups: presence (those who had hemorrhagic and/or thrombotic manifestations in the CNS) and absence (those who did not present hemorrhagic and/or thrombotic manifestations in the CNS). For risk assessment, relative risk and respective confidence intervals were estimated. Macroscopic or microscopic hemorrhages were found in twenty-three cases (52,27%). The postmortem gross examination of the brain revealed a broad spectrum of hemorrhages, from spots to large and confluent areas and, under microscopy, we observed mainly perivascular discharge. The association analyses showed that the use of corticosteroid, anticoagulant and antibiotic had no statistical significance with a risk of nervous system hemorrhagic manifestations. However, it is possible to infer a statistical tendency that indicates that individuals with diabetes had a higher risk for the same outcome (RR = 1.320, 95% CI = 0.7375 to 2.416, p = 0.3743), which was not observed in relation to other comorbidities. It is unknown whether the new variants of the virus can cause different clinical manifestations, such as those observed or indeed others. As a result, more studies are necessary to define clinical and radiologic monitoring protocols and strategic interventions for patients at risk of adverse and fatal events, such as the extensive hemorrhaging described here. It is imperative that clinicians must be aware of comorbidities and the drugs used to treat patients with COVID-19 to prevent CNS hemorrhagic and thrombotic events.

Acute and Chronic Glucose Control in Critically Ill Patients With Diabetes: The Impact of Prior Insulin Treatment

Article

Full-text available

Aug 2021

Background Emerging data highlight the interactions of preadmission glycemia, reflected by admission HbA1c levels, glycemic control during critical illness, and mortality. The association of preadmission insulin treatment with outcomes is unknown. Methods This observational cohort study includes 5245 patients admitted to the medical-surgical intensive care unit of a university-affiliated teaching hospital. Three groups were analyzed: patients with diabetes with prior insulin treatment (DM-INS, n = 538); patients with diabetes with no prior insulin treatment (DM-No-INS, n = 986); no history of diabetes (NO-DM, n = 3721). Groups were stratified by HbA1c level: <6.5%; 6.5%-7.9% and >8.0%. Results Among the three strata of HbA1c, mean blood glucose (BG), coefficient of variation (CV), and hypoglycemia increased with increasing HbA1c, and were higher for DM-INS than for DM-No-INS. Among patients with HbA1c < 6.5%, mean BG ≥ 180 mg/dL and CV > 30% were associated with lower severity-adjusted mortality in DM-INS compared to patients with mean BG 80-140 mg/dL and CV < 15%, ( P = .0058 and < .0001, respectively), but higher severity-adjusted mortality among DM-No-INS ( P = .0001 and < .0001, respectively) and NON-DM ( P < .0001 and < .0001, respectively). Among patients with HbA1c ≥ 8.0%, mean BG ≥ 180 mg/dL was associated with lower severity-adjusted mortality for both DM-INS and DM-No-INS than was mean BG 80-140 mg/dL ( p < 0.0001 for both comparisons). Conclusions Significant differences in mortality were found among patients with diabetes based on insulin treatment and HbA1c at home and post-admission glycemic control. Prospective studies need to confirm an individualized approach to glycemic control in the critically ill.

Hyperglycaemia in the Newborn Infant. Physiology Verses Pathology

Article

Full-text available

Jul 2021

Kathryn Beardsall

Hyperglycemia is common in newborns requiring intensive care, particularly in preterm infants, in sepsis and following perinatal hypoxia. The clinical significance, and optimal intervention strategy varies with context, but hyperglycaemia is associated with increased mortality and morbidity. The limited evidence for optimal clinical targets mean controversy remains regarding thresholds for intervention, and management strategies. The first consideration in the management of hyperglycaemia must be to ascertain potentially treatable causes. Calculation of the glucose infusion rate (GIR) to insure this is not excessive, is critical but the use of insulin is often helpful in the extremely preterm infant, but is associated with an increased risk of hypoglycaemia. The use of continuous glucose monitoring (CGM) has recently been demonstrated to be helpful in targeting glucose control, and reducing the risk from hypoglycaemia in the preterm infant. Its use in other at risk infants remains to be explored, and further studies are needed to provide a better understanding of the optimal glucose targets for different clinical conditions. In the future the combination of CGM and advances in computer algorithms, to provide intelligent closed loop systems, could allow a safer and more personalized approached to management.

Effects of Des-acyl Ghrelin on Insulin Sensitivity and Macrophage Polarization in Adipose Tissue

Article

Full-text available

Jul 2021

Background and Objectives Obesity is the accumulation of adipose tissue caused by excess energy in the body, accompanied by long-term chronic low-grade inflammation of adipose tissue. More than 50% of interstitial cells in adipose tissue are macrophages, which produce cytokines closely related to insulin resistance. Macrophage biology is driven by two polarization phenotypes, M1 (proinflammatory) and M2 (anti-inflammatory). This study aimed to investigate the effect of gastric hormone des-acyl ghrelin (DAG) on the polarization phenotype of macrophages and elucidate the role of macrophages in adipose tissue inflammation and insulin sensitivity and its molecular mechanism. Methods Mice were subcutaneously administrated with DAG in osmotic minipumps. The mice were fed a normal diet or a high-fat diet (HFD). Different macrophage markers were detected by real-time revere transcription polymerase chain reaction. Results Exogenous administration of DAG significantly inhibited the increase of adipocyte volume caused by HFD and reduced the number of rosette-like structures in adipose tissue. HFD in the control group significantly increased M1 macrophage markers, tumor necrosis factor α (TNFα), and inducible NO synthase (iNOS). However, these increases were reduced or even reversed after DAG administration in vitro . The M2 markers, macrophage galactose type C-type Lectin-1 (MGL1), arginase 1 (Arg1), and macrophage mannose receptor 1 (MRC1) were decreased by HFD, and the downward trend was inhibited or reversed after DAG administration. Although Arg1 was elevated after HFD, the fold increase after DAG administration in vitro was much greater than that in the control group. Conclusion DAG inhibits adipose tissue inflammation caused by HFD, reduces infiltration of macrophages in adipose tissue, and promotes polarization of macrophages to M2, thus alleviating obesity and improving insulin sensitivity.

Soluble Epoxide Hydrolase Blockade after Stroke Onset Protects Normal but Not Diabetic Mice

Article

Full-text available

May 2021
INT J MOL SCI

Soluble epoxide hydrolase (sEH) is abundant in the brain, is upregulated in type 2 diabetes mellitus (DM2), and is possible mediator of ischemic injury via the breakdown of neuroprotective epoxyeicosatrienoic acids (EETs). Prophylactic, pre-ischemic sEH blockade with 4-[[trans-4-[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]cyclohexyl]oxy]-benzoic acid (tAUCB) reduces stroke-induced infarct in normal and diabetic mice, with larger neuroprotection in DM2. The present study tested whether benefit occurs in normal and DM2 mice if tAUCB is administered after stroke onset. We performed 60 min middle cerebral artery occlusion in young adult male C57BL mice divided into four groups: normal or DM2, with t-AUCB 2 mg/kg or vehicle 30 min before reperfusion. Endpoints were (1) cerebral blood flow (CBF) by laser Doppler, and (2) brain infarct at 24 h. In nondiabetic mice, t-AUCB reduced infarct size by 30% compared to vehicle-treated mice in the cortex (31.4 ± 4 vs. 43.8 ± 3 (SEM)%, respectively) and 26% in the whole hemisphere (26.3 ± 3 vs. 35.2 ± 2%, both p < 0.05). In contrast, in DM2 mice, tAUCB failed to ameliorate either cortical or hemispheric injury. No differences were seen in CBF. We conclude that tAUCB administered after ischemic stroke onset exerts brain protection in nondiabetic but not DM2 mice, that the neuroprotection appears independent of changes in gross CBF, and that DM2-induced hyperglycemia abolishes t-AUCB-mediated neuroprotection after stroke onset.

Loss of FOXO Transcription Factors in the Liver Mitigates Stress-Induced Hyperglycemia

Article

Full-text available

May 2021

Objective: Stress-induced hyperglycemia is associated with poor outcomes in nearly all critical illnesses. This acute elevation in glucose after injury or illness is associated with increased morbidity and mortality including multiple organ failure. Stress-induced hyperglycemia is often attributed to insulin resistance as controlling glucose levels via exogenous insulin improves outcomes, but mechanisms are unclear. Forkhead box O (FOXO) transcription factors are direct targets of insulin signaling in the liver that regulate glucose homeostasis via direct and indirect pathways. Loss of hepatic FOXO transcription factors reduces hyperglycemia in chronic insulin-resistance; however, the role of FOXOs in stress-induced hyperglycemia is unknown. Methods: We subjected mice lacking FOXO transcription factors in liver to a model of injury known to cause stress-induced hyperglycemia. Glucose, insulin, glycerol, fatty acids, cytokines, and adipokines were assessed before and after injury. Liver and adipose tissue were analyzed for changes in glycogen, FOXO target gene expression, and insulin signaling. Results: Stress-induced hyperglycemia was associated with reduced hepatic insulin signaling and increased hepatic FOXO target gene expression while loss of FOXO1, 3, and 4 in the liver attenuated hyperglycemia and prevented hyperinsulinemia. Mechanistically, loss of FOXO transcription factors mitigated the stress-induced hyperglycemia response by directly altering gene expression and glycogenolysis in the liver and indirectly suppressing lipolysis in adipose tissue. Reductions were associated with decreased IL-6, TNF-α, and follistatin and increased FGF21, suggesting that cytokines and FOXO-regulated hepatokines contribute to the stress-induced hyperglycemia response. Conclusions: This work implicates FOXO transcription factors as a predominant driver of stress-induced hyperglycemia through means that include cross talk between liver and adipose, highlighting a novel mechanism underlying acute hyperglycemia and insulin resistance in stress.

Alternatives to Insulin for the Regulation of Blood Sugar Levels in Type 2 Diabetes

Article

Full-text available

Nov 2020
INT J MOL SCI

This short overview focuses on the causation and treatment of type 2 diabetes (T2D). Emphasis is given to the historical basis of understanding this disease and the background leading to emergence of the central role of insulin. The strengths of insulin administration in the treatment of diabetes are profound, but these need to be balanced against several serious shortcomings of its extended use. Some alternative approaches to T2D management are considered. Insulin is no longer considered as the first choice for type 2 diabetes, and an expanding range of new therapeutic possibilities is emerging. While these may lack the potency of insulin, at a minimum, they allow a major reduction in the intensity of insulin use. In view of the rising worldwide incidence of this disease, it is imperative to develop safe and inexpensive means of limiting its potential for impairment of normal functioning.

Admission fasting plasma glucose is an independent risk factor for 28‐day mortality in patients with COVID‐19

Article

Oct 2020

Hyperglycemia commonly occurred in severe cases with COVID‐19. In this study, we explored the associations between admission fasting plasma glucose (FPG) and 28‐day mortality in COVID‐19 patients. In this single centre retrospective study, 263 adult patients with COVID‐19 were included. Demographic and clinical information were collected and compared between patients with and without diabetes. Cox regression analyses was used to investigate the risk factors of 28‐day mortality in hospital. Of 263 patients, 161 (61.2%) were male, 62 (25.6%) had a known history of diabetes, and 135 (51.3%) experienced elevated FPG (> 7.0 mmol/L) at hospital admission. The median FPG in patients with diabetes was much higher than in patients without diabetes (12.79 mmol/L versus 6.47 mmol/L). Patients with diabetes had higher neutrophil count and D‐dimer, less lymphocyte count, lower albumin level, and more fatal complications. Multivariable Cox regression analyses showed that age (per 10‐year increase) (hazard ratio [HR], 1.41; 95% confidence interval [CI], 1.13–1.74), admission FPG between 7.0 and 11.0 mmol/L and ≥11.1 mmol/L (HR, 1.90, 95% CI, 1.11–3.25; HR, 2.09, 95% CI, 1.21–3.64, respectively), chronic obstructive pulmonary disease (HR, 2.89, 95% CI, 1.31–6.39), and cardiac injury (HR, 2.14; 95% CI, 1.33–3.47) were independent predictors of 28‐day mortality in COVID‐19 patients. Hyperglycemia on admission predicted worse outcome in hospitalized patients with COVID‐19. Intensive monitoring and optimal glycemic control may improve the prognosis of COVID‐19 patients. This article is protected by copyright. All rights reserved.

