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Defining human diabetic nephropathy on the molecular level: Integration of transcriptomic profiles with biological knowledge
Abstract and Figures
Diabetic nephropathy (DN) is the most common cause for end stage renal disease (ESRD). Next to environmental factors, genetic predispositions determine the susceptibility for DN and its rate of progression to ESRD. With the availability of genome wide expression profiling we have the opportunity to define relevant pathways activated in the individual diabetic patient, integrating both environmental exposure and genetic background. In this review we summarize current understanding of how to link comprehensive gene expression data sets with biomedical knowledge and present strategies to build a transcriptional network of DN. Information about the individual disease processes of DN might allow the implementation of a personalized molecular medicine approach with mechanism-based patient management. Web based search engines like Nephromine are essential tools to facilitate access to molecular data of genomics, proteomics and metabolomics of DN.
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... The pathogenesis of DN encompasses a number of functional alterations involving increased intraglomerular pressure, stimulation of the renin-angiotensin system (RAS), oxidative stress, and fibrotic changes that are superimposed on an innate genetic predisposition [3]. In addition, increased circulating inflammatory mediators (adhesion molecules and chemokines) and intrarenal immune cell infiltration are observed in patients with DN [4,5]. ...
... DN begins with glomerular hyperfiltration, which abates with the onset of early renal damage [1,3,6,7]. This is accompanied by mild systemic hypertension, which worsens over time [1,3,6,7]. ...
... DN begins with glomerular hyperfiltration, which abates with the onset of early renal damage [1,3,6,7]. This is accompanied by mild systemic hypertension, which worsens over time [1,3,6,7]. Increased albumin excretion in the urine from early renal damage is manifested by microalbuminuria (30-299 mg/24 h) followed by macroalbuminuria (≥300 mg/24 h). Patients go from an asymptomatic stage to fluid retention, which is usually accompanied by clinically overt edema. ...
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) worldwide. Its pathogenesis encompasses functional alterations involving elevated intraglomerular and systemic pressure, increased activity of the renin-angiotensin system (RAS) and oxidative stress, and the eventual development of renal fibrosis. The management of DN involves the optimization of blood pressure (BP) and blood glucose targets. However, treatment of these risk factors slows down but does not stop the progression of DN. Innovative pharmacologic therapies for dyslipidemia and type 2 diabetes mellitus (T2DM) could play a key role in bridging this gap and attenuating the residual risk of DN beyond traditional risk factor management. Glucagon-like pep-tide-1 receptor agonists (GLP-1 RAs), sodium-glucose cotransporter-2 inhibitors (SGLT-2is), and inhibitors of mineralocorticoid receptor-mediated sodium reabsorption are recently introduced drug classes that have been shown to have positive effects on kidney function in individuals with T2DM. The aim of this review is to provide an update on the therapeutic options available in order to prevent or slow the onset and progression of DN in diabetic patients. Citation: Giglio, R.V.; Patti, A.M.; Rizvi, A.A.; Stoian, A.P.; Ciaccio, M.; Papanas, N.; Janez, A.; Sonmez, A.; Banach, M.; Sahebkar, A.; et al. Advances in the Pharmacological Management of Diabetic Nephropathy: A 2022 International Update. Biomedicines 2023, 11, 291.
... We next studied whether the metabolic actions of DHT were mediated by androgen receptor (AR), its main receptor, by exposing male and female PTECs to AR inhibitors flutamide (17) To further distill potential targetable regulators of DHT, we examined transcriptional regulators linked to male sex and sex hormones in the kidney. To identify regulators of sex effects, we analyzed four publicly available gene datasets of human healthy kidneys (NephroSeq) (19). We also studied genes encoding the proteins up-regulated by gonadal hormones in PTECs (20). ...
