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

In type 2 diabetes, chronic hyperglycemia has been suggested to be detrimental to beta-cell function, causing reduced glucose-stimulated insulin secretion and disproportionately elevated proinsulin. In the present study, we investigated the effect on several beta-cell functions of prolonged in vitro exposure of human pancreatic islet cultures to high glucose concentrations. Islets exposed to high glucose levels (33 mmol/l) for 4 and 9 days showed dramatic decreases in glucose-induced insulin release and in islet insulin content, with increased proportion of proinsulin-like peptides relative to insulin. The depletion in insulin stores correlated with the reduction in insulin mRNA levels and human insulin promoter transcriptional activity. We also demonstrated that high glucose dramatically lowered the binding activity of pancreatic duodenal homeobox 1 (the glucose-sensitive transcription factor), whereas the transcription factor rat insulin promoter element 3b1 activator was less influenced and insulin enhancer factor 1 remained unaffected. Most of these beta-cell impairments were partially reversible when islets first incubated for 6 days in high glucose were transferred to normal glucose (5.5 mmol/l) concentrations for 3 days. We conclude that cultured human islets are sensitive to the deleterious effect of high glucose concentrations at multiple functional levels, and that such mechanisms may play an important role in the decreased insulin production and secretion of type 2 diabetic patients.
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PMID:Impaired beta-cell functions induced by chronic exposure of cultured human pancreatic islets to high glucose. 1034 9

Glucokinase (GCK) is an enzyme that regulates insulin secretion, keeping glucose levels within a narrow range. Mutations in the glucokinase gene cause a rare form of diabetes called maturity-onset diabetes of the young (MODY). An early onset (less than 25 years), autosomal dominant inheritance and low insulin secretion stimulated by glucose characterize MODY patients. Specific insulin and proinsulin were measured in serum by immunofluorimetric assays (IFMA) during a 75-g oral glucose tolerance test (OGTT). Two kindreds (SA and LZ) were studied and compared to non-diabetic unrelated individuals (control group 1) matched for age and body mass index (BMI). In one kindred, some of these subjects were also obese (BMI > 26 kg/m2), and other family members also presented with obesity and/or late-onset NIDDM. The MODY patients were also compared to a group of five of their first-degree relatives with obesity and/or late-onset NIDDM. The proinsulin profile was different in members of the two MODY kindreds. Fasting proinsulin and the proinsulin/insulin ratio were similar in MODY members of kindred LZ and subjects from control group 1, but were significantly lower than in MODY members of kindred SA (P < 0.02 and P < 0.01, for proinsulin and proinsulin/insulin ratio, respectively). Moreover, MODY members of family SA had higher levels of proinsulin and proinsulin/insulin ratio, although not significantly different, when compared to their first-degree relatives and to subjects from control group 2. In conclusion, we observed variable degrees of proinsulin levels and proinsulin/insulin ratio in MODY members of two different kindreds. The higher values of these parameters found in MODY and non-MODY members of kindered SA is probably related to the obesity and late-onset NIDDM background present in this family.
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PMID:Specific insulin and proinsulin secretion in glucokinase-deficient individuals. 1034 5

Individuals with type 2 diabetes mellitus (n = 105; age 36-71 years) on diet therapy alone, and with quite good glycaemic control (mean HbA1c approximately 7.0%) were randomized to receive acarbose (100 mg three times daily) or placebo for 16 weeks, and changes in clinical and metabolic parameters indicative of Syndrome X were monitored. Fasting levels of glucose, glycosylated haemoglobin (HbA1c), true insulin, proinsulin, fibrinogen and lipids were measured four times weekly, and glucose, insulin, proinsulin and triglyceride responses to a standardized 1.6 MJ breakfast were determined at 0, 1 and 2 h post meal. Analysis was on an intention-to-treat basis. Fasting levels of glucose (P < 0.0001), triglycerides (P = 0.03) and HbA1c (P = 0.003) were reduced by acarbose over the 16 weeks of treatment. The mean change in HbA1c from week 0 to 16 differed by 0.4% (P = 0.003) between the two groups. Insulin (P = 0.06), proinsulin (P = 0.07) and glucose (P < 0.0001) responses to the standard meal were reduced. These data show that acarbose reduces fasting glucose and triglyceride levels, lowers HbA1c and limits the glycaemic and insulin response to food in individuals with type 2 diabetes mellitus with Syndrome X. Pharmacological agents that improve the metabolic environment and reduce insulin resistance have the potential to limit the progression of atherogenesis associated with type 2 diabetes mellitus.
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PMID:Will acarbose improve the metabolic abnormalities of insulin-resistant type 2 diabetes mellitus? 1036 27

