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)

The effects of tumor necrosis factor-alpha (TNF alpha) on glucose uptake and glycogen synthase (GS) activity were studied in human skeletal muscle cell cultures from nondiabetic and type 2 diabetic subjects. In nondiabetic muscle cells, acute (90-min) exposure to TNF alpha (5 ng/ml) stimulated glucose uptake (73 +/- 14% increase) to a greater extent than insulin (37 +/- 4%; P < 0.02). The acute uptake response to TNF alpha in diabetic cells (51 +/- 6% increase) was also greater than that to insulin (31 +/- 3%; P < 0.05). Prolonged (24-h) exposure of nondiabetic muscle cells to TNF alpha resulted in a further stimulation of uptake (152 +/- 31%; P < 0.05), whereas the increase in cells from type 2 diabetics was not significant compared with that in cells receiving acute treatment. After TNF alpha treatment, the level of glucose transporter-1 protein was elevated in nondiabetic (4.6-fold increase) and type 2 (1.7-fold) cells. Acute TNF alpha treatment had no effect on the fractional velocity of GS in either nondiabetic or type 2 cells. Prolonged exposure reduced the GS fractional velocity in both nondiabetic and diabetic cells. In summary, both acute and prolonged treatment with TNF alpha up-regulate glucose uptake activity in cultured human muscle cells, but reduce GS activity. Increased skeletal muscle glucose uptake in conditions of TNF alpha excess may serve as a compensatory mechanism in the insulin resistance of type 2 diabetes.
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PMID:Effects of tumor necrosis factor-alpha on glucose metabolism in cultured human muscle cells from nondiabetic and type 2 diabetic subjects. 983 15

Familial risk, pathogenesis, clinical onset, and treatment of diabetes mellitus vary according to etiology. Although Type 2 diabetes has a higher familial risk, more is known about the genetics of Type 1 diabetes. Genes contributing 60% to 65% of susceptibility to Type 1 diabetes mellitus are known. Type 1 diabetes is associated with susceptibility genes in the HLA region on chromosome 6p21 and the insulin gene on chromosome 11p15, and at least eight additional susceptibility genes are under investigation. Islet cytoplasmic antibodies provide humoral evidence of Type 1 diabetes risk. Only 10% of the genes contributing susceptibility to Type 2 diabetes mellitus are known, and they are primarily associated with uncommon subtypes of the disorder. The insulin receptor gene on chromosome 19p13 and at least five glucose transporter genes contribute to Type 2 diabetes susceptibility, and further associations may emerge from study of the glycogen synthase gene, the glucokinase gene, the MODY genes, and the leptin gene. Diabetes comorbidities may result from genetic and environmental susceptibilities independently or in combination.
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PMID:The genetic basis of diabetes mellitus. 985 64

Insulin-stimulated glucose uptake is defective in patients with type 2 diabetes. To determine whether transgenic glucose transporter overexpression in muscle can prevent diabetes induced by a high-fat, high-sugar diet, singly (GLUT-1, GLUT-4) and doubly (GLUT-1 and -4) transgenic mice were placed on a high-fat, high-sugar diet or a standard chow diet. On the high-fat, high-sugar diet, wild-type but not transgenic mice developed fasting hyperglycemia and glucose intolerance (peak glucose of 337 +/- 19 vs. 185-209 mg/dl in the same groups on the high-fat, high-sugar diet and 293 +/- 13 vs. 166-194 mg/dl on standard chow). Hyperinsulinemic clamps showed that transporter overexpression elevated insulin-stimulated glucose utilization on standard chow (49 +/- 4 mg. kg-1. min-1 in wild-type vs. 61 +/- 4, 67 +/- 5, and 63 +/- 6 mg. kg-1. min-1 in GLUT-1, GLUT-4, and GLUT-1 and -4 transgenic mice given 20 mU. kg-1. min-1 insulin, and 54 +/- 7, 85 +/- 4, and 98 +/- 11 in wild-type, GLUT-1, and GLUT-4 mice given 60-80 mU. kg-1. min-1 insulin). On the high-fat, high-sugar diet, wild-type and GLUT-1 mice developed marked insulin resistance, but GLUT-4 and GLUT-1 and -4 mice were somewhat protected (glucose utilization during hyperinsulinemic clamp of 28.5 +/- 3.4 vs. 42.4 +/- 5.9, 51.2 +/- 8.1, and 55.9 +/- 4. 9 mg. kg-1. min-1 in wild type, GLUT-1, GLUT-4, GLUT-1 and -4 mice). These data demonstrate that overexpression of GLUT-1 and/or GLUT-4 enhances whole body glucose utilization and prevents the development of fasting hyperglycemia and glucose intolerance induced by a high-fat, high-sugar diet. GLUT-4 overexpression improves the insulin resistance induced by the diet. We conclude that upregulation of glucose transporters in skeletal muscle may be an effective therapeutic approach to the treatment of human type 2 diabetes.
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PMID:GLUT-1 or GLUT-4 transgenes in obese mice improve glucose tolerance but do not prevent insulin resistance. 995 Aug 1