Diabetic kidney disease (DKD) is the main cause of chronic kidney disease (CKD) and progresses faster in males than in females. We identify sex-based differences in kidney metabolism and in the blood metabolome of male and female individuals with diabetes. Primary human proximal tubular epithelial cells (PTECs) from healthy males displayed increased mitochondrial respiration, oxidative stress, apoptosis, and greater injury when exposed to high glucose compared with PTECs from healthy females. Male human PTECs showed increased glucose and glutamine fluxes to the TCA cycle, whereas female human PTECs showed increased pyruvate content. The male human PTEC phenotype was enhanced by dihydrotestosterone and mediated by the transcription factor HNF4A and histone demethylase KDM6A. In mice where sex chromosomes either matched or did not match gonadal sex, male gonadal sex contributed to the kidney metabolism differences between males and females. A blood metabolomics analysis in a cohort of adolescents with or without diabetes showed increased TCA cycle metabolites in males. In a second cohort of adults with diabetes, females without DKD had higher serum pyruvate concentrations than did males with or without DKD. Serum pyruvate concentrations positively correlated with the estimated glomerular filtration rate, a measure of kidney function, and negatively correlated with all-cause mortality in this cohort. In a third cohort of adults with CKD, male sex and diabetes were associated with increased plasma TCA cycle metabolites, which correlated with all-cause mortality. These findings suggest that differences in male and female kidney metabolism may contribute to sex-dependent outcomes in DKD.
... Pathogenesis of DN included genetic and environmental factors that initiate more complicated pathological processes [9]. Intensive research on molecular and cellular aspects revealed that many immunological and inflammatory factors can play important roles in development and progression of DN [10]. ...
Background
Proinflammatory cytokines play an important role in the establishment of arteriolosclerosis and kidney injury. Inflammatory cytokines are involved in the development of microvascular diabetic complications, including diabetic nephropathy (DN). Interleukin-19 (IL-19) has vital functions in many inflammatory processes and also can induce the angiogenesis of endothelial cells.
Objective
To investigate the role of IL-19 in the development of DN.
Patients and methods
A total of 112 participants were included and classified into four main groups: group I was the control group, which included 28 age-matched and sex-matched persons; group II included 28 patients with type 2 diabetes without nephropathy (normoalbuminuria); group III included 28 patients with type 2 diabetes with nephropathy (microalbuminuria); and group IV included 28 patient with type 2 diabetes with nephropathy (macroalbuminuria). All participants were subjected to complete blood count, complete urine analysis, fasting and random blood glucose, glycosylated hemoglobin (HbA1c), serum creatinine and urea, urinary albumin excretion rate (UAE), albumin-creatinine ratio (ACR), lipid profile, and serum IL-19 level assays.
Results
C-reactive protein (CRP) and serum IL-19 levels were significantly higher in diabetic patients compared with controls. IL-19 levels were significantly positively correlated with serum creatinine, ACR, UAE, HbA1c, and CRP. Multivariable logistic regression analysis showed that IL-19 levels were independently associated with patients with DN.
Conclusion
IL-19 levels were elevated in patients with DN and were positively correlated with ACR, UAE, HbA1c, and CRP. IL-19 may play an important role that contributes to the progression of DN.
... More recent work by Wen et al. identified that mice with diabetes had reduced expression of exosomes at large by the tubular interstitial cells (Wen et al., 2020). More specifically, their in-vitro Nephroseq analysis revealed a potential role for the enolase 1 protein in the pathogenesis of the disease as it was differentially expressed in various areas within the diabetic kidney and between non-high glucose and high glucose treated renal cells (Martini et al., 2008;Wen et al., 2020). Tao et al. also conducted similar genetic network analysis but focused biomarker study in humans. ...
Type 2 diabetes mellitus (T2DM) is one of the most prevalent metabolic disorders worldwide. However, T2DM still remains underdiagnosed and undertreated resulting in poor quality of life and increased morbidity and mortality. Given this ongoing burden, researchers have attempted to locate new therapeutic targets as well as methodologies to identify the disease and its associated complications at an earlier stage. Several studies over the last few decades have identified exosomes, small extracellular vesicles that are released by cells, as pivotal contributors to the pathogenesis of T2DM and its complications. These discoveries suggest the possibility of novel detection and treatment methods. This review provides a comprehensive presentation of exosomes that hold potential as novel biomarkers and therapeutic targets. Additional focus is given to characterizing the role of exosomes in T2DM complications, including diabetic angiopathy, diabetic cardiomyopathy, diabetic nephropathy, diabetic peripheral neuropathy, diabetic retinopathy, and diabetic wound healing. This study reveals that the utilization of exosomes as diagnostic markers and therapies is a realistic possibility for both T2DM and its complications. However, the majority of the current research is limited to animal models, warranting further investigation of exosomes in clinical trials. This review represents the most extensive and up-to-date exploration of exosomes in relation to T2DM and its complications.
