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

R6/2 transgenic mice express exon 1 of the human Huntington's disease (HD) gene with an increased CAG repeat length. They develop a progressive neurological phenotype, die within 12-14 weeks of age and were also found to develop diabetes mellitus. Since R6/2 mice are broadly used to screen for potential therapies in HD, the aim of this study was (a) to search for behavioral tests that are best applicable to monitor the behavioral abnormalities in therapy studies and (b) to investigate the extent to which diabetes influences the disease phenotype. We found that the rotarod test for motor coordination and the open field test for spontaneous explorative behavior were useful to monitor the progressive behavioral deterioration of R6/2 mice. An accelerating rotarod paradigm was superior over testing with a rotarod at various fixed speeds since it leads to similar results with less repetitive daily trials so that exhaustion cannot contribute substantially to their decline in performance. With the Morris water maze, however, it was only possible to monitor cognitive decline in visuo-spatial learning in the first weeks of disease since, at later stages, mice were not able to learn the task adequately. A latent diabetes mellitus was found in all transgenic mice demonstrated by a pathological glucose tolerance. Only 26% of the mice, however, were found to develop a manifest diabetes with increasing blood glucose levels on normal diet over the disease period. R6/2 mice with manifest and latent diabetes showed no significant differences in survival, weight loss, motor coordination, or spontaneous explorative behavior. These results suggest that diabetes mellitus is not a major contributing factor to the disease phenotype.
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PMID:Evaluation of R6/2 HD transgenic mice for therapeutic studies in Huntington's disease: behavioral testing and impact of diabetes mellitus. 1170 63

Insulin is released from the pancreas in a biphasic manner in response to a square-wave increase in arterial glucose concentration. The first phase consists of a brief spike lasting approximately 10 min followed by the second phase, which reaches a plateau at 2-3 h. It is widely thought that diminution of first-phase insulin release is the earliest detectable defect of beta-cell function in individuals destined to develop type 2 diabetes and that this defect largely represents beta-cell exhaustion after years of compensation for antecedent insulin resistance. In this article, the origins of these concepts are reviewed and recent evidence is presented suggesting that reductions in both phases of insulin release are equally early, that they precede insulin resistance other than that simply due to obesity, and that they therefore may represent the primary genetic risk factor predisposing individuals to type 2 diabetes.
Diabetes 2002 Feb
PMID:Is reduced first-phase insulin release the earliest detectable abnormality in individuals destined to develop type 2 diabetes? 1181 69

First-phase insulin response to intravenous glucose is impaired both in type 2 diabetic patients and in subjects at risk for the disease. Hyperglycemia can modify beta-cell response by either inhibiting or potentiating both first- and second-phase insulin release. In normal subjects, the effect of acute hyperglycemia on insulin secretion is controversial. We measured (in 13 healthy volunteers) insulin secretion (by deconvolution of plasma C-peptide concentrations) during three consecutive 30-min hyperglycemic steps (2.8, 2.8, and 5.6 mmol/l), followed by an intravenous arginine bolus. First-phase insulin secretion in response to the first hyperglycemic step (456 +/- 83 pmol.min(-1).m(-2)) was significantly larger than that in response to the second step (311 +/- 37 pmol.min(-1).m(-2), P < 0.01); the subsequent increase in glycemia failed to stimulate first-phase secretion any further (377 +/- 60 pmol.min(-1).m(-2), NS vs. the previous value). This inhibition was also evident when insulin release rates were corrected for the respective increments (absolute or percentage) in plasma glucose levels and was not due to beta-cell exhaustion because the arginine bolus still elicited a large peak of insulin secretion (4,790 +/- 2,330 pmol.min(-1).m(-2)). In contrast, second-phase insulin secretion was related to the prevailing glucose levels across the three hyperglycemic steps in a direct quasilinear manner. We conclude that first-phase insulin secretion is inhibited by short-term modest hyperglycemia, whereas the second-phase insulin secretion increases linearly with hyperglycemia.
Diabetes 2002 Feb
PMID:Effect of acute hyperglycemia on insulin secretion in humans. 1181 71

