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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin stimulates glucose transport in skeletal muscle, heart, and adipose tissue by promoting the appearance of GLUT4, the major glucose transporter isoform present in these tissues, on the cell surface. This is achieved by differentially modulating GLUT4 exocytosis and endocytosis, between a specialized intracellular compartment and the plasma membrane. Ligands which activate the heterotrimeric GTP-binding proteins Gs and Gi appear to modulate insulin-stimulated glucose transport through effects on the fusion of docked GLUT4-containing vesicles with the plasma membrane. In insulin resistance states, reduced cellular GLUT4 levels in adipose cells fully account for the decreased glucose transport response to insulin in these cells. In contrast, although insulin-stimulated GLUT4 translocation is also impaired in muscle, total cellular levels of GLUT4 are not altered. The defect in muscle has been attributed to a GLUT4 trafficking problem and thus studies of this mechanism could provide clues as to the nature of the impairment. The movement of GLUT4-containing vesicles from an intracellular storage site to the plasma membrane and the fusion of docked GLUT4-containing vesicles with the plasma membrane are conceptually similar to some secretory processes. A general hypothesis called the SNARE hypothesis (soluble NSF attachment protein receptors where NSF stands for N-ethylmaleimide-sensitive fusion protein) postulates that the specificity of secretory vesicle targeting is generated by complexes that form between membrane proteins on the transport vesicle (v-SNARE's) and membrane proteins located on the target membrane (t-SNARE's). Several v- and t-SNARE's have been identified in adipose cells and muscle. VAMP2 and VAMP3/cellubrevin (v-SNARE's) have been shown to interact with the t-SNARE's syntaxin 4 and SNAP-23. The cytosolic protein NSF has the characteristic of binding to the v-/t-SNARE complex through its interaction with alpha-SNAP, another soluble factor. Furthermore, recent studies have demonstrated that VAMP2/3, syntaxin 4, SNAP-23, and NSF are functionally involved in insulin-stimulated GLUT4 translocation in adipose cells and thus are likely to be involved in the Gs- and Gi-mediated modulation of the glucose transport response to insulin as well. This review summarizes recent advances on the normal mechanism of GLUT4 translocation and discusses how this process could be affected in insulin resistant states such as type II diabetes.
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PMID:Role of SNARE's in the GLUT4 translocation response to insulin in adipose cells and muscle. 1021 32

In normal isolated beta-cells, the response to glucose is heterogeneous and characterized by an increasing number of secretory cells as glucose concentration rises (Pipeleers DG, Kiekens R, Ling Z, Wilikens A, Schuit F: Physiologic relevance of heterogeneity in the pancreatic beta-cell population. Diabetologia 37 (Suppl. 2):S57-S64, 1994). We hypothesized that fasting hyperinsulinemia in obesity might be explained by altered beta-cell heterogeneity of signal transduction mechanisms, possibly involving exocytotic proteins. Insulin secretion from individual beta-cells sorted according to the size of the islet donor (<125 microm, >250 microm, and intermediate diameter) was measured by reverse hemolytic plaque assay. Beta-cells from fa/fa rats were hypertrophied 25-40%, independent of donor islet size. This was accompanied by an increased proportion of secretory cells (recruitment) at 5.5-11.0 mmol/l glucose, increased secretion per cell at 2.8 mmol/l glucose, and decreased insulin content after acute glucose exposure without an increase in secretion per cell. Decreased expression of exocytotic (soluble N-ethylmaleimide-sensitive fusion protein receptor [SNARE]) proteins, vesicle-associated membrane protein isoform 2 (VAMP-2), synaptosomal protein of 25 kDa (SNAP-25), and syntaxin-1 and -2 in fa/fa beta-cells may contribute to the failure to sustain excessive plaque size at higher glucose concentrations. Fasting hyperinsulinemia may be maintained by increased recruitment and an exaggerated secretory response in all fa-derived islet populations. Glucose regulates beta-cell responsiveness in the short term, and these effects may involve altered expression of SNARE proteins.
Diabetes 1999 May
PMID:Beta-cell hypertrophy in fa/fa rats is associated with basal glucose hypersensitivity and reduced SNARE protein expression. 1033 3

