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)

Extracts of leaves from the plant Stevia rebaudiana Bertoni have been used in the traditional treatment of diabetes in Paraguay and Brazil. Recently, we demonstrated a direct insulinotropic effect in isolated mouse islets and the clonal beta cell line INS-1 of the glycoside stevioside that is present in large quantity in these leaves. Type 2 diabetes is a chronic metabolic disorder that results from defects in both insulin and glucagon secretion as well as insulin action. In the present study we wanted to unravel if stevioside in vivo exerts an antihyperglycaemic effect in a nonobese animal model of type 2 diabetes. An i.v. glucose tolerance test (IVGT) was carried out with and without stevioside in the type 2 diabetic Goto-Kakizaki (GK) rat, as well as in the normal Wistar rat. Stevioside (0.2 g/kg BW) and D-glucose (2.0 g/kg BW) were administered as i.v. bolus injections in anaesthetized rats. Stevioside significantly suppressed the glucose response to the IVGT in GK rats (incremental area under the curve (IAUC): 648 +/- 50 (stevioside) vs 958 +/- 85 mM x 120 min (control); P < 0.05) and concomitantly increased the insulin response (IAUC: 51116 +/- 10967 (stevioside) vs 21548 +/- 3101 microU x 120 min (control); P < 0.05). Interestingly, the glucagon level was suppressed by stevioside during the IVGT, (total area under the curve (TAUC): 5720 +/- 922 (stevioside) vs 8713 +/- 901 pg/ml x 120 min (control); P < 0.05). In the normal Wistar rat stevioside enhanced insulin levels above basal during the IVGT (IAUC: 79913 +/- 3107 (stevioside) vs 17347 +/- 2882 microU x 120 min (control); P < 0.001), however, without altering the blood glucose response (IAUC: 416 +/- 43 (stevioside) vs 417 +/- 47 mM x 120 min (control)) or the glucagon levels (TAUC: 5493 +/- 527 (stevioside) vs 5033 +/- 264 pg/ml x 120 min (control)). In conclusion, stevioside exerts antihyperglycaemic, insulinotropic, and glucagonostatic actions in the type 2 diabetic GK rat, and may have the potential of becoming a new antidiabetic drug for use in type 2 diabetes.
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PMID:Stevioside induces antihyperglycaemic, insulinotropic and glucagonostatic effects in vivo: studies in the diabetic Goto-Kakizaki (GK) rats. 1192 70

Maturity onset diabetes of the young, subtype 1 (MODY1), is associated with defective glucose-dependent insulin secretion from pancreatic beta cells. MODY1 is caused by mutation in the transcription factor hepatocyte nuclear factor 4 alpha (HNF4 alpha). To understand better the MODY1 phenotype, we tested whether HNF4 alpha was able to modulate directly the insulin gene promoter. Transfection of cultured 293T cells with an HNF4 alpha expression vector led to 10-fold activation of a cotransfected reporter plasmid containing the rat insulin I gene promoter. Computer analysis revealed a potential HNF4 alpha-binding site between nucleotides -57 and -69 of the promoter; mutation of this sequence led to reduced ability of HNF4 alpha to activate the promoter. The ability of HNF4 alpha to bind this sequence was confirmed using gel shift analysis. In transfected INS-1 beta cells, mutation of either the HNF1 alpha site or the HNF4 alpha site in the insulin gene promoter led to 50-75% reduction in reporter gene activity; expression of dominant negative HNF4 alpha led to significant reduction in the activity of wild type and both mutated promoters. Thus, in addition to the previously described indirect action of HNF4 alpha on insulin gene expression mediated through elevated HNF1 alpha levels, HNF4 alpha also activates the insulin gene directly, through a previously unrecognized cis element.
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PMID:Activation of the insulin gene promoter through a direct effect of hepatocyte nuclear factor 4 alpha. 1199 85