Insulin Use and Clinical Outcomes in Patients Undergoing Coronary Artery Bypass Graft Surgery

Article

Full-text available

Oct 2020

Objective: To describe insulin use and postoperative glucose control in patients undergoing coronary artery bypass graft (CABG) surgery. Methods: We examined 2,390 patients with and without diabetes enrolled in the Contemporary Analysis of Perioperative Cardiovascular Surgical Care (CAPS-Care) Study who underwent CABG surgery (01/2004 - 06/2005) to describe postoperative insulin use, variation in insulin use across different hospitals, and associated in-hospital complications and clinical outcomes. Logistic regression was used to assess the adjusted relationship between insulin use and clinical outcomes. Results: Overall, insulin was used in 82% (n=1,959) of patients, including 95% (n=1,203) with diabetes (n=1,258) and 67% (n=756) without diabetes (n=1,132). Continuous insulin was used in 35.5% of patients in the operating room and in 56% in the intensive care unit. Continuous insulin use varied significantly among centers from 8-100% in patients with diabetes. When compared with all patients not receiving insulin, insulin use in patients without diabetes was associated with a higher rate of death or major complication (adjusted odds ratio [OR]=1.54; 95% confidence interval [CI] 1.15-2.04; P=0.003). In patients with diabetes, insulin use was not associated with a higher risk of adverse outcomes (adjusted OR=1.01; 95% CI 0.52-1.98; P=0.98). Conclusion: The postoperative use of insulin is high among CABG patients in the United States of America. Insulin use in patients without diabetes was associated with worse clinical outcomes compared to patients (both with and without diabetes) who did not receive insulin. Further investigation is needed to determine the optimal use of postoperative insulin after CABG.

Probing Long-Term Impacts: Low-Dose Polystyrene Nanoplastics Exacerbate Mitochondrial Health and Evoke Secondary Glycolysis via Repeated and Single Dosing

Article

May 2024
ENVIRON SCI TECHNOL

Elevated Hemoglobin A1c and the Risk of Developing Acute Respiratory Distress Syndrome in Two Cohort Studies

Article

May 2024

Preoperative Considerations

Chapter

Jan 2024

Intrathecal drug delivery systems should be used when less-invasive therapies have failed and when a positive response to an epidural or intrathecal screening test is observed. Physicians decide which type of screening test to perform based largely on their level of comfort with the procedure and the type of test the patient’s health insurance will cover. Of all preoperative considerations, patient selection is most important in determining successful treatment outcomes. A multidisciplinary team approach, including psychologists, physical therapists, and spiritual leaders, is crucial to successful patient management through initial patient education, patient selection and screening test, preoperative care, postoperative care, and maintenance.

Diabetes mellitus, energy metabolism and COVID-19

Article

Full-text available

Nov 2023
ENDOCR REV

Obesity, diabetes mellitus (mostly type 2), and COVID-19 show mutual interactions because they are not only risk factors for both acute and chronic COVID-19 manifestations, but also because COVID-19 alters energy metabolism. Such metabolic alterations can lead to dysglycemia and long-lasting effects. Thus, the COVID-19 pandemic has the potential for a further rise of the diabetes pandemic. This review outlines how preexisting metabolic alterations spanning from excess visceral adipose tissue to hyperglycemia and overt diabetes may exacerbate COVID-19 severity. We also summarize the different effects of SARS-CoV-2 infection on the key organs and tissues orchestrating energy metabolism, including adipose tissue, liver, skeletal muscle, and pancreas. Last, we provide an integrative view of the metabolic derangements that occur during COVID-19. Altogether, this review allows for better understanding of the metabolic derangements occurring when a fire starts from a small flame, and thereby help reducing the impact of the COVID-19 pandemic.

Tight Blood-Glucose Control without Early Parenteral Nutrition in the ICU

Article

Sep 2023

Background: Randomized, controlled trials have shown both benefit and harm from tight blood-glucose control in patients in the intensive care unit (ICU). Variation in the use of early parenteral nutrition and in insulin-induced severe hypoglycemia might explain this inconsistency. Methods: We randomly assigned patients, on ICU admission, to liberal glucose control (insulin initiated only when the blood-glucose level was >215 mg per deciliter [>11.9 mmol per liter]) or to tight glucose control (blood-glucose level targeted with the use of the LOGIC-Insulin algorithm at 80 to 110 mg per deciliter [4.4 to 6.1 mmol per liter]); parenteral nutrition was withheld in both groups for 1 week. Protocol adherence was determined according to glucose metrics. The primary outcome was the length of time that ICU care was needed, calculated on the basis of time to discharge alive from the ICU, with death accounted for as a competing risk; 90-day mortality was the safety outcome. Results: Of 9230 patients who underwent randomization, 4622 were assigned to liberal glucose control and 4608 to tight glucose control. The median morning blood-glucose level was 140 mg per deciliter (interquartile range, 122 to 161) with liberal glucose control and 107 mg per deciliter (interquartile range, 98 to 117) with tight glucose control. Severe hypoglycemia occurred in 31 patients (0.7%) in the liberal-control group and 47 patients (1.0%) in the tight-control group. The length of time that ICU care was needed was similar in the two groups (hazard ratio for earlier discharge alive with tight glucose control, 1.00; 95% confidence interval, 0.96 to 1.04; P = 0.94). Mortality at 90 days was also similar (10.1% with liberal glucose control and 10.5% with tight glucose control, P = 0.51). Analyses of eight prespecified secondary outcomes suggested that the incidence of new infections, the duration of respiratory and hemodynamic support, the time to discharge alive from the hospital, and mortality in the ICU and hospital were similar in the two groups, whereas severe acute kidney injury and cholestatic liver dysfunction appeared less prevalent with tight glucose control. Conclusions: In critically ill patients who were not receiving early parenteral nutrition, tight glucose control did not affect the length of time that ICU care was needed or mortality. (Funded by the Research Foundation-Flanders and others; TGC-Fast ClinicalTrials.gov number, NCT03665207.).

The relationship between hyperglycaemia on admission and patient outcome is modified by hyperlactatemia and diabetic status: a retrospective analysis of the eICU collaborative research database

Article

Full-text available

Sep 2023

Both blood glucose and lactate are well-known predictors of organ dysfunction and mortality in critically ill patients. Previous research has shown that concurrent adjustment for glucose and lactate modifies the relationship between these variables and patient outcomes, including blunting of the association between blood glucose and patient outcome. We aim to investigate the relationship between ICU admission blood glucose and hospital mortality while accounting for lactate and diabetic status. Across 43,250 ICU admissions, weighted to account for missing data, we assessed the predictive ability of several logistic regression and generalised additive models that included blood glucose, blood lactate and diabetic status. We found that inclusion of blood glucose marginally improved predictive performance in all patients: AUC-ROC 0.665 versus 0.659 (p = 0.005), with a greater degree of improvement seen in non-diabetics: AUC-ROC 0.675 versus 0.663 (p < 0.001). Inspection of the estimated risk profiles revealed the standard U-shaped risk profile for blood glucose was only present in non-diabetic patients after controlling for blood lactate levels. Future research should aim to utilise observational data to estimate whether interventions such as insulin further modify this effect, with the goal of informing future RCTs of interventions targeting glycaemic control in the ICU.

Pathophysiology and Hypermetabolic Response to Burn

Chapter

Jul 2023

Burns account for an estimated 300,000 deaths per year worldwide, with a dearth of patients necessitating medical attention—ranking fourth in incidence compared to all injury types. What distinguishes burns from other forms of trauma is the persistent, severe metabolic and inflammatory response after the initial insult, which has a critical impact on patient outcomes. In particular, the post-burn hypermetabolic response is a key contributor to burn-related complications, necessitating a better understanding of this response beyond identification of its components. In this chapter, we define the hypermetabolic response and aim to discuss the key sequelae, focusing first on metabolic then organ-specific consequences. We conclude with a discussion on current management of hypermetabolism, including conservative and pharmacological intervention. Early identification and management of hypermetabolic consequences can improve outcomes in burn patients.KeywordsHypermetabolismHyperinflammationBurnCatabolismBrowningInsulin resistance

Glucose and Nutrition

Chapter

Jan 2013

Glucose Metabolism and Stress Hyperglycemia in Critically Ill Children

Article

Jan 2023

Vijay Srinivasan

Abnormalities in glucose metabolism and stress hyperglycemia (SH) are commonly seen in critically ill children. While SH may represent an adaptive stress response as a source of fuel for the body during the “fight or flight response” of critical illness, several studies have observed the association of SH with worse outcomes in different disease states. In addition to alterations in glucose metabolism and acquired insulin resistance from inflammation and organ dysfunction, specific intensive care unit (ICU) interventions can also affect glucose homeostasis and SH during critical illness. Common ICU interventions can mediate the development of SH in critical illness. The strategy of tight glucose control combined with intensive insulin therapy (TGC-IIT) has been well studied to improve outcomes in both adult and pediatric critical illness. Though early single-center studies of TGC-IIT observed benefits with better outcomes albeit with greater incidence of hypoglycemia, subsequent larger multicenter studies in both children and adults have not conclusively demonstrated benefits and have even observed harm. Several possible reasons for these contrasting results include differences in patient populations, glycemic control targets, and glucose control protocols including nutrition support, and variability in achieving these targets, measurement methods, and expertise in protocol implementation. Future studies may need to individualize management of SH in critically ill children with improved monitoring of indices of glycemia utilizing continuous sensors and closed-loop insulin administration.

Difficulties in managing hyperglycemia in extremely low birth weight infants – case report

Article

Jan 2022

Surface charge modulation enhanced high stability of gold oxidation intermediate for electrochemical glucose sensors

Article

Nov 2022

Rapid and accurate blood glucose detection is significant for diagnosing and treating diabetes. Herein, ultra-low-content gold nanoparticles were loaded on different metal foams and applied to electrochemical enzyme-free glucose sensors via simple displacement reactions. The structures and properties of the produced catalysts were determined by various characterization methods. The performance of the glucose sensor was examined in relation to the interactions between three different metal substrates and gold. The one with the best performance is the sample of gold nanoparticles grown on copper foam (Au300 Cu Foam). It has the advantage of a porous three-dimensional network, a large electroactive surface area, and the high catalytic activity of gold. The combination of Cu and Au increased the valence state of Au, thus favoring the catalytic activity for glucose oxidation. Cyclic voltammetry and chronoamperometry measurements revealed that Au is responsible for the electrocatalytic oxidation of glucose. The sensitivity of Au300 Cu Foam was found to be 10 839 μA mM-1 cm-2 in the linear range of 0.00596-0.0566 mM, with a detection limit (LOD) of 0.223 μM, and 2-3 s response time at 0.4 V vs. Ag/AgCl. The Au300 Cu Foam glucose sensor also offered outstanding stability and anti-interference performance. The prepared Au300 Cu Foam electrode was also successfully applied to detect different levels of glucose in human body fluids, such as saliva. These characteristics make Au300 Cu Foam promising for non-invasive glucose detection.

Clinical outcome and gut development after insulin-like growth factor-1 supplementation to preterm pigs

Article

Full-text available

Aug 2022

Background Elevation of circulating insulin-like growth factor-1 (IGF-1) within normal physiological levels may alleviate several morbidities in preterm infants but safety and efficacy remain unclear. We hypothesized that IGF-1 supplementation during the first 1–2 weeks after preterm birth improves clinical outcomes and gut development, using preterm pigs as a model for infants. Methods Preterm pigs were given vehicle or recombinant human IGF-1/binding protein-3 (rhIGF-1, 2.25 mg/kg/d) by subcutaneous injections for 8 days (Experiment 1, n = 34), or by systemic infusion for 4 days (Experiment 2, n = 19), before collection of blood and organs for analyses. Results In both experiments, rhIGF-1 treatment increased plasma IGF-1 levels 3-4 fold, reaching the values reported for term suckling piglets. In Experiment 1, rhIGF-1 treatment increased spleen and intestinal weights without affecting clinical outcomes like growth, blood biochemistry (except increased sodium and gamma-glutamyltransferase levels), hematology (e.g., red and white blood cell populations), glucose homeostasis (e.g., basal and glucose-stimulated insulin and glucose levels) or systemic immunity variables (e.g., T cell subsets, neutrophil phagocytosis, LPS stimulation, bacterial translocation to bone marrow). The rhIGF-1 treatment increased gut protein synthesis (+11%, p < 0.05) and reduced the combined incidence of all-cause mortality and severe necrotizing enterocolitis (NEC, p < 0.05), but had limited effects on intestinal morphology, cell proliferation, cell apoptosis, brush-border enzyme activities, permeability and levels of cytokines (IL-1β, IL-6, IL-8). In Experiment 2, rhIGF-1 treated pigs had reduced blood creatine kinase, creatinine, potassium and aspartate aminotransferase levels, with no effects on organ weights (except increased spleen weight), blood chemistry values, clinical variables or NEC. Conclusion Physiological elevation of systemic IGF-1 levels for 8 days after preterm birth increased intestinal weight and protein synthesis, spleen weight and potential overall viability of pigs, without any apparent negative effects on recorded clinical parameters. The results add further preclinical support for safety and efficacy of supplemental IGF-1 to hospitalized very preterm infants.

Correlation between serum glucose/potassium ratio and the severity of mushroom poisoning at the time of admission to the emergency departments.

