Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Studies were made on the effectiveness of caloric restriction in preventing the development of diabetes mellitus in a model rat (Otsuka-Long-Evans-Tokushima Fatty; OLETF) with non-insulin-dependent diabetes mellitus (NIDDM). Groups of 8 male OLETF rats aged 5 weeks were supplied with rat chow ad libitum (100% group) and 85% and 70% of the amount of food consumed by the 100% group (85% and 70% groups, respectively). The average weights of the 100%, 85% and 70% groups were 617, 536 and 450 g at 19 weeks of age and their abdominal fat deposits were 50, 38 and 21 g, respectively, at 22 weeks of age when they were killed. At 20 weeks of age, the cumulative incidences of diabetes mellitus in the 100%, 85% and 70% groups were 67%, 13% and zero, respectively. The plasma immunoreactive insulin (IRI) levels 60 and 120 min after oral glucose administration were significantly lower in the 70% group than in the other groups. In vivo insulin-stimulated glucose uptake measured by a euglycemic clamp technique, was significantly higher in the 70% group than in the 100% group. There was no significant difference in the glucose transporter 4 protein levels of skeletal muscles in the three groups, but the highest ratio of glucose transporter 4 in the plasma membrane to that in intracellular membranes was observed in the 70% group. Morphological studies on the pancreas of rats in the 100% group showed enlarged multilobulated fibrotic islets, whereas sections of islets of rats in the other groups appeared normal, though slightly enlarged. These results demonstrate that caloric restriction is effective in preventing NIDDM in diabetes-prone rats, probably due to increased insulin sensitivity.
Diabetes Res Clin Pract 1995 Feb
PMID:Is caloric restriction effective in preventing diabetes mellitus in the Otsuka Long Evans Tokushima fatty rat, a model of spontaneous non-insulin-dependent diabetes mellitus? 760 57

20 normoglycemic first degree relatives of non-insulin-dependent diabetes mellitus (NIDDM) patients were compared with 20 matched subjects without any family history of diabetes using the intravenous glucose tolerance test with minimal model analysis of glucose disappearance and insulin kinetics. Intravenous glucose tolerance index (Kg) was similar in both groups (1.60 +/- 0.14 vs 1.59 +/- 0.18, x 10(-2) min-1, NS). However, insulin sensitivity (Si) was reduced (3.49 +/- 0.43 vs 4.80 +/- 0.61, x 10(-4) min-1 per mU/liter, P = 0.05), whereas glucose effectiveness (Sg) was increased (1.93 +/- 0.14 vs 1.52 +/- 0.16, x 10(-2) min-1, P < 0.05) in the relatives. Despite insulin resistance neither fasting plasma insulin concentration (7.63 +/- 0.48 vs 6.88 +/- 0.45, mU/liter, NS) nor first phase insulin responsiveness (Phi1) (3.56 +/- 0.53 vs 4.13 +/- 0.62, mU/liter min-1 per mg/dl, NS) were increased in the relatives. Phi1 was reduced for the degree of insulin resistance in the relatives so that the Phi1 x Si index was lower in the relatives (11.5 +/- 2.2 vs 16.7 +/- 2.0, x 10(-4) min-2 per mg/dl, P < 0.05). Importantly, glucose effectiveness correlated with Kg and with basal glucose oxidation but not with total glucose transporter 4 (GLUT4) content in a basal muscle biopsy. In conclusion we confirm the presence of insulin resistance in first degree relatives of NIDDM patients. However, insulin secretion was altered and reduced for the degree of insulin resistance in the relatives, whereas glucose effectiveness was increased. We hypothesize that increased glucose effectiveness maintains glucose tolerance within normal limits in these "normoinsulinemic" relatives of NIDDM patients.
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PMID:Increased glucose effectiveness in normoglycemic but insulin-resistant relatives of patients with non-insulin-dependent diabetes mellitus. A novel compensatory mechanism. 808 60

1. The anti-obesity and anti-diabetic effects of mazindol were evaluated in obese diabetic yellow KK mice and C57Bl control mice. 2. The study compound was fed through a gastric tube at a rate of 1 or 2 mg/kg per day (0.01 mol/L HCl as control) for 2 weeks. The following parameters were compared in treated and control animals: bodyweight, food intake, white adipose tissue (WAT) weight, brown adipose tissue (BAT) weight and its thermogenesis, noradrenaline (NA) turnover, blood glucose and serum insulin levels and glucose transporter 4 (GLUT4). 3. Furthermore, bodyweight loss of mice pair-fed the same amount of food as the mazindol-treated mice for 2 weeks was measured. 4. Mazindol significantly decreased food intake and significantly increased guanosine-5'-diphosphate-binding in BAT mitochondria and NA turnover in BAT in both yellow KK and C57Bl groups. The amounts of WAT in subcutaneous, mesenteric and retroperitoneal regions and bodyweights were significantly decreased in both groups. Bodyweight loss in mice pair fed with the mazindol-treated groups was approximately 70% compared with that in the mazindol-treated groups. Furthermore, mazindol decreased the levels of blood glucose and serum insulin during the glucose overloading test in yellow KK mice, but it did not influence the GLUT4 protein concentration in WAT and muscle. 5. These observations suggest that mazindol possesses both an anti-obesity action, due to the inhibition of appetite as well as the activation of BAT thermogenesis via increased NA turnover in BAT, and an anti-diabetic action. Consequently, mazindol may be useful for the treatment of obesity as well as non-insulin-dependent diabetes mellitus in obese persons.
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PMID:Anti-obesity and anti-diabetic effects of mazindol in yellow KK mice: its activating effect on brown adipose tissue thermogenesis. 880 May 69