... According to the Nephroseq database (www.nephroseq.org, University of Michigan, Ann Arbor, MI) (13), hypoexpression of METTL3, METTL14 and WTAP has been reported in diabetic mice, in patients with chronic kidney disease (CKD) and patients with focal segmental glomerulosclerosis, indicating the feedback disruption of m 6 A. It has been demonstrated that METTL14induced m 6 A methylation could posttranscriptionally modulate Sirt1 mRNA, contributing to podocyte injury (14). Other studies discovered the METTL14-YAP1 pathway participated in the renal ischemia-reperfusion injury (15) and METTL14-regulated PI3K/Akt signaling pathway is involved in renal tubular cell epithelial-mesenchymal transition in diabetic nephropathy (16). ...
Background
Congenital anomalies of the kidneys and urinary tracts (CAKUT) represent the most prevalent cause for renal failure in children. The RNA epigenetic modification N ⁶ -methyladenosine (m ⁶ A) methylation modulates gene expression and function post-transcriptionally, which has recently been revealed to be critical in organ development. However, it is uncertain whether m ⁶ A methylation plays a role in the pathogenesis of CAKUT. Thus, we aimed to explore the pattern of m ⁶ A methylation in CAKUT.
Methods
Using m ⁶ A-mRNA epitranscriptomic microarray, we investigated the m ⁶ A methylomic landscape in the ureter tissue of children with obstructive megaureter (M group) and primary vesicoureteral reflux (V group).
Results
A total of 228 mRNAs engaged in multiple function-relevant signaling pathways were substantially differential methylated between the “V” and “M” groups. Additionally, 215 RNA-binding proteins that recognize differentially methylated regions were predicted based on public databases. The M group showed significantly higher mRNA levels of m ⁶ A readers/writers (YTHDF1, YTHDF2, YTHDC1, YTHDC2 and WTAP) and significantly lower mRNA levels of m ⁶ A eraser (FTO) according to real-time PCR. To further investigate the differentially methylated genes, m ⁶ A methylome and transcriptome data were integrated to identified 298 hypermethylated mRNAs with differential expressions (265 upregulation and 33 downregulation) and 489 hypomethylated mRNAs with differential expressions (431 upregulation and 58 downregulation) in the M/V comparison.
Conclusion
The current results highlight the pathogenesis of m ⁶ A methylation in obstructive and reflux uropathy.
... Importantly, diabetic patients display a reduction in bacteria producing short chain fatty acids (SCFAs) when compared with healthy individuals. SCFAs are generally associated with beneficial effects on the vascular system, as they help to reduce both oxidative stress and pro-inflammatory stimuli [1]. ...
BACKGROUND AND AIMS
Diabetic Nephropathy (DN) is the major causes of end-stage renal failure. DN diagnosis is based on typical histological features (Kimmelstiel–Wilson lesions, glomerular basal membrane thickening and proliferation of mesangial matrix). Not all diabetic patients with kidney disease develop true DN: kidney impairment can be due to a nondiabetic renal disease (NDRD) in the presence or absence of real DN. Thus, there is the need for noninvasive biomarkers, related to specific pathogenic processes, to discriminate DN and NDRD, and/or to predict DN onset. In the case of DN, there is extensive evidence in literature of genetic contribution to disease susceptibility and lots of efforts aim at the identification of specific loci. The research group demonstrated that a characteristic feature of DN is an increase in Lys63-ubiquitinated proteins at tubular level that leads to epithelial-to-mesenchymal transition (EMT) and finally to the progression of the tubular-interstitial fibrosis and the renal damage in DN patients (Pontrelli P et al. FASEB J 2017). Ube2V1 is the unique E2 enzyme known for producing Lys63-linked ubiquitin chains. Moreover, two miRNAs (miR27b-3p e miR1228-3p), which interact specifically with Ube2V1 transcript, predict the type of renal damage in diabetic patients and are related with kidney fibrosis (Conserva F et al. Sci Rep 2019). The goal of this project was to identify single nucleotide polymorphisms (SNPs) able to predict the different kind of renal damage and the progression of kidney disease in diabetic patients.
METHOD
We selected by UCSC genome, 10 HapMap SNPs of patients within coding and regulatory sequences both of miR27b-3p and miR1228-3p and Ube2V1 gene in order to evaluate their diagnostic and prognostic potential.
The patients enrolled in this study were diabetic patients with a biopsy-proven DN diagnosis (DN), diabetic patients with a biopsy-proven diagnosis of other nephropathy than DN (NDRD), diabetic patients without clinical signs of impaired renal function (T2D), diabetic patients with a biopsy-proven coexistence of both conditions (ND + NDRD), non-diabetic patients with glomerulonephritis (CKD), non-diabetic patients without renal damage (CTRL).