Article

Mar 2022

Sandwich structure confined gold as highly sensitive and stable electrochemical non-enzymatic glucose sensor with low oxidation potential

Article

Mar 2022
J MATER SCI TECHNOL

The preparation of highly sensitive and stable non-enzymatic glucose sensors is critical to the prevention and treatment of diabetes. Fe3O4@[email protected] is prepared through a spontaneous galvanic displacement reaction. A series of structural characterizations testify the successful formation of Fe3O4@[email protected] electrocatalyst, with the Au intercalating between Fe3O4 and LDH to form the sandwich structure. Cyclic voltammetry tests indicate that Au is responsible for the electrocatalytic oxidation of glucose. The characterizations of the electrochemical sensor for glucose detection indicate that Fe3O4@[email protected] possesses high sensitivity of 6342 μA mM⁻¹ cm⁻², with an extremely low oxidation potential of 0.82 V vs. RHE. Even with the high glucose concentration of 15 mM, the sensitivity remains at 4359 μA mM⁻¹ cm⁻². Due to the broad linear detection range (0.0375 to 15.64 mM) and the low limit of detection (12.7 μM), Fe3O4@[email protected] is applicable towards practical application. Thanks to the sandwich structure, which confines the Au in between Fe3O4 and CoFe-LDH, the Fe3O4@[email protected] glucose sensor shows high long-term stability and satisfactory selectivity. The successful synthesis of the sandwich-structured Fe3O4@[email protected] provides a new conception for the design of highly sensitive and stable non-enzymatic glucose electrodes.

Diabetes Management in Patients with Critical and Non‐Critical Illness

Chapter

Dec 2021

During acute illness, hyperglycemia is exacerbated in people with diabetes as a consequence of the release of counterregulatory hormones and cytokines. This chapter addresses mechanisms of hyperglycemia‐related morbidity and mortality in the critically ill and undertakes a detailed review of the evidence supporting the use of insulin infusion in the ICU, with emphasis on ten large clinical trials. It discusses the importance of hypoglycemia, nutritional support, and imprecision in blood glucose testing in interpreting the results of these trials. The chapter reviews in detail the results of ten large clinical trials that have produced disparate, difficult‐to‐reconcile results. It attempts to identify features of the studies that might explain divergent findings leading to conflicting conclusions and recommendations. The chapter concludes that there is strong evidence to support the use of insulin infusion to control hyperglycemia in the critically ill, but very little evidence to indicate what the blood glucose target should be.

Developing a highly-sensitive aptasensor based on surface energy transfer between InP/ZnS quantum dots and Ag-nanoplates for the determination of insulin

Article

Oct 2021
J PHOTOCH PHOTOBIO A

A novel optical aptasensor with excellent sensitivity and high selectivity was fabricated as a tool for insulin determination in human blood plasma. The performance of the probe is based on surface energy transfer (SET) between thioglycolic acid capped indium phosphide/zinc sulfide quantum dots (TGA-InP/ZnS QDs) (donor) and Ag-nanoplates (acceptor). Initially, low-risk TGA-InP/ZnS core-shell QDs with high fluorescence quantum yield (ФF =73%) were synthesized via the stepwise method. Ag-nanoplates with well surface plasmon resonance (SPR), high extinction coefficient, viability, good optical and chemical stability act as fluorescence signal quencher. Insulin aptamer strands (Ap) was used as the biorecognition element and linked to the QDs surface by the covalent bonds (Ap-QDs). In the absence of insulin, Ap-QDs are adsorbed on the Ag-nanoplates surface and fluorescence intensity quenched. By adding insulin to the media, due to the high aptamer affinity to the insulin, AP-QDs getting away from Ag-nanoplates and the fluorescence signal of QDs was restored related to the insulin quantity. In the optimized situations probe works in the dynamic range (DR) (0.001-5000 nM) with a limit of detection (LOD = 0.5 pM). This method was used to measure insulin in blood plasma and its accuracy was estimated by comparison obtained results with the standard method (HPLC).

Çocuklarda ve ergenlerde Beslenme

Book

Full-text available

May 2017

Nutrition of the Sick Animal

Chapter

Jan 2020

Harnessing molecular recognition for localized drug delivery

Article

Jan 2021
ADV DRUG DELIVER REV

A grand challenge in drug delivery is providing the right dose, at the right anatomic location, for the right duration of time to maximize therapeutic efficacy while minimizing off-target toxicity and other deleterious side-effects. Two general modalities are receiving broad attention for localized drug delivery. In the first, referred to as “targeted accumulation”, drugs or drug carriers are engineered to have targeting moieties that promote their accumulation at a specific tissue site from circulation. In the second, referred to as “local anchoring”, drugs or drug carriers are inserted directly into the tissue site of interest where they persist for a specified duration of time. This review surveys recent advances in harnessing molecular recognition between proteins, peptides, nucleic acids, lipids, and carbohydrates to mediate targeted accumulation and local anchoring of drugs and drug carriers.

Understanding cellular and molecular mechanisms of pathogenesis of diabetic tendinopathy

Article

Full-text available

Nov 2020

There is accumulating evidence of an increased incidence of tendon disorders in people with diabetes mellitus. Diabetic tendinopathy is an important cause of chronic pain, restricted activity, and even tendon rupture in individuals. Tenocytes and tendon stem/progenitor cells (TSPCs) are the dominant cellular components associated with tendon homeostasis, maintenance, remodeling, and repair. Some previous studies have shown alterations in tenocytes and TSPCs in high glucose or diabetic conditions that might cause structural and functional variations in diabetic tendons and even accelerate the development and progression of diabetic tendinopathy. In this review, the biomechanical properties and histopathological changes in diabetic tendons are described. Then, the cellular and molecular alterations in both tenocytes and TSPCs are summarized, and the underlying mechanisms involved are also analyzed. A better understanding of the underlying cellular and molecular pathogenesis of diabetic tendinopathy would provide new insight for the exploration and development of effective therapeutics.

Inhibiting the Piezo1 channel protects microglia from acute hyperglycaemia damage through the JNK1 and mTOR signalling pathways

Article

Oct 2020
LIFE SCI

Aim Diabetes is a high-risk factor for neurocognitive dysfunction. Diabetic acute hyperglycaemia accompanied by high osmotic pressure can induce immune cell dysfunction, but its mechanism of action in brain microglia remains unclear. This study aimed to evaluate the role of the mechanically sensitive ion channel Piezo1 in the dysfunction of microglia in acute hyperglycaemia. Materials and methods To construct an in vitro acute hyperglycaemia model using the BV2 microglial cell line, Piezo1 in microglia was inhibited by GsMTx4 and siRNA, and the changes in microglial function were further evaluated. Key findings High concentrations of glucose upregulated the expression of Piezo1, led to weakened cell proliferation and migration, and reduced the immune response to inflammatory stimulating factors (Aβ and LPS). Additionally, LPS upregulated Piezo1 in BV2 microglial cultures in vitro. The activation of Piezo1 channels increased the intracellular Ca²⁺ concentration and reduced the phosphorylation of JNK1 and mTOR. Inhibiting Piezo1 did not affect cell viability at average glucose concentrations but improved acute HCG-induced cell damage and increased the phosphorylation of JNK1 and mTOR, suggesting that the latter modification may be a potential downstream mechanism of Piezo1. Significance Piezo1 is necessary for microglial damage in acute hyperglycaemia and may become a promising target to treat hyperglycaemic brain injury.

Tata Laksana Hiperglikemia dengan Insulin Tight Controlled di Ruang Intensif Anak

Article

Full-text available

May 2020

Latar belakang. Penelitian tata laksana hiperglikemia dengan insulin dan pengaruhnya terhadap keluaran klinis anak sakit kritis belum banyak dilakukan. Tujuan. Mengetahui keluaran kejadian hipoglikemia, lama rawat inap di ruang intensif, dan angka kematian dalam tata laksana hiperglikemia dengan insulin menggunakan metode tight controlled (gula darah sewaktu/GDS diturunkan sampai kadar 80-120mg/dL) dan metode permissive controlled (GDS diturunkan sampai 150mg/dL dalam dua kali pengukuran pada 24 jam pertama perawatan. Subyek dibagi menjadi dua kelompok terapi, yaitu kelompok dengan metode tight controlled dan permissive controlled. Keluaran yang dinilai adalah kejadian hipoglikemia, lama rawat di ruang intensif dan kematian. Hasil. Lima belas anak masuk dalam kriteria inklusi. Sembilan pasien masuk dalam tight controlled dan 6 pasien dalam permissive controlled. Tidak terdapat keluaran hipoglikemia pada kedua kelompok. Didapatkan 66,7% subyek meninggal baik pada grup tight dan perminssive controlled (p=1). Rerata lama rawat tight dan permissive controlled adalah 8,89±5,69 dan 13±9,32 hari (p=0,407). Kesimpulan. Tidak terdapat keluaran hipoglikemia pada kedua kelompok dan tidak ada perbedaan bermakna secara statistik pada mortalitas.

Role of Brain Insulin Receptor in Control of Body Weight and Reproduction

Article

Full-text available

Sep 2000
SCIENCE

Insulin receptors (IRs) and insulin signaling proteins are widely distributed throughout the central nervous system (CNS). To study the physiological role of insulin signaling in the brain, we created mice with a neuron-specific disruption of the IR gene (NIRKO mice). Inactivation of the IR had no impact on brain development or neuronal survival. However, female NIRKO mice showed increased food intake, and both male and female mice developed diet-sensitive obesity with increases in body fat and plasma leptin levels, mild insulin resistance, elevated plasma insulin levels, and hypertriglyceridemia. NIRKO mice also exhibited impaired spermatogenesis and ovarian follicle maturation because of hypothalamic dysregulation of luteinizing hormone. Thus, IR signaling in the CNS plays an important role in regulation of energy disposal, fuel metabolism, and reproduction.

Intensive Insulin Therapy in Critically Ill Patients

Article

Full-text available

Nov 2001
NEW ENGL J MED

Hyperglycemia and insulin resistance are common in critically ill patients, even if they have not previously had diabetes. Whether the normalization of blood glucose levels with insulin therapy improves the prognosis for such patients is not known. We performed a prospective, randomized, controlled study involving adults admitted to our surgical intensive care unit who were receiving mechanical ventilation. On admission, patients were randomly assigned to receive intensive insulin therapy (maintenance of blood glucose at a level between 80 and 110 mg per deciliter [4.4 and 6.1 mmol per liter]) or conventional treatment (infusion of insulin only if the blood glucose level exceeded 215 mg per deciliter [11.9 mmol per liter] and maintenance of glucose at a level between 180 and 200 mg per deciliter [10.0 and 11.1 mmol per liter]). At 12 months, with a total of 1548 patients enrolled, intensive insulin therapy reduced mortality during intensive care from 8.0 percent with conventional treatment to 4.6 percent (P<0.04, with adjustment for sequential analyses). The benefit of intensive insulin therapy was attributable to its effect on mortality among patients who remained in the intensive care unit for more than five days (20.2 percent with conventional treatment, as compared with 10.6 percent with intensive insulin therapy, P=0.005). The greatest reduction in mortality involved deaths due to multiple-organ failure with a proven septic focus. Intensive insulin therapy also reduced overall in-hospital mortality by 34 percent, bloodstream infections by 46 percent, acute renal failure requiring dialysis or hemofiltration by 41 percent, the median number of red-cell transfusions by 50 percent, and critical-illness polyneuropathy by 44 percent, and patients receiving intensive therapy were less likely to require prolonged mechanical ventilation and intensive care. Intensive insulin therapy to maintain blood glucose at or below 110 mg per deciliter reduces morbidity and mortality among critically ill patients in the surgical intensive care unit.

Regulation of expression of glucose transporters by glucose: A review of studies in vivo and in cell cultures

Article

Full-text available

Feb 1994

Glucose transporters are membrane-embedded proteins that mediate the uptake of glucose from the surrounding medium into the cell. Glucose is the main fuel for most cells, and its uptake is rate-limiting for glucose utilization. For this reason, it is expected that glucose transport is tightly regulated. Whereas rapid regulation of glucose transporters by hormones has been known for some time, the regulation of glucose transporters by substrate availability (i.e., by glucose itself) is less well understood. This question has been approached by scientists from two angles: one, by measuring the consequence of diabetic states (in which there is surplus of glucose availability) on the expression of glucose transporter genes, and another one, by measuring the effect of glucose availability and glucose deprivation in cell cultures on glucose transporter gene expression. The results from both camps are unfortunately not coincident, due in part to the coexistence of other variables in the diabetic animals, and to the lack of ideal cell cultures. In spite of these caveats, the profuse literature on both approaches propelled us to find commonalities within each approach. This review concludes that in animal studies, one isoform of glucose transporters, the GLUT4 type, is down-regulated by high levels of circulating glucose in muscle but not in fat cells. This down-regulation of the protein is independent of regulation of transcription. In contrast, in fat cells, high glucose levels depress GLUT4 mRNA levels. In cell culture studies, high glucose levels lead to lower expression of the GLUT1 transporter isoform relative to glucose-deprived cultures. Glucose levels do not affect the amount of GLUT4 transporter isoform. The down-regulation of the GLUT1 transporter protein is caused by pre- and post-transcriptional mechanisms, the prevalence of each being cell-type specific. No glucose-responsive elements have been identified on either the GLUT1 or GLUT4 genes, and no information is available on the glucose metabolites that mediate the response of glucose transporter gene expression to glucose availability.