The hallmark of type 2 diabetes, the most common metabolic disorder, is a defect in insulin-stimulated glucose transport in peripheral tissues. Although a role for phosphoinositide-3-kinase (PI3K) activity in insulin-stimulated glucose transport and glucose transporter isoform 4 (Glut4) translocation has been suggested in vitro, its role in vivo and the molecular link between activation of PI3K and translocation has not yet been elucidated. To determine the role of PI3K in glucose homeostasis, we generated mice with a targeted disruption of the gene encoding the p85alpha regulatory subunit of PI3K (Pik3r1; refs 3-5). Pik3r1-/- mice showed increased insulin sensitivity and hypoglycaemia due to increased glucose transport in skeletal muscle and adipocytes. Insulin-stimulated PI3K activity associated with insulin receptor substrates (IRSs) was mediated via full-length p85 alpha in wild-type mice, but via the p50 alpha alternative splicing isoform of the same gene in Pik3r1-/- mice. This isoform switch was associated with an increase in insulin-induced generation of phosphatidylinositol(3,4,5)triphosphate (PtdIns(3,4,5)P3) in Pik3r1-/- adipocytes and facilitation of Glut4 translocation from the low-density microsome (LDM) fraction to the plasma membrane (PM). This mechanism seems to be responsible for the phenotype of Pik3r1-/- mice, namely increased glucose transport and hypoglycaemia. Our work provides the first direct evidence that PI3K and its regulatory subunit have a role in glucose homeostasis in vivo.
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PMID:Increased insulin sensitivity and hypoglycaemia in mice lacking the p85 alpha subunit of phosphoinositide 3-kinase. 998 80

Hexosamines have been hypothesized to mediate aspects of glucose sensing and toxic effects of hyperglycemia. For example, insulin resistance results when the rate-limiting enzyme for hexosamine synthesis, glutamine:fructose-6-phosphate amidotransferase (GFA), is overexpressed in muscle and adipose tissue of transgenic mice. The glucose infusion rates required to maintain euglycemia at insulin infusion rates of 0.5, 2, 15, and 20 mU/kg x min were 39-90% lower in such transgenic mice, compared with their control littermates (P < or = 0.01). No differences were observed in hepatic glucose output, serum insulin levels, or muscle ATP levels. Uptake of 2-deoxyglucose, measured under conditions of hyperinsulinemia, was significantly lower in transgenic hindlimb muscle, compared with controls (85.9 +/- 17.8 vs. 166.8 +/- 15.1 pmol deoxyglucose/g x min). The decrease in glucose uptake by transgenic muscle was associated with a disruption in the translocation of the insulin-stimulated glucose transporter GLUT4. Fractionation of muscle membranes on a discontinuous sucrose gradient revealed that insulin stimulation of control muscle led to a 28.8% increase in GLUT4 content in the 25% fraction and a 61.2% decrease in the 35% fraction. In transgenic muscle, the insulin-stimulated shifts in GLUT4 distribution were inhibited by over 70%. Treatment of the transgenic animals with the thiazolidinedione troglitazone completely reversed the defect in glucose disposal without changing GFA activity or the levels of uridine 5'-diphosphate-N-acetylglucosamine. Overexpression of GFA in skeletal muscle thus leads to defects in glucose transport similar to those seen in type 2 diabetes. These data support the hypothesis that excess glucose metabolism through the hexosamine pathway may be responsible for the diminished insulin sensitivity and defective glucose uptake that are seen with hyperglycemia.
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PMID:Mechanism of hexosamine-induced insulin resistance in transgenic mice overexpressing glutamine:fructose-6-phosphate amidotransferase: decreased glucose transporter GLUT4 translocation and reversal by treatment with thiazolidinedione. 1006 38

