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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Impaired insulin secretion is a hallmark in both type I and type II diabetic individuals. Whereas type I (insulin-dependent diabetes mellitus) implies ss-cell destruction, type II (non-insulin dependent diabetes mellitus), responsible for 75% of diabetic syndromes, involves diminished glucose-dependent secretion of insulin from pancreatic beta-cells. Although a clear demonstration of a direct effect of 17beta-estradiol on the pancreatic ss-cell is lacking, an in vivo insulinotropic effect has been suggested. In this report we describe the effects of 17beta-estradiol in mouse pancreatic ss-cells. 17beta-Estradiol, at physiological concentrations, closes K(ATP) channels, which are also targets for antidiabetic sulfonylureas, in a rapid and reversible manner. Furthermore, in synergy with glucose, 17beta-estradiol depolarizes the plasma membrane, eliciting electrical activity and intracellular calcium signals, which in turn enhance insulin secretion. These effects occur through a receptor located at the plasma membrane, distinct from the classic cytosolic estrogen receptor. Specific competitive binding and localization of 17beta-estradiol receptors at the plasma membrane was demonstrated using confocal reflective microscopy and immunocytochemistry. Gaining deeper knowledge of the effect induced by 17beta-estradiol may be important in order to better understand the hormonal regulation of insulin secretion and for the treatment of NIDDM. receptor.
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PMID:Rapid insulinotropic effect of 17beta-estradiol via a plasma membrane receptor. 976 77

Non-insulin dependent diabetes mellitus (NIDDM) has a substantial genetic component. Impaired insulin secretion, insulin insensitivity in muscle and adipose tissue, and elevated hepatic glucose production are the major pathophysiological features of NIDDM. Insulin insensitivity is also a feature of the insulin resistance syndrome, which describes the epidemiological association of glucose intolerance, upper body obesity, hyperinsulinaemia, hypertension, increased triglyceride levels and decreased high-density-lipoprotein (HDL)-cholesterol concentrations. Insulin insensitivity has been found to be a familial trait, and this raises the hypothesis that the insulin resistance syndrome may also occur as a familial trait in caucasian families in association with the development of NIDDM. The 90 first degree relatives of 50 caucasian subjects with NIDDM were studied with a continuous infusion glucose tolerance test to quantitate glucose tolerance, insulin sensitivity and beta-cell function. Body mass index (BMI), blood pressure, fasting triglyceride and HDL-cholesterol measurements were obtained, and the intercorrelations between these variables were examined. As a group the first degree relatives had a median insulin sensitivity of 65% (interquartile range 46-99%). Insulin sensitivity was univariately correlated with systolic and diastolic blood pressure, triglyceride and HDL-cholesterol. These associations were present in both the hyperglycaemic and the normoglycaemic relatives. The hyperglycaemic relatives were significantly more insulin insensitive than the normoglycaemic relatives, but this additional insulin insensitivity was not associated with significant differences in blood pressure, triglyceride or HDL-cholesterol concentrations. Our data indicate that the insulin insensitivity present in the first degree relatives of subjects with NIDDM is correlated with the cardiovascular risk factors which make up the insulin resistance syndrome, and that glycaemic status does not appear to be the major determinant of these associations. Interventions targeting obesity and insulin insensitivity in these subjects may reduce cardiovascular risk.
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PMID:The relationship between the insulin resistance syndrome and insulin sensitivity in the first-degree relatives of subjects with non-insulin dependent diabetes mellitus. 988 45

The metabolic characteristics of type 2 diabetes, insulin resistance, and diminished insulin secretion are costly to measure directly. To evaluate the utility of several simple indices derived from insulin and glucose measurements, the indices were examined from 1982 to 1997 with respect to correlation with more sophisticated measures of insulin sensitivity and secretion in Pima Indians in the Gila River Indian Community of Arizona. Ability to predict the incidence of diabetes in 1,731 persons was also examined. Indices were calculated from fasting and 2-hour glucose (G0, G120) and insulin (I0, I120) concentrations obtained during an oral glucose tolerance test. Fasting serum insulin concentration and the insulin sensitivity index (10(4)/(I0 x G0)) each showed a moderate correlation with the estimate of insulin sensitivity derived from the hyperinsulinemic-euglycemic clamp (absolute value r approximately 0.60). They also strongly predicted the incidence of diabetes (incidence rate ratio comparing the most and least insulin-resistant tertile groups approximately 3.0). Corrected insulin response (I120/(G120 x (G120 - 70))) was modestly correlated with insulin secretion as measured by an intravenous glucose tolerance test (r = 0.35). Impaired insulin secretion assessed by this index predicted incidence of diabetes, particularly after control for insulin sensitivity index (incidence rate ratio = 1.6). Thus, simple indices of insulin sensitivity and secretion may be reasonable surrogates for more sophisticated measures in epidemiologic studies.
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PMID:Evaluation of simple indices of insulin sensitivity and insulin secretion for use in epidemiologic studies. 1064 22

