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The effects of insulin in response to the increase in glucose levels in the blood. The increase in glucose in the blood stimulates beta cells in the pancreas to produce insulin. Circulating insulin exerts several effects in different tissues. In skeletal muscle, it promotes glucose utilization and storage by increasing glucose transport and glycogen synthesis. In the liver, insulin promotes glycogen synthesis, and inhibits glycogenolysis, gluconeogenesis, and ketogenesis. In white adipocyte tissue, insulin promotes the deposition of triglycerides, inhibits lipolysis, and promotes the absorption of glucose and fatty acids.
Source publication
Insulin resistance (IRES) is a pathophysiological condition characterized by the reduced response to insulin of several tissues, including myocardial and skeletal muscle. IRES is associated with obesity, glucose intolerance, dyslipidemia, and hypertension, evolves toward type 2 diabetes, and increases the risk of developing cardiovascular diseases....
Context in source publication
Context 1
... is a peptide hormone produced in the pancreas by the β cells of the Langerhans islets in response to the increase in plasma glucose levels. It induces the rapid absorption of glucose, protein, and fatty acids by tissues for metabolism, storage, and energy production [1] (Figure 1). Alterations in insulin signaling and production, as observed in insulin resistance, significantly impair glucose homeostasis in several pathological conditions, such as diabetes, hypertension, and heart failure. ...
Citations
... 42,43 Given its profound impact on both cognitive and physical health, targeting insulin resistance presents a promising approach in hypertension management. [30][31][32]35,[44][45][46] It is important to emphasize the role of the TyG index as an easy, pragmatic, and reproducible marker. [47][48][49][50] The gold standard method for assessing insulin resistance, the hyper-insulinemic-euglycemic clamp, is often impractical due to its complexity and costs. ...
INTRODUCTION: Prediabetes has garnered increasing attention due to its association with cardiovascular conditions, especially hypertension, which heightens the risk of pre-frailty and frailty among older individuals.
METHODS: We screened pre-frail hypertensive elders from March 2021 to January 2023. We assessed the correlation linking cognitive dysfunction (MoCA score: Montreal Cognitive Assessment), insulin resistance (TyG: Triglyceride-to-Glucose index), and physical impairment (5-meter gait speed: 5mGS). We then evaluated the risk of frailty after a one-year follow-up period, adjusting the outcome using multivariable Cox regression analysis. We also investigated the impact of administering 500 mg of metformin once daily to a subset of frail subjects for an additional six months.
RESULTS: We assessed the relationship between the TyG index and MoCA Score, observing a significant correlation (r: 0.880; p<0.0001). Similarly, we analyzed the association between the TyG index and 5mGS, uncovering a significant link between insulin resistance and physical impairment (r: 0.809; p<0.0001). Prediabetes was found to significantly (p<0.0001) elevate the risk of frailty development compared to non-prediabetic individuals by the end of the 1-year follow-up, a finding confirmed via multivariable analysis with Cox regression. Furthermore, among the subgroup of subjects who developed frailty, those who received metformin exhibited a significant decrease in frailty levels (p<0.0001).
CONCLUSIONS: Insulin resistance and prediabetes play substantial roles in the development of cognitive and physical impairments, highlighting their importance in managing hypertension, even before the onset of frank diabetes. The use of metformin, a well-established drug, has demonstrated potential in mitigating frailty, possibly due to its anti-aging properties.
... Interestingly, besides its canonical role in the desensitization of numerous GPCRs, GRK2 affects many other cellular pathways by phosphorylating non-GPCR substrates or by directly binding to various signaling proteins [14e16]. While whole-body GRK2 knockout (KO) mice die during embryogenesis [17], studies with heterozygous GRK2 mutant mice and other experimental approaches suggest that GRK2 plays a role in the development of various metabolic disorders including impaired glucose homeostasis and insulin resistance [12,18]. So far, it remains unclear which specific tissues or cell types mediate the metabolic effects of GRK2 on glucose homeostasis and related metabolic functions. ...
