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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin resistance is a characteristic feature of non-insulin dependent diabetes mellitus (NIDDM) due to target tissue defects in insulin action. Abnormalities of cellular insulin action can be divided into receptor and post-receptor defects. Patients with impaired glucose tolerance are insulin resistant due to decreased insulin receptors resulting in decreased insulin sensitivity and rightward shifted in vivo dose response curves. Patients with NIDDM are insulin resistant due to a combination of receptor and post-receptor defects. The greater the severity of the diabetes (greater fasting hyperglycemia) the greater the post-receptor defect, and in those patients with more significant fasting hyperglycemia the post-receptor defect is the predominant abnormality leading to the insulin resistant state. At least one of the abnormalities underlying this post-receptor defect involves a decrease in glucose transport system activity in freshly isolated adipocytes. This defect in glucose transport, is not expressed in cultured fibro-blasts, indicating that the abnormality in glucose disposal seen in vivo and in glucose transport seen in freshly isolated cells is an acquired phenomenon. Consistent with this, the post-receptor defect is partially reversible by insulin therapy, which leads to a 50-70% reversal of the reduced rates of in vivo glucose disposal and in vitro glucose transport. Insulin resistance also exists in poorly controlled IDDM patients, due to a postreceptor defect in insulin action. This insulin resistance is not present in well controlled IDDM patients, and is completely reversible when poorly controlled patients are treated with intensive insulin therapy. Insulin is produced in the pancreatic beta cell as the primary biosynthetic product preproinsulin. This peptide is rapidly converted to proinsulin (MW approximately 9000). Proinsulin is converted to insulin (MW approximately 6000) plus C-peptide in the secretory granule with a small amount (approximately 5 percent) of the proinsulin remaining unconverted. After a brief time in the peripheral circulation (half-life six to 10 minutes), insulin interacts with target tissues to exert its biologic effects. One of insulin's major biologic effects is the promotion of overall glucose metabolism, and abnormalities of this aspect of insulin action can lead to a number of important clinical and pathophysiologic states including Type II diabetes, also known as non-insulin-dependent diabetes mellitus (NIDDM). Since insulin travels from the beta cell through the circulation to the target tissues, abnormalities at any of these loci can influence the ultimate action of the hormone. These abnormalities, all
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PMID:Insulin resistance in non-insulin dependent (type II) and insulin dependent (type I) diabetes mellitus. 389 63

The biosynthetic process of insulin in pancreatic beta cells consists of many steps including transcription of insulin gene to mRNA, translation of mRNA to preproinsulin, production of proinsulin by cleavage of signal peptide, and conversion of proinsulin to insulin and C-peptide. This process also includes intra-cellular trafficking (nucleus, cytoplasm, endoplasmic reticulum, Golgi apparatus, secretary granule, and extra-cellular secretion). The factors concerning and regulating these steps are discussed, although some of these have not been fully understood. The possible influences of insulin gene mutations (mutant insulin gene syndrome) to these steps are also discussed. Understanding of the molecular mechanism of insulin biosynthesis might be usefull to explain the defective insulin production of NIDDM.
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PMID:[The molecular mechanism of insulin biosynthesis and mutant insulin gene syndrome]. 798 72

The pancreatic beta cell normally maintains a stable balance among insulin secretion, insulin production, and insulin degradation to keep optimal intracellular stores of the hormone. Elevated levels of FFA markedly enhance insulin secretion; however, the effects of FFA on insulin production and intracellular stores remain unclear. In this study, twofold elevation in total circulating FFA effected by infusion of lard oil and heparin into rats for 6 h under normoglycemic conditions resulted in a marked elevation of circulating insulin levels evident after 4 h, and a 30% decrease in pancreatic insulin content after a 6-h infusion in vivo. Adding 125 muM oleate to isolated rat pancreatic islets cultured with 5.6 mM glucose caused a 50% fall in their insulin content over 24 h, coupled with a marked enhancement of basal insulin secretion. Both effects of fatty acid were blocked by somatostatin. In contrast to the stimulatory effects of oleate on insulin secretion, glucose-induced proinsulin biosynthesis was inhibited by oleate up to 24 h, but was unaffected thereafter. This result was in spite of a two- to threefold oleate-induced increase in preproinsulin mRNA levels, underscoring the importance of translational regulation of proinsulin biosynthesis in maintaining beta cell insulin stores. Collectively, these results suggest that chronically elevated FFA contribute to beta cell dysfunction in the pathogenesis of NIDDM by significantly increasing the basal rate of insulin secretion. This increase in turn results in a decrease in the beta cell's intracellular stores that cannot be offset by commensurate FFA induction of proinsulin biosynthesis.
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PMID:Chronic exposure to free fatty acid reduces pancreatic beta cell insulin content by increasing basal insulin secretion that is not compensated for by a corresponding increase in proinsulin biosynthesis translation. 948 80