Impaired insulin secretion in type 2 diabetes is characterized by decreased first-phase insulin secretion, an increased proinsulin-to-insulin molar ratio in plasma, abnormal pulsatile insulin release, and heightened disorderliness of insulin concentration profiles. In the present study, we tested the hypothesis that these abnormalities are at least partly reversed by a period of overnight suspension of beta-cell secretory activity achieved by somatostatin infusion. Eleven patients with type 2 diabetes were studied twice after a randomly ordered overnight infusion of either somatostatin or saline with the plasma glucose concentration clamped at approximately 8 mmol/l. Controls were studied twice after overnight saline infusions and then at a plasma glucose concentration of either 4 or 8 mmol/l. We report that in patients with type 2 diabetes, 1) as in nondiabetic humans, insulin is secreted in discrete insulin secretory bursts; 2) the frequency of pulsatile insulin secretion is normal; 3) the insulin pulse mass is diminished, leading to decreased insulin secretion, but this defect can be overcome acutely by beta-cell rest with somatostatin; 4) the reported loss of orderliness of insulin secretion, attenuated first-phase insulin secretion, and elevated proinsulin-to-insulin molar ratio also respond favorably to overnight inhibition by somatostatin. The results of these clinical experiments suggest the conclusion that multiple parameters of abnormal insulin secretion in patients with type 2 diabetes mechanistically reflect cellular depletion of immediately secretable insulin that can be overcome by beta-cell rest.
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PMID:Overnight inhibition of insulin secretion restores pulsatility and proinsulin/insulin ratio in type 2 diabetes. 1095 Aug 18

Type 2 diabetes mellitus is a heterogeneous disorder characterized by chronic hyperglycaemia. The aetiological heterogeneity is suggested by genetic inheritance and its interplay with environmental factors. Impaired insulin secretion and decreased insulin sensitivity are the main pathophysiological features, responsible for development of hyperglycaemia in type 2 diabetes. However, the genetic basis of these defects has been demonstrated only in small subgroups of patients. Whether impaired secretion or action of insulin is the primary defect in the majority of patients is not known, although it is generally agreed that defective insulin release is a requirement for the disease to develop.
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PMID:The pathophysiology of type 2 diabetes mellitus: an overview. 1141 36

Impaired insulin secretion and insulin resistance are thought to be two major causes of type 2 diabetes mellitus. There are two kinds of diabetic model mice: one is a K(ATP) channel knockout (Kir6.2KO) mouse which is defective in glucose-induced insulin secretion, and the other is a transgenic mouse expressing the tyrosine kinase-deficient (dominant-negative form of) human insulin receptor (hIR(KM)TG), and which has insulin resistance in muscle and fat. However, all of these mice have no evidence of overt diabetes. To determine if the double mutant Kir6.2KO/hIR(KM)TG mice would have diabetes, we generated mutant mice by crossbreeding, which would show both impaired glucose-induced insulin secretion and insulin resistance in muscle and fat. We report here that: 1) blood glucose levels of randomly fed and 6 h fasted double mutant (Kir6.2KO/hIR(KM)TG) mice were comparable with those of wild type mice; 2) in intraperitoneal glucose tolerance test (ipGTT), Kir6.2KO/hIR(KM)TG mice had an impaired glucose tolerance; and 3) during ipGTT, insulin secretion was not induced in either Kir6.2KO/hIR(KM)TG or Kir6.2KO mice, while the hIR(KM)TG mice showed a more prolonged insulin secretion than did wild type mice; 4) hyperinsulinemic euglycemic clamp test revealed that Kir6.2KO, Kir6.2KO/hIR(KM)TG and hIR(KM)TG mice, showed decreased whole-body glucose disposal compared with wild type mice; 5) Kir6.2KO, but not Kir6.2KO/hIR(KM)TG mice had some obesity and hyperleptinemia compared with wild type mice. Thus, the defects in glucose-induced insulin secretion (Kir6.2KO) and an insulin resistance in muscle and fat (hIR(KM)TG) were not sufficient to lead to overt diabetes.
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PMID:K(ATP) channel knockout mice crossbred with transgenic mice expressing a dominant-negative form of human insulin receptor have glucose intolerance but not diabetes. 1511 62