The DNA of 201 subjects (patients and controls) was isolated from blood samples, and 10 HapMap SNPs (rs3802456, rs4744422, rs10761364, rs7853195 in the control region of miR27b-3p; rs2306692, rs4759277, rs4759044, rs17547610, rs4759275 in the control region of miR1228-3p; rs761214 in the UBE2v1 gene) for each patient were analyzed using TaqMan real-time PCR. Glomerular and tubulointerstitial fibrosis in kidney biopsies was quantified on Sirius Red staining using the Aperio Imagescope software.
RESULTS
The analyzed SNPs showed a different genotype frequency among all the patients’ classes. Interestingly, SNPs rs4759275, rs4759277, rs4744422 and rs3802456 showed a statistically significant difference in genotype frequency comparing DN patients with CEU Population (Northern and Western European Ancestry in Utah) (P < 0.04, 0.05, 0.002, 0.001, respectively) and a control cohort enclosing CTRL and T2D (P < 0.02, 0.05, 0.001 and 0.04, respectively). SNPs rs761214, rs10761364 and rs2306692 genotypes frequency was statistically different among DN patients and the control cohort (P < 0.001). The genotype frequencies of the SNPs rs10761364 (P < 0.01) and rs7853195 (P < 0.04) resulted significantly related to tubular fibrosis in DN patients, while the SNPs rs4744422 (P < 0.03) and rs761214 (P < 0.02) to the glomerular one. In order to evaluate the diagnostic power of the identified SNPs, we used a logistic regression model, and we observed that the SNP rs10761364, adjusted for age, sex, eGFR and glycaemic index, discriminate DN from NDRD {P < 0.05; OR = 1.002–1.008; [95% confidence interval (CI)]}.
CONCLUSION
Our data demonstrated that the allelic forms of the analyzed SNPs are related to the different kind of renal damage in diabetic patients. Their prognostic and diagnostic potential could represent the starting point to create a new noninvasive diagnosis system based on clinical and genotyping data.
Tetramethylpyrazine (TMP) is one of the active ingredients of Chuan Xiong that has been reported to have effects on numerous diseases, including diabetic nephropathy (DN). Whereas, related molecular mechanisms are not fully elucidated. We aimed to explore circACTR2’s role in TMP-mediated protective effects on DN. In vitro DN condition was established in human kidney cells (HK-2) by treating high glucose (HG). CCK-8 assay and flow cytometry assay were used to observe cell viability and survival. Oxidative stress was determined by the associated markers using kits. The release of inflammatory factors was detected using ELISA kits. Quantitative real-time PCR (qPCR) and western blot were utilized for expression analysis of cricACTR2, miR-140-5p, and GLI pathogenesis-related 2 (GLIPR2). The binding between miR-140-5p and circACTR2 or GLIPR2 was confirmed by dual-luciferase, RIP, and pull-down studies. HG largely induced HK-2 cell apoptosis, oxidative stress, and inflammation, which were alleviated by TMP. CircACTR2’s expression was enhanced in HG-treated HK-2 cells but attenuated in HG + TMP-treated HK-2 cells. CircACTR2 overexpression attenuated the functional effects of TMP and thus restored HG-induced cell apoptosis, oxidative stress, and inflammation. CircACTR2 bound to miR-140-5p to enhance the expression of GLIPR2. MiR-140-5p restoration or GLIPR2 inhibition reversed the role of circACTR2 overexpression. CircACTR2 attenuated the protective effects of TMP on HG-induced HK-2 cell damages by regulating the miR-140-5p/GLIPR2 network, indicating that circACTR2 was involved in the functional network of TMP in DN.
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease and is an enormous burden on both patients and society. There is an urgent need for effective alternative therapeutic strategies for the treatment of DN, as medical treatment is currently limited. The anti-inflammatory, antioxidative, anti-apoptotic, and anti-fibrosis properties of curcumin, a polyphenol curcuminoid, have been demonstrated in research on diabetic nephropathy. The clinical and preclinical trials and mechanisms by which curcumin affects DN have been discussed in this review. A deeper understanding of the pharmacological effects of curcumin on diabetic nephropathy may provide new therapies to improve the development and occurrence of diabetic nephropathy.