Fatty acids may promote type 2 diabetes by altering insulin secretion from pancreatic beta cells, a process known as lipotoxicity. The underlying mechanisms are poorly understood. To test the hypothesis that peroxisome proliferator-activated receptor alpha (PPARalpha) has a direct effect on islet function, we treated INS-1 cells, an insulinoma cell line, with a PPARalpha adenovirus (AdPPARalpha) as well as the PPARalpha agonist clofibric acid. AdPPARalpha-infected INS-1 cells showed PPARalpha agonist- and fatty acid-dependent transactivation of a PPARalpha reporter gene. Treatment with either AdPPARalpha or clofibric acid increased both catalase activity (a marker of peroxisomal proliferation) and palmitate oxidation. AdPPARalpha induced carnitine-palmitoyl transferase-I (CPT-I) mRNA, but had no effect on insulin gene expression. AdPPARalpha treatment increased cellular triglyceride content but clofibric acid did not. Both AdPPARalpha and clofibric acid decreased basal and glucose-stimulated insulin secretion. Despite increasing fatty acid oxidation, AdPPARalpha did not increase cellular ATP content suggesting the stimulation of uncoupled respiration. Consistent with these observations, UCP2 expression doubled in PPARalpha-treated cells. Clofibric acid-induced suppression of glucose-simulated insulin secretion was prevented by the CPT-I inhibitor etomoxir. These data suggest that PPARalpha-stimulated fatty acid oxidation can impair beta cell function.
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PMID:PPARalpha suppresses insulin secretion and induces UCP2 in insulinoma cells. 1203 69

Glucagon-like peptide 1 (GLP-1) is an incretin hormone that is secreted from the enteroendocrine L-cells of the gut in response to nutrient ingestion. GLP-1 enhances both insulin secretion and insulin gene expression in a glucose-dependent manner via activation of its putative G-protein-coupled receptor on pancreatic beta-cells. In the presence of DMSO (0.5-2.5%), these functional responses were enhanced significantly (2- to 2.5-fold) in a concentration-dependent manner in the beta-cell line INS-1, although basal levels were not affected. Rat insulin 1 (rINS1) promoter activity appeared to be augmented in a cAMP-response element (CRE)-dependent manner as the effect of DMSO was abolished following a mutation in the CRE of the rINS1 promoter. Also, expression of a generic cAMP-driven reporter gene was enhanced by 1.5% DMSO in response to GLP-1 (3.5-fold), forskolin (2-fold), and 3-isobutyl-1-methylxanthine (2-fold). Analysis of intracellular signaling components revealed that DMSO did not elevate cAMP levels, protein kinase A activity, or phosphorylated levels of CRE-binding protein (CREB), CRE-modulator (CREM), and activating transcription factor-1 (ATF-1). These data suggest that GLP-1 induces insulin gene transcription in a CREB, CREM, and ATF-1-independent manner in beta-cells. The mechanism by which DMSO imparts this amplifying action is unclear but may involve redistribution of intracellular compartments or a direct molecular interaction with a downstream target of the GLP-1 receptor signaling pathway in the beta-cell. These effects of DMSO on incretin action may provide novel applications with respect to further characterizing GLP-1 receptor signaling, identifying incretin-like compounds in screening assays, and as a therapeutic treatment in type 2 diabetes.
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PMID:Synergistic effect of dimethyl sulfoxide on glucagon-like peptide 1 (GLP-1)-stimulated insulin secretion and gene transcription in INS-1 cells: characterization and implications. 1216 88