Proinsulin release is increased relative to insulin secretion in subjects with type 2 diabetes, indicative of islet dysfunction. However, it has not been conclusively shown whether there is an increased relative proinsulin release in subjects with impaired glucose tolerance (IGT), i.e. whether it precedes the development of diabetes. We therefore determined the proinsulin to insulin ratios in the fasting state and after acute stimulation of insulin secretion in 23 postmenopausal women, aged 61-62 yr (mean +/- SD, 61.7 +/- 0.5 yr). Ten women had normal glucose tolerance (NGT), and 13 had IGT. The groups were matched for insulin sensitivity and did not differ in body mass index. Proinsulin and insulin secretion were measured after arginine stimulation (5 g, i.v.) at three glucose levels (fasting, 14 mmol/L, and >25 mmol/L), and the acute insulin (AIR(arg)) and proinsulin responses (APIR(arg)) were calculated as the mean 2-5 min postload increase. At fasting glucose, levels of insulin, proinsulin, or the proinsulin/insulin ratio (13.6 +/- 5.0% vs. 11.1 +/- 2.7%; P = NS) did not differ between NGT and IGT. Although the AIR(arg) values were decreased in the IGT group at all glucose levels (P < 0.05), the absolute proinsulin levels and the APIRs(arg) were similar between IGT and NGT women. Therefore, the IGT women had higher proinsulin/insulin ratios at 14 mmol/L (10.7 +/- 4.4% vs. 6.4 +/- 1.8%; P = 0.006) and more than 25 mmol/L glucose (11.4 +/- 5.2% vs. 6.7 +/- 2.1%; P = 0.007). The IGT group had increased APIR(arg)/AIR(arg) at fasting (2.2 +/- 1.4% vs. 1.3 +/- 0.6%; P = 0.047) and more than 25 mmol/L glucose (3.5 +/- 1.6% vs. 2.3 +/- 0.7%; P = 0.037). We conclude that women with IGT exhibit increased relative proinsulin secretion, suggesting a defect in the intracellular proinsulin processing before diabetes develops.
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PMID:Relative hyperproinsulinemia as a sign of islet dysfunction in women with impaired glucose tolerance. 1037 12

The author presents a review on candidate genes of proteins involved in the metabolism of glucose, lipids and other metabolites (glucose carriers, insulin receptors, proinsulin, glucokinase, amyline, glycogen synthase). One of the main causes of enhanced atherogenesis in patients with type II diabetes (NIDDM) are marked genetically conditioned deviations of the lipid, lipoprotein and apolipoprotein metabolism. In the metabolic dyshomeostasis of multiple metabolic syndrome participate in the process of atherogenesis also: isoforms of apolipoprotein E4, isoforms of apolipoprotein A-IV-1/1, hyperuricaemia, raised levels of the plasminogen activator inhibitor 1 (PAI-1), hyperfibrinogenaemia, hyperhomocysteinaemia and other metabolites (cytokines, endothelin etc.). Patients with a greated genetic sensitivity manifest diabetes sooner and more intensely and die at a younger age in particular from cardiovascular disease, but also on account of a higher incidence of tumours diseases.
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PMID:[Genetic predisposition in multiple metabolic syndrome. Part 2. Candidate genes in type II diabetes mellitus]. 1037 88

