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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 contributes to the pathogenesis of NIDDM. We have investigated the molecular mechanisms of insulin resistance in patients with genetic syndromes caused by mutations in the insulin-receptor gene. In general, patients with two mutant alleles of the insulin-receptor gene are more severely insulin-resistant than are patients who are heterozygous for a single mutant allele. These mutations can be put into five classes, depending upon the mechanisms by which they impair receptor function. Some mutations lead to a decrease in the number of insulin receptors on the cell surface. For example, some mutations decrease the level of insulin receptor mRNA or impair receptor biosynthesis by introducing a premature chain termination codon (class 1). Class 2 mutations impair the transport of receptors through the endoplasmic reticulum and Golgi apparatus to the plasma membrane. Mutations that accelerate the rate of receptor degradation (class 5) also decrease the number of receptors on the cell surface. Other mutations cause insulin resistance by impairing receptor function--either by decreasing the affinity to bind insulin (class 3) or by impairing receptor tyrosine kinase activity (class 4). The prevalence of mutations in the insulin receptor gene is not known. However, theoretical calculations suggest that approximately 0.1-1% of the general population are heterozygous for a mutation in the insulin-receptor gene; the prevalence is likely to be higher among people with NIDDM. Accordingly, it is likely that mutations in the insulin-receptor gene may be a contributory cause of insulin resistance in a subpopulation with NIDDM.
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PMID:Lilly Lecture: molecular mechanisms of insulin resistance. Lessons from patients with mutations in the insulin-receptor gene. 132 27

Addition of phenobarbital, an inducer of the liver mixed function oxidase system, to sulphonylurea regimen improves insulin sensitivity and intracellular glucose handling in patients with non-insulin dependent diabetes mellitus. The inducer also activates liver NADPH synthesis and its availability for mono-oxygenase reactions. In this study we further evaluated the mutual relationship between glucose and drug metabolism and the effect of sulphonylurea therapy by using genetically obese female mice. The mice were treated with glibenclamide, phenobarbital or both. Glibenclamide reduced blood glucose and plasma insulin levels indicating improved insulin sensitivity in the mice. Total glucose phosphorylating, delivering and NADPH generating enzyme activities were reduced together with decreased microsomal protein content and the amount of smooth endoplasmic reticulum in the liver. Phenobarbital had an opposite effect: the drug induced liver drug metabolism and increased hepatic glucose phosphorylating and NADPH generating enzyme activities. Treatment with glibenclamide seems to reduce serum immunoreactive insulin levels, microsomal enzyme function and NADPH generating enzyme activities in genetically obese mice.
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PMID:Reduced glucose-6-phosphorylase and NADPH generating enzyme activities associated with glibenclamide induced hypoglycemia and hypoinsulinemia in genetically obese mice. 217 90

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

Non-insulin-dependent diabetes mellitus (NIDDM) is a metabolic disease associated with abnormal insulin secretion, the underlying mechanisms of which are unknown. Glucose-dependent signal transduction pathways were investigated in pancreatic islets derived from the db/db mouse, an animal model of NIDDM. After stimulation with glucose (4-12 mM), the changes in intracellular Ca2+ concentration ([Ca2+]i) were different; unlike control islets, db/db islets lacked an initial reduction of [Ca2+]i and the subsequent [Ca2+]i oscillations following stimulation with 12 mM glucose. The severity of these defects in Ca2+ signaling correlated with the age-dependent development of hyperglycemia. Similarly defective glucose-induced Ca2+ signaling were reproduced in control islets by pre-exposure to thapsigargin, a selective inhibitor of endoplasmic reticulum (ER) Ca(2+)-ATPase. Estimation of ATPase activities from rates of ATP hydrolysis and by immunoblot hybridization with an antiserum directed against the sarco/endoplasmic reticulum Ca(2+)-ATPase both demonstrated that the ER Ca(2+)-ATPase was almost entirely absent from db/db islets. The effects of inhibition of ER Ca(2+)-ATPase on insulin secretion were also examined; a 4-day exposure of control islets to 1 microM thapsigargin resulted in basal and glucose-stimulated insulin secretion levels similar to those found in db/db islets. These results suggest that aberrant ER Ca2+ sequestration underlies the impaired glucose responses in the db/db mouse and may play a role in defective insulin secretion associated with NIDDM.
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PMID:Defective glucose-dependent endoplasmic reticulum Ca2+ sequestration in diabetic mouse islets of Langerhans. 803 70