In diabetic rodents and humans, glucose transporter 4 (GLUT4) expression is suppressed in adipocytes in association with insulin resistance. Transgenic mice overexpressing GLUT4 selectively in fat have enhanced glucose disposal in vivo and massively increased glucose transport in adipocytes. To determine whether overexpression can be maintained in diabetes and whether it can prevent insulin resistance, we rendered wild-type and transgenic mice diabetic with streptozotocin. After 12-14 days, blood glucose was more than 21.4 mM and plasma insulin was 1.06 ng/ml or less in both diabetic groups in the fed state. Body weight was reduced and gonadal fat pad weight and adipocyte size were 52-75% smaller in both nontransgenic and transgenic diabetic mice, compared with nondiabetic. Basal and maximally-stimulated rates of lipolysis were similar in adipocytes from nontransgenic and transgenic mice, but the ED50 for isoproterenol stimulation was 50% lower in transgenic mice. There was no difference in the sensitivity to insulin to inhibit lipolysis. In adipocytes of nontransgenic diabetic mice, GLUT4 protein was reduced 34%, with a 46% reduction in insulin stimulated glucose transport. In contrast, in adipocytes of transgenic diabetic mice, GLUT4 remained 21-fold overexpressed, resulting in 21-fold increased basal and 10-fold increased insulin stimulated glucose transport. Injection of insulin (0.7 mU/g BW) resulted in a 35% decrease in blood glucose in transgenic diabetic mice (P < 0.05), with no effect in nontransgenic diabetic mice. Thus, high-level overexpression of GLUT4 driven by a fat specific promoter can be maintained with insulinopenic diabetes, even when fat cell metabolism is markedly altered. Overexpression of GLUT4 in adipocytes prevents insulin resistant glucose transport at the cellular level and improves insulin action in vivo, even with overt diabetes.
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PMID:Amelioration of insulin resistance in streptozotocin diabetic mice by transgenic overexpression of GLUT4 driven by an adipose-specific promoter. 907 21

The anti-obesity and anti-diabetic effects of a highly specific beta 3-adrenoceptor agonist, CL316,243 (CL; beta 1: beta 2: beta 3 = 0:1:100,000), were investigated in Otsuka Long-Evans Tokushima Fatty (fatty) and Long-Evans Tokushima Otsuka (control) rats. Daily injection of CL (0.1 mg/kg, s.c.) to these rats (10 weeks old) for 14 weeks caused a significant reduction in body weight (fatty, 27%; control, 15%), associated with a marked decrease in fat pad weight (inguinal: fatty, 60%; control, 36%; retroperitoneal: fatty, 75%; control, 77%) without affecting food intake. The levels of uncoupling protein mRNA and protein levels of uncoupling protein (UCP), as well as guanosine 5'-diphosphate-binding (a reliable index of thermogenesis) in brown adipose tissue, were lower in the fatty than in the control rats. However, after CL treatment, these parameters in brown adipose tissue increased significantly 2- to 3-fold in both groups. Furthermore, uncoupling protein was induced in white adipose tissue as well as in brown adipose tissue. The fatty rats showed hyperglycemia and hyperinsulinemia during the glucose tolerance test, but CL ameliorated these parameters. These findings suggest that decreased thermogenesis in brown adipose tissue may be one of the causes of obesity in the fatty rats and that administration of CL prevents obesity by decreasing white fat mass, by activating brown adipose tissue thermogenesis, and by inducing uncoupling protein in white adipose tissue. Furthermore, CL treatment may inhibit diabetes mellitus by ameliorating obesity and by activating glucose transporter 4 in white adipose tissue and brown adipose tissue.
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PMID:Anti-obesity and anti-diabetic effects of CL316,243, a highly specific beta 3-adrenoceptor agonist, in Otsuka Long-Evans Tokushima Fatty rats: induction of uncoupling protein and activation of glucose transporter 4 in white fat. 915 Jun 93

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.
Diabetes 1999 Apr
PMID:Prevention of insulin resistance and diabetes in mice heterozygous for GLUT4 ablation by transgenic complementation of GLUT4 in skeletal muscle. 1010 94