Recent studies into the physiology of the incretins glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) have added stimulation of beta-cell growth, differentiation, and cell survival to well-documented, potent insulinotropic effects. Unfortunately, the therapeutic potential of these hormones is limited by their rapid enzymatic inactivation in vivo by dipeptidyl peptidase IV (DP IV). Inhibition of DP IV, so as to enhance circulating incretin levels, has proved effective in the treatment of type 2 diabetes both in humans and in animal models, stimulating improvements in glucose tolerance, insulin sensitivity, and beta-cell function. We hypothesized that enhancement of the cytoprotective and beta-cell regenerative effects of GIP and GLP-1 might extend the therapeutic potential of DP IV inhibitors to include type 1 diabetes. For testing this hypothesis, male Wistar rats, exposed to a single dose of streptozotocin (STZ; 50 mg/kg), were treated twice daily with the DP IV inhibitor P32/98 for 7 weeks. Relative to STZ-injected controls, P32/98-treated animals displayed increased weight gain (230%) and nutrient intake, decreased fed blood glucose ( approximately 26 vs. approximately 20 mmol/l, respectively), and a return of plasma insulin values toward normal (0.07 vs. 0.12 nmol/l, respectively). Marked improvements in oral glucose tolerance, suggesting enhanced insulin secretory capacity, were corroborated by pancreas perfusion and insulin content measurements that revealed two- to eightfold increases in both secretory function and insulin content after 7 weeks of treatment. Immunohistochemical analyses of pancreatic sections showed marked increases in the number of small islets (+35%) and total beta-cells (+120%) and in the islet beta-cell fraction (12% control vs. 24% treated) in the treated animals, suggesting that DP IV inhibitor treatment enhanced islet neogenesis, beta-cell survival, and insulin biosynthesis. In vitro studies using a beta-(INS-1) cell line showed a dose-dependent prevention of STZ-induced apoptotic cell-death by both GIP and GLP-1, supporting a role for the incretins in eliciting the in vivo results. These novel findings provide evidence to support the potential utility of DP IV inhibitors in the treatment of type 1 and possibly late-stage type 2 diabetes.
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PMID:Dipeptidyl peptidase IV inhibitor treatment stimulates beta-cell survival and islet neogenesis in streptozotocin-induced diabetic rats. 1260 16

Stevioside, a glycoside present in the leaves of the plant, Stevia rebaudiana Bertoni (SrB), has acute insulinotropic effects in vitro. Its potential antihyperglycemic and blood pressure-lowering effects were examined in a long-term study in the type 2 diabetic Goto-Kakizaki (GK) rat. Rats were fed 0.025 g x kg(-1) x d(-1) of stevioside (purity > 99.6%) for 6 weeks. An intra-arterial catheter was inserted into the rats after 5 weeks, and conscious rats were subjected to arterial glucose tolerance test (2.0 g x kg(-1)) during week 6. Stevioside had an antihyperglycemic effect (incremental area under the glucose response curve [IAUC]): 985 +/- 20 (stevioside) versus 1,575 +/- 21 (control) mmol/L x 180 minutes, (P <.05), it enhanced the first-phase insulin response (IAUC: 343 +/- 33 [stevioside] v 136 +/- 24 [control] microU/mL insulin x 30 minutes, P <.05) and concomitantly suppressed the glucagon levels (total AUC: 2,026 +/- 234 [stevioside] v 3,535 +/- 282 [control] pg/mL x 180 minutes, P <.05). In addition, stevioside caused a pronounced suppression of both the systolic (135 +/- 2 v 153 +/- 5 mm Hg; P <.001) and the diastolic blood pressure (74 +/- 1 v 83 +/- 1 mm Hg; P <.001). Bolus injections of stevioside (0.025 g x kg(-1)) did not induce hypoglycemia. Stevioside augmented the insulin content in the beta-cell line, INS-1. Stevioside may increase the insulin secretion, in part, by induction of genes involved in glycolysis. It may also improve the nutrient-sensing mechanisms, increase cytosolic long-chain fatty acyl-coenzyme A (CoA), and downregulate phosphodiesterase 1 (PDE1) estimated by the microarray gene chip technology. In conclusion, stevioside enjoys a dual positive effect by acting as an antihyperglycemic and a blood pressure-lowering substance; effects that may have therapeutic potential in the treatment of type 2 diabetes and the metabolic syndrome.
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PMID:Antihyperglycemic and blood pressure-reducing effects of stevioside in the diabetic Goto-Kakizaki rat. 1264 78

