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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

High levels of some but not all dietary fats lead to insulin resistance in rats. The aim of this study was to investigate the important determinants underlying this observation. Insulin action was assessed with the euglycemic clamp. Diets high in saturated, monounsaturated (omega-9), or polyunsaturated (omega-6) fatty acids led to severe insulin resistance; glucose infusion rates [GIR] to maintain euglycemia at approximately 1000 pM insulin were 6.2 +/- 0.9, 8.9 +/- 0.9, and 9.7 +/- 0.4 mg.kg-1. min-1, respectively, versus 16.1 +/- 1.0 mg.kg-1.min-1 in chow-fed controls. Substituting 11% of fatty acids in the polyunsaturated fat diet with long-chain omega-3 fatty acids from fish oils normalized insulin action (GIR 15.0 +/- 1.3 mg.kg-1.min-1). Similar replacement with short-chain omega-3 (alpha-linolenic acid, 18:3 omega 3) was ineffective in the polyunsaturated diet (GIR 9.9 +/- 0.5 mg.kg-1.min-1) but completely prevented the insulin resistance induced by a saturated-fat diet (GIR 16.0 +/- 1.5 mg.kg-1.min-1) and did so in both the liver and peripheral tissues. Insulin sensitivity in skeletal muscle was inversely correlated with mean muscle triglyceride accumulation (r = 0.95 and 0.86 for soleus and red quadriceps, respectively; both P less than 0.01). Furthermore, percentage of long-chain omega-3 fatty acid in phospholipid measured in red quadriceps correlated highly with insulin action in that muscle (r = 0.97). We conclude that 1) the particular fatty acids and the lipid environment in which they are presented in high-fat diets determine insulin sensitivity in rats; 2) impaired insulin action in skeletal muscle relates to triglyceride accumulation, suggesting intracellular glucose-fatty acid cycle involvement; and 3) long-chain omega-3 fatty acids in phospholipid of skeletal muscle may be important for efficient insulin action.
Diabetes 1991 Feb
PMID:Influence of dietary fat composition on development of insulin resistance in rats. Relationship to muscle triglyceride and omega-3 fatty acids in muscle phospholipid. 199 75

To identify the primary disorder causing diabetes mellitus in a model rat (Otsuka Long-Evans Tokushima Fatty [OLETF]) with non-insulin-dependent diabetes mellitus (NIDDM), we studied the temporal relationship between insulin resistance and impairment of pancreatic beta-cell function. Groups of 28 male OLETF rats and male nondiabetic control Long-Evans Tokushima Otsuka (LETO) rats were given an intravenous (i.v.) glucose and glucagon tolerance test (IVGTT) and hyperinsulinemic euglycemic clamp tests at 10, 16, 24, and 40 weeks of age. After the euglycemic clamp test, abdominal fat was measured and the pancreas was examined histologically. At 16 weeks of age, insulin-mediated whole-body glucose uptake as measured by the hyperinsulinemic euglycemic clamp technique was significantly reduced in OLETF rats (glucose infusion rat [GIR], 40.9 +/- 4.2 mumol/kg.min) as compared with LETO rats (78.4 +/- 6.9). On the other hand, plasma insulin responses to glucose and glucagon in OLETF rats were higher than those in LETO rats at 16 and 24 weeks of age, but clearly decreased at 40 weeks of age (sigma immunoreactive insulin [IRI] to glucagon, 8.81 +/- 1.81 v 27.32 +/- 4.59 nmol.min in OLETF and LETO rats, respectively, P < .01). Abdominal fat deposition was significantly greater in OLETF rats than in LETO rats at all ages tested except 10 weeks. Pancreatic islets of OLETF rats became enlarged and fibrotic. These results demonstrated that insulin resistance preceded impairment of pancreatic beta-cell function in OLETF rats, and that insulin resistance seemed closely related to fat deposition in the abdominal cavity.
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PMID:Which is the primary etiologic event in Otsuka Long-Evans Tokushima Fatty rats, a model of spontaneous non-insulin-dependent diabetes mellitus, insulin resistance, or impaired insulin secretion? 761 55