Chylomicrons alter the fate of endotoxin, decreasing tumor necrosis factor release and preventing death

Article

Full-text available

Apr 1993

The hypertriglyceridemia of infection was traditionally thought to represent the mobilization of substrate to fuel the body's response to the infectious challenge. However, we have previously shown that triglyceride-rich lipoproteins can protect against endotoxin-induced lethality. The current studies examine the mechanism by which this protection occurs. Rats infused with a lethal dose of endotoxin preincubated with chylomicrons had a reduced mortality compared with rats infused with endotoxin alone (15 vs. 76%, P < 0.001). Preincubation with chylomicrons increased the rate of clearance of endotoxin from plasma and doubled the amount of endotoxin cleared by the liver (30 +/- 1 vs. 14 +/- 2% of the total infused radiolabel, P < 0.001). In addition, autoradiographic studies showed that chylomicrons directed more of the endotoxin to hepatocytes and away from hepatic macrophages. Rats infused with endotoxin plus chylomicrons also showed reduced peak serum levels of tumor necrosis factor as compared with controls (14.2 +/- 3.3 vs. 44.9 +/- 9.5 ng/ml, mean +/- SEM, P = 0.014). In separate experiments, chylomicrons (1,000 mg triglyceride/kg) or saline were infused 10 min before the infusion of endotoxin. Chylomicron pretreatment resulted in a reduced mortality compared with rats infused with endotoxin alone (22 vs. 78%, P < 0.005). Therefore, chylomicrons can protect against endotoxin-induced lethality with and without preincubation with endotoxin. The mechanism by which chylomicrons protect against endotoxin appears to involve the shunting of endotoxin to hepatocytes and away from macrophages, thereby decreasing macrophage activation and the secretion of cytokines.

The hypertriglyceridemia of acquired immunodeficiency syndrome is associated with an increased prevalence of low density lipoprotein subclass pattern B

Article

Full-text available

Jul 1993

Plasma low density lipoproteins (LDL) comprise multiple discrete subclasses, differing in size, density, and chemical composition. Gradient gel electrophoresis of LDL has demonstrated three common subclass patterns based on the predominant LDL subclass: large LDL, designated subclass pattern A; small LDL particles, designated subclass pattern B; and an intermediate pattern. Genetic studies have demonstrated that these patterns are inherited, but several lines of evidence suggest that environmental factors are important in the phenotypic expression of the pattern. The LDL B pattern is associated with increased levels of plasma triglyceride, reduced high density lipoprotein (HDL), and obesity. To better define the role of environmental factors on LDL phenotypic expression, we determined LDL patterns in patients with the acquired immunodeficiency syndrome (AIDS), an infection characterized by hypertriglyceridemia and weight loss. Similar to previous studies, plasma triglyceride levels were increased, whereas plasma cholesterol, LDL cholesterol, and HDL cholesterol levels were decreased in the AIDS subjects compared to those in age-matched controls. The percentage of AIDS subjects with the LDL B phenotype was increased 2.5-fold, demonstrating an increased prevalence of the LDL B phenotype in an acquired form of hypertriglyceridemia. For each LDL phenotype in AIDS, serum triglyceride levels were higher than the same phenotypic pattern in controls, with the most marked elevations in triglycerides found in AIDS subjects with the LDL B phenotype. In contrast to what was observed in controls, HDL cholesterol levels were decreased in all AIDS subjects and were unrelated to LDL pattern. Total and LDL cholesterol levels were higher in controls with the LDL B phenotype than in those with the LDL A phenotype, but there was no difference in total and LDL cholesterol in AIDS subjects with LDL B compared to A. On multiple regression analysis in subjects with AIDS, plasma triglyceride levels, age, and HDL cholesterol all contribute to the occurrence of the LDL B phenotype, but elevations in plasma triglyceride levels are the strongest independent predictor. Body mass index was not a predictor of LDL B phenotype in AIDS. These results suggest that disturbances in triglyceride metabolism that are caused by AIDS lead to the appearance of the LDL subclass B phenotype and provide further evidence that environmental or disease states that perturb lipid metabolism can produce an increased prevalence of the LDL B phenotype.

Amato MB, Barbas CS, Medeiros DM: Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med 338: 347-354

Article

Full-text available

Feb 1998

In patients with the acute respiratory distress syndrome, massive alveolar collapse and cyclic lung reopening and overdistention during mechanical ventilation may perpetuate alveolar injury. We determined whether a ventilatory strategy designed to minimize such lung injuries could reduce not only pulmonary complications but also mortality at 28 days in patients with the acute respiratory distress syndrome. We randomly assigned 53 patients with early acute respiratory distress syndrome (including 28 described previously), all of whom were receiving identical hemodynamic and general support, to conventional or protective mechanical ventilation. Conventional ventilation was based on the strategy of maintaining the lowest positive end-expiratory pressure (PEEP) for acceptable oxygenation, with a tidal volume of 12 ml per kilogram of body weight and normal arterial carbon dioxide levels (35 to 38 mm Hg). Protective ventilation involved end-expiratory pressures above the lower inflection point on the static pressure-volume curve, a tidal volume of less than 6 ml per kilogram, driving pressures of less than 20 cm of water above the PEEP value, permissive hypercapnia, and preferential use of pressure-limited ventilatory modes. After 28 days, 11 of 29 patients (38 percent) in the protective-ventilation group had died, as compared with 17 of 24 (71 percent) in the conventional-ventilation group (P<0.001). The rates of weaning from mechanical ventilation were 66 percent in the protective-ventilation group and 29 percent in the conventional-ventilation group (P=0.005): the rates of clinical barotrauma were 7 percent and 42 percent, respectively (P=0.02), despite the use of higher PEEP and mean airway pressures in the protective-ventilation group. The difference in survival to hospital discharge was not significant; 13 of 29 patients (45 percent) in the protective-ventilation group died in the hospital, as compared with 17 of 24 in the conventional-ventilation group (71 percent, P=0.37). As compared with conventional ventilation, the protective strategy was associated with improved survival at 28 days, a higher rate of weaning from mechanical ventilation, and a lower rate of barotrauma in patients with the acute respiratory distress syndrome. Protective ventilation was not associated with a higher rate of survival to hospital discharge.

Reactivation of Pituitary Hormone Release and Metabolic Improvement by Infusion of Growth Hormone-Releasing Peptide and Thyrotropin-Releasing Hormone in Patients with Protracted Critical Illness 1

Article

Full-text available

May 1999

Protracted critical illness is marked by protein wasting resistant to feeding, by accumulation of fat stores, and by suppressed pulsatile release of GH and TSH. We previously showed that the latter can be reactivated by brief infusion of GH-releasing peptide (GHRP-2) and TRH. Here, we studied combined GHRP-2 and TRH infusion for 5 days, which allowed a limited evaluation of the metabolic effectiveness of this novel trophic endocrine strategy. Fourteen patients (mean ± sd age, 68 ± 11 yr), critically ill for 40 ± 28 days, were compared to a matched group of community-living control subjects at baseline and subsequently received 5 days of placebo and 5 days of GHRP-2 plus TRH (1+1μ g/kg·h) infusion in random order. At baseline, impaired anabolism, as indicated by biochemical markers (osteocalcin and leptin), was linked to hyposomatotropism [reduced pulsatile GH secretion, as determined by deconvolution analysis, and low GH-dependent insulin-like growth factor and binding protein (IGFBP) levels]. Biochemical markers of accelerated catabolism (increased protein degradation and bone resorption) were related to tertiary hypothyroidism and the serum concentration of IGFBP-1, but not to hyposomatotropism. Metabolic markers were independent of elevated serum cortisol. After 5 days of GHRP-2 plus TRH infusion, osteocalcin concentrations increased 19% vs. −6% with placebo, and leptin had rose 32% vs. -15% with placebo. These anabolic effects were linked to increased IGF-I and GH-dependent IGFBP, which reached near-normal levels from day 2 onward. In addition, protein degradation was reduced, as indicated by a drop in the urea/creatinine ratio, an effect that was related to the correction of tertiary hypothyroidism, with near-normal thyroid hormone levels reached and maintained from day 2 onward. Concomitantly, a spontaneous tendency of IGFBP-1 to rise and of insulin to decrease was reversed. Cortisol concentrations were not detectably altered. In conclusion, 5-day infusion of GHRP-2 plus TRH in protracted critical illness reactivates blunted GH and TSH secretion, with preserved pulsatility, peripheral responsiveness, and feedback inhibition and without affecting serum cortisol, and induces a shift toward anabolic metabolism. This provides the first evidence of the metabolic effectiveness of short term GHRP-2 plus TRH agonism in this particular wasting condition.

Characterization of the selective resistance to insulin signaling in the vasculature of obese Zucker (

Article

Full-text available

Sep 1999

Both insulin resistance and hyperinsulinemia have been reported to be independent risk factors for cardiovascular diseases. However, little is known regarding insulin signaling in the vascular tissues in insulin-resistant states. In this report, insulin signaling on the phosphatidylinositol 3-kinase (PI 3-kinase) and mitogen-activated protein (MAP) kinase pathways were compared in vascular tissues of lean and obese Zucker (fa/fa) rats in both ex vivo and in vivo studies. Ex vivo, insulin-stimulated tyrosine phosphorylation of insulin receptor beta subunits (IRbeta) in the aorta and microvessels of obese rats was significantly decreased compared with lean rats, although the protein levels of IRbeta in the 2 groups were not different. Insulin-induced tyrosine phosphorylation of insulin receptor substrates 1 and 2 (IRS-1 and IRS-2) and their protein levels were decreased in the aorta of obese rats compared with lean rats. The association of p85 subunit to the IRS proteins and the IRS-associated PI 3-kinase activities stimulated by insulin in the aorta of obese rats were significantly decreased compared with the lean rats. In addition, insulin-stimulated serine phosphorylation of Akt, a downstream kinase of PI 3-kinase pathway, was also reduced significantly in isolated microvessels from obese rats compared with the lean rats. In euglycemic clamp studies, insulin infusion greatly increased tyrosine phosphorylation of IRbeta- and IRS-2-associated PI 3-kinase activity in the aorta of lean rats, but only slight increases were observed in obese rats. In contrast, insulin stimulated tyrosine phosphorylation of MAP kinase (ERK-1/2) equally in isolated microvessels of lean and obese rats, although basal tyrosine phosphorylation of ERK-1/2 was higher in the obese rats. To our knowledge, these data provided the first direct measurements of insulin signaling in the vascular tissues, and documented a selective resistance to PI 3-kinase (but not to MAP kinase pathway) in the vascular tissues of obese Zucker rats.

Insulin resistant differentially affects PI-3 kinase and MAP-kinase-mediated signaling in human muscle

Article

Full-text available

Mar 2000

The broad nature of insulin resistant glucose metabolism in skeletal muscle of patients with type 2 diabetes suggests a defect in the proximal part of the insulin signaling network. We sought to identify the pathways compromised in insulin resistance and to test the effect of moderate exercise on whole-body and cellular insulin action. We conducted euglycemic clamps and muscle biopsies on type 2 diabetic patients, obese nondiabetics and lean controls, with and without a single bout of exercise. Insulin stimulation of the phosphatidylinositol 3-kinase (PI 3-kinase) pathway, as measured by phosphorylation of the insulin receptor and IRS-1 and by IRS protein association with p85 and with PI 3-kinase, was dramatically reduced in obese nondiabetics and virtually absent in type 2 diabetic patients. Insulin stimulation of the MAP kinase pathway was normal in obese and diabetic subjects. Insulin stimulation of glucose-disposal correlated with association of p85 with IRS-1. Exercise 24 hours before the euglycemic clamp increased phosphorylation of insulin receptor and IRS-1 in obese and diabetic subjects but did not increase glucose uptake or PI 3-kinase association with IRS-1 upon insulin stimulation. Thus, insulin resistance differentially affects the PI 3-kinase and MAP kinase signaling pathways, and insulin-stimulated IRS-1-association with PI 3-kinase defines a key step in insulin resistance.