In NIDDM, first-phase insulin release to glucose is (almost) absent. However, in contrast to older studies which suggested that in NIDDM the B-cell is "blind" for glucose, recent evidence indicates that the B-cell is not insensitive for glucose as far as second phase release is concerned. This suggests that the metabolism of glucose is probably not deranged in NIDDM, since glucose leads to insulin release after it has been metabolized. Hyperglycaemia itself has a deleterious effect on insulin release, so-called glucose toxicity. Various mechanisms have been proposed, whereby hyperglycaemia may diminish insulin release: inhibition of Ca2+ mobilization from the endoplasmic reticulum by glucose-6-phosphate, Ca2+ uptake in the ER by glucose and inhibitory effects of protein kinase C. Whatever may prove to be the underlying mechanism(s), glucose toxicity is unlikely to be the only cause of insulin secretory disturbances in NIDDM, since the glucose level would have to be elevated before it could be toxic. Non-insulin-dependent diabetes mellitus (NIDDM) is characterized by both defects in insulin action and insulin secretion. With regard to the defects in insulin release, much research has originated from two (partly) opposing hypotheses, namely the presence of pancreatic B-cell glucose blindness and the hypothesis of pancreatic B-cell glucose toxicity in NIDDM.
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PMID:Defects in insulin secretion in NIDDM: B-cell glucose insensitivity or glucose toxicity? 844 21

Glucose-dependent sequestration of Ca2+ into endoplasmic reticulum and its subsequent release play an important role in the control of intracellular Ca2+ concentration, which regulates insulin secretion in pancreatic beta-cells. The active uptake of cytosolic Ca2+ into endoplasmic reticulum is mediated by sarco-(endo)plasmic reticulum Ca(2+)-ATPases (SERCAs). We found, using RT-PCR with isoform-specific primers, that SERCA 2 and SERCA 3 mRNAs are co-expressed in human and rat islets of Langerhans and in the RINm5F beta-cell line. Immunochemical analysis also revealed the existence of two SERCA proteins with molecular masses of 110 and 115 kDa in beta-cell membranes. The 115 kDa protein was identified as SERCA 2b by its reaction with an isoform-specific antibody and the 110 kDa protein most probably corresponds to SERCA 3. The presence of two functionally different SERCA isoforms raises the possibility that they are located in distinct Ca2+ stores. There is evidence that altered Ca2+ handling in the beta-cell may contribute to the decreased insulin secretion seen in non-insulin dependent diabetes mellitus (NIDDM). We therefore investigated SERCA 2 and SERCA 3 mRNA expression by quantitative RT-PCR in islets prepared from Goto-Kakizaki (GK) rats, a non-obese spontaneous model of NIDDM. We found a significant reduction (about 68%) in SERCA 3 isoform expression. Since SERCA 2 expression was not significantly reduced, these genes are independently regulated and probably play distinct roles in islets of Langerhans. The marked decrease of SERCA 3 expression may constitute a defect in Ca2+ signalling in GK rat islets which could be a component of NIDDM.
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PMID:Isoforms of endoplasmic reticulum Ca(2+)-ATPase are differentially expressed in normal and diabetic islets of Langerhans. 891 90

Patients with diabetes mellitus experience impaired wound healing often resulting in chronic foot ulcers. Hospital discharge data indicate that 6-20% of all diabetic individuals hospitalized (mostly with type 2 diabetes) have a lower extremity ulcer. Maintaining glucose levels at acceptable levels (below 10 mmol/l) is considered to be an important part of the clinical treatment, but the exact mechanism by which diabetes delays wound repair is not yet known. We studied this phenomenon by determining the potential of fibroblasts isolated from the ulcer sites of four patients with non-insulin-dependent diabetes mellitus to proliferate in vitro. Controls were fibroblasts isolated from normal skin of the upper leg of five healthy age-matched volunteers and of six non-insulin-dependent diabetes patients. Proliferative capacity was analysed by evaluation of plates after trypsinization and [3H]thymidine incorporation. Fibroblast morphology was studied by light and transmission electron microscopy. Diabetic ulcer fibroblasts, measured by [3H]thymidine incorporation, proliferated significantly more slowly than the nonlesional control fibroblasts (P < 0.00047) and age-matched control fibroblasts (P < 0.00003). After culturing the fibroblasts for a prolonged period in high-glucose (27.5 mM) and low-glucose (5.5 mM, i.e. physiological) medium, this difference in proliferation rate between diabetic ulcer fibroblasts and nonlesional diabetic fibroblasts remained (P < 0.0001 for high-glucose and P < 0.0009 for low-glucose on day 7). Fibroblast proliferation in all three groups was slightly lower in high-glucose than in low-glucose medium, although not significantly at any time-point. Light microscopy showed diabetic ulcer fibroblasts to be large and widely spread. Transmission electron microscopy of cultured diabetic ulcer fibroblasts and nonlesional diabetic skin fibroblasts revealed a large dilated endoplasmic reticulum, a lack of microtubular structures and multiple lamellar and vesicular bodies. These results show a diminished proliferative capacity and abnormal morphology of fibroblasts derived from diabetic ulcers of non-insulin-dependent diabetes patients.
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PMID:Cultured fibroblasts from chronic diabetic wounds on the lower extremity (non-insulin-dependent diabetes mellitus) show disturbed proliferation. 1019 96

