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)

Glucagon-like peptide-1 (GLP-1), an intestinal gut hormone, is rapidly emerging as a new therapeutic agent for the treatment of diabetes mellitus. GLP-1, released from intestinal L-cells, is renowned for its potent stimulation of insulin biosynthesis and release from pancreatic b-cells. Exogenous administration of GLP-1 to subjects with type 2 diabetes results in the normalization of plasma glucose concentrations, in part, as a result of augmented glucose-stimulated insulin secretion. However, it is now recognized that GLP-1 has several other anti-diabetic actions that collectively improve the type 2 diabetic phenotype, and may also prove beneficial in the treatment of type 1 diabetes. These effects include the deceleration of gastric emptying and promotion of satiety, thereby reducing the availability of nutrients for absorption and reducing the requirement for insulin secretion. GLP-1 also reduces plasma glucose levels by suppressing glucagon secretion from pancreatic a-cells and potentially by improving insulin sensitivity in peripheral tissues. Further-more, GLP-1 upregulates expression of b-cell genes (GLUT2, glucokinase, insulin, and PDX-1) and promotes b-cell neogenesis and differentiation of ductal cells into insulin secreting cells. Although initial clinical trials indicate GLP-1 has excellent therapeutic potential, its relatively short-lived biological activity and delivery difficulties limit its appeal. Several approaches that are currently being explored to overcome these limitations include mobilizing endogenous GLP-1 release, preserving the biological activity of the native peptide, and developing GLP-1 analogues with extended durations of action.
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PMID:The multifaceted potential of glucagon-like peptide-1 as a therapeutic agent. 1196 1

The ability of insulin to suppress gluconeogenesis in type II diabetes mellitus is impaired; however, the cellular mechanisms for this insulin resistance remain poorly understood. To address this question, we generated transgenic (TG) mice overexpressing the phosphoenolpyruvate carboxykinase (PEPCK) gene under control of its own promoter. TG mice had increased basal hepatic glucose production (HGP), but normal levels of plasma free fatty acids (FFAs) and whole-body glucose disposal during a hyperinsulinemic-euglycemic clamp compared with wild-type controls. The steady-state levels of PEPCK and glucose-6-phosphatase mRNAs were elevated in livers of TG mice and were resistant to down-regulation by insulin. Conversely, GLUT2 and glucokinase mRNA levels were appropriately regulated by insulin, suggesting that insulin resistance is selective to gluconeogenic gene expression. Insulin-stimulated phosphorylation of the insulin receptor, insulin receptor substrate (IRS)-1, and associated phosphatidylinositol 3-kinase were normal in TG mice, whereas IRS-2 protein and phosphorylation were down-regulated compared with control mice. These results establish that a modest (2-fold) increase in PEPCK gene expression in vivo is sufficient to increase HGP without affecting FFA concentrations. Furthermore, these results demonstrate that PEPCK overexpression results in a metabolic pattern that increases glucose-6-phosphatase mRNA and results in a selective decrease in IRS-2 protein, decreased phosphatidylinositol 3-kinase activity, and reduced ability of insulin to suppress gluconeogenic gene expression. However, acute suppression of HGP and glycolytic gene expression remained intact, suggesting that FFA and/or IRS-1 signaling, in addition to reduced IRS-2, plays an important role in downstream insulin signal transduction pathways involved in control of gluconeogenesis and progression to type II diabetes mellitus.
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PMID:Phosphoenolpyruvate carboxykinase overexpression selectively attenuates insulin signaling and hepatic insulin sensitivity in transgenic mice. 1196 95

Type 2 diabetes is characterized by a susceptibility to beta-cell failure. However, subjects at risk of developing type 2 diabetes, such as those with obesity or a family history of diabetes, have been shown to display hyperinsulinemia. Although this hyperinsulinemia may be an adaptive response to insulin resistance, the possibility that insulin hypersecretion may be a primary defect has not been thoroughly investigated. The DBA/2 mouse is a model of pancreatic islet susceptibility. Unlike the resistant C57BL/6 mouse strain, the DBA/2 mouse islet fails when stressed with insulin resistance or when exposed to chronic high glucose concentrations. The aim of this study was to compare insulin secretory function in the DBA/2 and C57BL/6 strains in the absence of insulin resistance or high glucose. Insulin secretion was assessed in vivo using the iv glucose tolerance test and in vitro using isolated islets in static incubations. It was shown that DBA/2 mice hypersecreted insulin in vivo, compared with C57BL/6 mice, at 1 d and at 4 and 10 wk of age. This hypersecretion was not attributable to insulin resistance (as assessed by the insulin tolerance test) or increased parasympathetic nervous system outflow. Insulin hypersecretion was also demonstrated in vitro. This was associated with higher glycolysis and glucose oxidation, and elevated activity (but not protein levels) of islet glucokinase and hexokinase. Furthermore, GLUT2 protein levels were higher, which may explain an increase in glucokinase activity in DBA/2 mouse islets. In summary, the DBA/2 mouse, a model of islet failure, has increased glucose-mediated insulin secretion from a very early age, which is associated with an increase in glucose utilization. Further studies will determine whether there is a link between insulin hypersecretion and subsequent beta-cell failure.
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PMID:Comparison of insulin secretory function in two mouse models with different susceptibility to beta-cell failure. 1202 Nov 73