In type 2 diabetes, beta-cells become glucose unresponsive, contributing to hyperglycemia. To address this problem, we recently created clonal insulin-producing cell lines from the INS-1 insulinoma line, which exhibit glucose responsiveness ranging from poor to robust. Here, mechanisms that determine secretory performance were identified by functionally comparing glucose-responsive 832/13 beta-cells with glucose-unresponsive 832/2 beta-cells. Thus, insulin secretion from 832/13 cells maximally rose 8-fold in response to glucose, whereas 832/2 cells responded only 1.5-fold. Insulin content in both lines was similar, indicating that differences in stimulus-secretion coupling account for the differential secretory performance. Forskolin or isobutylmethylxanthine markedly enhanced insulin secretion from 832/13 but not from 832/2 cells, suggesting that cAMP is essential for the enhanced secretory performance of 832/13 cells. Indeed, 8-bromoadenosine-3',5'-cyclic monophosphorothioate, rp-isomer (Rp-8-Br-cAMPS) an inhibitor of protein kinase A (PKA), inhibited insulin secretion in response to glucose with or without forskolin. Interestingly, whereas forskolin markedly increased cAMP in 832/2 cells, 832/13 cells exhibited only a marginal rise in cAMP. This suggests that 832/13 cells are more sensitive to cAMP. Indeed, the cAMP-induced exocytotic response in patch-clamped 832/13 cells was 2-fold greater than in 832/2 cells. Furthermore, immunoblotting revealed that expression of the catalytic subunit of PKA was 2-fold higher in 832/13 cells. Moreover, when the regulatory subunit of PKA was overexpressed in 832/13 cells, to reduce the level of unbound and catalytically active kinase, insulin secretion and PKA activity were blunted. Our findings show that cAMP-PKA signaling correlates with secretory performance in beta-cells.
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PMID:Enhanced cAMP protein kinase A signaling determines improved insulin secretion in a clonal insulin-producing beta-cell line (INS-1 832/13). 1516 55

The importance of elevated levels of fatty acids in the pathogenesis of the deteriorated beta-cell function present in type 2 diabetes has been established. Long-term exposure of the beta-cell to high levels of fatty acids causes enhanced insulin secretion at low glucose (basal insulin release), while glucose-stimulated insulin secretion (GSIS) is decreased or unchanged. We have previously demonstrated that the spatial configuration of fatty acids (cis and trans isomers) is of importance for the acute impact on the beta-cell function. In this study we aimed to elucidate whether the spatial configuration also influenced beta-cell function after long-term exposure. Thus, we compared the effect of 3 days culture of INS-1 cells with cis (cis C 18:1-11) and trans vaccenic acid (trans C 18:1-11), as well as oleic (cis C 18:1-9) and elaidic acid (trans C 18:1-9), on basal and glucose-stimulated insulin release. All fatty acids tested increased basal insulin release; however, a significantly lower basal insulin release was demonstrated for cells cultured with 0.3 to 0.4 mmol/L trans vaccenic acid compared to equimolar levels of the cis isomer. GSIS was not changed by cis or trans vaccenic acid or by oleic acid, whereas it was stimulated by 0.3 to 0.4 mmol/L elaidic acid. The mechanisms behind the fatty acid-induced changes in the beta cells have been linked to changes in glucose and fatty acid oxidation. We demonstrated an increased fatty acid oxidation in beta cells after long-term exposure to all of the tested fatty acids. Interestingly, both trans isomers (trans vaccenic and elaidic acid) induced higher fatty acid oxidation than the cis isomers (cis vaccenic and oleic acid, respectively). No changes in glucose oxidation were found when INS-1 cells were cultured with either of the fatty acids. The increased fatty acid oxidation was associated with an increased content of carnitine palmitoyltransferase I (CPT-I) mRNA, but no difference in the content of CPT-I mRNA to the different fatty acids was found. Insulin mRNA expression in beta cells was not affected by the fatty acids. In conclusion, we have demonstrated that the pathological changes in insulin secretion from INS-1 cells to long-term culture with elevated levels of fatty acids are more pronounced for the cis (cis vaccenic acid and oleic acid) rather than the trans isomers (trans vaccenic acid and elaidic acid). We suggest that this, at least in part, may be explained by a lower fatty acid oxidation in cells cultured with the cis compared to the trans fatty acid isomers. Apparently, the difference in fatty acid oxidation was not caused by an increased induction of CPT-I mRNA, nor by changes in glucose oxidation or insulin mRNA in beta cells chronically exposed to the fatty acids.
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PMID:Long-Term exposure of INS-1 cells to cis and trans fatty acids influences insulin release and fatty acid oxidation differentially. 1533 78