... GRK2 plays a key role in regulating numerous physiological and pathophysiological processes [10,12,18]. For example, increased GRK2 levels and/or enhanced GRK2 activity are of critical importance for the development of heart failure [10]. ...
... For this reason, pharmacological inhibitors of cardiac GRK2 activity are predicted to prove useful as cardioprotective drugs [10]. Additional studies have shown that changes in GRK2 activity can also affect systemic glucose homeostasis and insulin sensitivity of peripheral tissues, suggesting that GRK2 inhibitors could be beneficial for treating type 2 diabetes and related metabolic disorders [12,18]. Given the central role of the liver in regulating glucose and lipid homeostasis, this study was designed to investigate the potential role of hepatocyte GRK2 in regulating glucose homeostasis and other key metabolic functions. ...
... It has been observed that insulin resistance is present not only in type 2 diabetes but also in various organs and tissues, including the skeletal muscle, adipose tissue, and hepatic parenchyma, as well as the vascular tissue and cardiac muscle, which in majority cases are just evaluated in circumstances of the progression of chronic diseases. 1 It has been proposed that the heart is an organ that is not only a brand of systemic insulin resistance, as well as of myocardial insulin resistance (MIR), with MIR being an independent risk factor for heart disease. ...
Background: Low availability of Glut-4 transporters in the sarcolemma of cardiac cells characterizes myocardial insulin resistance (MIR), which is triggered separately from generalized insulin resistance. Insulin receptors are quite evident in the heart muscle and vessels, and mitochondrial activity performs a significant role in MIR preserving cellular homeostasis through cell reproduction, cells livelihoods, and energy generation. Objective: To evaluate the MIR mechanism and its association with hypertension by signaling pathways design. Methods: PubMed database was employed to search for reviews publications with MIR. The referenced data of the signaling pathway was chosen by aggregating references from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. A signaling pathway was designed based on MIR research manuscripts, where we show several mechanisms included in the MIR. The KEGG server was employed to exploit the interrelationship protein-protein, and elaborate signaling pathway diagram. The signaling pathway mapping was carried out with PathVisio software. Results: We selected 42 articles from a total of 450 articles in the PubMed database that presented a significant association between the terms “insulin resistance myocardial” AND “signaling pathway” AND “systemic arterial hypertension”. Founded on database-validated research papers, we chose well-founded pathways and we succeeded in representative description of these pathways. The reproduction contigs taken from the KEGG database designed the signaling pathway of the bio-molecules that lead to MIR. Thus, the acting among multiple mechanisms releases factors that participate in the development of MIR. Conclusion: The interaction among various mechanisms and molecular interactions are important factors in developing MIR.
... Several other approaches have been tested for peripheral indications, including small molecules, peptides, or aptamers. 17 They are worth trying for central nervous system indications, possibly through direct intracerebral infusion, to avoid peripheral side effects. ...
Background:
Multiple system atrophy (MSA) is a sporadic adult-onset rare neurodegenerative synucleinopathy for which counteracting central nervous system insulin resistance bears the potential of being neuroprotective. G-protein-(heterotrimeric guanine nucleotide-binding protein)-coupled receptor kinase 2 (GRK2) is emerging as a physiologically relevant inhibitor of insulin signaling.
Objectives:
We tested whether lowering brain GRK2 abundance may reverse insulin-resistance.
Methods:
We lowered brain GRK2 abundance through viral-mediated delivery of a GRK2-specific miRNA and quantified the reversion of a developing or an established insulin-resistant phenotype using the transgenic PLP-SYN mouse model of MSA.
Results:
Viral vector delivery of a GRK2 miRNA demonstrated a neuroprotective capacity when administered (1) in utero intracerebroventricularly in developing PLP-SYN mice and (2) intrastriatally in adult PLP-SYN mice. Decreased striatal GRK2 levels correlated in both designs with neuroprotection of the substantia nigra dopamine neurons, reduction in high-molecular-weight species of α-synuclein, and reduced insulin resistance.