In intense exercise (>80% VO(2max)), unlike at lesser intensities, glucose is the exclusive muscle fuel. It must be mobilized from muscle and liver glycogen in both the fed and fasted states. Therefore, regulation of glucose production (GP) and glucose utilization (GU) have to be different from exercise at <60% VO(2max), in which it is established that the portal glucagon-to-insulin ratio causes the less than or equal to twofold increase in GP. GU is subject to complex regulation by insulin, plasma glucose, alternate substrates, other humoral factors, and muscle factors. At lower intensities, plasma glucose is constant during postabsorptive exercise and declines during postprandial exercise (and often in persons with diabetes). During such exercise, insulin secretion is inhibited by beta-cell alpha-adrenergic receptor activation. In contrast, in intense exercise, GP rises seven- to eightfold and GU rises three- to fourfold; therefore, glycemia increases and plasma insulin decreases minimally, if at all. Indeed, even an increase in insulin during alpha-blockade or during a pancreatic clamp does not prevent this response, nor does pre-exercise hyperinsulinemia due to a prior meal or glucose infusion. At exhaustion, GU initially decreases more than GP, which leads to greater hyperglycemia, requiring a substantial rise in insulin for 40--60 min to restore pre-exercise levels. Absence of this response in type 1 diabetes leads to sustained hyperglycemia, and mimicking it by intravenous infusion restores the normal response. Compelling evidence supports the conclusion that the marked catecholamine responses to intense exercise are responsible for both the GP increment (that occurs even during glucose infusion and postprandially) and the restrained increase of GU. These responses are normal in persons with type 1 diabetes, who often report exercise-induced hyperglycemia, and in whom the clinical challenge is to reproduce the recovery period hyperinsulinemia. Intense exercise in type 2 diabetes requires additional study.
Diabetes 2002 Feb
PMID:Intense exercise has unique effects on both insulin release and its roles in glucoregulation: implications for diabetes. 1181 92

Depression is associated with increased cardiovascular disease, but the underlying mechanisms are not well understood. This study examines associations of depressive symptoms with inflammation and coagulation factors in persons aged > 65 years. Blood samples were obtained from 4,268 subjects free of cardiovascular disease (age 72.4 +/- 5.5 years, 2,623 women). Inflammation markers were C-reactive protein (CRP), white blood cell (WBC) count, total platelet count, and albumin; coagulation factors included factors VIIc and VIIIc and fibrinogen. Depression was assessed with the Center for Epidemiologic Studies Depression scale, and states of energy depletion with a validated exhaustion index. Statistical adjustments were made for risk factors (age, sex, race, systolic blood pressure, smoking status, diabetes mellitus) and physical measures of frailty (isometric handgrip, timed 15-feet walk test, activity level). Depression was associated with elevated CRP (3.31 +/- 0.10 vs 3.51 +/- 0.21 mg/L), WBC (6.14 +/- 0.03 vs 6.43 +/- 0.11 10(6)/L), fibrinogen (319 +/- 1 vs 326 +/- 3 mg/dl), and factor VIIc (124.6 +/- 0.6% vs 127.2 +/- 1.3%; all p <0.05). Exhaustion also was related to elevated inflammation and coagulation markers (p < 0.05). Exhausted men had markedly elevated CRP levels (6.82 +/- 2.10 mg/L) versus nonexhausted men (3.05 +/- 0.16: p = 0.007). After adjustment for control variables, exhaustion remained associated with albumin (p = 0.033), fibrinogen (p = 0.017), CRP (p = 0.066), and WBC (p = 0.060), whereas associations of depressive symptoms with biochemistry measures lost statistical significance. Thus, depression and exhaustion are associated with low-grade inflammation and elevated coagulation factors in persons aged > 65 years.
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PMID:Inflammation and coagulation factors in persons > 65 years of age with symptoms of depression but without evidence of myocardial ischemia. 1183 23

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

The possibility that high, long-term intake of carbohydrates that are rapidly absorbed as glucose may increase the risk of type 2 diabetes has been a long-standing controversy. Two main mechanisms have been hypothesized, one mediated by increases in insulin resistance and the other by pancreatic exhaustion as a result of the increased demand for insulin. During the past decade, several lines of evidence have collectively provided strong support for a relation between such diets and diabetes incidence. In animals and in short-term human studies, a high intake of carbohydrates with a high glycemic index (a relative measure of the incremental glucose response per gram of carbohydrate) produced greater insulin resistance than did the intake of low-glycemic-index carbohydrates. In large prospective epidemiologic studies, both the glycemic index and the glycemic load (the glycemic index multiplied by the amount of carbohydrate) of the overall diet have been associated with a greater risk of type 2 diabetes in both men and women. Conversely, a higher intake of cereal fiber has been consistently associated with lower diabetes risk. In diabetic patients, evidence from medium-term studies suggests that replacing high-glycemic-index carbohydrates with a low-glycemic-index forms will improve glycemic control and, among persons treated with insulin, will reduce hypoglycemic episodes. These dietary changes, which can be made by replacing products made with white flour and potatoes with whole-grain, minimally refined cereal products, have also been associated with a lower risk of cardiovascular disease and can be an appropriate component of recommendations for an overall healthy diet.
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PMID:Glycemic index, glycemic load, and risk of type 2 diabetes. 1208 51