Effects of insulin on prenylation as a mechanism of potentially detrimental influence of hyperinsulinemia

Article

Full-text available

May 2000

To investigate the cause and effect relationship between hyperinsulinemia and the increased amounts of farnesylated p21Ras, we performed hyperinsulinemic euglycemic clamps in normal weight volunteers as well as in normal mice and dogs. Insulin infusions significantly raised the amounts of farnesylated p21Ras in the white blood cells of humans, in liver samples of mice and dogs, and in aorta samples of mice. Obese hyperinsulinemic individuals and dogs (made hyperinsulinemic by surgical diversion of the pancreatic outflow from the portal vein into the vena cava) displayed increased amounts of farnesylated p21Ras before the hyperinsulinemic clamps. Infusions of insulin did not alter the already increased levels of farnesylated p21Ras in these experimental models. To further investigate the role of acquired insulin resistance in modulating insulin's effect on p21Ras prenylation, we induced insulin resistance in rats by glucosamine infusion. Insulin-resistant glucosamine-treated animals displayed significantly increased farnesylated p21Ras in response to insulin infusion compared to that in control saline-treated animals. Transgenic models of insulin resistance (heterozygous insulin receptor substrate-1 knockout mice, A-ZIP/F-1 fatless mice, and animals overexpressing glutamine:fructose-6-phosphate amidotransferase) contained increased amounts of farnesylated p21Ras. We conclude that hyperinsulinemia, either endogenous (a prominent feature of insulin resistance) or produced by infusions of insulin, increases the amounts of farnesylated p21Ras in humans, mice, and dogs. This aspect of insulin action may represent one facet of the molecular mechanism of the potentially detrimental influence of hyperinsulinemia.

for the Recombinat Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) Study Group

Article

Full-text available

Apr 2001

Drotrecogin alfa (activated), or recombinant human activated protein C, has antithrombotic, antiinflammatory, and profibrinolytic properties. In a previous study, drotrecogin alfa activated produced dose-dependent reductions in the levels of markers of coagulation and inflammation in patients with severe sepsis. In this phase 3 trial, we assessed whether treatment with drotrecogin alfa activated reduced the rate of death from any cause among patients with severe sepsis. We conducted a randomized, double-blind, placebo-controlled, multicenter trial. Patients with systemic inflammation and organ failure due to acute infection were enrolled and assigned to receive an intravenous infusion of either placebo or drotrecogin alfa activated (24 microg per kilogram of body weight per hour) for a total duration of 96 hours. The prospectively defined primary end point was death from any cause and was assessed 28 days after the start of the infusion. Patients were monitored for adverse events; changes in vital signs, laboratory variables, and the results of microbiologic cultures; and the development of neutralizing antibodies against activated protein C. A total of 1690 randomized patients were treated (840 in the placebo group and 850 in the drotrecogin alfa activated group). The mortality rate was 30.8 percent in the placebo group and 24.7 percent in the drotrecogin alfa activated group. On the basis of the prospectively defined primary analysis, treatment with drotrecogin alfa activated was associated with a reduction in the relative risk of death of 19.4 percent (95 percent confidence interval, 6.6 to 30.5) and an absolute reduction in the risk of death of 6.1 percent (P=0.005). The incidence of serious bleeding was higher in the drotrecogin alfa activated group than in the placebo group (3.5 percent vs. 2.0 percent, P=0.06). Treatment with drotrecogin alfa activated significantly reduces mortality in patients with severe sepsis and may be associated with an increased risk of bleeding.

Montagnani M, Chen H, Barr VA, Quon MJ. Insulin-stimulated activation of eNOS is independent of Ca2+ but requires phosphorylation by Akt at Ser. J Biol Chem 2001; 276: 30392-30398

Article

Full-text available

Sep 2001

Vasodilator actions of insulin are mediated by activation of endothelial nitric-oxide synthase (eNOS) and subsequent production of NO. Phosphatidylinositol 3-kinase and Akt play important roles in insulin-signaling pathways leading to production of NO in vascular endothelium. Here we dissected mechanisms whereby insulin activates eNOS by using the fluorescent dye DAF-2 to directly measure NO production in single cells. Insulin caused a rapid increase in intracellular NO in NIH-3T3(IR) cells transiently transfected with eNOS. The stimulation of NO production by lysophosphatidic acid (LPA) was abrogated by pretreatment of cells with the calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid. Remarkably, in the same cells, insulin-stimulated production of NO was unaffected. However, cells expressing the eNOS-S1179A mutant (disrupted Akt phosphorylation site) did not produce detectable NO in response to insulin, whereas the response to LPA was similar to that observed in cells expressing wild-type eNOS. Moreover, production of NO in response to insulin was blocked by coexpression of an inhibitory mutant of Akt, whereas the response to LPA was unaffected. Phosphorylation of eNOS at Ser(1179) was observed only in response to treatment with insulin, but not with LPA. Interestingly, platelet-derived growth factor treatment of cells activated Akt but not eNOS. Results from human vascular endothelial cells were qualitatively similar to those obtained in transfected NIH-3T3(IR) cells, although the magnitude of the responses was smaller. We conclude that insulin regulates eNOS activity using a Ca(2+)-independent mechanism requiring phosphorylation of eNOS by Akt. Importantly, phosphorylation-dependent mechanisms that enhance eNOS activity can operate independently from Ca(2+)-dependent mechanisms.

Insulin inhibits intranuclear nuclear factor kappaB and stimulates IkappaB in mononuclear cells in obese subjects

Article

Full-text available

Aug 2001

In view of the fact that insulin resistance is associated with atherogenesis and that troglitazone, an insulin sensitizer, has anti-inflammatory effects, which may be potentially antiatherogenic in the long term, we have now investigated whether insulin has potential anti-inflammatory effects. We infused 2.0 to 2.5 IU/h in 5% dextrose (100 mL/h) iv into 10 obese subjects for 4 h followed by 5% dextrose alone for 2 h. The rate of insulin infusion was varied to maintain glucose concentrations as close to the baseline as possible. Blood samples were obtained before and at 2, 4, and 6 h. Subjects were also infused with 5% dextrose without insulin and with saline on separate occasions. Intranuclear nuclear factor kappaB (NFkappaB) in mononuclear cells fell at 2 and further at 4 h, reverting toward the baseline at 6 h (P < 0.05). IkappaB increased significantly at 2 h, increasing further at 4 h and remaining elevated at 6 h (P < 0.001). Reactive oxygen species (ROS) generation by mononuclear cells fell significantly at 2 h and fell further at 4 h; it partially reverted to baseline at 6 h (P < 0.005). p47(phox) subunit, the key protein of nicotinamide adenine dinucleotide phosphate oxidase also fell at 2 h and 4 h, reverting toward the baseline at 6 h (P < 0.05). In addition, soluble intercellular adhesion molecule-1 (sICAM-1), monocyte chemoattractant protein-1 (MCP-1), and plasminogen activator inhibitor-1 (PAI-1) fell significantly following insulin infusion. Glucose or saline infusions without insulin caused no alteration in NFkappaB, IkappaB, ROS generation, p47(phox) subunit, sICAM-1, MCP-1, or PAI-1. We conclude that insulin has a potent acute anti-inflammatory effect including a reduction in intranuclear NFkappaB, an increase in IkappaB, and decreases in ROS generation, p47(phox) subunit, plasma soluble intercellular adhesion molecule-1 (sICAM-1), monocyte chemoattractant protein-1 (MCP-1), and plasminogen activator inhibitor-1 (PAI-1. This acute anti-inflammatory effect, if demonstrated in the long term, may have implications for atherosclerosis and its complications.

Inhibition of Phosphatidylinositol 3-Kinase Enhances Mitogenic Actions of Insulin in Endothelial Cells

Article

Full-text available

Feb 2002

The concept of “selective insulin resistance” has emerged as a unifying hypothesis in attempts to reconcile the influence of insulin resistance with that of hyperinsulinemia in the pathogenesis of macrovascular complications of diabetes. To explore this hypothesis in endothelial cells, we designed a set of experiments to mimic the “typical metabolic insulin resistance” by blocking the phosphatidylinositol 3-kinase pathway and exposing the cells to increasing concentrations of insulin (“compensatory hyperinsulinemia”). Inhibition of phosphatidylinositol 3-kinase with wortmannin blocked the ability of insulin to stimulate increased expression of endothelial nitric-oxide synthase, did not affect insulin-induced activation of MAP kinase, and increased the effects of insulin on prenylation of Ras and Rho proteins. At the same time, this experimental paradigm resulted in increased expression of vascular cellular adhesion molecules-1 and E-selectin, as well as increased rolling interactions of monocytes with endothelial cells. We conclude that inhibition of the metabolic branch of insulin signaling leads to an enhanced mitogenic action of insulin in endothelial cells.

Early Goal-Directed Therapy In The Treatment Of Severe Sepsis And Septic Shock

Article

Full-text available

Nov 2001

Goal-directed therapy has been used for severe sepsis and septic shock in the intensive care unit. This approach involves adjustments of cardiac preload, afterload, and contractility to balance oxygen delivery with oxygen demand. The purpose of this study was to evaluate the efficacy of early goal-directed therapy before admission to the intensive care unit. We randomly assigned patients who arrived at an urban emergency department with severe sepsis or septic shock to receive either six hours of early goal-directed therapy or standard therapy (as a control) before admission to the intensive care unit. Clinicians who subsequently assumed the care of the patients were blinded to the treatment assignment. In-hospital mortality (the primary efficacy outcome), end points with respect to resuscitation, and Acute Physiology and Chronic Health Evaluation (APACHE II) scores were obtained serially for 72 hours and compared between the study groups. Of the 263 enrolled patients, 130 were randomly assigned to early goal-directed therapy and 133 to standard therapy; there were no significant differences between the groups with respect to base-line characteristics. In-hospital mortality was 30.5 percent in the group assigned to early goal-directed therapy, as compared with 46.5 percent in the group assigned to standard therapy (P = 0.009). During the interval from 7 to 72 hours, the patients assigned to early goal-directed therapy had a significantly higher mean (+/-SD) central venous oxygen saturation (70.4+/-10.7 percent vs. 65.3+/-11.4 percent), a lower lactate concentration (3.0+/-4.4 vs. 3.9+/-4.4 mmol per liter), a lower base deficit (2.0+/-6.6 vs. 5.1+/-6.7 mmol per liter), and a higher pH (7.40+/-0.12 vs. 7.36+/-0.12) than the patients assigned to standard therapy (P < or = 0.02 for all comparisons). During the same period, mean APACHE II scores were significantly lower, indicating less severe organ dysfunction, in the patients assigned to early goal-directed therapy than in those assigned to standard therapy (13.0+/-6.3 vs. 15.9+/-6.4, P < 0.001). Early goal-directed therapy provides significant benefits with respect to outcome in patients with severe sepsis and septic shock.

Nitric oxide mediates the antiapoptotic effect of insulin in myocardial ischemia-reperfusion: The roles of PI3-kinase, Akt, and endothelial nitric oxide synthase phosphorylation

Article

Full-text available

Apr 2002
CIRCULATION

Recent evidence from cultured endothelial cell studies suggests that phosphorylation of endothelial nitric oxide synthase (eNOS) through the PI3-kinase-Akt pathway increases NO production. This study was designed to elucidate the signaling pathway involved in the antiapoptotic effect of insulin in vivo and to test the hypothesis that phosphorylation of eNOS by insulin may participate in the cardioprotective effect of insulin after myocardial ischemia and reperfusion. Male Sprague-Dawley rats were subjected to 30 minutes of myocardial ischemia and 4 hours of reperfusion. Rats were randomized to receive vehicle, insulin, insulin plus wortmannin, or insulin plus L-NAME. Treatment with insulin resulted in 2.6-fold and 4.3-fold increases in Akt and eNOS phosphorylation and a significant increase in NO production in ischemic/reperfused myocardial tissue. Phosphorylation of Akt and eNOS and increase of NO production by insulin were completely blocked by wortmannin, a PI3-kinase inhibitor. Pretreatment with L-NAME, a nonselective NOS inhibitor, had no effect on Akt and eNOS phosphorylation but significantly reduced NO production. Moreover, treatment with insulin markedly reduced myocardial apoptotic death (P<0.01 versus vehicle). Pretreatment with wortmannin abolished the antiapoptotic effect of insulin. Most importantly, pretreatment with L-NAME also significantly reduced the antiapoptotic effect of insulin (P<0.01 versus insulin). These results demonstrated that in vivo administration of insulin activated Akt through the PI3-kinase-dependent mechanism and reduced postischemic myocardial apoptotic death. Phosphorylation of eNOS and the concurrent increase of NO production contribute significantly to the antiapoptotic effect of insulin.