Fat feeding produces whole-body insulin resistance and decreased glucose uptake in muscle tissue of rats. To examine the effect of glucocorticoid blockade on the insulin resistance caused by high-fat feeding, four groups of rats were fed diets high in starch (70% of calories) or fat (59% of calories) for 4 weeks with or without the antiglucocorticoid RU486 (69.8 mumol.kg-1.day-1) in the food. Whole-body insulin action was assessed by the euglycemic clamp technique at an upper physiological insulin level with bolus 2-[3H]deoxyglucose to determine individual tissue insulin-stimulated glucose uptake. Whole-body glucose utilization (clamp glucose infusion rate [GIR]) was decreased by high-fat feeding (GIR 68.3 +/- 12.2 vs. 182.6 +/- 12.8 mumol.kg-1.min-1 for the starch-fed group; P < 0.001). Addition of RU486 to the diet significantly improved (GIR 133.9 +/- 12.8 mumol.kg-1.min-1; P < 0.01), but did not fully reverse, the insulin resistance caused by fat feeding. RU486 was without effect in the starch-fed rats. In skeletal muscles, RU486 ameliorated 62 and 68% of the insulin resistance produced by fat feeding in red quadriceps and extensor digitorum longus hindlimb muscles, respectively, but had no effect in heart or white adipose tissue. These results suggest that glucocorticoids play, in a tissue-specific manner, a role in the maintenance and/or production of insulin resistance produced by high-fat feeding.
Diabetes 1995 Jun
PMID:Amelioration of high-fat feeding-induced insulin resistance in skeletal muscle with the antiglucocorticoid RU486. 778 38

Insulin resistance and impaired insulin secretion can be involved in the development of non-insulin-dependent diabetes mellitus (NIDDM), but their relative importance or temporal relationship are poorly understood. To elucidate this issue, we studied 51 subjects with borderline glucose intolerance (BGI) and 18 normal glucose tolerant subjects (NGT) according to the Japan Diabetes Society criteria. The glucose infusion rate (GIR, mg/kg/min), an index of whole body insulin resistance (IR), was measured by the euglycemic (80 mg/dl) hyperinsulinemic clamp technique (insulin infusion rate 1.12 mU/kg/min). Insulinogenic index (delta IRI/delta BS at 30 min) and the insulin area under the curve during a 75-g oral glucose tolerance test (OGTT) were estimated. In the BGI subjects, the GIR values showed marked variation ranging from 2.24 to 10.44 mg/kg/min (5.54 +/- 0.31, mean +/- S.E.M.). The GIR values were lower in obese BGI subjects compared with non-obese BGI and NGT subjects, and the insulin area was markedly higher in BGI subjects with increased insulin resistance. There was a significant negative correlation between the GIR values and the insulin area or delta IRI/delta BS (30') ratio in the subjects with BGI either in the whole group or solely in the non-obese group. We conclude that the increased insulin secretion compensates for the peripheral insulin resistance of subjects with slightly deteriorated glucose tolerance, implying that insulin resistance plays an important role in the pathogenesis of NIDDM in some fraction of Japanese population.
Diabetes Res Clin Pract 1995 Oct
PMID:The relationship between insulin resistance and insulin secretion in Japanese subjects with borderline glucose intolerance. 874 6

The aims of this study were to determine the change in the rate of insulin-stimulated glucose disposal (insulin sensitivity) and the ability of insulin to inhibit its own secretion in four pancreas-kidney transplant recipients with insulin-dependent diabetes mellitus. Insulin sensitivity (glucose infusion rate, GIR) was measured by a euglycemic hyperinsulinemic clamp technique before and 2, 6 and 12 months after transplantation. The GIR values in the four recipients were normalized within 2 months and remained normal for 12 months after transplantation, despite long-term steroid therapy for immunosuppression. Physiological hyperinsulinemia (50-70 microU/ml) suppressed plasma C-peptide, but its nadirs were still higher than the basal levels in normal controls. Taking into account evidence of a minimal increase in the concentration of circulating insulin that inhibits insulin secretion in healthy subjects and evidence of increased insulin secretion in pancreas recipients, the authors speculate that defective feedback inhibition of insulin secretion could contribute, at least in part, to the disproportionate basal hyperinsulinemia in patients with a denervated, transplanted pancreas in the absence of insulin resistance.
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PMID:Insulin sensitivity and negative insulin feedback after pancreas transplantation in insulin-dependent diabetic patients. 882 15