The aims of our study were to assess whether endurance training strengthens glutathione-dependent antioxidant defenses and decreases oxidative stress in experimental diabetes. Streptozotocin-induced diabetic rats were divided into trained and untrained groups, which were further divided into resting and acute exercise groups. Endurance training consisted of treadmill running for 8 weeks. For acute exhaustive exercise, graded treadmill running was conducted until exhaustion. Eight weeks' treadmill training increased the endurance, favorably decreased lipid peroxidation as measured by thiobarbituric acid reactive substances but not conjugated dienes levels in kidney and vastus lateralis muscle and upregulated glutathione peroxidase in red gastrocnemius muscle. However, it adversely decreased total glutathione level and glutathione peroxidase activity in kidney. Acute exhaustive exercise up-regulated glutathione peroxidase activity in liver. Endurance training did not prevent the increase in thiobarbituric acid reactive substances level in liver due to acute exhaustive exercise. Activities of glutathione disulfide reductase and glutathione S-transferase were not affected. Even though endurance training appeared to upregulate glutathione dependent antioxidant defense in skeletal muscle and to decrease lipid peroxidation in kidney and vastus lateralis muscle as measured by TBARS, our results suggests that beneficial effects of 8 weeks of endurance training are limited in this rat model of uncontrolled diabetes mellitus.
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PMID:Effects of endurance training on tissue glutathione homeostasis and lipid peroxidation in streptozotocin-induced diabetic rats. 1213 49

Type 1 diabetes is an autoimmune disease leading to a progressive exhaustion of the insulin secretion and a destruction of the B-cells. Attempts of preservation of insulin-producing B-cells can be performed at an early, most often silent, stage of the disease in well-selected at high risk subjects or during the period immediately following the clinical diagnosis based upon classical signs of hyperglycaemia. In the "Diabetes Prevention Trial-Type 1", the prophylactic subcutaneous administration of low-dose ultralente insulin was not able to prevent the development of type 1 diabetes nor to preserve residual insulin secretion in young relatives at very high-risk of diabetes, selected upon genetic, immunological and metabolic criteria. In contrast, a pilot randomized trial shows that a treatment with a nonactivating humanized monoclonal antibody against CD3 mitigates the deterioration in insulin production and improves metabolic control, with lower dose of exogenous insulin, during the first year of type 1 diabetes mellitus in 9 out of 12 treated patients. Besides a better understanding of the natural history of the disease, these clinical trials open new perspectives for prevention of type 1 diabetes mellitus, currently assessed by the Belgian Diabetes Registry.
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PMID:[Clinical study of the month. Attempt at preservation of B cells during the initial phase of type 1 diabetes: negative results with ultralente insulin, but promising results with an anti-CD3 monoclonal antibody]. 1218 38

In this study, we attempted to demonstrate the possibility of rescuing beta-cell exhaustion by chronic intervention with an ATP-sensitive K(+) channel opener, diazoxide, which reduces the stress of insulin secretion, using rats with streptozotocin-induced diabetes. Three groups of male Wistar rats: (i) controls (n = 7), (ii) streptozotocin (30 mg/kg i.v.)-induced diabetic rats (n = 10), and (iii) streptozotocin-induced diabetic rats treated with diazoxide 30 mg/kg for 6 weeks (n = 10), were studied. Intraperitoneal 2-g glucose tolerance testing was performed every 2 weeks, and pancreatic tissue was examined after 6 weeks of treatment with diazoxide. The insulin concentration in diabetic rats treated with diazoxide was significantly higher than in diabetic rats without diazoxide (6.6 +/- 1.6 vs. 2.4 +/- 1.0 ng/ml, P < 0.05). The islet size and its cell number were reduced in diabetic rats compared to those in normal control rats. In normal control rats, 88% of pancreatic islet cells were insulin-positive, while 50% or less were positive in diabetic rats. However, islet size and its cell size appeared to be well preserved by diazoxide treatment. The average mass of islets in diazoxide-treated rats was significantly larger than that in untreated control animals. In addition, the degree of immunostaining for insulin was obviously higher in rats treated with diazoxide than in rats without diazoxide. Pancreatic proinsulin mRNA was restored in rats treated with diazoxide. The present study demonstrated that diazoxide protected from further damage the pancreatic beta-cells both functionally and morphologically in streptozotocin-induced diabetic rats by suppression of excessive insulin secretion. Our results strongly suggest the possibility that chronic intervention with an ATP-sensitive K(+) channel opener prevents the progress of deranged beta-cell function even after the development of diabetes mellitus.
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PMID:Rescue of beta-cell exhaustion by diazoxide after the development of diabetes mellitus in rats with streptozotocin-induced diabetes. 1239 69


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