Defective exocytosis could underlie clinical and metabolic abnormalities in Type 2 diabetes. Because many SNARE proteins appear to be common mediators of exocytosis, we examined phorbol myristate acetate-stimulated expression of CD11b and CD69 on polymorphonuclear leukocytes (PMN) from Type 2 diabetic subjects with hypertension and microalbuminuria (D-htma), hypertension only (D-ht) or uncomplicated (D-uc), and normal controls (NC) by flow cytometry. CD11b expression was rapid (half maximal by 7 min), initially on all PMN. CD69 expression took place subsequently but on PMN that did not express CD11b. The proportion of CD11b-positive PMN at 30 min was higher in all diabetic groups than in NC. Expression of CD11b was higher and CD69 lower in D-uc and D-htma but were similar in NC and D-ht. In Type 2 diabetes the transition from the CD11b-positive to CD69-positive state is impaired. The defect in the process of CD69 expression appeared most marked in diabetic subjects with hypertension and microalbuminuria.
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PMID:Dysregulation of PMN antigen expression in Type 2 diabetes may reflect a generalized defect of exocytosis: influence of hypertension and microalbuminuria. 1038 Sep 2

The mechanisms underlying the first phase of glucose-stimulated insulin release, the deterioration of which marks the early stages of both type 1 and type 2 diabetes, are essentially unknown. Among many hypotheses, one holds that the first phase is due to a readily releasable pool of insulin-containing granules. We used current knowledge of the mechanisms of exocytosis and the proteins involved in docking granules at the plasma membrane to test this hypothesis. A docked pool of readily releasable granules was identified by immunoprecipitation of the plasma membrane protein syntaxin with a specific antibody and by co-immunoprecipitation of soluble N-ethylmaleimide-sensitive factor attachment protein-25 (SNAP-25) and the granule proteins synaptobrevin and synaptotagmin. The four SNARE proteins co-immunoprecipitated each other, thus identifying the core complex associated with docked granules. Using co-immunoprecipitation as a marker for docked granules, we found that the docked pool was rapidly discharged during the first phase of glucose-stimulated insulin release and refilled during the second phase. Other secretagogues also released the pool, whereas the physiological inhibitor norepinephrine blocked its release. Further studies on the nature of this pool of granules should shed light on the causes of its deterioration in the early stages of diabetes and the reasons for deficient insulin release.
Diabetes 1999 Sep
PMID:Identification of the docked granule pool responsible for the first phase of glucose-stimulated insulin secretion. 1048 May 95

The physiological role of soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) receptor (SNARE) proteins in insulin exocytosis has been reported in pancreatic beta-cells. To determine whether the beta-cells of GK rats, a nonobese rodent model of type 2 diabetes, exhibit abnormalities in their SNARE proteins, we studied the expression and function of target (t)-SNAREs, syntaxin 1A, and synaptosomal-associated protein of 25 kDa (SNAP-25) in GK rat islets. Although insulin release and insulin content of islets isolated from 12-week-old GK rats were reduced, the proinsulin biosynthetic rate was about twofold higher than that in control rat islets, and no change in the preproinsulin mRNA level was observed. Pulse-chase experiments suggested the increased degradation of insulin in GK rat islets. Immunoblot analysis revealed that protein levels of syntaxin 1A and SNAP-25 in GK rat islets decreased to approximately 60% of the levels in control rat islets. We then examined whether the restoration of the decreased expression of t-SNAREs to the normal level in GK rat islets affected insulin secretion. Restoration was achieved by the overexpression of syntaxin 1A and SNAP-25 via the recombinant adenovirus-mediated gene transduction system, which recovered levels of these proteins to almost control levels. Glucose-stimulated insulin release from AdexlCA syntaxin 1A and Adex1CA SNAP-25-infected GK rat islets increased up to approximately 135 and 200%, respectively, of those from uninfected GK rat islets, although no difference in basal (2.2 mmol/l glucose) insulin release was evident between them. We conclude that decreased expression of t-SNAREs in GK rat islets is in part the defect responsible for impaired insulin secretion.
Diabetes 1999 Dec
PMID:Decreased expression of t-SNARE, syntaxin 1, and SNAP-25 in pancreatic beta-cells is involved in impaired insulin secretion from diabetic GK rat islets: restoration of decreased t-SNARE proteins improves impaired insulin secretion. 1058 Apr 25