BACKGROUND AND AIMS
Diabetic kidney disease (DKD) is thought to be a consequence of hyperglycemia and driven by early glomerular hemodynamic changes and progressive expansion of the mesangium. The molecular mechanism behind the pathophysiological alterations of the mesangium is yet to be elucidated. This study aimed at investigating whether lipid signaling might be the missing link.
METHOD
Human mesangial cells (HMCs) were stimulated with high glucose, IL-1β or PDGF-BB. Production of IL-1β and PDGF-BB, COX-2 induction and cPLA2 activation and prostaglandin secretion were investigated using a combination of ELISA, western blot, lipidomics, qPCR and activity assays. Inhibition of cPLA2 was evaluated using ELISA, migration and proliferation assays. Validation of data was performed in silico using the Nephroseq database [1] and a recently published glomerular transcriptomic DKD database. [2]
RESULTS
Stimulation of HMCs with high glucose primed IL-1β secretion through inflammasome NLRP3 signaling. In turn, IL-1β was able to stimulate PDGF-BB release. PDGF-BB increased IL-1β secretion synergistically. Both IL-1β and PDGF-BB stimuli caused lipid metabolism variations and in particular triggered the formation of phosphorylated sphingoid bases (PSBs) and the activation of the enzymes cPLA2 and COX-2. This led to the formation of prostanoids from arachidonic acid produced by cPLA2. As a result, prostaglandins were secreted. Another product of cPLA2 activation was lysophosphatidic acid (LPA), a proliferation effector. Blocking cPLA2-mediated release of arachidonic acid could in fact reduce HMCs’ proliferation and secretion of prostaglandins.
CONCLUSION
Hyperglycemia primes glomerular inflammatory and proliferative stimuli triggering lipid metabolism modifications in HMCs. The upregulation of cPLA2 was found to be critical in this setting. cPLA2 inhibition with AACOCF3 reduced mesangial secretion of prostaglandins and proliferation, making it a potential target for DKD therapy.
BACKGROUND AND AIMS
Beyond the glucose control, anti-diabetic drugs need to demonstrate benefits on metabolic comorbidities. An animal model that recapitulates obesity and type 2 diabetes (T2D) comorbidities [i.e. non-alcoholic steato-hepatitis (NASH), nephropathy and heart failure with preserved ejection fraction (HFpEF)] is still needed for preclinical drug development. To overcome this limitation, we evaluated the effects of a high fat/cholesterol/fructose (HFCF) diet in the Lund MetS rat, a congenic BBDR.cg-lepr.cp model generated by introgression of the Koletsky leptin receptor mutation into the BioBreeding Diabetes Resistant (BBDR) rat.
METHOD
17-week-old, male, lean control (ctrl) or Lund MetS obese T2D rats were fed a control chow (CC) diet or a HFCF diet, respectively for 8 weeks. Blood biochemistry was measured at 0, 4 and 8 weeks of diet. Kidney, heart and liver parameters were assessed at the end of the 8-week diet period.
RESULTS
Compared with ctrl, Lund MetS rats were obese (56% higher body weight) and diabetic with significantly higher %HbA1c (up to + 3%) and blood glucose levels (up to 3-fold higher) during the 8-week HFCF diet period. Significantly higher plasma insulin (up to 11-fold), total cholesterol (up to 5-fold), triglycerides (up to 8-fold), transaminases (up to 10-fold higher) levels were also observed in Lund MetS rats, as compared with ctrl. Hepatic total cholesterol, triglycerides and fatty acids levels were significantly higher in Lund Mets rats (14-, 7.3- and 6.7-fold higher as compared to ctrl, respectively). Liver histopathological scoring confirmed a NASH phenotype in Lund MetS rats fed the HFCF diet with strong liver steatosis, hepatic inflammation and portal to bridging fibrosis. Kidney function was substantially altered with a 60% decline in glomerular filtration rate and a 16-fold increase in urine albumin-to-creatinine ratio (both P < 0.0001 versus ctrl). Finally, echocardiography indicated diastolic dysfunction with significantly reduced E/A and greater E/e’ ratios, along with a preserved ejection fraction in Lund MetS rats, as compared with lean ctrl.
CONCLUSION
The present data demonstrate that the Lund MetS rat fed an HFCF diet that recapitulates the major metabolic comorbidities of obesity/T2D and may be a useful model for preclinical drug development.