This study was performed to observe the changes of glucose-related hormones and the morphological change including ultrastructure of the pancreatic islets in the male Otsuka Long-Evans Tokushima Fatty rat. Area under the curve (AUC) of glucose at the 30th (709 plus minus 73 mg.h/dL) and at the 40th week (746 plus minus 87 mg.h/ dL) of age were significantly higher than that at the 10th week (360 plus minus 25 mg.h/ dL). AUC of insulin of the 10th week was 2.4 plus minus 0.9 ng.h/mL, increased gradually to 10.8 plus minus 8.3 ng.h/mL at the 30th week, and decreased to 1.8 plus minus 1.2 ng.h/mL at the 40th week. The size of islet was increased at 20th week of age and the distribution of peripheral alpha cells and central beta cells at the 10th and 20th weeks was changed to a mixed pattern at the 40th week. On electron microscopic examination, beta cells at the 20th week showed many immature secretory granules, increased mitochondria, and hypertrophied Golgi complex and endoplasmic reticulum. At the 40th week, beta cell contained scanty intracellular organelles and secretory granules and apoptosis of acinar cell was observed. In conclusion, as diabetes progressed, increased secretion of insulin was accompanied by increases in size of islets and number of beta-cells in male OLETF rats showing obese type 2 diabetes. However, these compensatory changes could not overcome the requirement of insulin according to the continuous hyperglycemia after development of diabetes.
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PMID:Insulin and glucagon secretions, and morphological change of pancreatic islets in OLETF rats, a model of type 2 diabetes mellitus. 1185 May 86

Overload of pancreatic beta cells in conditions such as hyperglycemia, obesity, and long-term treatment with sulfonylureas leads to beta cell exhaustion and type 2 diabetes. Because beta cell mass declines under these conditions, apparently as a result of apoptosis, we speculated that overload kills beta cells as a result of endoplasmic reticulum (ER) stress. The Akita mouse, which carries a conformation-altering missense mutation (Cys96Tyr) in Insulin 2, likewise exhibits hyperglycemia and a reduced beta cell mass. In the development of diabetes in Akita mice, mRNAs for the ER chaperone Bip and the ER stress-associated apoptosis factor Chop were induced in the pancreas. Overexpression of the mutant insulin in mouse MIN6 beta cells induced Chop expression and led to apoptosis. Targeted disruption of the Chop gene delayed the onset of diabetes in heterozygous Akita mice by 8-10 weeks. We conclude that ER overload in beta cells causes ER stress and leads to apoptosis via Chop induction. Our findings suggest a new therapeutic approach for preventing the onset of diabetes by inhibiting Chop induction or by increasing chaperone capacity in the ER.
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PMID:Targeted disruption of the Chop gene delays endoplasmic reticulum stress-mediated diabetes. 1185 14

We report the first combined light and electron microscopic analysis of the pancreas during the development of type 2 diabetes in the New Zealand Obese (NZO) mouse. As in most other polygenic rodent models of type 2 diabetes, hyperglycemia associated with beta cell destruction is male sex-limited. Increasing degrees of hyperinsulinemia and transition to diabetes were clearly reflected by the islet volume fraction, by the beta cell granulation state, and by ultrastructural changes, primarily of the endoplasmic reticulum. One of the unusual histopathologic features of NZO mice of both sexes was the presence of B-lymphocyte enriched leukocytic aggregates in the pancreas. Immunocytochemical analysis of the pancreas of 52-week-old diabetic males indicated enrichment for CD19(+) B lymphocytes. Staining of adjacent sections for CD3 and CD5 indicated CD5 coexpression on some of the CD19(+) cells, suggesting the presence of the B1-B subset associated with generation of natural autoantibodies in other autoimmune-prone New Zealand mouse strains. In addition, plasma cells in peri-insular leukocytic infiltrates were identified by electron microscopy. Hence, although autoimmunity has previously proven to be a secondary manifestation of beta cell destruction in most rodent models of type 2 diabetes, the present observations suggest that B lymphocyte function, in association with male gender, may contribute to the development of insulin resistance and chronic hyperglycemia in the NZO model.
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PMID:The diabetes-prone NZO/Hl strain. II. Pancreatic immunopathology. 1211 86


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