Although peroxisome proliferator-activated receptor (PPAR)gamma agonists ameliorate insulin resistance, they sometimes cause body weight gain, and the effect of PPAR agonists on insulin secretion is unclear. We evaluated the effects of combination therapy with a PPARgamma agonist, pioglitazone, and a PPARalpha agonist, bezafibrate, and a dual agonist, KRP-297, for 4 wk in male C57BL/6J mice and db/db mice, and we investigated glucose-stimulated insulin secretion (GSIS) by in situ pancreatic perfusion. Body weight gain in db/db mice was less with KRP-297 treatment than with pioglitazone or pioglitazone + bezafibrate treatment. Plasma glucose, insulin, triglyceride, and nonesterified fatty acid levels were elevated in untreated db/db mice compared with untreated C57BL/6J mice, and these parameters were significantly ameliorated in the PPARgamma agonist-treated groups. Also, PPARgamma agonists ameliorated the diminished GSIS and insulin content, and they preserved insulin and GLUT2 staining in db/db mice. GSIS was further increased by PPARgamma and -alpha agonists. We conclude that combination therapy with PPARgamma and PPARalpha agonists may be more useful with respect to body weight and pancreatic GSIS in type 2 diabetes with obesity.
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PMID:Combination therapy with PPARgamma and PPARalpha agonists increases glucose-stimulated insulin secretion in db/db mice. 1267 49

beta cell dysfunction is an important component of type 2 diabetes, but the molecular basis for this defect is poorly understood. The transcriptional coactivator PGC-1alpha mRNA and protein levels are significantly elevated in islets from multiple animal models of diabetes; adenovirus-mediated expression of PGC-1alpha to levels similar to those present in diabetic rodents produces a marked inhibition of glucose-stimulated insulin secretion from islets in culture and in live mice. This inhibition coincides with changes in metabolic gene expression associated with impaired beta cell function, including the induction of glucose-6-phosphatase and suppression of GLUT2, glucokinase, and glycerol-3-phosphate dehydrogenase. These changes result in blunting of the glucose-induced rise in cellular ATP levels and membrane electrical activity responsible for Ca(2+) influx and insulin exocytosis. These results strongly suggest that PGC-1alpha plays a key functional role in the beta cell and is involved in the pathogenesis of the diabetic phenotype.
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PMID:Suppression of beta cell energy metabolism and insulin release by PGC-1alpha. 1285 53

In the present study, we show that the expression of type 2 glucose transporter isoform (GLUT2) could be regulated by PPAR-gamma in the liver. Rosiglitazone, PPAR-gamma agonist, activated the GLUT2 mRNA level in the primary cultured hepatocytes and Alexander cells, when these cells were transfected with PPAR-gamma/RXR-alpha. We have localized the peroxisome proliferator response element in the mouse GLUT2 promoter by serial deletion studies and site-directed mutagenesis. Chromatin immunoprecipitation assay using ob/ob mice also showed that PPAR-gamma rather than PPAR-alpha binds to the -197/-184 region of GLUT2 promoter. Taken together, liver GLUT2 may be a direct target of PPAR-gamma ligand contributing to glucose transport into liver in a condition when PAPR-gamma expression is increased as in type 2 diabetes or in severe obesity.
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PMID:Identification and characterization of peroxisome proliferator response element in the mouse GLUT2 promoter. 1588 23

GLUT2 is mainly expressed in the liver, beta-cells of the pancreas, and the basolateral membrane of kidney proximal tubules and plays an important role in glucose homeostasis in living organisms. The transcription of the GLUT2 gene is known to be upregulated in the liver during postprandial hyperglycemic states or in type 2 diabetes. However, a molecular mechanism by which glucose activates GLUT2 gene expression is not known. In this study, we report evidence that sterol response element-binding protein (SREBP)-1c plays a key role in glucose-stimulated GLUT2 gene expression. The GLUT2 promoter reporter is activated by SREBP-1c, and the activation is inhibited by a dominant-negative form of SREBP-1c (SREBP-1c DN). Adenoviral expression of SREBP-1c DN suppressed glucose-stimulated GLUT2 mRNA level in primary hepatocytes. An electrophoretic mobility shift assay and mutational analysis of the GLUT2 promoter revealed that SREBP-1c binds to the -84/-76 region of the GLUT2 promoter. Chromatin immunoprecipitation revealed that the binding of SREBP-1c to the -84/-76 region was increased by glucose concentration in a dose-dependent manner. These results indicate that SREBP-1c mediates glucose-stimulated GLUT2 gene expression in hepatocytes.
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PMID:Glucose-stimulated upregulation of GLUT2 gene is mediated by sterol response element-binding protein-1c in the hepatocytes. 1591 89