Diabetic nephropathy is the leading cause of end-stage renal disease in developed countries. We evaluated the renoprotective effects of dual blockade of the renin-angiotensin-aldosterone system by adding treatment with aliskiren, an oral direct renin inhibitor, to treatment with the maximal recommended dose of losartan (100 mg daily) and optimal antihypertensive therapy in patients who had hypertension and type 2 diabetes with nephropathy.
We enrolled 599 patients in this multinational, randomized, double-blind study. After a 3-month, open-label, run-in period during which patients received 100 mg of losartan daily, patients were randomly assigned to receive 6 months of treatment with aliskiren (150 mg daily for 3 months, followed by an increase in dosage to 300 mg daily for another 3 months) or placebo, in addition to losartan. The primary outcome was a reduction in the ratio of albumin to creatinine, as measured in an early-morning urine sample, at 6 months.
The baseline characteristics of the two groups were similar. Treatment with 300 mg of aliskiren daily, as compared with placebo, reduced the mean urinary albumin-to-creatinine ratio by 20% (95% confidence interval, 9 to 30; P<0.001), with a reduction of 50% or more in 24.7% of the patients who received aliskiren as compared with 12.5% of those who received placebo (P<0.001). A small difference in blood pressure was seen between the treatment groups by the end of the study period (systolic, 2 mm Hg lower [P=0.07] and diastolic, 1 mm Hg lower [P=0.08] in the aliskiren group). The total numbers of adverse and serious adverse events were similar in the groups.
Aliskiren may have renoprotective effects that are independent of its blood-pressure-lowering effect in patients with hypertension, type 2 diabetes, and nephropathy who are receiving the recommended renoprotective treatment. (ClinicalTrials.gov number, NCT00097955 [ClinicalTrials.gov].).
Objective:
Diabetes is the fifth leading cause of death by disease in the U.S. Diabetes also contributes to higher rates of morbidity-people with diabetes are at higher risk for heart disease, blindness, kidney failure, extremity amputations, and other chronic conditions. The objectives of this study were 1). to estimate the direct medical and indirect productivity-related costs attributable to diabetes and 2). to calculate and compare the total and per capita medical expenditures for people with and without diabetes.
Research design and methods:
Medical expenditures were estimated for the U.S. population with and without diabetes in 2002 by sex, age, race/ethnicity, type of medical condition, and health care setting. Health care use and total health care expenditures attributable to diabetes were estimated using etiological fractions, calculated based on national health care survey data. The value of lost productivity attributable to diabetes was also estimated based on estimates of lost workdays, restricted activity days, prevalence of permanent disability, and mortality attributable to diabetes. RESULTS-Direct medical and indirect expenditures attributable to diabetes in 2002 were estimated at 132 billion US dollars. Direct medical expenditures alone totaled 91.8 billion US dollars and comprised 23.2 billion US dollars for diabetes care, 24.6 billion US dollars for chronic complications attributable to diabetes, and 44.1 billion US dollars for excess prevalence of general medical conditions. Inpatient days (43.9%), nursing home care (15.1%), and office visits (10.9%) constituted the major expenditure groups by service settings. In addition, 51.8% of direct medical expenditures were incurred by people >65 years old. Attributable indirect expenditures resulting from lost workdays, restricted activity days, mortality, and permanent disability due to diabetes totaled 39.8 billion US dollars. U.S. health expenditures for the health care components included in the study totaled 865 billion US dollars, of which 160 billion US dollars was incurred by people with diabetes. Per capita medical expenditures totaled 13243 US dollars for people with diabetes and 2560 US dollars for people without diabetes. When adjusting for differences in age, sex, and race/ethnicity between the population with and without diabetes, people with diabetes had medical expenditures that were approximately 2.4 times higher than expenditures that would be incurred by the same group in the absence of diabetes.
Conclusions:
The estimated 132 billion US dollars cost likely underestimates the true burden of diabetes because it omits intangibles, such as pain and suffering, care provided by nonpaid caregivers, and several areas of health care spending where people with diabetes probably use services at higher rates than people without diabetes (e.g., dental care, optometry care, and the use of licensed dietitians). In addition, the cost estimate excludes undiagnosed cases of diabetes. Health care spending in 2002 for people with diabetes is more than double what spending would be without diabetes. Diabetes imposes a substantial cost burden to society and, in particular, to those individuals with diabetes and their families. Eliminating or reducing the health problems caused by diabetes through factors such as better access to preventive care, more widespread diagnosis, more intensive disease management, and the advent of new medical technologies could significantly improve the quality of life for people with diabetes and their families while at the same time potentially reducing national expenditures for health care services and increasing productivity in the U.S. economy.