Impaired skeletal muscle glucose utilization under insulin action is a major defect in the etiology of type 2 diabetes. This is underscored by a new mouse model of type 2 diabetes generated by genetic disruption of one allele of glucose transporter 4 (GLUT4+/-), the insulin-responsive glucose transporter in muscle and adipose tissue. Male GLUT4+/- mice exhibited decreased GLUT4 expression and glucose uptake in muscle that accompanied impaired whole-body glucose utilization, hyperinsulinemia, hyperglycemia, and heart histopathology. To determine whether development of the diabetic phenotype in GLUT4+/- mice can be forestalled by preventing the onset of impaired muscle GLUT4 expression and glucose utilization, standard genetic crossing was performed to introduce a fast-twitch muscle-specific GLUT4 transgene--the myosin light chain (MLC) promoter-driven transgene MLC-GLUT4--into GLUT4+/- mice (MLC-GLUT4+/- mice). GLUT4 expression and 2-deoxyglucose uptake levels were normalized in fast-twitch muscles of MLC-GLUT4+/- mice. In contrast to GLUT4+/- mice, MLC-GLUT4+/- mice exhibited normal whole-body glucose utilization. In addition, development of hyperinsulinemia and hyperglycemia observed in GLUT4+/- mice was prevented in MLC-GLUT4+/- mice. The occurrence of diabetic heart histopathology in MLC-GLUT4+/- mice was reduced to control levels. Based on these results, we propose that the onset of a diabetic phenotype in GLUT4+/- mice can be avoided by preventing decreases in muscle GLUT4 expression and glucose uptake.
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PMID:Prevention of insulin resistance and diabetes in mice heterozygous for GLUT4 ablation by transgenic complementation of GLUT4 in skeletal muscle. 1010 94

Many recent data provide new, original insights into the mechanisms of action of the antidiabetic Metformin. Careful selection of most relevant data in terms of dosage prompted this original review, largely devoted to the drug action at the cell level and whose hypotheses/conclusions are tentatively interpreted according to corresponding basic scientific knowledge. Metformin interferes with several processes linked to HGP (gluconeogenesis, glycogenolysis and their regulatory mechanisms), lowering glucose production and resensitizing the liver to insulin. The hepatic drug effect is largely favoured by prevailing glycemia. In peripheral tissues, metformin potentiates the effects of both hyperglycemia and hyperinsulinemia. Increase in glucose-mediated glucose transport is mainly mediated by an improvement in the glucose transporter's intrinsic activity. Potentiation of the hormone effect relates to an increase in insulin receptor tyrosine kinase activity. Both mechanisms (insulin signalling and glucose transport) result in the activation of glycogen synthase, a limiting enzyme in the causal defects of NIDDM. Exciting findings show that, conversely, priming cells with very low insulin concentrations also leads to full expression of metformin's antidiabetic activity. Specific investigations confirm a working hypothesis defining the site of action as the cell membrane level. Indeed metformin corrects membrane fluidity and protein configuration disturbed by the diabetic state and which interfere with normal protein-protein or protein-lipid interactions required for proper functioning of the processes regulating glucose transport/metabolism. It is proposed that membrane changes largely represent a common denominator explaining metformin effects on various systems involved in receptor signalling and related functions.
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PMID:Membrane physiology as a basis for the cellular effects of metformin in insulin resistance and diabetes. 1044 22

