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)

(+/-)-5-([4-[2-Methyl-2(pyridylamino)ethoxy]phenyl]methyl) 2,4-thiazolidinedione (BRL 49653) is a new potent antidiabetic agent that improves insulin sensitivity in animal models of NIDDM. In C57BL/6 obese (ob/ob) mice, BRL 49653, included in the diet for 8 days, improved glucose tolerance. The half-maximal effective dose was 3 mumol/kg diet, which is equivalent to approximately 0.1 mg/kg body wt. Improvements in glucose tolerance were accompanied by significant reductions in circulating triacylglycerol, nonesterified fatty acids, and insulin. The insulin receptor number of epididymal white adipocytes prepared from obese mice treated with BRL 49653 (30 mumol/kg diet) for 14 days was increased twofold. The affinity of the receptor for insulin was unchanged. In the absence of added insulin, the rates of glucose transport in adipocytes from untreated and BRL 49653-treated obese mice were similar. Insulin (73 nmol/l) produced only a 1.5-fold increase in glucose transport in adipocytes from control obese mice, whereas after BRL 49653 treatment, insulin stimulated glucose transport 2.8-fold. BRL 49653 did not alter the sensitivity of glucose transport to insulin. The increase in insulin responsiveness was accompanied by a 2.5-fold increase in the total tissue content of the glucose transporter GLUT4. Glucose transport in adipocytes from lean littermates was not altered by BRL 49653. To establish the contribution of changes in glucose transporter trafficking to the BRL 49653-mediated increase in insulin action, the cell-impermeant bis-mannose photolabel 2-N-[4-(1-azi-2,2,2-trifluoroethyl)benzoyl]-1,3-bis-(D-mannos++ +-4-yloxy) -2-[2-3H]-propylamine was used to measure adipocyte cell-surface-associated glucose transporters.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Repeat treatment of obese mice with BRL 49653, a new potent insulin sensitizer, enhances insulin action in white adipocytes. Association with increased insulin binding and cell-surface GLUT4 as measured by photoaffinity labeling. 765 33

Non-insulin-dependent diabetes mellitus is characterized by concurrent loss of beta-cells and deposition of islet amyloid derived from islet amyloid polypeptide (IAPP). We have previously demonstrated that IAPP-derived amyloid forms intracellularly in humans with chronic excess insulin expression (eg, insulinoma and insulin receptor antibody-induced insulin resistance). To determine whether overexpression of IAPP results in intracellular amyloid in mammalian cells, we transfected COS cells with vectors expressing amyloidogenic human IAPP or non-amyloidogenic rat IAPP. Transfected COS-1 cells secreted comparable amounts of human IAPP and rat IAPP (2.1 to 2.8 nmol/L/48 hours). After 96 hours, 90% of cells expressing human IAPP contained amyloid fibrils and were degenerating or dead, whereas cells transfected with rat IAPP lacked amyloid and were viable. Thus, overexpression of human IAPP can result in intracellular amyloid formation that is associated with cell death, suggesting that intracellular amyloid may play a role in beta-cell loss in non-insulin-dependent diabetes mellitus.
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PMID:Human islet amyloid polypeptide expression in COS-1 cells. A model of intracellular amyloidogenesis. 767 75

Two alternative forms of the insulin receptor with different affinities for insulin are expressed as a result of alternative splicing of RNA corresponding to exon 11 of the IR gene. The percentage of IR-RNA molecules without exon 11, encoding the high-affinity isoform, was determined by cDNA-mediated PCR amplification of RNA extracts from the quadriceps femoris muscle of healthy control subjects (n = 9) and NIDDM patients (n = 7). In both patients and control individuals, a majority of the IR-RNA molecules contained exon 11. In addition, the proportion of IR-RNA molecules without exon 11 was decreased in patients (21 +/- 1%) compared with control subjects (31 +/- 3%) (P = 0.018). Careful investigation of the kinetics of the PCR-based assay system, as well as the conditions for separation of the PCR products, allowed us to suggest a possible explanation of the discrepant results concerning the alternative splicing presented in previous reports. The diabetic subjects as a group had higher fasting insulin levels and lower insulin-mediated glucose uptake during a euglycemic-hyperinsulinemic clamp (P = 0.042). However, identification of the regulatory pathways leading to the splicing alteration in NIDDM patients requires further investigation.
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PMID:Differences in the ratio of RNA encoding two isoforms of the insulin receptor between control and NIDDM patients. The RNA variant without Exon 11 predominates in both groups. 768 88