Adipocytes and muscle cells play a major role in blood glucose homeostasis. This is dependent upon the expression of Glut4, an insulin-responsive facilitative glucose transporter. Glut4 is localised to specialised intracellular vesicles that fuse with the plasma membrane in response to insulin stimulation. The insulin-induced translocation of Glut4 to the cell surface is essential for the maintenance of optimal blood glucose levels, and defects in this system are associated with insulin resistance and type II diabetes. Therefore, a major focus of recent research has been to identify and characterise proteins that regulate Glut4 translocation. Cysteine-string protein (Csp) is a secretory vesicle protein that functions in presynaptic neurotransmission and also in regulated exocytosis from non-neuronal cells. We show that Csp1 is expressed in 3T3-L1 adipocytes and that cellular levels of this protein are increased following cell differentiation. Combined fractionation and immunofluorescence analyses reveal that Csp1 is not a component of intracellular Glut4-storage vesicles (GSVs), but is associated with the adipocyte plasma membrane. This association is stable, and not affected by either insulin stimulation or chemical depalmitoylation of Csp1. We also demonstrate that Csp1 interacts with the t-SNARE syntaxin 4. As syntaxin 4 is an important mediator of insulin-stimulated GSV fusion with the plasma membrane, this suggests that Csp1 may play a regulatory role in this process. Syntaxin 4 interacts specifically with Csp1, but not with Csp2. In contrast, syntaxin 1A binds to both Csp isoforms, and actually exhibits a higher affinity for the Csp2 protein. The results described raise a number of interesting questions concerning the intracellular targeting of Csp in different cell types, and suggest that the composition and synthesis of GSVs may be different from synaptic and other secretory vesicles. In addition, the interaction of Csp1 with syntaxin 4 suggests that this Csp isoform may play a role in insulin-stimulated fusion of GSVs with the plasma membrane.
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PMID:The synaptic vesicle protein, cysteine-string protein, is associated with the plasma membrane in 3T3-L1 adipocytes and interacts with syntaxin 4. 1114 45

Regulated exocytosis forms the basis for many intercellular signaling processes, for example, in hormone secretion or neurotransmitter release. During regulated exocytosis, the membrane of a secretory vesicle fuses with the plasma membrane in a tightly controlled reaction that is most often triggered by calcium. Recent advances have allowed major insights into the molecular mechanisms that mediate regulated exocytosis. In the present review, we will briefly discuss two key features of regulated exocytosis that have been particularly well studied recently. First, we will examine the current understanding of the membrane fusion reaction that underlies regulated exocytosis and that is effected by SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) and munc18-like proteins similar to other membrane fusion reactions. Second, we will describe the role of the major candidates for the calcium sensors that trigger exocytosis, a protein family called synaptotagmins. Although our understanding of regulated exocytosis is as yet incomplete, the results from the studies of SNAREs, munc18s, and synaptotagmins have provided a molecular anchor for a more complete future description.
Diabetes 2002 Feb
PMID:Molecular determinants of regulated exocytosis. 1181 50