Type 2 diabetes is a polygenic and genetically heterogeneous disease . The age of onset of the disease is usually late and environmental factors may be required to induce the complete diabetic phenotype. Susceptibility genes for diabetes have not yet been identified. Islet-brain-1 (IB1, encoded by MAPK8IP1), a novel DNA-binding transactivator of the glucose transporter GLUT2 (encoded by SLC2A2), is the homologue of the c-Jun amino-terminal kinase-interacting protein-1 (JIP-1; refs 2-5). We evaluated the role of IBi in beta-cells by expression of a MAPK8IP1 antisense RNA in a stable insulinoma beta-cell line. A 38% decrease in IB1 protein content resulted in a 49% and a 41% reduction in SLC2A2 and INS (encoding insulin) mRNA expression, respectively. In addition, we detected MAPK8IP1 transcripts and IBi protein in human pancreatic islets. These data establish MAPK8IP1 as a candidate gene for human diabetes. Sibpair analyses performed on i49 multiplex French families with type 2 diabetes excluded MAPK8IP1 as a major diabetogenic locus. We did, however, identify in one family a missense mutation located in the coding region of MAPK8IP1 (559N) that segregated with diabetes. In vitro, this mutation was associated with an inability of IB1 to prevent apoptosis induced by MAPK/ERK kinase kinase 1 (MEKK1) and a reduced ability to counteract the inhibitory action of the activated c-JUN amino-terminal kinase (JNK) pathway on INS transcriptional activity. Identification of this novel non-maturity onset diabetes of the young (MODY) form of diabetes demonstrates that IB1 is a key regulator of 3-cell function.
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PMID:The gene MAPK8IP1, encoding islet-brain-1, is a candidate for type 2 diabetes. 1070 Jan 86

Insulin stimulates glucose transport in muscle and adipose tissue by promoting the appearance of GLUT4, the main glucose transporter isoform in these tissues, on the cell surface. Insulin resistance is instrumental in pathogenesis of type 2 diabetes mellitus and involves decreased glucose transport activity in these tissues. No significant differences are observed between the diabetic and non-diabetic subjects in muscle GLUT4 levels. Polymorphism in the GLUT4 gene, which is very rare, has the same prevalence between subjects with type 2 diabetes mellitus and the non-diabetic subjects. The most likely explanation for the insulin resistance is a defect in insulin signaling pathways or GLUT4 intracellular trafficking pathways.
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PMID:[Insulin resistance and glucose transporter]. 1070 50

Type 2 diabetes mellitus is characterized by impaired glucose uptake. With a photometric method of recording the erythrocyte suspension absorption during the course of glucose transport across the membranes, we observed that the initial rate of glucose zero-trans entry was decreased significantly in 30 Chinese type 2 diabetic patients as compared to 25 healthy controls. The rate of glucose infinite-cis efflux exhibited no difference between the patients and controls. The measurement of temperature dependence of glucose transport showed that the activation energy for glucose entry was increased in diabetic patients. The inhibitory constant of glucose entry by cytochalasin B (CB) in patients was similar to that of the controls. However, we found that the inhibitory constant was increased significantly in the patient erythrocytes after phloretin treatment. After the erythrocytes were made into stripped white ghosts, the fluorescence quenching experiment was performed. Glucose, CB and phloretin can quench the fluorescence of tryptophan residues in the glucose transporter 1, GLUT1. The abnormality of fluorescence quenching in the erythrocyte membranes of patients was observed. The transfer tendency of tryptophan residues from the hydrophilic environment to the hydrophobic environment was decreased in patient ghosts as binding with glucose, and the opposite tendency appeared as CB and phloretin instead of glucose. We conclude that the decreased in glucose entry in the erythrocyte membranes of diabetic patients was due to the GLUT1 change in structure - mostly the outer domain of the glucose transporter.
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PMID:The abnormality of glucose transporter in the erythrocyte membrane of Chinese type 2 diabetic patients. 1082 51


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