Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Retinopathy has been increasing in prevalence as a consequence of type 2 diabetes and a cluster of coexisting risk factors characterized as the metabolic syndrome. However, the combined effects of these conditions on the retina are poorly understood. Therefore, we focused on the spontaneously hypertensive corpulent rat (SHR/N-cp), a model with type 2 diabetes, obesity and features of the metabolic syndrome to characterize retinal changes at a structural and functional level. SHR/N-cp males at 4 and 8 months of age were used in this study. Metabolic parameters and blood pressure were measured by standard methods. Morphology was investigated by histological techniques supplemented by nicotinamide adenine dinucleotide phosphate-diaphorase staining of whole mounts and fluorescein angiography to analyze the retinal vasculature. The in vivo function of the retina was examined by electroretinography (ERG). Obese SHR/N-cp rats were hypertensive and showed significant increases in body weight, serum levels of glucose, triglycerides, total cholesterol and urinary glucose excretion compared with lean controls (P < 0.01 for each). Histology indicated an overall intact integrity of the retina and aspects of microangiopathy in obese SHR/N-cp rats. ERG revealed intact processing of light signals but significantly decreased amplitudes of b-waves for all (P < 0.01) and of a-waves for some examined light intensities (P < 0.05). Oscillatory potentials were significantly protracted (P < 0.01), whereas amplitudes were not reduced. Microangiopathy and electroretinographic deficits combine to produce an early non-proliferative retinopathy phenotype in the obese SHR/N-cp rats. Thus, this model represents a valuable experimental tool to obtain further insights into the mechanisms of retinopathy in the context of obesity, type 2 diabetes and metabolic syndrome.
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PMID:Microangiopathy and visual deficits characterize the retinopathy of a spontaneously hypertensive rat model with type 2 diabetes and metabolic syndrome. 2092 14

Recent genetic and clinical evidence has implicated glucokinase regulatory protein (GKRP) in the pathogenesis of type 2 diabetes and related traits. The primary role of GKRP is to bind and inhibit hepatic glucokinase (GCK), a critically important protein in human health and disease that exerts a significant degree of control over glucose metabolism. As activation of GCK has been associated with improved glucose tolerance, perturbation of the GCK-GKRP interaction represents a potential therapeutic target for pharmacological modulation. Recent structural and kinetic advances are beginning to provide insight into the interaction of these two proteins. However, tools to comprehensively assess the GCK-GKRP interaction, particularly in the context of small molecules, would be a valuable resource. We therefore developed three robust and miniaturized assays for assessing the interaction between recombinant human GCK and GKRP: an HTRF assay, a diaphorase-coupled assay, and a luciferase-coupled assay. The assays are complementary, featuring distinct mechanisms of detection (luminescence, fluorescence, FRET). Two assays rely on GCK enzyme activity modulation by GKRP while the FRET-based assay measures the GCK-GKRP protein-protein interaction independent of GCK enzymatic substrates and activity. All three assays are scalable to low volumes in 1536-well plate format, with robust Z' factors (>0.7). Finally, as GKRP sequesters GCK in the hepatocyte nucleus at low glucose concentrations, we explored cellular models of GCK localization and translocation. Previous findings from freshly isolated rat hepatocytes were confirmed in cryopreserved rat hepatocytes, and we further extended this study to cryopreserved human hepatocytes. Consistent with previous reports, there were several key differences between the rat and human systems, with our results suggesting that human hepatocytes can be used to interrogate GCK translocation in response to small molecules. The assay panel developed here should help direct future investigation of the GCK-GKRP interaction in these or other physiologically relevant human systems.
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PMID:A panel of diverse assays to interrogate the interaction between glucokinase and glucokinase regulatory protein, two vital proteins in human disease. 2458 96

Skeletal myocytes are metabolically active and susceptible to insulin resistance and are thus implicated in type 2 diabetes (T2D). This complex disease involves systemic metabolic changes, and their elucidation at the systems level requires genome-wide data and biological networks. Genome-scale metabolic models (GEMs) provide a network context for the integration of high-throughput data. We generated myocyte-specific RNA-sequencing data and investigated their correlation with proteome data. These data were then used to reconstruct a comprehensive myocyte GEM. Next, we performed a meta-analysis of six studies comparing muscle transcription in T2D versus healthy subjects. Transcriptional changes were mapped on the myocyte GEM, revealing extensive transcriptional regulation in T2D, particularly around pyruvate oxidation, branched-chain amino acid catabolism, and tetrahydrofolate metabolism, connected through the downregulated dihydrolipoamide dehydrogenase. Strikingly, the gene signature underlying this metabolic regulation successfully classifies the disease state of individual samples, suggesting that regulation of these pathways is a ubiquitous feature of myocytes in response to T2D.
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PMID:Proteome- and transcriptome-driven reconstruction of the human myocyte metabolic network and its use for identification of markers for diabetes. 2593 84

Mitochondrial dihydrolipoamide dehydrogenase (DLDH) is a redox enzyme involved in decarboxylation of pyruvate to form acetyl-CoA during the cascade of glucose metabolism and mitochondrial adenine triphosphate (ATP) production. Depending on physiological or pathophysiological conditions, DLDH can either enhance or attenuate the production of reactive oxygen species (ROS) and reactive nitrogen species. Recent research in our laboratory has demonstrated that inhibition of DLDH induced antioxidative responses and could serve as a protective approach against oxidative stress in stroke injury. In this perspective article, we postulated that chronic inhibition of DLDH could also attenuate oxidative stress in type 2 diabetes. We discussed DLDH-involving mitochondrial metabolic pathways and metabolic intermediates that could accumulate upon DLDH inhibition and their corresponding roles in abrogating oxidative stress in diabetes. We also discussed a couple of DLDH inhibitors that could be tested in animal models of type 2 diabetes. It is our belief that DLDH inhibition could be a novel approach to fighting type 2 diabetes.
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PMID:Chronic Inhibition of Mitochondrial Dihydrolipoamide Dehydrogenase (DLDH) as an Approach to Managing Diabetic Oxidative Stress. 3071 46

5-Methoxyindole-2-carboxylic acid (MICA) is a well-established reversible inhibitor of mitochondrial dihydrolipoamide dehydrogenase (DLDH). This chemical, as an indole derivative, has been shown to be neuroprotective against ischemic stroke injury when administered either before or after ischemic stroke in animal models. MICA has also been studied as a potential antidiabetic agent by numerous investigators, though the underlying mechanisms remain sketchy. To attempt to elucidate the mechanisms of its antidiabetic action, we tested the effect of MICA on ZSF1 rat, a widely used rodent model of type 2 diabetes. ZSF1 rats as well as its healthy controls were fed with control diet or MICA-containing diet (200 mg/kg/day) for 9 weeks. Unexpectedly, comparison of body weight changes and blood glucose levels at the end of the 9-week's feeding period indicated that MICA failed to show any anti-diabetic effect in the ZSF1 diabetic rats. The reasons for this failure were discussed.
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PMID:5-Methoxyindole-2-Carboylic Acid (MICA) Fails to Retard Development and Progression of Type II Diabetes in ZSF1 Diabetic Rats. 3255 63