To explore the role of chronically elevated free fatty acids (FFAs) in the pathogenesis of the hyperproinsulinemia of type 2 diabetes, we have investigated the effect of FFAs on proinsulin processing and prohormone convertases PC2 and PC1/PC3 in MIN6 cells cultured in Dulbecco's modified Eagle's medium with or without 0.5 mmol/l FFA mixture (palmitic acid:oleic acid = 1:2). After 7 days of culture, the percent of proinsulin in FFA-exposed cells was increased (25.9 +/-0.3% intracellular and 75.4 +/- 1.2% in medium vs. 13.5 +/-0.2 and 56.2 +/- 4.1%, respectively, in control cells). The biosynthesis and secretion of proinsulin and insulin were analyzed by comparing the incorporation of [3H]Leu and [35S]Met. In pulse-chase studies, proinsulin-to-insulin conversion was inhibited, and proinsulin in the medium was increased by 50% after 3 h of chase, while insulin secretion was decreased by 50% after FFA exposure. Levels of cellular PC2 and PC3 analyzed by Western blotting were decreased by 23 and 15%, respectively. However, PC2, PC3, proinsulin, and 7B2 mRNA levels were not altered by FFA exposure. To test for an effect on the biosynthesis of PC2, PC3, proinsulin, and 7B2, a protein required for PC2 activation, MIN6 cells were labeled with [35S]Met for 10-15 min, followed by a prolonged chase. Most proPC2 was converted after 6 h of chase in control cells, but conversion was incomplete even after 6 h of chase in FFA-exposed MIN6 cells. Media from chase incubations showed that FFA-exposed cells secreted more proPC2 than controls. Similar inhibitory effects were noted on the processing of proPC3, proinsulin, and 7B2. In conclusion, prolonged exposure of beta-cells to FFAs may affect the biosynthesis and posttranslational processing of proinsulin, PC2, PC3, and 7B2, and thereby contribute to the hyperproinsulinemia of type 2 diabetes. The mechanism of inhibition of secretory granule processing by FFAs may be through changes in Ca2+ concentration, the pH in the secretory granules, and/or other factors that may influence the activation and function of the convertases.
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PMID:Long-term elevation of free fatty acids leads to delayed processing of proinsulin and prohormone convertases 2 and 3 in the pancreatic beta-cell line MIN6. 1038 44

Relative hypersecretion of proinsulin is a feature of type 2 diabetes. We investigated to what extent this feature can be induced in human pancreatic islets by elevated glucose or fatty acids, two major abnormalities of the diabetic state. A 48-h culture period with 27 mmol/l glucose increased the intraislet proinsulin-to-insulin (PI/I) ratio 5.0-fold, owing to preferential decrease of insulin. The PI/I ratio in culture medium was enhanced 1.9-fold versus islets cultured with 5.5 mmol/l glucose. This effect of elevated glucose persisted after normalization of glucose levels: during 60-min postculture incubations at a basal glucose concentration (3.3 mmol/l), the PI/I ratio of secretion increased 4.9-fold. The ratio was also increased (14-fold) after renewed postculture stimulation with 16.7 mmol/l glucose. Diazoxide was added to culture medium to block glucose-induced insulin secretion and thus investigate the importance of overstimulation. In cultures at 27 mmol/l glucose, the presence of diazoxide decreased the PI/I ratio of islet contents by 76%, the accumulated secretion to culture medium by 70%, and the release at 3.3 or 16.7 mmol/l glucose during postculture incubations by 85 and 86%, respectively. None of these PI/I-decreasing effects of diazoxide were reproduced during or after coculture with 5.5 mmol/l glucose. Culture with 0.2 mmol/l palmitate and 5.5 mmol/l glucose decreased islet contents of proinsulin and insulin and increased the secreted products in culture media without affecting PI/I ratios. During postculture conditions, however, prior palmitate culture enhanced the PI/I ratio of release at 3.3 mmol/l glucose (from 2.2 +/- 0.4 to 5.4 +/- 0.9%, P < 0.05). Culture with palmitate together with 27 mmol/l glucose decreased islet contents of proinsulin and insulin and further enhanced intraislet PI/I ratios (from 9.3 +/- 1.1 to 13.4 +/- 2.5%, P < 0.05). However, palmitate failed to affect PI/I ratios in culture medium. In contrast, in postculture incubations at 3.3 mmol/l glucose, prior palmitate culture further elevated the PI/I ratio of secretion (from 10.8 +/- 1.2 after previous 27 mmol/l glucose alone to 13.9 +/- 2.8% after palmitate and glucose, P < 0.05). We conclude that 1) long-term exposure of human islets to elevated glucose leads to preferential secretion of proinsulin, and this effect persists also after glucose normalization; 2) the glucose effect appears secondary to depletion of mature insulin granules; and 3) elevated fatty acids influence PI/I ratios of secretion by mechanisms that are, in part, incongruous with an over-stimulation effect.
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PMID:Enhancing effects of long-term elevated glucose and palmitate on stored and secreted proinsulin-to-insulin ratios in human pancreatic islets. 1038 46