We determined the metabolic effects of insulin derived from renal subcapsular islet grafts, either with systemic delivery of insulin through renal venous drainage (REN) or with portal delivery of insulin after renal vein-to-superior mesenteric vein anastomosis (RMA), in streptozotocin-induced diabetic Lewis rats, in comparison with normal rats. After gavage glucose, the plasma glucose responses were similar to normal in REN and RMA rats; however, hyperinsulinemia occurred in REN rats (area under the concentration curves [AUCs] of insulin, 27 +/- 3 nmol x 1(-l) min) in comparison with RMA (14 +/- 2) and normal rats (19 +/- 2), P < 0.003, with no difference in C-peptide responses. The ratio of AUC C-peptide to AUC insulin was lower in REN (2.0 +/- 0.2) than in RMA (3.4 +/- 0.3) and normal animals (3.2 +/- 0.3), P < 0.0005. In euglycemic-hyperinsulinemic clamp studies using the same insulin infusion rate (10 pmol x kg(-1) x min(-1), insulin resistance was found in REN animals (mean glucose infusion rate [GIR], REN: 7.5 +/- 1.2; RMA: 12.0 +/- 1.2; normal: 12.7 +/- 1.0 mg x kg(-1) x min(-1); P < 0.008), with higher steady-state insulin levels in REN (554 +/- 63 pmol/l) than in RMA (291 +/- 26) and normal rats (269 +/- 60), P < 0.0001. With matching steady-state insulin levels in RMA and REN rats during infusion of insulin at 20 pmol x kg(-1) x min(-1) in RMA rats (steady-state insulin 623 +/- 64 pmol/l), GIR was 15.7 +/- 0.7 mg x kg(-1) x min(-1). Thus, systemic delivery of insulin from islet grafts is associated with hyperinsulinemia, insulin resistance, and decreased metabolic clearance of insulin. These abnormalities are prevented by portal delivery of insulin from islet grafts in the same site. The findings are consistent with the hypothesis that portal delivery of insulin is important in maintenance of normal whole-body insulin sensitivity.
Diabetes 1997 Mar
PMID:Insulin resistance prevented by portal delivery of insulin in rats with renal subcapsular islet grafts. 903 91

Microalbuminuria has been reported to precede the development of NIDDM and to be a risk marker for cardiovascular disease. Therefore, the present study investigated the relationship between urinary albumin excretion rate (UAER) and the degree of insulin resistance in Japanese subjects with impaired glucose tolerance (IGT). Thirty-three normotensive IGT subjects were divided into three groups and twenty hypertensive IGT subjects were divided into two groups according to the degree of insulin resistance (GIR value) estimated by the euglycemic hyperinsulinemic clamp method. UAER was significantly higher in the lower GIR group in normotensive subjects (highest GIR group, 6.6 +/- 0.9 mg/24 h; intermediate group, 10.5 +/- 3.0 mg/24 h; lowest group, 21.3 +/- 3.8 mg/24 h; P<0.01 between highest and both of the other groups), but not in hypertensive subjects. The lowest GIR was associated with higher fasting plasma insulin, increased insulin response to glucose, higher plasma triglyceride and uric acid, and lower high-density-lipoprotein cholesterol, but not with increased creatinine clearance rate in normotensive subjects. A similar tendency was also found in hypertensive subjects. It is concluded that UAER is related to insulin resistance in normotensive subjects with IGT through a mechanism other than glomerular hyperfiltration.
Diabetes Res Clin Pract 1997 Jan
PMID:Urinary albumin excretion rate is related to insulin resistance in normotensive subjects with impaired glucose tolerance. 906 67

To determine the role of the glucose gradient between the hepatoportal system (HPS) and the central nervous system (CNS) in regulating hepatic glucose uptake, experiments were conducted with seven conscious dogs using a hepatic venous catheterization technique. With the infusion of somatostatin (0.8 microg x kg(-1) x min(-1)), glucagon (0.65 ng x kg(-1) x min(-1)), and insulin (27 pmol x kg(-1) x min(-1)), arterial glucose levels could be maintained at 8 mmol/l by adjusting the intravenous glucose infusion (G(inf)) according to the following three periods: 1) peripheral glucose infusion period (PE), G(inf) alone; 2) portal glucose infusion period (PO), G(inf) plus constant glucose infusion into the portal vein (GIR(PV), 55.6 micromol x kg(-1) x min(-1)); 3) portal and brain glucose infusion period (PO+CNS), G(inf) and GIR(PV) plus additional glucose infusion into the unilateral carotid and vertebral arteries to abolish the positive glucose gradient between HPS and CNS. Arterial plasma glucose levels were clamped during the three periods (8.1 +/- 0.1, PE; 8.2 +/- 0.1, PO; 8.2 +/- 0.1 mmol/l, PO+CNS). During PO, when a positive glucose gradient was promoted between HPS and CNS, the net hepatic glucose balance (NHGB) determined by the difference between hepatic glucose inflow and outflow was significantly lower than that of PE (-41.5 +/- 5.3, PO vs. -7.5 +/- 3.4 micromol x kg(-1) x min(-1), PE; P < 0.01). However, this decrease in the NHGB significantly increased during PO+CNS, when the glucose gradient between HPS and CNS was minimized, compared with PO (-21.7 +/- 3.2 micromol x kg(-1) x min(-1), P < 0.05). We conclude that a positive glucose gradient between HPS and CNS is an important regulatory factor of hepatic glucose uptake, but other factors also play important roles because minimizing the glucose gradient between HPS and CNS diminished the net hepatic glucose uptake by 50%.
Diabetes 1997 Jul
PMID:Augmentation of hepatic glucose uptake by a positive glucose gradient between hepatoportal and central nervous systems. 920 Jun 42