The mechanism of insulin resistance in obesity is not fully understood. In muscle cells, the number of insulin receptor, the function of glucose transporter 4 and the activity of tyrosine kinase decrease. The rink of body fat accumulation and insulin resistance in muscle is thought through free fatty acid and tumor necrosis factor alpha secreted in adipose tissue. Thiazolidinediones (TZDs) are useful to reduce insulin resistance especially in obesity. TZDs seem to cause small weight gain, but to reduce visceral fat in 12-24 weeks. In longer period, it hasn't been studied very much. There are some unsolved problems. So now, targets of TZDs are obese diabetes failed in other medicines. When using TZDs, be cautious of excess eating and physical inactivity.
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PMID:[Obesity, insulin resistance and the implication of thiazolidinediones]. 1070 67

Recent studies suggest that the serine/threonine kinase protein kinase B (PKB or Akt) is involved in the pathway for insulin-stimulated glucose transporter 4 (GLUT4) translocation and glucose uptake. In this study we examined the components of the Akt signaling pathway in skeletal muscle and adipose tissue in vivo from C57BL/KsJ-Lepr(db/db) mice (db/db), a model of obesity, insulin resistance, and type II diabetes. There were no changes in the protein levels of GLUT4, p85alpha, or Akt in tissues from db/db mice compared with non-diabetic littermate controls (+/+). In response to acute insulin administration, GLUT4 recruitment to the plasma membrane increased twofold in muscle and adipose tissue from +/+ mice, but was significantly reduced by 42-43% (P<0.05) in both tissues from db/db mice. Insulin increased Akt-Ser(473) phosphorylation by two- to fivefold in muscle and adipose tissue from all mice. However, in db/db mice, maximal Akt-Ser(473) phosphorylation was decreased by 32% (P<0.05) and 69% (P<0.05) in muscle and adipose tissue respectively. This decreased phosphorylation in db/db mice corresponded with a significant decrease in maximal Akt kinase activity using a glycogen synthase kinase-3 fusion protein as a substrate (P<0.05). The level of insulin-stimulated tyrosine phosphorylation of p85alpha from phosphatidylinositol 3 (PI 3)-kinase, which is upstream of Akt, was also reduced in muscle and adipose tissue from db/db mice (P<0.05); however, there was no change in extracellular signal-regulated kinase-1 or -2 phosphorylation. These data implicate decreased insulin-stimulated Akt kinase activity as an important component underlying impaired GLUT4 translocation and insulin resistance in tissues from db/db mice. However, impaired insulin signal transduction appears to be specific for the PI 3-kinase pathway of insulin signaling, while the MAP kinase pathway remained intact.
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PMID:Decreased Akt kinase activity and insulin resistance in C57BL/KsJ-Leprdb/db mice. 1101 58

Resistance to the normal action of insulin contributes to the pathogenesis of a number of common human disorders, Type II (non-insulin-dependent) diabetes mellitus. This review is focused on current understanding of the molecular mechanisms regulating insulin action and the factors contributing to insulin resistance in skeletal muscle. Since skeletal muscle is considered the major organ responsible for glucose uptake under insulin-stimulated conditions, defects in this target tissue are likely to contribute to metabolic disregulation in Type II diabetes mellitus. Defects in insulin signal transduction through the insulin-receptor substrate-1/phosphatidylinositol 3-kinase pathway is associated with reduced insulin-stimulated glucose transport activity in skeletal muscle from Type II diabetic patients. Glucose transport, the rate limiting step in glucose metabolism, is mediated by glucose transporter 4 (GLUT4) translocation and can be activated in skeletal muscle by two separate and distinct signaling pathways; one stimulated by insulin and the second by muscle contractions. Level of physical exercise has been linked to improved glucose homeostasis and enhanced insulin sensitivity. Understanding the molecular mechanism for the activation of signal transduction pathways by which insulin and muscle contraction increase glucose transport will provide a link to defining new strategies to enhance glucose metabolism in the diabetic patient.
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PMID:Skeletal muscle and insulin sensitivity: pathophysiological alterations. 1117 54

Regular physical exercise has been known to be beneficial in the treatment of type 2 diabetes. Epidemiological studies of physical exercise: previous non-randomized studies suggested that a life-style intervention program involving diet and/or exercise reduced the progression of impaired glucose tolerance (IGT) to type 2 diabetes. Recent randomized controlled intervention trials also showed that diet and/or exercise intervention led to a significant decrease in the incidence of diabetes among those with IGT. Endocrinological and metabolic effects of exercise: in well controlled diabetic patients, physical exercise promotes utilization of blood glucose and lowers blood glucose levels. On the other hand, in poorly controlled diabetic patients with ketosis, physical exercise results in further rises in blood glucose, free fatty acids and ketone body concentrations. Long-term gentle regular jogging increases insulin action in respect of both carbohydrate and lipid metabolism despite no influence on body mass index or maximal oxygen uptake. A significant correlation was observed between deltaMCR (insulin sensitivity) and average daily steps Our recent data suggested that the improvement of insulin action by physical exercise was attributed, at least in part, to the increase in insulin-sensitive GLUT4 (glucose transporter 4) on the plasma membrane in skeletal muscle. In conclusion, as an adjunct to other forms of therapy, mild regular physical exercise will play an important role in primarily preventing type 2 diabetes.
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PMID:Diabetes and life-styles: role of physical exercise for primary prevention. 1124 67


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