The insulin receptor is expressed as two isoforms that differ by a 12-amino acid region at the carboxy-terminus of the alpha-subunit encoded by exon 11. These isoforms are produced by tissue-specific alternate splicing of the insulin receptor mRNA. To determine whether the relative expression of the isoforms is altered in skeletal muscle in two insulin-resistant states, NIDDM and obesity, relative mRNA levels were measured using a polymerase chain reaction technique. There were no differences in the relative amounts of skeletal muscle mRNA encoding the exon 11-containing form compared to the exon 11-lacking form of the insulin receptor among lean normal (30 +/- 2% Ex11-), obese nondiabetic (32 +/- 2%), and NIDDM (31 +/- 1%) subjects. We conclude that altered expression of insulin receptor isoform mRNAs does not account for skeletal muscle insulin resistance in NIDDM and obesity.
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PMID:Relative expression of insulin receptor isoforms does not differ in lean, obese, and noninsulin-dependent diabetes mellitus subjects. 768 96

The results of many cross-sectional studies have indicated that insulin resistance is a consistent, abnormal metabolic characteristic of people with NIDDM. Recently many investigators studying different populations have reported that insulin resistance is a prediabetic abnormality and is a major risk factor for the disease. Although deficient insulin secretion is also characteristic of people with NIDDM, there are no data to indicate that it precedes the onset of the disease, except in rare instances of families with glucokinase mutations. Therefore, in most cases, it appears that deficient insulin secretion occurs secondarily to insulin resistance, and there is experimental evidence indicating the mechanism of this effect. The clearest examples of this pathophysiologic mechanism are persons with insulin receptor mutations and severe insulin resistance in whom NIDDM develops despite normal insulin secretion. In addition, prospective studies have indicated that NIDDM rarely develops in the most insulin-sensitive subjects, and the relatively lower insulin concentrations in patients with a known beta-cell defect--that is a glucokinase mutation--are compatible with normal glucose tolerance if ideal whole body insulin sensitivity is maintained. These data indicate beyond a reasonable doubt that insulin resistance is a sufficient cause of NIDDM and in most instances is necessary for its development.
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PMID:Agonist: the case for insulin resistance as a necessary and sufficient cause of type II diabetes mellitus. 773 20

Obesity is considered to be one of the major risk factors for developing non-insulin dependent diabetes mellitus (NIDDM). Our cohort study for NIDDM in Aito, Shiga 1980-1990 confirmed that aging, higher body mass index (obesity) and high blood pressure were independent risk factors for developing NIDDM in Japan. In Pima Indians, decreased glucose disposal rate (GDR) is significantly related to percentage of body fat (%fat). Insulin signaling for glycogen synthesis in the skeletal muscles is impaired in the early stages of obesity. Although the molecular mechanism for insulin resistance in obesity is still unknown, hyperinsulinemia induces insulin receptor loss by means of the down regulation mechanism, and prolonged hyperglycemia may induce the impairment of insulin receptor kinase in the skeletal muscles in obese subjects. These dysfunctions in insulin signaling may cause the deterioration of insulin sensitivity, resulting in worsening glycemic control. Thus dysfunction of insulin receptor signaling in skeletal muscles may be a target for preventing diabetes in obese subjects.
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PMID:[Obesity as a risk factor for developing non-insulin dependent diabetes mellitus--obesity and insulin resistance]. 775 Jun 30

NIDDM is likely to have a major genetic component in view of the different prevalence between ethnic groups, the familial clustering, and the high concordance in monozygotic twins. Linkage analysis of extended pedigrees of patients with maturity-onset diabetes of the young (MODY) identified the glucokinase gene mutations. Specific phenotypes have also led to the discovery of the insulin gene mutations in patients with high insulin or proinsulin levels, to the insulin receptor mutations in patients with marked insulin resistance, and to the mutations in mitochondrial DNA associated with deafness and maternal inheritance. These four types of diabetogenic gene mutations account for only a minor proportion of NIDDM. Direct screening for mutations in candidate genes with single-strand conformation polymorphism or heteroduplex screening or with direct sequencing in the diabetic patients with the appropriate pathophysiological abnormality can be a successful strategy. Genetic diagnosis provides clear definite diagnosis and specific therapies, such as IGF-1 for the insulin receptor mutations and coenzyme Q10 for the mitochondrial gene mutations.
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PMID:[Genetic diagnosis of diabetes mellitus]. 778 64