The OLETF rat, a genetic model of spontaneous development of NIDDM, exhibits hyperglycemic obesity with hyperinsulinemia and insulin resistance similar to that in humans. It is still unclear whether a defect in the beta-cell proliferation per se is the primary pathogenetic event in this model rat. To clarify this matter, we used partially pancreatectomized rats as a model. Male rats of 6 weeks of age were allocated at random to two groups: 70% pancreatectomy (Px) and sham-pancreatectomy (sham). Each group was divided into 4 subgroups by the date of sacrifice after surgery. Sustained hyperglycemia was evident in the Px OLETF rats after surgery. This was associated with insufficient proliferation of beta-cells, characterized by a decrease in beta-cell labeling with 5-bromo-2' deoxyuridine in proportion to a decrease in beta-cell mass and reduction in insulin content in the remnant pancreas. Administration of nicotinamide, however, ameliorated the sustained hyperglycemia by increasing beta-cell proliferation. These findings suggest that OLETF rats have a poor capacity for proliferation of pancreatic beta-cells, and that this change may be the critical pathogenetic event prior to the onset of overt diabetes. OLETF rats following long-term caloric restriction and spontaneous exercise training show normal glucose tolerance accompanied by an increase in GIR as shown by a euglycemic clamp. Both exercise training and caloric restriction normalize the abnormalities in the pancreas such as marked hypertrophy of islets and hyperplasia of connective tissues in islets. It is particularly noteworthy that exercise training significantly elevated the beta-cell mass/body weight ratio. This evidence obtained from OLETF rats may be of value when the mechanism of diet and exercise effects on diabetic patients are considered.
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PMID:Pathoetiology and prevention of NIDDM lessons from the OLETF rat. 1068 6

We investigated the relationship of codon 972 polymorphism of the insulin receptor substrate-1 (IRS-1) gene with insulin resistance in the Japanese population. Among 130 patients with type-2 diabetes mellitus (DM), we identified 6 who were heterozygous for the Gly972Arg mutation. Among 144 healthy subjects, 6 were heterozygous and 1 was homozygous for the mutation. A hyperinsulinemic euglycemic clamp study was performed in 3 of 6 diabetic patients with the heterozygous Gly972Arg mutation and in 60 without it. Both groups showed almost the same levels of insulin sensitivity (glucose infusion rate, GIR = 50.2 +/- 3.0 vs. 51.3 +/- 12.1 micromol/kg/min). Similarly, there was no difference in insulin sensitivity between healthy subjects with and without the mutation using the homeostasis model assessment (HOMA index = 1.14 +/- 0.50 vs. 1.02 +/- 0.63). The frequency of the Gly972Arg allele was not increased in diabetic patients compared with control subjects even in aged (>50 years old) or obese (BMI >/=25) subjects. Among healthy subjects, we identified a 25-year-old male with the homozygous Gly972Arg allele. He was slightly obese (BMI = 25.5) but showed relatively high insulin sensitivity, almost equal to that of healthy subjects without the mutation (GIR = 67.2 vs. 71.8 +/- 22.0 micromol/kg/min). Because the GIR in healthy subjects was significantly higher compared with that in type-2 DM patients, we speculate that another genetic or environmental factor producing a more deleterious effect on insulin sensitivity may exist in diabetic patients. We conclude that this gene abnormality does not play a role in the pathogenesis of insulin resistance and type-2 DM.
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PMID:Insulin sensitivity is not affected by mutation of codon 972 of the human IRS-1 gene. 1084 12


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