Conclusions:
These data support GRK2 as a potential therapeutic target in MSA. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
... Arterial hypertension (AH) is a global public health problem, and its treatment is primarily aimed at reducing associated cardiovascular (CV) morbidity and mortality [1,2]. AH affected more than 1.13 billion individuals in 2015, and the prevalence appears to affect approximately 35-45% of Campo's overall population [3]. ...
... Moreover, the definition of "hypertension" recapitulates several different sub-phenotypes influenced by multiple variables: gender, BMI, lifestyle conditions, and so on [9]. Furthermore, the pharmacological therapy used to treat essential AH has remained substantially unchanged in the last 20 years and is mainly focused on regulating vascular resistance [1,10]. Therefore, there is an evident gap in the knowledge required to deepen the multifaced aspects of AH and prompt the research and development of novel approaches. ...
Arterial hypertension (AH) is a progressive issue that grows in importance with the increased average age of the world population. The potential role of artificial intelligence (AI) in its prevention and treatment is firmly recognized. Indeed, AI application allows personalized medicine and tailored treatment for each patient. Specifically, this article reviews the benefits of AI in AH management, pointing out diagnostic and therapeutic improvements without ignoring the limitations of this innovative scientific approach. Consequently, we conducted a detailed search on AI applications in AH: the articles (quantitative and qualitative) reviewed in this paper were obtained by searching journal databases such as PubMed and subject-specific professional websites, including Google Scholar. The search terms included artificial intelligence, artificial neural network, deep learning, machine learning, big data, arterial hypertension, blood pressure, blood pressure measurement, cardiovascular disease, and personalized medicine. Specifically, AI-based systems could help continuously monitor BP using wearable technologies; in particular, BP can be estimated from a photoplethysmograph (PPG) signal obtained from a smartphone or a smartwatch using DL. Furthermore, thanks to ML algorithms, it is possible to identify new hypertension genes for the early diagnosis of AH and the prevention of complications. Moreover, integrating AI with omics-based technologies will lead to the definition of the trajectory of the hypertensive patient and the use of the most appropriate drug. However, AI is not free from technical issues and biases, such as over/underfitting, the “black-box” nature of many ML algorithms, and patient data privacy. In conclusion, AI-based systems will change clinical practice for AH by identifying patient trajectories for new, personalized care plans and predicting patients’ risks and necessary therapy adjustments due to changes in disease progression and/or therapy response.
... In relation to cardiovascular and metabolic function, the group of Giuseppe Rengo reviews current information regarding the possible use of lymphocyte GRK2 levels as a surrogate marker of hyperactivation of the cardiac adrenergic nervous system as a hallmark of heart failure in humans that may provide independent prognostic information for the improvement of other currently available techniques [15]. In addition, Guido Iaccarino and collaborators analyze current knowledge on the metabolic role of GRK2 in conditions related to insulin resistance such as obesity, hypertension or glucose intolerance and the potential of inhibiting GRK2 as a therapeutic strategy in cardiovascular or metabolic diseases [16]. In this context, a review by the group of Frank Lezoualc'h summarizes the pathophysiological roles of GRK isoforms and Epac1 (exchange protein directly activated by cAMP 1) in the heart, focusing on how these proteins cross-talk in nodal signalosomes that contribute to impaired cardiac function and tissue remodelling during stress conditions [17]. ...
The relevance of the family of G protein-coupled receptor kinases (GRKs) is based on its key participation in the regulation and intracellular dynamics of the largest family of membrane receptors, namely G protein-coupled receptors (GPCRs) [...]
... e TyG index is a reliable and simple diagnostic indicator of insulin resistance [29,30]. When the body is in the IR state, the PI3K pathway is affected, with the MAPK pathway unaffected; and the balance between the two pathways is therefore disrupted [31,32]. Inhibition of the PI3K pathway leads to a reduction in the production of NO in endothelial cells, which in turn reduces ED and glucose transporters and results in a reduction in glucose uptake [33]. ...