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.
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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

We investigated whether adenovirus-mediated preproinsulin gene transfer into insulin target tissues (adipocytes) ameliorates hyperglycemia in diabetic mice. KKA(y) mice, a genetically obese type 2 diabetic animal model, were treated with a single subcutaneous injection of recombinant adenovirus, Adex1CA-human preproinsulin (Adex1CA-pchi), into the epididymal fat pads. pchi mRNA was expressed only in adipose tissue in which mature insulin was produced. Three days after virus injection these mice showed a marked decrease of blood glucose levels (from about 400 to 200 mg/dl), and an intraperitoneal glucose tolerance test revealed the markedly improved glucose tolerance. There was no significant difference in serum insulin levels between control and recombinant adenovirus-treated KKA(y) mice. The normalized glucose levels in diabetic mice were maintained for at least 2 weeks after the virus injection. This strategy could provide a novel and, most importantly, a simple and convenient gene therapy for obese type 2 diabetes patients.
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PMID:Adenovirus-mediated preproinsulin gene transfer into adipose tissues ameliorates hyperglycemia in obese diabetic KKA(y) mice. 1173 15

Obese individuals are more likely to suffer from diseases termed the "metabolic syndrome," which includes type 2 diabetes. It is now recognized that early life dietary experiences play an important role in the etiology of such diseases. In this context, the consequences of a high carbohydrate (HC) dietary intervention in neonatal rats is being studied in our laboratory. Artificial rearing of 4-day-old rat pups on a HC milk formula up to Day 24 results in the immediate onset of hyperinsulinemia, which persists throughout the period of dietary intervention. Several adaptations at the biochemical, cellular, and molecular levels in the islets of these HC rats support the onset and persistence of the hyperinsulinemic condition during this period. Some of these adaptations include a distinct leftward shift in the insulin secretory capacity, increased hexokinase activity, increased gene expression of preproinsulin and related transcription factors and specific kinases in 12-day-old HC islets, and alterations in the number and size of islets. These adaptations are programmed and expressed in adulthood thereby sustain the hyperinsulinemic condition in the postweaning period and form the basis for adult-onset obesity. HC females spontaneously transmit the HC phenotype (chronic hyperinsulinemia and adult-onset obesity) to their progeny. Collectively, our results indicate that even a mere switch in the nature of the source of calories (from fat rich in rat milk to carbohydrate rich in the HC milk formula) during critical phases of early development in the rat results in metabolic programming of islet functions leading to chronic hyperinsulinemia (throughout life) and adult-onset obesity. This metabolic programming, once established, forms a vicious cycle because HC female rats spontaneously transmit the HC phenotype to their progeny. The results from our laboratory in the context of metabolic programming due to neonatal nutritional experiences are discussed in this review.
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PMID:Neonatal nutrition: metabolic programming of pancreatic islets and obesity. 1252 68

AMP-activated protein kinase (AMPK) has recently been implicated in the control of preproinsulin gene expression in pancreatic islet beta-cells [da Silva Xavier, Leclerc, Salt, Doiron, Hardie, Kahn and Rutter (2000) Proc. Natl. Acad. Sci. U.S.A. 97, 4023-4028]. Using pharmacological and molecular strategies to regulate AMPK activity in rat islets and clonal MIN6 beta-cells, we show here that the effects of AMPK are exerted largely upstream of insulin release. Thus forced increases in AMPK activity achieved pharmacologically with 5-amino-4-imidazolecarboxamide riboside (AICAR), or by adenoviral overexpression of a truncated, constitutively active form of the enzyme (AMPK alpha 1.T(172)D), blocked glucose-stimulated insulin secretion. In MIN6 cells, activation of AMPK suppressed glucose metabolism, as assessed by changes in total, cytosolic or mitochondrial [ATP] and NAD(P)H, and reduced increases in intracellular [Ca(2+)] caused by either glucose or tolbutamide. By contrast, inactivation of AMPK by expression of a dominant-negative form of the enzyme mutated in the catalytic site (AMPK alpha 1.D(157)A) did not affect glucose-stimulated increases in [ATP], NAD(P)H or intracellular [Ca(2+)], but led to the unregulated release of insulin. These results indicate that inhibition of AMPK by glucose is essential for the activation of insulin secretion by the sugar, and may contribute to the transcriptional stimulation of the preproinsulin gene. Modulation of AMPK activity in the beta-cell may thus represent a novel therapeutic strategy for the treatment of type 2 diabetes mellitus.
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PMID:Role for AMP-activated protein kinase in glucose-stimulated insulin secretion and preproinsulin gene expression. 1258 7