The insulin receptor exists in two isoforms differing by the absence (HIR-A) or presence (HIR-B) of 12 amino acids in the COOH-terminus of the alpha-subunit as a consequence of alternative splicing of exon 11. In this study, we developed a radioimmunoassay for the two isoforms employing antibodies raised against two peptides, one (Pep-12) corresponding to residues encoded by exon 11, and the other (Pep-13) corresponding to a COOH-terminal domain of the alpha-subunit which is common to both HIR-A and HIR-B isoforms. These peptides were iodinated and used as both ligands and standards. The assay is specific, highly reproducible, and sensitive with a detection limit of 10 fmol of receptor. One mole of purified insulin receptor, measured by Scatchard analysis, is read as one mole of receptor in the radioimmunoassay with either Pep-12 or Pep-13 as standards. The radioimmunoassay is applicable to the measurement of total content and relative abundance of the two isoforms in extracts from various tissues. We applied the radioimmunoassay to measure the relative abundance of the two isoforms in fat and muscle from normal, obese non-diabetic and non-insulin-dependent diabetic (NIDDM) subjects. Results demonstrate that expression of the low-affinity HIR-B form is significantly increased in obese and NIDDM subjects compared with control subjects. In addition, the increased expression of the HIR-B isoform was significantly correlated with both body mass index (r = 0.52; p = 0.006) and fasting glucose levels (r = 0.59; p = 0.001).
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PMID:Peptide-based radioimmunoassay for the two isoforms of the human insulin receptor. 779 85

Insulin resistance of the skeletal muscle plays a key role in the development of the metabolic endocrine syndrome and its further progression to non-insulin dependent diabetes (NIDDM). Available data suggest that insulin resistance is caused by an impaired signal from the insulin receptor to the glucose transport system and to glycogen synthase. The impaired response of the insulin receptor tyrosine kinase which is found in NIDDM appears to contribute to the pathogenesis of the signalling defect. The reduced kinase activation is not caused by mutations within the insulin receptor gene. We investigated two potential mechanisms that might be relevant for the abnormal function of the insulin receptor in NIDDM, i.e. changes in the expression of the receptor isoforms and the effect of hyperglycaemia on insulin receptor tyrosine kinase activity. The insulin receptor is expressed in two different isoforms (HIR-A and HIR-B). We found that HIR-B expression in the skeletal muscle is increased in NIDDM. However, the characterisation of the functional properties of HIR-A and HIR-B revealed no difference in their tyrosine kinase activity in vivo. The increased expression of HIR-B might represent a compensatory event. In contrast, hyperglycaemia might directly inhibit insulin-receptor function. We have found that in rat-1 fibroblasts which overexpressing human insulin receptor an inhibition of the tyrosine kinase activity of the receptor may be induced by high glucose levels. This appears to be mediated through activation of certain protein kinase C isoforms which form stable complexes with the insulin receptor and modulate the tyrosine kinase activity of the insulin receptor through serine phosphorylation of the receptor beta subunit.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulation of insulin receptor signalling: significance of altered receptor isoform patterns and mechanism of hyperglycaemia-induced receptor modulation. 782 30

Non-insulin-dependent diabetes mellitus is a complex metabolic disorder that involves numerous biochemical abnormalities, a heterogenous clinical picture, and a polygenic hereditary component. The pathophysiologic state involves increased basal hepatic glucose production, decreased insulin-mediated glucose utilization in target tissues, and altered pancreatic function with decreased beta cell function and enhanced glucagon secretion. Prospective studies indicate that insulin resistance and hyperinsulinemia exist in the prediabetic state at a time when glucose tolerance is normal. When hyperglycemia supervenes, both insulin secretion and insulin-mediated glucose utilization are further compromised, mediated in part by sustained hyperglycemia itself. Insulin resistance may occur at any level in the biologic action of insulin, from initial binding to cell surface receptors to the phosphorylation cascade that is initiated by autophosphorylation of the insulin receptor. Receptors isolated from patients with non-insulin-dependent diabetes mellitus have compromised autophosphorylation-kinase activity when isolated from adipocytes, liver, erythrocytes, and skeletal muscle. The magnitude of the decrease in insulin receptor kinase activity is correlated with the degree of fasting hyperglycemia. However, the defect in insulin receptor kinase activity is normalized after weight reduction or other measures that reduce hyperglycemia, indicating the secondary nature of the defect. Clarification of the mechanisms underlying insulin resistance in non-insulin-dependent diabetes mellitus will lead to new treatment modalities for this disease.
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PMID:Insulin resistance and non-insulin-dependent diabetes mellitus: cellular and molecular mechanisms. 790 Jun 97


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