The slower kinetics of insulin release from pancreatic islet beta cells, as compared with other regulated secretory processes such as chromaffin granule secretion, can in part be explained by the small number of the insulin granules that are docked to the plasma membrane and readily releasable. In type-2 diabetes, the kinetics of insulin secretion become grossly distorted, and, to therapeutically correct this, it is imperative to elucidate the mechanisms that regulate priming and secretion of insulin secretory granules. Munc13-1, a synaptic protein that regulates SNARE complex assembly, is the major protein determining the priming of synaptic vesicles. Here, we demonstrate the presence of Munc13-1 in human, rat, and mouse pancreatic islet beta cells. Expression of Munc13-1, along with its cognate partners, syntaxin 1a and Munc18a, is reduced in the pancreatic islets of type-2 diabetes non-obese Goto-Kakizaki and obese Zucker fa/fa rats. In insulinoma cells, overexpressed Munc13-1-enhanced green fluorescent protein is translocated to the plasma membrane in a temperature-dependent manner. This, in turn, greatly amplifies insulin exocytosis as determined by patch clamp capacitance measurements and radioimmunoassay of the insulin released. The potentiation of exocytosis by Munc13-1 is dependent on endogenously produced diacylglycerol acting on the overexpressed Munc13-1 because it is blocked by a phospholipase C inhibitor (U73122) and abrogated when the diacylglycerol binding-deficient Munc13-1H567K mutant is expressed instead of the wild type protein. Our data demonstrate that Munc13-mediated vesicle priming is not restricted to neurotransmitter release but is also functional in insulin secretion, where it is subject to regulation by the diacylglycerol second messenger pathway. In view of our findings, Munc13-1 is a potential drug target for therapeutic optimization of insulin secretion in diabetes.
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PMID:Regulation of insulin exocytosis by Munc13-1. 1287 71

Soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein receptor (SNARE) protein syntaxin-1A (STX-1A) plays a role not only in exocytosis, but also binds and regulates Ca(2+) and K(+) (voltage-gated K(+) and ATP-sensitive K(+) channels) to influence the sequence of events leading to secretion. Islet levels of STX-1A and cognate SNARE proteins are reduced in type 2 diabetic rodents, suggesting their role in dysregulated insulin secretion contributing to the abnormal glucose homeostasis. We investigated the specific role of STX-1A in pancreatic beta-cells by generating transgenic mice, which express a moderately increased level ( approximately 30% higher) of STX-1A in pancreatic islets (hereafter called STX-1A mice). The STX-1A mice displayed fasting hyperglycemia and a more sustained elevation of plasma glucose levels after an intraperitoneal glucose tolerance test, with correspondingly reduced plasma insulin levels. Surprisingly, beta-cells from the STX-1A male mice also exhibited abnormal insulin tolerance. To unequivocally determine the beta-cell secretory defects, we used single-cell analyses of exocytosis by patch clamp membrane capacitance measurements and ion channel recordings. Depolarization-evoked membrane capacitance increases were reduced in the STX-1A mouse islet beta-cells. The STX-1A mouse also exhibited reduced currents through the Ca(2+) channels but little change in the voltage-gated K(+) channel or ATP-sensitive K(+) channel. These results suggest that fluctuation of islet STX-1A levels in diabetes could influence the pathological and differential regulation of beta-cell ion channels and the exocytotic machinery, collectively contributing to the impaired insulin secretion.
Diabetes 2005 Sep
PMID:Transgenic mouse overexpressing syntaxin-1A as a diabetes model. 1612 65

Tight glycemic control in individuals with diabetes mellitus is essential to prevent or delay its complications. Present treatments to reduce hyperglycemia mainly target the ATP-sensitive K(+) (K(ATP)) channel of pancreatic beta cells to increase insulin secretion. These current approaches are often associated with the side effect of hypoglycemia. Here we show that inhibition of the activity of cyclin-dependent kinase 5 (Cdk5) enhanced insulin secretion under conditions of stimulation by high glucose but not low glucose in MIN6 cells and pancreatic islets. The role of Cdk5 in regulation of insulin secretion was confirmed in pancreatic beta cells deficient in p35, an activator of Cdk5. p35-knockout mice also showed enhanced insulin secretion in response to a glucose challenge. Cdk5 kinase inhibition enhanced the inward whole-cell Ca(2+) channel current and increased Ca(2+) influx across the L-type voltage-dependent Ca(2+) channel (L-VDCC) upon stimulation with high glucose in beta cells, but had no effect on Ca(2+) influx without glucose stimulation. The inhibitory regulation by Cdk5 on the L-VDCC was attributed to the phosphorylation of loop II-III of the alpha(1C) subunit of L-VDCC at Ser783, which prevented the binding to SNARE proteins and subsequently resulted in a decrease of the activity of L-VDCC. These results suggest that Cdk5/p35 may be a drug target for the regulation of glucose-stimulated insulin secretion.
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PMID:Cdk5-dependent regulation of glucose-stimulated insulin secretion. 1615 76


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