Cytopathic Hypoxia: Mitochondrial Dysfunction as a Potential Mechanism Contributing to Organ Failure in Sepsis

Chapter

Jan 2002

M. P. Fink

Effect of a protective ventilation strategy on mortality in the acute respiratory distress syndrome

Article

Jan 1998

Outcome benefit of intensive insulin therapy in critically ill patients: insulin dose versus glycemic control

Article

Jan 2003
CRIT CARE MED

A Paradoxical Gender Dissociation within the Growth Hormone/Insulin-Like Growth Factor I Axis during Protracted Critical Illness

Article

Jan 2000

Guy van den Berghe

Low Lipid Concentrations in Critical Illness

Article

Apr 1996
CRIT CARE MED

Objectives: To determine the prevalence and clinical significance of hypolipidemia found in critically ill patients, and whether the addition of a reconstituted lipoprotein preparation could inhibit the generation of tumor necrosis factor-alpha (TNF-alpha) in acute-phase blood taken from these patients. Setting: Surgical intensive care unit (ICU) of a large urban university hospital. Design: Prospective case series. Patients: A total of 32 patients with a variety of critical illnesses had lipid and lipoprotein concentrations determined. Six patients and six age- and gender-matched control subjects had whole blood in vitro studies of the effect of lipoprotein on lipopolysaccharide mediated TNF-alpha production. Interventions: Blood samples were drawn on admission to the ICU and over a subsequent 8-day period. Measurements and Main Results: Mean serum lipid and lipoprotein values obtained from patients within 24 hrs of transfer to the surgical ICU were extremely low: mean total cholesterol was 117 mg/dL (3.03 mmol/L), low-density lipoprotein cholesterol 71 mg/dL (1.84 mmol/L), and high-density lipoprotein cholesterol 25 mg/dL (0.65 mmol/L). Only the mean triglyceride concentration of 105 mg/dL (1.19 mmol/L), and the mean lipoprotein(a) concentration of 25 mg/dL (0.25 g/L) were within the normal range. During the first 8 days following surgical ICU admission, there were trends toward increasing lipid and lipoprotein concentrations that were significant for triglycerides and apolipoprotein B. Survival did not correlate with the lipid or lipoprotein concentrations, but patients with infections had significantly lower (p equals .008) high-density lipoprotein cholesterol concentrations compared with noninfected patients. Lipopolysaccharide-stimulated production of TNF-alpha in patient and control blood samples was completely suppressed by the addition of 2 mg/mL of a reconstituted high-density lipoprotein preparation. Conclusions: Patients who are critically ill from a variety of causes have extremely low cholesterol and lipoprotein concentrations. Correction of the hypolipidemia by a reconstituted highdensity lipoprotein preparation offers a new strategy for the prevention and treatment of endotoxemia. (Crit Care Med 1996; 24:584-589)

Nitric Oxide Mediates the Antiapoptotic Effect of Insulin in Myocardial Ischemia-Reperfusion: The Roles of PI3-Kinase, Akt, and Endothelial Nitric Oxide Synthase Phosphorylation

Article

Mar 2002

Feng Gao

Background— Recent evidence from cultured endothelial cell studies suggests that phosphorylation of endothelial nitric oxide synthase (eNOS) through the PI3-kinase– Akt pathway increases NO production. This study was designed to elucidate the signaling pathway involved in the antiapoptotic effect of insulin in vivo and to test the hypothesis that phosphorylation of eNOS by insulin may participate in the cardioprotective effect of insulin after myocardial ischemia and reperfusion. Methods and Results— Male Sprague-Dawley rats were subjected to 30 minutes of myocardial ischemia and 4 hours of reperfusion. Rats were randomized to receive vehicle, insulin, insulin plus wortmannin, or insulin plus L-NAME. Treatment with insulin resulted in 2.6-fold and 4.3-fold increases in Akt and eNOS phosphorylation and a significant increase in NO production in ischemic/reperfused myocardial tissue. Phosphorylation of Akt and eNOS and increase of NO production by insulin were completely blocked by wortmannin, a PI3-kinase inhibitor. Pretreatment with L-NAME, a nonselective NOS inhibitor, had no effect on Akt and eNOS phosphorylation but significantly reduced NO production. Moreover, treatment with insulin markedly reduced myocardial apoptotic death ( P <0.01 versus vehicle). Pretreatment with wortmannin abolished the antiapoptotic effect of insulin. Most importantly, pretreatment with L-NAME also significantly reduced the antiapoptotic effect of insulin ( P <0.01 versus insulin). Conclusions— These results demonstrated that in vivo administration of insulin activated Akt through the PI3-kinase–dependent mechanism and reduced postischemic myocardial apoptotic death. Phosphorylation of eNOS and the concurrent increase of NO production contribute significantly to the antiapoptotic effect of insulin.

The hypertriglyceridemia of acquired immunodeficiency syndrome is associated with an increased prevalence of low density lipoprotein subclass pattern B

Article

Jun 1993

Kenneth R Feingold

Insulin Inhibits Intranuclear Nuclear Factor B and Stimulates I B in Mononuclear Cells in Obese Subjects: Evidence for an Anti-inflammatory Effect?

Article

Jul 2001

Paresh Dandona

Glucose Control and Mortality in Critically Ill Patients

Conference Paper

Apr 2004

Objective: Hyperglycemia is common in critically ill patients, even in those without diabetes mellitus. Aggressiveglycemic control may reduce mortality in this population. However, the relationship between mortality, the control of hyperglycemia, and the administration of exogenous insulin is unclear. The objective was to determine whether blood glucose level or quantity of insulin administered is associated with reduced mortality in critically ill patients. Methods: This was a single-center, prospective, observational study of 531 patients (median age, 64 years) newly admitted over the first 6 months of 2002 to an adult intensive care unit (ICU) in a UK national referral center for cardiorespiratory surgery and medicine. The primary end point was intensive care unit (ICU) mortality. Secondary end points were hospital mortality, ICU and hospital length of stay, and predicted threshold glucose level associated with risk of death. Results: Of 531 patients admitted to the ICU, 523 under-went analysis of their glycemic control. Twenty-four-hour control of blood glucose levels was variable. Rates of ICU and hospital mortality were 5.2% and 5.7%, respectively; median lengths of stay were 1.8 (interquartile range, 0.9 to 3.7) days and 6 (inter-quartile range, 4.5 to 8.3) days, respectively. Multivariable logistic regression demonstrated that increased administration of insulin was positively and significantly associated with ICU mortality (odds ratio, 1.02 [95% confidence interval, 1.01 to 1.04] at a prevailing glucose level of 111 to 144 mg/dL [6.1 to 8.0 mmol/L] for a 1-IU/day increase), suggesting that mortality benefits are attributable to glycemic control rather than increased administration of insulin. Also, the regression models suggest that a mortality benefit accrues below a predicted threshold glucose level of 144 to 200 mg/dL (8.0 to 11.1 mmol/L), with a speculative upper limit of 145 mg/dL (8.0 mmol/L) for the target blood glucose level. Conclusions: Increased insulin administration is positively associated with death in the ICU, regardless of the prevailing blood glucose level. Thus control of glucose levels rather than of absolute levels of exogenous insulin appears to account for the mortality benefit associated with intensive insulin therapy demonstrated by others.

Effects of an intravenous infusion of K-glucose-insulin solution on the ECG signs of myocardial infarction

Article

Feb 1962
AM J CARDIOL

The glucose hypothesis: Relation to acute myocardial ischaemia

Article

Jun 1970

L.H. Opie

Biochemistry and molecular biology of diabetic complications

Article

Jan 2001
NATURE

Michael Brownlee

Activation of the fibrinolytic system and utilization of the coagulation inhibitors in sepsis: Comparison with severe sepsis and septic shock

Article

Dec 2001

Objectives: To determine whether the fibrinolytic system is activated and coagulation inhibitors are utilized in sepsis, to compare the findings detected in sepsis with those found in severe sepsis and septic shock, and to compare the role played by different infectious pathogens on fibrinolysis and coagulation inhibitors. Design and setting: Prospective study comparing patients with sepsis, severe sepsis, and septic shock and healthy volunteers in the general intensive care unit of a tertiary university hospital. Patients: Eighty-two consecutive septic patients (47 with sepsis, 18 with severe sepsis, and 17 with septic shock), and 14 healthy volunteers (controls). Measurements and results: After blood sampling we measured activation markers of fibrinolysis [plasmin/alpha(2)-antiplasmin complexes (PAP), complexes of tissue plasminogen activator/plasminogen activator inhibitor (tPA/PAI), fibrin(ogen) degradation products (FDPs), D-dimmers fibrin degradation products (D-d)], the utilization marker of antithrombin III (ATIII) thrombin/antithrombin complexes (TAT), several factors of fibrinolysis [plasminogen, tissue plasminogen activator (tPA), plasminogen activator inhibitor 1 (PAI-1), alpha(2)-antiplasmin], and the natural coagulation inhibitors [ATIII, protein C (PrC), protein S (PrS)]. In sepsis, PAP, FDPs, D-d, and TAT were increased to 439.8+/-32.35 microg/l, 57% positive, 49% positive, and 3.46+/-0.27 microg/l, respectively, compared with control subjects (205.57+/-28.58 microg/l, 0% positive, 7% positive, and 1.61+/-0.1 microg/l, respectively). These markers further increased in severe sepsis and septic shock. With the exception of a decrease in ATIII and an increase in tPA and PAI-1, coagulation inhibitors and factors of fibrinolysis were not changed in sepsis. In severe sepsis and mainly in septic shock, coagulation inhibitors (ATIII, PrC) and plasminogen were markedly decreased, whereas tPA and PAI-1 were further increased. All changes were independent of the causative infectious pathogen. Conclusions: Fibrinolysis is strongly activated and ATIII is utilized in sepsis. These findings are further enhanced in severe sepsis and septic shock. In sepsis only ATIII is decreased. In contrast, in severe sepsis and mainly in septic shock plasminogen and the main coagulation inhibitors (i.e., ATIII, PrC) are depleted, indicating exhaustion of fibrinolysis and coagulation inhibitors. Finally, Gram-positive, Gram-negative and other micro-organisms produce identical impairment.

Glucose metabolism in man: Responses to intravenous glucose infusion

Article

Apr 1979
METABOLISM

We have determined the effect of unlabeled glucose infusions, with and without added insulin, on glucose metabolism in normal male volunteers by means of the simultaneous primed-constant infusion of 6-3H and U-13C-glucose. Glucose kinetics were measured after 90 min of infusion. When steady state had been reached, endogenous glucose production (2.53 +/- .058 mg/kg . min, X +/- SEM) was suppressed at all rates of exogenous glucose tested (1, 2, and 4 mg/kg . min). The absolute degree of suppression was most marked (75%) at the highest rate of infusion, but the greatest degree of suppression, relative to infusion rate, was at the lowest infusion rate. The control of plasma glucose concentration during the glucose infusion was achieved primarily through regulation of endogenous Ra. The rate of uptake of glucose only increased during the 4 mg/kg . min infusion, even though there were significant elevations in the plasma glucose and insulin concentrations during the 2 mg/kg . min infusion as well. The glucose clearance rate increased only when sufficient insulin was infused with the 4 mg/kg . min glucose infusion to control the hyperglycemia that developed if no insulin was administered. Approximately 43% of the infused glucose was directly oxidized when the infusion rate was 1 or 2 mg/kg . min. That value fell to 32% when the infusion rate was increased to 4 mg/kg . min, regardless of whether insulin was infused or not.

Coagulation and fibrinolytic system impairment in insulin dependent diabetes mellitus

Article

Sep 1992
THROMB RES

Selected coagulation and fibrinolytic parameters were assessed in 40 insulin dependent diabetes mellitus patients with varying degrees of metabolic control; 30 healthy subjects matched for age and sex formed the control group. Activated Partial Thromboplastin Time, Prothrombin Time, Fibrinogen, Factor VII, Antithrombin III, Protein C, Plasminogen, alpha 2-Plasmin Inhibitor, Plasminogen Activator Inhibitor-1, tissue-Plasminogen Activator were functionally evaluated. Antigenic levels of tissue-Plasminogen Activator, Thrombin-Antithrombin complexes and fibrinolytic specific product B beta 15-42 were also determined. Compared to the control group diabetic patients displayed significantly higher levels of Fibrinogen (p < 0.01), Factor VII (p < 0.01), Thrombin-Antithrombin complexes (p < 0.01) and Plasminogen Activator Inhibitor-1 activity (p < 0.01). Regardless of the normal level of the tissue-Plasminogen Activator-related antigen, diabetic patients had tissue-Plasminogen Activator activity lower than the control group (p < 0.05). Coagulation Factor VII and Thrombin-Antithrombin complexes were increased only in the patients with poor metabolic control (p < 0.01). Activated Partial Thromboplastin Time, Prothrombin Time, Antithrombin III, Protein C, Plasminogen, alpha 2-Plasmin Inhibitor, B beta 15-42 fibrin peptide were found to be in the normal range. Fibrinogen correlated positively with fasting blood glucose (p < 0.05) and Thrombin-Antithrombin complexes with glycosylated haemoglobin (p < 0.05), whereas Factor VII was positively correlated with glycemia (p < 0.01) and glycosylated haemoglobin (p < 0.05). Higher levels of Fibrinogen were found in patients affected by nephropathy (p < 0.005) or neuropathy (p < 0.05). These results demonstrate an impairment of the haemostatic balance in diabetic patients, that is a possible hypercoagulable state, which represents an important factor in the pathogenesis of atherosclerotic complications.