Objective:
We herein aim to explore the relationship between the triglyceride-glucose (TyG) index and metabolic syndrome (MS).
Methods:
We enrolled 298,652 individuals with an average age of 47.08 ± 12.94 years and who underwent health check-ups at the First Affiliated Hospital of Wuhu Wannan Medical College in this cross-sectional study from 2014 to 2016. We enlisted 125,025 women (41.86%) and 173,627 men (58.14%). The survey information included a questionnaire survey, a physical examination, and a laboratory examination.
Results:
The prevalence of MS increased gradually in the TyG-index subgroups (Q1, TyG <8.30; Q2, 8.30≤ TyG <8.83; and Q3, TyG ≥8.83). We noted significant differences in hypertension, hyperlipidemia, hyperglycemia, sex, age, body mass index (BMI), smoking and drinking habits, and estimated glomerular filtration rate between the TyG-index subgroups. Multiclass logistic regression analysis showed that the group with TyG <8.30 was the reference group, and the 8.30≤ TyG <8.83 and the TyG ≥8.83 groups exhibited a higher TyG index with MS, and a lower TyG index without MS disease. In the linear curve analysis of the TyG index and MS components, BMI, systolic blood pressure, and diastolic blood pressure showed upward trends, while high-density lipoprotein cholesterol showed no obvious trend in the TyG index at a range of 7.8-11.0. Receiver operating characteristic analysis was used to evaluate the predictive value of the TyG index, triglycerides, and fasting blood glucose for MS, and we found that the area under the TyG index curve was the largest (AUC = 0.89).
Conclusion:
There were associations between the TyG index and MS and its components, and the TyG index is therefore of great value in the early diagnosis of MS.
... The result seemed to conflict with 18 F-FDG uptake and Western blot results since the Akt/mTOR pathway was upregulated in Huh7/SR cells. Akt is known to suppress glycogen synthase kinase-3 (GSK-3) and enhance glycogen synthesis [69]. HK2, GAPDH, and PKM2 are the glycolytic enzymes, and elevated glycolysis is related to tumor progression and treatment resistance [70]. ...
Sorafenib is one of the options for advanced hepatocellular carcinoma treatment and has been shown to extend median overall survival. However, sorafenib resistance often develops a few months after treatment. Hence, developing various strategies to overcome sorafenib resistance and understand the possible mechanisms is urgently needed. We first established sorafenib-resistant hepatocellular carcinoma (HCC) cells. Then, we found that sorafenib-resistant Huh7 cells (Huh7/SR) exhibit higher glucose uptakes and express elevated fatty acid synthesis and glucose metabolism-related proteins than their parental counterparts (Huh7). The current study investigated whether sorafenib resistance could be reversed by suppressing fatty acid synthesis, using a fatty acid synthase (FASN) inhibitor, orlistat, in HCC cells. FASN inhibition-caused changes in protein expressions and cell cycle distribution were analyzed by Western blot and flow cytometry, and changes in glucose uptakes were also evaluated by 18F-FDG uptake. Orlistat remarkably enhanced the cytotoxicity of sorafenib in both Huh7 and Huh7/SR cells, and flow cytometry showed that combination treatment significantly increased the sub-G1 population in both cell lines. Western blot revealed that the combination treatment effectively increased the ratio of Bax/Bcl-2 and decreased expressions of pERK; additionally, the combination treatment also strongly suppressed fatty acid synthesis-related proteins (e.g., FASN and SCD) in both cell lines. Lastly, the 18F-FDG uptake was repressed by the combination treatment in both cell lines. Our results indicated that orlistat-mediated FASN inhibition could overcome sorafenib resistance and enhance cell killing in HCC by changing cell metabolism.