Impaired insulin secretion is a fundamental defect in type 2 diabetes. The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) in the genes regulating insulin secretion (SLC2A2 [encoding GLUT2], GCK, TCF1 [encoding HNF-1alpha], HNF4A, GIP, and GLP1R) are associated with the conversion from impaired glucose tolerance (IGT) to type 2 diabetes in participants of the Finnish Diabetes Prevention Study. With the exception of SLC2A2, other genes were not associated with the risk of type 2 diabetes. All four SNPs of SLC2A2 predicted the conversion to diabetes, and rs5393 (AA genotype) increased the risk of type 2 diabetes in the entire study population by threefold (odds ratio 3.04, 95% CI 1.34-6.88, P = 0.008). The risk for type 2 diabetes in the AA genotype carriers was increased in the control group (5.56 [1.78-17.39], P = 0.003) but not in the intervention group. We conclude that the SNPs of SLC2A2 predict the conversion to diabetes in obese subjects with IGT.
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PMID:Polymorphisms in the SLC2A2 (GLUT2) gene are associated with the conversion from impaired glucose tolerance to type 2 diabetes: the Finnish Diabetes Prevention Study. 1598 30

The bulk of glucose that is filtered by the renal glomerulus is reabsorbed by the glucose transporters of the proximal convoluted tubular epithelium. However, it has been difficult to investigate this in diseases such as type 2 diabetes because of the inability to isolate primary renal cells from patients without a renal biopsy. We report here a method for the immunomagnetic isolation and novel primary culture of human exfoliated proximal tubular epithelial cells (HEPTECs) from fresh urine. The primary isolates are highly enriched and differentiated and express characteristic proximal tubular phenotypic markers. They continue to express the proximal tubular markers CD13/aminopeptidase-N, sodium glucose cotransporter (SGLT) 2, and alkaline phosphatase through up to six subsequent subcultures in a similar way to human proximal cells isolated from renal biopsies. In a hyperglycemic environment, HEPTECs isolated from patients with type 2 diabetes expressed significantly more SGLT2 and the facilitative glucose transporter GLUT2 than cells from healthy individuals. We also demonstrated a markedly increased renal glucose uptake in HEPTECs isolated from patients with type 2 diabetes compared with healthy control subjects. Our findings indicate for the first time in a human cellular model that increased renal glucose transporter expression and activity is associated with type 2 diabetes.
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PMID:Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin-dependent diabetes. 1630 58

Inadequate islet adaptation to insulin resistance leads to glucose intolerance and type 2 diabetes. Here we investigate whether beta-cell cAMP is crucial for islet adaptation and prevention of glucose intolerance in mice. Mice with a beta-cell-specific, 2-fold overexpression of the cAMP-degrading enzyme phosphodiesterase 3B (RIP-PDE3B/2 mice) were metabolically challenged with a high-fat diet. We found that RIP-PDE3B/2 mice early and rapidly develop glucose intolerance and insulin resistance, as compared with wild-type littermates, after 2 months of high-fat feeding. This was evident from advanced fasting hyperinsulinemia and early development of hyper-glycemia, in spite of hyperinsulinemia, as well as impaired capacity of insulin to suppress plasma glucose in an insulin tolerance test. In vitro analyses of insulin-stimulated lipogenesis in adipocytes and glucose uptake in skeletal muscle did not reveal reduced insulin sensitivity in these tissues. Significant steatosis was noted in livers from high-fat-fed wild-type and RIP-PDE3B/2 mice and liver triacyl-glycerol content was 3-fold higher than in wild-type mice fed a control diet. Histochemical analysis revealed severe islet perturbations, such as centrally located alpha-cells and reduced immunostaining for insulin and GLUT2 in islets from RIP-PDE3B/2 mice. Additionally, in vitro experiments revealed that the insulin secretory response to glucagon-like peptide-1 stimulation was markedly reduced in islets from high-fat-fed RIP-PDE3B/2 mice. We conclude that accurate regulation of beta-cell cAMP is necessary for adequate islet adaptation to a perturbed metabolic environment and protective for the development of glucose intolerance and insulin resistance.
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PMID:Early and rapid development of insulin resistance, islet dysfunction and glucose intolerance after high-fat feeding in mice overexpressing phosphodiesterase 3B. 1673 93


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