Chronic exposure to elevated levels of fatty acids impairs pancreatic beta cell function, a phenomenon thought to contribute to the progressive deterioration of insulin secretion in type 2 diabetes. We have previously demonstrated that prolonged exposure of isolated islets to elevated levels of palmitate inhibits preproinsulin mRNA levels in the presence of high glucose concentrations. However, whether this occurs via transcriptional or post-transcriptional mechanisms has not been determined. In addition, the nature of the lipid metabolites involved in palmitate inhibition of insulin gene expression is unknown. In this study, we show that palmitate decreases glucose-stimulated preproinsulin mRNA levels in isolated rat islets, an effect that is not mediated by changes in preproinsulin mRNA stability, but is associated with inhibition of glucose-stimulated insulin promoter activity. Prolonged culture of isolated islets with palmitate is associated with increased levels of intracellular ceramide. Palmitate-induced ceramide generation is prevented by inhibitors of de novo ceramide synthesis. Further, exogenous ceramide inhibits insulin mRNA levels, whereas blockade of de novo ceramide synthesis prevents palmitate inhibition of insulin gene expression. We conclude that prolonged exposure to elevated levels of palmitate affects glucose-stimulated insulin gene expression via transcriptional mechanisms and ceramide synthesis.
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PMID:Palmitate inhibition of insulin gene expression is mediated at the transcriptional level via ceramide synthesis. 1277 Nov 45

Thiazolidinediones (TZDs) have been suggested to act beneficially on pancreatic islet function and on beta-cell viability but data concerning direct effects on isolated islets are controversial. Therefore, we have examined parameters of pancreatic insulin and glucagon secretion and biosynthesis in TZD-exposed rat pancreatic islets under physiological glucose level conditions and under conditions of glucolipotoxicity. Primary rat islets were incubated for 2.5 h with or without troglitazone (10 microM) in 5.6 mM glucose (standard glucose levels) and 16.7 mM glucose (high glucose levels); a subgroup was additionally treated with oleate (200 microM) to simulate acute glucolipotoxicity. Insulin and glucagon secretion, intracellular content and their respective mRNAs were quantified. Newly synthesized insulin was determined by pulse-labeling experiments. Troglitazone reduced insulin secretion at standard and high glucose levels by about one-third (P<or=0.05). Insulin content was decreased at 5.6 mM glucose but increased at 16.7 mM glucose by the presence of troglitazone (P<or=0.05). Newly synthesized insulin mRNA and preproinsulin mRNA decreased by about 20% at standard glucose levels (P<or=0.05). Glucagon secretion was augmented by troglitazone in islets under high glucose conditions by an additional 50% (P<or=0.05). No clear beneficial troglitazone effects were observed under glucolipotoxic conditions. The reduced insulin secretion and biosynthesis at standard glucose levels can be interpreted as an insulin-sparing effect. Troglitazone effects were less pronounced at high glucose alone or in combination with oleate. From a clinical point of view, these results indicate a greater benefit of troglitazone for beta-cell function in hyperinsulinemic, but normoglycemic patients with insulin resistance or early type 2 diabetes without major insulin secretion deficits and/or pronounced hyperglycemia.
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PMID:Insulin-sparing effects of troglitazone in rat pancreatic islets. 1291 25

Obesity is highly associated with type 2 diabetes where free fatty acids (FFAs) may be a trigger factor. To examine this hypothesis, in this study, we investigated the role of FFAs in the pathogenic development of type 2 diabetes. The release of insulin, the expression of preproinsulin (PPI), glucose transporter2 (GLUT2) and pancreatic duodenal homeobox-1 (PDX-1), and levels of intracellular free Ca++([Ca++]i) were measured in rat pancreatic islets treated with or without high concentrations of FFA (0.1 and 1.0 mM oleic acid) for 24 h. In comparison with untreated control, islets exposed to oleic acid showed an increase in basal insulin release and a decrease in glucose induced insulin secretion (GSIS). Elevated expression of PPI, PDX-1 and GLUT2 was also observed after treatment of the islets with oleic acid, which may partially contribute to the increased basal insulin secretion. Moreover, [Ca++]i levels increased after oleic acid exposure, which most likely accounts for the decrease of GSIS. Our findings, thus strongly suggest, that the increased levels of basal insulin secretion involved in glucose sensing, insulin producing and insulin secreting induced by high levels of FFAs may cause hyperinsulinemia in patients with type 2 diabetes, and thus long-term hyperinsulinemia could desensitize insulin receptors. We hypothesize that hyperinsulinemia may be a primary and independent event in the pathogenesis of diabetes. If proven, it may be possible to create novel and effective approaches for the prevention and treatment of type 2 diabetes.
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PMID:Mechanisms of oleic acid deterioration in insulin secretion: role in the pathogenesis of type 2 diabetes. 1593 94


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