... Heart failure (HF) shows phases of exacerbation interrupted by periods of clinical stability. Despite many pharmacological advances, morbidity and mortality in HF remain an important burden to patients, caregivers, and national healthcare systems (1)(2)(3). Advanced HF, defined as severe symptoms despite optimal medical therapy (OMT) and device, affects up to 25% of patients with HF (4). Treatments for such patients are limited. ...
During the last years, the management of heart failure (HF) made substantial progress, focusing on device-based therapies to meet the demands of this complex syndrome. In this case report, we present a multistep approach to deal with HF. Specifically, we report the first patient subjected to the implantation of both Optimizer Smart ® (Impulse Dynamics Inc., Marlton, NJ, USA) and CardioMEMS devices. A 72-year-old male patient with HF and reduced ejection fraction (HFrEF) was admitted to our cardiology department in January 2021, following a progressive shortening of the time between hospitalizations for levosimendan infusions. Specifically, the patient was monitored daily by CardioMEMS, and a strategy of levosimendan infusions guided by the device had been adopted. He was also a carrier of MitraClips and cardiac resynchronization therapy defibrillator (CRT-D) and had optimized HF medical therapy. In January 2021, the patient implanted Optimizer Smart ® device for cardiac contractility modulation (CCM) therapy because of poor response to therapy and elevated pulmonary artery pressure (PAP). CCM significantly reduced PAP values following discharge (systolic PAP 33.67 ± 2.92 vs. 40.6 ± 3.37 mmHg, diastolic PAP 14.5 ± 2.01 vs. 22.5 ± 2.53 mmHg, mean PAP 22.87 ± 2.20 vs. 30.9 ± 2.99 mmHg, HR 60.93 ± 1.53 vs. 80.83 ± 3.66 bpm; p < 0.0001), with persisting effect at 9 months. The usefulness of CCM is objectively demonstrated for the first time by continuous invasive monitoring of PAP by CardioMEMS, which can suggest the correct timing for CCM implantation.
... Insulin resistance is a clinical/pathological status recognized through of hyperinsulinemia and altered glucose homeostasis, transforming various functions of the cell and contributing to the onset of several diseases. It has been observed that insulin resistance is present not only in type 2 diabetes but also in various organs and tissues, including the skeletal muscle, adipose tissue, and hepatic parenchyma, as well as the vascular tissue and cardiac muscle, which in majority cases are just evaluated in circumstances of the progression of chronic diseases 1 . It has been proposed that the heart is an organ that is not only a brand of systemic insulin resistance, as well as of myocardial insulin resistance (MIR), with MIR being an independent risk factor for heart disease. ...
Background: The low available of Glut-4 transporters in sarcolemma of the cardiac cells is what characterizes the myocardial insulin resistance (MIR), which is triggered separately of generalized insulin resistance. Insulin receptors are quite evident in the heart muscle and vessels, and mitochondrial activity performs a significant function in MIR preserving cellular homeostasis by cell reproduction, cells livelihoods, and energy generation. Objective: To evaluate the MIR mechanism and through the signaling pathway design. Methods: PubMed database was employed to search for reviews publications with MIR. The referenced data of the signaling pathway was chosen aggregating references of the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. A signaling pathway was designed based on MIR research manuscripts, where we show several mechanisms included in the MIR. The KEGG server was employed to exploit the interrelationship protein-protein, and elaborate signaling pathway diagram. The signaling pathway mapping was carried out with PathVisio software. Results: We selected 42 articles from a total of 450 articles in the PubMed database that presented a significant association between the terms "insulin resistance myocardial" AND "signaling pathway". Founded on database-validated research papers, we choose well-founded pathways and we succeeded representative description of these pathways. The reproduction contigs taken from the KEGG database designed the signaling pathway of the bio-molecules that lead to MIR. Thus, the acting among multiple mechanisms releases factors that participate of the development of MIR. Conclusion: The interaction among various mechanisms and molecular interactions are important factors in development of MIR.