Atherogenesis in the vasculature is accelerated by changes in the dynamic equilibrium between endogenous tissue plasminogen activator and plasminogen activator inhibitor-1 (PAI-1). Increased expression of PAI-1, decreased expression of tissue plasminogen activator, or both can lead to decreased fibrinolytic activity and predispose to thrombosis. Increased concentrations of insulin (and proinsulin) in the plasma increase plasma PAI-1, although the mechanisms of this effect are not known. In addition, it has been observed that basal fibrinolytic activity is decreased in patients with type 2 diabetes; this may accelerate atherosclerosis by exposing vascular luminal wall surfaces to persistent and recurrent thrombi. Abnormalities in the vessel wall appear to contribute to the increased risk. There is also evidence that PAI-1 content is increased in atherosclerotic lesions of patients with type 2 diabetes, suggesting that interventions to reduce insulin resistance and improve glycemic control may improve the fibrinolytic response. Clinical studies in patients with polycystic ovary syndrome (characterized by insulin resistance, hyperinsulinemia, ovarian androgen overproduction, and impaired fibrinolytic capacity) demonstrated that treatment with troglitazone, an insulin-sensitizing agent, can markedly reduce blood levels of PAI-1. There is also clinical evidence that these agents may contribute to regression of intimal medial thickness in patients with type 2 diabetes, providing further indication that antidiabetic interventions may help inhibit the progression of early atherosclerotic lesions.
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PMID:Insulin resistance and thrombosis: a cardiologist's view. 1041 58

Hypofibrinolysis caused by increased PAI-1 levels in patients with insulin resistance (IR) is one of the most common acquired prothrombotic states with higher risk of arterial thrombosis associated with atherosclerosis. Increased PAI-1 levels are caused by PAI-1 hyperproduction in various compartments owing to various factors (multicompartmental and multifactorial model). Metabolic compartment, including visceral adipocytes and hepatocytes, is sensitive on stimulative action of insulin, proinsulin and some cytokines. This pool is responsible for elevated PAI-1 levels in obesity. Vascular compartment, including mainly endothelium, is sensitive on thrombin, angiotensin IV, cytokines, biological active lipids and oxidative stress effect, while insulin inhibits cytokine induced PAI-1 production on contrary. This compartment is responsible for elevated PAI-1 levels in patients with type 2 diabetes mellitus and hypertension with endothelial dysfunction. PAI-1 levels in patients with IR represent cumulative production in described compartments.
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PMID:[A multicomparmental and multifactorial model of production of plasminogen activator inhibitor (PAI-1). I. Experimental studies]. 1042 16

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


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