A high-capacity system was developed to monitor the expression of many genes in parallel. Microarrays prepared by high-speed
robotic printing of complementary DNAs on glass were used for quantitative expression measurements of the corresponding genes.
Because of the small format and high density of the arrays, hybridization volumes of 2 microliters could be used that enabled
detection of rare transcripts in probe mixtures derived from 2 micrograms of total cellular messenger RNA. Differential expression
measurements of 45 Arabidopsis genes were made by means of simultaneous, two-color fluorescence hybridization.
Empirical evidence and theoretical studies suggest that the phenotype, i.e., cellular- and molecular-scale dynamics, including proliferation rate and adhesiveness due to microenvironmental factors and gene expression that govern tumor growth and invasiveness, also determine gross tumor-scale morphology. It has been difficult to quantify the relative effect of these links on disease progression and prognosis using conventional clinical and experimental methods and observables. As a result, successful individualized treatment of highly malignant and invasive cancers, such as glioblastoma, via surgical resection and chemotherapy cannot be offered and outcomes are generally poor. What is needed is a deterministic, quantifiable method to enable understanding of the connections between phenotype and tumor morphology. Here, we critically assess advantages and disadvantages of recent computational modeling efforts (e.g., continuum, discrete, and cellular automata models) that have pursued this understanding. Based on this assessment, we review a multiscale, i.e., from the molecular to the gross tumor scale, mathematical and computational "first-principle" approach based on mass conservation and other physical laws, such as employed in reaction-diffusion systems. Model variables describe known characteristics of tumor behavior, and parameters and functional relationships across scales are informed from in vitro, in vivo and ex vivo biology. We review the feasibility of this methodology that, once coupled to tumor imaging and tumor biopsy or cell culture data, should enable prediction of tumor growth and therapy outcome through quantification of the relation between the underlying dynamics and morphological characteristics. In particular, morphologic stability analysis of this mathematical model reveals that tumor cell patterning at the tumor-host interface is regulated by cell proliferation, adhesion and other phenotypic characteristics: histopathology information of tumor boundary can be inputted to the mathematical model and used as a phenotype-diagnostic tool to predict collective and individual tumor cell invasion of surrounding tissue. This approach further provides a means to deterministically test effects of novel and hypothetical therapy strategies on tumor behavior.
The prevalence of Type 2 diabetes is increasing rapidly and is associated with significant cardiovascular adverse effects. The authors tested the hypothesis that, in patients with type II diabetes, intensive glucose control as evidenced by lowering the glycated hemoglobin level to to ≤6.5% would result in lower rates of major microvascular and macrovascular events. There were 11,140 patients with Type 2 diabetes who were randomly assigned to undergo standard glucose control or intensive glucose control. Intensive glucose control was achieved with the use of gliclazide (modified release) and other drugs as required to reach a glycated hemoglobin ≤6.5%. Primary end points were composites of major microvascular events (new or worsening nephropathy or retinopathy) or macrovascular events (death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke). End points were assessed both jointly and separately. Yes Yes
Plasma renin exists in an active form or as an inactive zymogen that resembles a prorenin present in homogenates of human kidneys. We examined the relation of diabetes and its microvascular complications with the level of plasma inactive renin activated by dialysis to pH 3.3. Plasma inactive renin was measured in 235 diabetic patients and 90 nondiabetic controls. In the controls, the level of plasma inactive renin increased slightly with age but was never above 50 ng per milliliter per hour. In young diabetic patients studied within three years of the onset of diabetes the concentration of inactive renin was normal, and in some older diabetics without complications it remained within the age-adjusted normal range for many years. However, in patients with retinopathy or albuminuria, plasma inactive renin was above the normal range with few exceptions, reaching levels 50 to 200 per cent above the upper limits of normal in patients with nephropathy. The frequency of neuropathy was also significantly higher among patients with levels above the normal range. In 37 per cent of the diabetics followed during one to three years of conventional treatment, plasma inactive renin increased significantly, but in another group of diabetics under intensive treatment, the level rose in only 7 per cent and fell in 43 per cent. We conclude that there is a close association between a high level of plasma inactive renin and the presence of microvascular complications, and that the level of inactive renin can be modified by intensive treatment of diabetes.