Disturbance in the composition of plasma lipoproteins during gram-negative sepsis in the rat

Article

Apr 1992
Biochim Biophys Acta

Hyperlipidemia is associated with gram-negative sepsis. In this study we characterized the plasma lipoproteins of fasted and fed septic and control rats with respect to their lipid and apolipoprotein composition. Sepsis was induced by i.v. injection of 8 x 10(7) live Escherichia coli colonies/100 g body wt. Food was removed from fasted control and fasted E. coli-treated rats after injection. Fed rats were infused intragastrically with a nutritionally complete diet for 5 days prior to E. coli treatment. 24 h after treatment with E. coli, lipid and protein concentrations of very-low-density lipoprotein (VLDL) were over 2-fold higher in the fasted E. coli-treated rats than those of the fasted control rats. This appears to be due to a decrease in the clearance of VLDL. The relative composition of apolipoprotein B-48 and apolipoprotein E were lower while that of apolipoprotein B-100 was higher in fasted E. coli-treated rats than in fasted controls. Low-density lipoprotein (LDL) and high-density lipoprotein lipids were also significantly elevated, indicating greater synthesis of these particles during sepsis and food deprivation. By contrast, VLDL-triacyglycerol from fed, E. coli-treated did not differ from that of their respective controls although the total cholesterol remained elevated. Percentages of apolipoprotein B-48 and apolipoprotein B-100 increased while apolipoprotein E contributed significantly less to the total protein of VLDL from the E. coli-treated rats compared with controls. LDL lipids were also increased. In conclusion, gram-negative sepsis leads to marked changes in the plasma lipoprotein composition which may be attributed to altered hepatic synthesis, peripheral metabolism or hepatic uptake of lipoproteins and their remnants. These in turn may be a function of the nutritional status.

Insulin Regulates the Serum Levels of Low Molecular Weight Insulin-Like Growth Factor-Binding Protein*

Article

Mar 1988

The serum levels of 34K insulin-like growth factor (IGF)-binding protein were measured by RIA in 88 type 1 diabetic patients, 9 patients with type 2 diabetes, 7 patients with insulinoma, 19 normal subjects (all after an overnight fast), and 82 normal subjects after a breakfast meal. In addition, the effect of 2- to 3-h euglycemic steady state hyperinsulinemia on serum IGF-binding protein and IGF-1 levels was studied in some subjects in each of the fasted groups. Compared with normal subjects, the mean serum IGF-binding protein levels were 4-fold (P less than 0.001) higher in type I diabetic patients treated with conventional insulin injections, 2.5-fold (P less than 0.001) higher in those treated with continuous sc insulin infusion, and 2-fold (P less than 0.05) higher in patients with type 2 diabetes. In the patients with insulinoma, the mean IGF-binding protein level was 63% below normal (P less than 0.001), and it normalized after removal of the tumor. There was a slight negative correlation between the IGF-binding protein level and insulin dose in the diabetic patients (r = -0.22; P less than 0.05). In normal subjects, serum insulin concentrations were 2-fold higher (P less than 0.001) and the IGF-binding protein level was 29% lower after a meal (P less than 0.05) than in the fasting state. Serum IGF-I concentrations were virtually identical in the type 1 and 2 diabetic patients, insulinoma patients, and normal subjects. During steady state euglycemic hyperinsulinemia, the IGF-binding protein level fell by 40-70% in each group (P less than 0.001), whereas the IGF-I level declined (P less than 0.05) in the type 2 diabetic patients only. The decline of binding protein was closely related to the baseline level (r = 0.94; P less than 0.001). No correlation was found between serum IGF-I and binding protein levels in any group. In conclusion, 1) serum 34K IGF-binding protein levels are elevated in type 1 and 2 diabetic patients and decreased in patients with insulinoma; 2) the serum binding protein, but not IGF-I concentration is decreased by acute hyperinsulinemia; and 3) these data suggest that the serum insulin concentration plays a role in regulation of the serum 34K IGF-binding protein concentration.

Inhibition of Polymorphonuclear Leukocyte Respiratory Burst by Elevated Glucose Concentrations in Vitro

Article

Sep 1989
DIABETES

Although impaired polymorphonuclear leukocyte (PMN) function may be a cause of infectious complications in diabetic patients, the mechanisms of altered cell function are not understood. Our studies of PMN function in healthy subjects demonstrated significant reduction in the respiratory burst after 30 min of in vitro cell exposure to glucose concentrations greater than 11 mM (200 mg/dl). The respiratory burst was reduced 28 +/- 5 and 74 +/- 7% in PMNs incubated with 11 and 56 mM glucose, respectively. The impairment was independent of the cell stimulus (chemotactic peptide, calcium ionophore, or phorbol ester) and was not affected by sorbinil or myo-inositol. Because both D- and L-glucose had similar inhibitory effects, a nonenzymatic mechanism appeared to be the cause of impaired PMN function. Although mannitol and sorbitol did not affect cell function, monosaccharides (glucose, mannose, fructose) that form Schiff-base adducts with protein inhibited PMN function. These findings suggest a potential role for protein glycosylation in glucose-induced impairment of PMN function.

Changes in fibrinolysis in the intensive care patient

Article

Oct 1987
THROMB RES

Critically ill patients have been described as having blood coagulation abnormalities that predispose to bleeding and thrombosis. We have studied plasminogen activators, alpha 2-antiplasmin, X-oligomers fibrin fragments, fibronectin, antithrombin III, fibrinogen, platelets, kaolin-cephalin clotting time and prothrombin time on admission to the intensive care unit and sequentially after 24 and 48 hours in 39 adult patients: ARDS (n = 6), trauma (n = 12), sepsis (n = 8) and a miscellanea (n = 13). A decrease in plasminogen activators associated with an increase in X-oligomers, the earliest form of cross linked fibrin degradation products, indicate that fibrin deposition and the consumption of components of fibrinolysis is a widespread condition in the ICU patients. Low fibronectin levels were related to prognosis. These findings suggest that critically ill patients must be evaluated in respect to fibrinolysis and supported when necessary with prophylactic treatment.

Diabetes, a Hypercoagulable State? Haemostatic Variables in Newly Diagnosed Type 2 Diabetic Patients

Article

Feb 1983

37 type 2 diabetic patients with no clinical evidence of retinopathy or vascular disease were studied at diagnosis and following control of hyperglycaemia for evidence of abnormalities of coagulation, fibrinolysis and platelet behaviour. 38% showed hyperactive platelets, demonstrating either in vitro hyperaggregability, circulating platelet aggregates, or raised plasma beta-thromboglobulin levels. 36% showed abnormally raised factor VIII coagulant activity (FVIIIc) levels, though this was mainly in female patients. The mean level of FVIIIc decreased with treatment. Anti-thrombin III (AT-III) levels were decreased, and 33% of the patients had levels less than 80%. In this group AT-III increased following treatment. No abnormalities of fibrinolysis were demonstrated. These findings support the concept that diabetes can be associated with a hypercoagulable state, which is not necessarily dependent on the presence of overt vascular disease, or correlated with the degree of chronic hyperglycaemia (HbA1c levels).

Infection and diabetes: The case for glucose control

Article

Apr 1982
AM J MED

This review summarizes data concerning the host resistance to infection in diabetes and the influence of an acute infection upon the endocrinologic-metabolite status of the diabetic patient. While it is well known that acute infections lead to difficulty in controlling blood sugar levels and the infection is the most frequently documented cause of ketoacidosis, controversy persists as to whether or not patients with diabetes mellitus are more susceptible to infection than age- and sex-matched nondiabetic control subjects. Our data obtained from the charts of 241 diabetic patients who were being followed as outpatients show a striking direct correlation between the overall prevalence of infection (p less than 0.001) and the mean plasma glucose levels (representing three or more fasting glucose determinations taken at times when no evidence of infection existed). There is a significant diminution in intracellular bactericidal activity of leukocytes with Staphylococcus aureus and Escherichia coli in subjects with poorly controlled diabetes in comparison with the control group. Serum opsonic activity for both Staph. Aureus and E. coli were significantly lower than in the control subjects. Taken together, the results from published reports as well as our data suggest to us that good control of blood sugar in diabetic patients is a desirable goal in the prevention of certain infections (Candida vaginitis, for example) and to ensure maintenance of normal host defense mechanisms that determine resistance and response to infection.

Electron microscopic studies of vessels in diabetic peripheral neuropathy

Article

Jun 1980

the results of an electron microscopical study of sural nerve biopsies from 11 patients with diabetic neuropathy are presented. Thrombi were seen in six cases in at least one intraneural vessel; nine cases showed hyperplasia of endothelial cells, and in seven out of these nine the hyperplasia was sufficient to occlude completely the lumen of small vessels; six cases showed degenerate pericytes and endothelial cells, and in some cases endothelial cells had been shed from the vessel wall, exposing the blood within the vessel to the underlying basement membrane; in five cases large lipid droplets were seen within endothelial cells. Abnormalities of the vessel wall would result in decreased fibrinolytic activity and a reduction of the antiplatelet aggregating proprties of the vessel. Desquamation of endothelial cells from the vessel wall, with exposure of platelets to underlying collagen, may act as a trigger for thrombus formation, particularly as the blood of diabetic patients is often in a hypercoagulable state. The significance of hyperplasia of endothelial cells is at present unknown but, once established, this too would result in profound alterations of loal blood flow and ischaemia of nerve. Damage to endothelial cells may also allow seepage of haematological constituents into the vessel wall, resulting in its progressive thickening.

Randomized Trial of Insulin-Glucose Infusion Followed by Subcutaneous Insulin Treatment in Diabetic Patients With Acute Myocardial Infarction (DIGAMI Study): effects on mortality at 1 year

Article

Jul 1995
J AM COLL CARDIOL

We tested how insulin-glucose infusion followed by multidose insulin treatment in diabetic patients with acute myocardial infarction affected mortality during the subsequent 12 months of follow-up. Despite significant improvements in acute coronary care, diabetic patients with acute myocardial infarction still have a high mortality rate. A total of 620 patients were studied: 306 randomized to treatment with insulin-glucose infusion followed by multidose subcutaneous insulin for > or = 3 months and 314 to conventional therapy. The two groups were well matched for baseline characteristics. Blood glucose decreased from 15.4 +/- 4.1 to 9.6 +/- 3.3 mmol/liter (mean +/- SD) in the infusion group during the 1st 24 h, and from 15.7 +/- 4.2 to 11.7 +/- 4.1 among control patients (p < 0.0001). After 1 year 57 subjects (18.6%) in the infusion group and 82 (26.1%) in the control group had died (relative mortality reduction 29%, p = 0.027). The mortality reduction was particularly evident in patients who had a low cardiovascular risk profile and no previous insulin treatment (3-month mortality rate 6.5% in the infusion group vs. 13.5% in the control group [relative reduction 52%, p = 0.046]; 1-year mortality rate 8.6% in the infusion group vs. 18.0% in the control group [relative reduction 52%, p = 0.020]). Insulin-glucose infusion followed by a multidose insulin regimen improved long-term prognosis in diabetic patients with acute myocardial infarction.

Low lipid concentrations in critical illness: Implications for preventing and treating endotoxemia

Article

May 1996
CRIT CARE MED

To determine the prevalence and clinical significance of hypolipidemia found in critically ill patients, and whether the addition of a reconstituted lipoprotein preparation could inhibit the generation of tumor necrosis factor-alpha (TNF-alpha) in acute-phase blood taken from these patients. Surgical intensive care unit (ICU) of a large urban university hospital. Prospective case series. A total of 32 patients with a variety of critical illnesses had lipid and lipoprotein concentrations determined. Six patients and six age- and gender-matched control subjects had whole blood in vitro studies of the effect of lipoprotein on lipopolysaccharide mediated TNF-alpha production. Blood samples were drawn on admission to the ICU and over a subsequent 8-day period. Mean serum lipid and lipoprotein values obtained from patients within 24 hrs of transfer to the surgical ICU were extremely low: mean total cholesterol was 117 mg/dL (3.03 mmol/L), low-density lipoprotein cholesterol 71 mg/dL (1.84 mmol/L), and high-density lipoprotein cholesterol 25 mg/dL (0.65 mmol/L). Only the mean triglyceride concentration of 105 mg/dL (1.19 mmol/L), and the mean lipoprotein(a) concentration of 25 mg/dL (0.25 g/L) were within the normal range. During the first 8 days following surgical ICU admission, there were trends toward increasing lipid and lipoprotein concentrations that were significant for triglycerides and apolipoprotein B. Survival did not correlate with the lipid or lipoprotein concentrations, but patients with infections had significantly lower (p = .008) high-density lipoprotein cholesterol concentrations compared with noninfected patients. Lipopolysaccharide-stimulated production of TNF-alpha in patient and control blood samples was completely suppressed by the addition of 2 mg/mL of a reconstituted high-density lipoprotein preparation. Patients who are critically ill from a variety of causes have extremely low cholesterol and lipoprotein concentrations. Correction of the hypolipidemia by a reconstituted high-density lipoprotein preparation offers a new strategy for the prevention and treatment of endotoxemia.