Glucagon-like peptide-1 (GLP-1) stimulates glucose-dependent insulin secretion and inhibits food intake, gastric emptying, and glucagon secretion, actions that promote reduction of fasting and postprandial glycemia in subjects with type 2 diabetes. The rapid degradation of native GLP-1 has engendered interest in more stable longer-acting GLP-1 receptor agonists such as exendin-4 (Ex-4); however, the potential consequences of sustained GLP-1 receptor activation leading to receptor desensitization has not been extensively studied. We have now examined a range of GLP-1 receptor-dependent responses following treatment with Ex-4 using INS-1 cells in vitro and both wild-type control and MT-Ex-4 transgenic mice in vivo. Although both GLP-1 and Ex-4 acutely desensitized GLP-1 receptor-dependent cAMP accumulation in INS-1 cells, Ex-4 produced more sustained receptor desensitization, relative to GLP-1, in both acute (5-120 min) and chronic (24-72 h) experiments. PMA (4-phorbol 12-myristate 13-acetate) but not glucagon, glucose-dependent insulinotropic polypeptide (GIP), or epinephrine produced heterologous desensitization in vitro. MT-Ex-4 transgenic mice exhibited a reduced glycemic response to oral but not intraperitoneal glucose challenge following acute Ex-4 administration. In contrast, no differences in glycemic excursion or plasma insulin were observed after 1 week of twice-daily Ex-4 administration to wild-type versus MT-Ex-4 mice. Similarly, the levels of insulin, pdx-1, and GLP-1 receptor mRNA transcripts were comparable in wild-type and MT-Ex-4 transgenic mice after 1 week of Ex-4 administration. However, repeated Ex-4 administration significantly reduced food intake in MT-Ex-4 but not in wild-type mice. These findings illustrate that although Ex-4 is more potent than native GLP-1 in producing GLP-1 receptor desensitization in vitro, chronic exposure to Ex-4 in normal or transgenic mice is not associated with significant downregulation of GLP-1 receptor-dependent responses coupled to glucose homeostasis in vivo.
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PMID:Chronic exposure to GLP-1R agonists promotes homologous GLP-1 receptor desensitization in vitro but does not attenuate GLP-1R-dependent glucose homeostasis in vivo. 1556 12

Mutations in the hepatocyte nuclear factor (HNF) 4alpha gene cause a form of maturity-onset diabetes of the young (MODY1), which is a monogenic form of type 2 diabetes characterized by impaired insulin secretion by pancreatic beta-cells. HNF4alpha is a transcription factor expressed in the liver, kidney, intestine, and pancreatic islet. Multiple splice variants of the HNF4alpha gene have been identified and an isoform of HNF4alpha8, an N-terminal splice variant, is expressed in pancreatic beta-cells. However, expression levels of HNF4alpha protein in pancreatic beta-cells and the transcriptional activity of HNF4alpha8 are not yet understood. In the present study, we investigated the expression of HNF4alpha in beta-cells and examined its functional properties. Western blotting and immunohistochemical analysis revealed that the expression of HNF4alpha protein in pancreatic islets and INS-1 cells was much lower than in the liver. A reporter gene assay showed that the transactivation potential of HNF4alpha8 was significantly weaker than that of HNF4alpha2, which is a major isoform in the liver, suggesting that the total level of HNF4alpha activity is very weak in pancreatic beta-cells. We also showed that the N-terminal A/B region of HNF4alpha8 possessed no activation function and C-terminal F region negatively regulated the transcriptional activity of HNF4alpha8. The information presented here would be helpful for the better understanding of MODY1/HNF4alpha diabetes.
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PMID:Functional characterization of the HNF4alpha isoform (HNF4alpha8) expressed in pancreatic beta-cells. 1575 52


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