Type 2 diabetes: One disease, multiple cardiovascular risk factors

Article

Feb 1999
Coron Artery Dis

Type 2 diabetes mellitus is a major independent risk factor for coronary artery disease. Atherosclerosis accounts for about 80% of all deaths from type 2 diabetes, of which roughly 75% are attributable to coronary artery disease and the remainder to cerebrovascular or peripheral vascular events [1]. The earlier onset and accelerated course of atherosclerosis in individuals with type 2 diabetes mellitus is multifactorial. Type 2 diabetes is associated with abnormalities in lipoprotein metabolism and increased propensity for oxidative damage. The hyperglycemia of patients with type 2 diabetes, in itself, may accelerate vascular damage. Type 2 diabetes is a hypercoagulable state attributable to enhanced coagulation and decreased fibrinolysis, as well as platelet hyperaggregability and endothelial dysfunction. Hypertension is common in individuals with type 2 diabetes and has a major impact in the accelerated atherosclerosis of this disease. This review provides an overview of selected aspects of these alterations.

Insulin Infusion Improves Neutrophil Function in Diabetic Cardiac Surgery Patients

Article

May 1999
ANESTH ANALG

Unlabelled: Diabetic patients are at increased risk of wound infection after major surgery, but the effect of perioperative glucose control on postoperative wound infection rates after surgery is uncertain. We tested the effect of an insulin infusion on perioperative neutrophil function in diabetic patients scheduled for coronary artery bypass surgery. Participants (n = 26) were randomly allocated to receive either aggressive insulin therapy (AIT) or standard insulin therapy (SIT) during surgery. Blood was drawn for neutrophil testing before surgery, 1 h after the completion of cardiopulmonary bypass, and on the first postoperative day. Neutrophil phagocytic activity decreased to 75% of baseline activity in the AIT group and to 47% of baseline activity in the SIT group (P < 0.05 between groups). No important differences in neutrophil antibody-dependent cell cytotoxicity were found. This study documents a potentially beneficial effect of continuous insulin therapy in diabetic patients who require major surgery. Implications: A continuous insulin infusion and glucose control during surgery improves white cell function in diabetic patients and may increase resistance to infection after surgery.

Thorell A, Nygren J, Ljungqvist O. Insulin resistance: a marker of surgical stress

Article

Feb 1999

Elective surgery causes a marked, transient reduction in insulin sensitivity. The degree of the reduction is related to the magnitude of the operation. The type and duration of surgery performed, perioperative blood loss, and also the degree of postoperative insulin resistance have significant influences on the length of hospital stay. A novel approach to minimize insulin resistance after surgery is being presented and suggests that simply pretreating the elective surgical patient with sufficient amounts of carbohydrates instead of fasting can significantly reduce postoperative insulin resistance. It is not clear which mediators are the most important for the development of insulin resistance after surgery. Nevertheless, marked insulin resistance can develop after elective surgery without concomitant elevations in cortisol, catecholamines or glucagon. The main sites for insulin resistance seem to be extrahepatic tissues, probably skeletal muscle, where preliminary data suggest that the glucose transporting system is involved.

Mitochondrial dysfunction in sepsis

Article

Feb 1999

The current mainstream view of organ failure induced by sepsis revolves around inflammation and loss of vascular control. However, there has been a resurgence in interest in bioenergetic failure due to mitochondrial dysfunction. This concept is not new--studies date back 30 years; however, the data have been highly conflicting with findings of either decreased, increased or unchanged mitochondrial activity and/or nucleotide levels. These studies are virtually all based on non-human cells, isolated perfused organs or in vivo animal models that have received a variety of insults ranging from mild to severe, and monitored for different durations ranging from minutes to weeks. As a generalization, there does appear to be depression of mitochondrial function with longer-duration models of greater severity. This is confirmed by the scanty human data currently available. This chapter provides an overview, and attempts to relate the biochemical changes to the clinical condition. The potential roles of nitric oxide, intracellular calcium and reactive oxygen species are highlighted.

Stress-Induced Hyperglycemia

Article

Feb 2001
CRIT CARE CLIN

Stress hyperglycemia is common and likely to be associated with at least some of the same complications as hyperglycemia in true diabetes mellitus, such as poor wound healing and a higher infection rate. The predominant cause is the intense counterregulatory hormone and cytokine responses of critical illness, often compounded by excessive dextrose administration, usually as TPN. Although randomized data suggesting benefit of controlling hyperglycemia in hospitalized patients are paltry, prospective controlled trials are feasible and should be initiated. In the interim, the practice at the authors' institution is to use insulin to lower plasma glucose concentrations to a safe range of 150 mg/dL to 200 mg/dL in all patients.

Sustained endotoxemia leads to marked down-regulation of early steps in the insulin-signaling cascade

Article

May 2001
CRIT CARE MED

To determine the effects of sustained, 3-day endotoxin infusion on early steps of the insulin-signaling pathway in rat liver and skeletal muscle in vivo; to examine insulin signaling in well-established acute endotoxin models of insulin resistance. Prospective, controlled animal study. University research laboratory. Male Sprague-Dawley rats: 24 in the 3-day endotoxin study, 22 in each acute endotoxin study. In prolonged endotoxemia studies, endotoxin (1 mg.kg-1.24 hrs-1) was administered via jugular venous catheter for 74 hrs. Insulin was then injected, and liver and skeletal muscle were removed after 5 mins. In acute endotoxemia studies, an endotoxin bolus (1 mg/kg) was administered, and insulin-signaling responses were studied after 4 hrs. In liver of rats with sustained endotoxemia, there were significant decreases in insulin-stimulated tyrosine phosphorylation of insulin receptors (74%), insulin receptor substrate (IRS)-1 (74%), and IRS2 (53%); binding of the p85 subunit of phosphatidylinositide 3-kinase to IRS1 (80%); and IRS1-precipitable phosphatidylinositide 3-kinase activity (>90%). These findings were associated with significant reductions in abundance of insulin receptors (37%), IRS1 (60%), and IRS2 (23%). Signaling in skeletal muscle was similarly affected, with reduced IRS1 phosphorylation (49%), IRS1 abundance (50%), and binding of p85 to IRS1 (57%). Insulin signaling 4 hrs after endotoxin administration was not different from controls. Prolonged endotoxemia is associated with marked deficits in early steps of the insulin-signaling pathway, which are at least partly explained by reduced abundance of the insulin receptor and IRS proteins. Signaling defects were not evident 4 hrs after endotoxin administration under conditions of adequate nutrition, indicating that insulin resistance develops gradually, may require concomitant malnutrition, and is not reversed by the development of endotoxin tolerance.

Das UN. Is insulin an antiinflammatory molecule? Nutrition 17, 409-413

Article

Jun 2001
NUTRITION

Undurti Das

I suggest that insulin suppresses the secretion and antagonizes the harmful effects of tumor necrosis factor-alpha, macrophage migration-inhibitory factor, and superoxide anion. Therefore, the glucose-insulin-potassium regimen might be beneficial in acute myocardial infarction and useful in the management of patients with septicemia, septic shock, and other inflammatory diseases in which tumor necrosis factor-alpha and macrophage migration-inhibitory factor have important roles.

Myocardial Protection by Insulin at Reperfusion Requires Early Administration and Is Mediated via Akt and p70s6 Kinase Cell-Survival Signaling

Article

Dec 2001
CIRC RES

The "metabolic cocktail" comprising glucose-insulin-potassium administrated at reperfusion reduces infarct size in the in vivo rat heart. We propose that insulin is the major component mediating this protection and acts via Akt prosurvival signaling. This hypothesis was studied in isolated perfused rat hearts (measuring infarct size to area of risk [%]) subjected to 35 minutes regional myocardial ischemia and 2 hours reperfusion. Insulin administered at the onset of reperfusion attenuated infarct size by >/=45% versus control hearts (P<0.001). Insulin-mediated cardioprotection was found to be independent of the presence of glucose at reperfusion. Moreover, the cell survival benefit of insulin is temporally dependent, in that insulin administration from the onset of reperfusion and maintained for either 15 minutes or for the duration of reperfusion reduced infarct size. In contrast, protection was abrogated if insulin administration was delayed until 15 minutes into reperfusion. Pharmacological inhibition of both upstream and downstream signals in the Akt prosurvival pathway abolished the cardioprotective effects of insulin. Here coadministration of insulin with the tyrosine kinase inhibitor lavendustin A, the phosphatidylinositol3-kinase (PI3-kinase) inhibitor wortmannin, and mTOR/p70s6 kinase inhibitor rapamycin abolished cardioprotection. Steady-state levels of activated/phosphorylated Akt correlated with insulin administration. Finally, downstream prosurvival targets of Akt including p70s6 kinase and BAD were modulated by insulin. In conclusion, insulin administration at reperfusion reduces myocardial infarction, is dependent on early administration during reperfusion, and is mediated via Akt and p70s6 kinase dependent signaling pathway. Moreover, BAD is maintained in its inert phosphorylated state in response to insulin therapy.

A Novel in Vivo Rabbit Model of Hypercatabolic Critical Illness Reveals a Biphasic Neuroendocrine Stress Response

Article

Apr 2002

High doses of GH, used to induce anabolism in prolonged critically ill patients, unexpectedly increased mortality. To further explore underlying mechanisms, a valid animal model is needed. Such a model is presented in this study. Seven days after arterial and venous cannulae placement, male New Zealand White rabbits were randomly allocated to a control or a critically ill group. To induce prolonged critical illness, a template controlled 15% deep dermal burn injury was imposed under combined general and regional (paravertebral) anesthesia. Subsequently, critically ill rabbits received supplemental analgesia and were parenterally fed with glucose, insulin, amino acids, and lipids. On d 1 and d 8 after randomization, acute and chronic spontaneous hormonal profiles of GH, TSH, and PRL secretion were obtained by sampling blood every 15 min for 7 h. Furthermore, GH, TSH, and PRL responses to an iv bolus of GH-releasing peptide 2 (GHRP-2) + TRH were documented on d 0, 1, and 8. Hemodynamic status and biochemical parameters were evaluated on d 0, 1, 3, 5, and 8, after which animals were killed and relative wet weight and water content of organs was determined. Compared with controls, critically ill animals exhibited transient metabolic acidosis on d 1 and weight loss, organ wasting, systolic hypertension, and pronounced anemia on d 8. On d 1, pulsatile GH secretion doubled in the critically ill animals compared with controls, and decreased again on d 8 in the presence of low plasma IGF-I concentrations from d 1 to d 8. GH responses to GHRP-2 + TRH were elevated on d 1 and increased further on d 8 in the critically ill animals. Mean TSH concentrations were identical in both groups on d 1 and 8, in the face of dramatically suppressed plasma T(4) and T(3) concentrations in the critically ill animals. PRL secretion was impaired in the critically ill animals exclusively on d 8. TSH and PRL responses to GHRP-2 and TRH were increased only on d 1. In conclusion, this rabbit model of acute and prolonged critical illness reveals several of the clinical, biochemical, and endocrine manifestations of the human counterpart.

Oxidative Stress and Programmed Cell Death in Diabetic Neuropathy

Article

May 2002

Recent evidence in both animal models and human sural nerve biopsies indicates an association with oxidative stress, mitochondrial (Mt) membrane depolarization (MMD), and induction of programmed cell death (PCD). In streptozotocin (STZ)-treated diabetic rats, hyperglycemia induces typical apoptotic changes as well as swelling and disruption of the Mt cristae in diabetic dorsal root ganglion neurons (DRG) and Schwann cells (SC), but these changes are only rarely observed in control neurons. In human sural nerve biopsies, from patients with diabetic sensory neuropathy, there is transmission electromicrograph evidence of swelling and disruption of the Mt and cristae compared to patients without peripheral neuropathy. In human SH-SY5Y neurons, rat sensory neurons, and SC, in vivo, there is an increase in reactive oxygen species (ROS) after exposure to 20 mM added glucose. In parallel, there is an initial Mt membrane hyperpolarization followed by depolarization (MMD). In turn, MMD is coupled with cleavage of caspases. Various strategies aimed at inhibiting the oxidative burst, or stabilizing the DeltaPsi(M), block induction of PCD. First, growth factors such as NGF can block induction of ROS and/or stabilize the DeltaPsi(M). This, in turn, is associated with inhibition of PCD. Second, reduction of ROS generation in neuronal Mt prevents neuronal PCD. Third, up-regulation of uncoupling proteins (UCPs), which stabilize the DeltaPsi(M), blocks induction of caspase cleavage. Collectively, these findings indicate that hyperglycemic conditions observed in diabetes mellitus are associated with oxidative stress-induced neuronal and SC death, and targeted therapies aimed at regulating ROS may prove effective in therapy of diabetic neuropathy.

How does blood glucose control with insulin save lives in intensive care?

Abstract

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