Insulin resistance is a common pathogenetic feature of type 2 diabetes. However, hyperglycemia would not develop if a concomitant defect in insulin secretion were not present. Impaired insulin secretion results from functional and survival defects of the beta-cell. The functional defects can be demonstrated early in the natural history of diabetes and they are hallmarked by abnormal pulsatility of basal insulin secretion and loss of first-phase insulin release in response to a glucose challenge. Moreover, a significant reduction of the beta-cell mass is apparent at the time of the diagnosis of diabetes. The progressive increase in glucose levels, that seems to characterize the natural history of type 2 diabetes, has been claimed to be largely due to progressive reduction of function and mass of beta-cells. Although a genetic predisposition is likely to account for impaired insulin secretion, chronic exposure to hyperglycemia and high circulating FFA is likely to contribute to both functional and survival defects. The disturbance in the endocrine activity of the pancreas is not limited to insulin, since a concomitant increase in fasting plasma glucagon and impaired suppression after the ingestion of an oral glucose load are often observed. This alteration becomes prominent after the ingestion of a mixed meal, when plasma glucagon remains much higher in the diabetic patient as compared to normal individuals. The disproportionate changes in the plasma concentration of the two pancreatic hormones is clearly evident when the insulin:glucagon molar ratio is considered. It is the latter that mainly affects hepatic glucose production. Because of the reduction of the insulin:glucagon molar ratio basal endogenous glucose concentration will be higher causing fasting hyperglycemia, while the hepatic glucose output will not be efficiently suppressed after the ingestion of a meal, contributing to excessive post-prandial glucose rise. Correcting beta- and alpha-cell dysfunction becomes, therefore, an attractive and rational therapeutic approach, particularly in the light of new treatments that may directly act on these pathogenetic mechanisms of type 2 diabetes.
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PMID:Beta- and alpha-cell dysfunction in type 2 diabetes. 1565 8

Impaired insulin secretion is a fundamental defect in type 2 diabetes. The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) in the genes regulating insulin secretion (SLC2A2 [encoding GLUT2], GCK, TCF1 [encoding HNF-1alpha], HNF4A, GIP, and GLP1R) are associated with the conversion from impaired glucose tolerance (IGT) to type 2 diabetes in participants of the Finnish Diabetes Prevention Study. With the exception of SLC2A2, other genes were not associated with the risk of type 2 diabetes. All four SNPs of SLC2A2 predicted the conversion to diabetes, and rs5393 (AA genotype) increased the risk of type 2 diabetes in the entire study population by threefold (odds ratio 3.04, 95% CI 1.34-6.88, P = 0.008). The risk for type 2 diabetes in the AA genotype carriers was increased in the control group (5.56 [1.78-17.39], P = 0.003) but not in the intervention group. We conclude that the SNPs of SLC2A2 predict the conversion to diabetes in obese subjects with IGT.
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PMID:Polymorphisms in the SLC2A2 (GLUT2) gene are associated with the conversion from impaired glucose tolerance to type 2 diabetes: the Finnish Diabetes Prevention Study. 1598 30

Impaired insulin secretion and decreased insulin sensitivity are the main pathophysiologic features responsible for development of hyperglycemia in type 2 diabetes mellitus. Insulin resistance is often associated with increased adipose tissue mass. To examine which variables influence insulin sensitivity, we compared metabolic parameters, serum resistin, leptin, and adiponectin concentrations to the insulin sensitivity, obtained by frequently sampled intravenous glucose tolerance test using the minimal model analysis, in 113 Japanese patients with type 2 diabetes mellitus. Duration of diabetes, fasting plasma glucose, fasting insulin, homeostasis model assessment of insulin resistance index, and serum resistin concentration were significantly higher in the insulin-resistant subgroup compared with the insulin-sensitive subgroup and correlated with insulin sensitivity. Stepwise regression analysis also identified these parameters as independent regulators of insulin sensitivity. The present study reconfirmed that fasting insulin level or homeostasis model assessment of insulin resistance would be a surrogate measure of insulin resistance and demonstrated that insulin resistance increases progressively after the onset of overt diabetes and that the serum resistin level is associated with insulin sensitivity, suggesting that resistin plays an important role in the development of insulin resistance in Japanese patients with type 2 diabetes mellitus.
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PMID:Serum resistin level is associated with insulin sensitivity in Japanese patients with type 2 diabetes mellitus. 1744 46

Impaired insulin secretion occurs early in the pathogenesis of type 2 diabetes mellitus (T2DM) and is chronic and progressive, resulting initially in impaired glucose tolerance (IGT) and eventually in T2DM. As most patients with T2DM have both insulin resistance and insulin deficiency, therapy for T2DM should aim to control not only fasting, but also postprandial plasma glucose levels. While oral glucose-lowering treatment with metformin and thiazolidinediones corrects fasting plasma glucose, these agents do not address the problem of mealtime glucose spikes that have been shown to trigger atherogenic processes. Nateglinide is a derivative of the amino acid D-phenylalanine, which acts directly on the pancreatic beta-cells to stimulate insulin secretion. Nateglinide monotherapy controls significantly mealtime hyperglycemia and results in improved overall glycemic control in patients with T2DM by reducing glycosylated hemoglobin (HbA1c) levels. The combination of nateglinide with insulin-sensitising agents, such as metformin and thiazolidinediones, targets both insulin deficiency and insulin resistance and results in reductions in HbA1c that could not be achieved by monotherapy with other antidiabetic agents. In prediabetic subjects with IGT, nateglinide restores early insulin secretion and reduces postprandial hyperglycemia. Nateglinide has an excellent safety and tolerability profile and provides a lifetime flexibility that other antidiabetic agents could not accomplish. The aim of this review is to identify nateglinide as an effective "gate-keeper" in T2DM, since it restores early-phase insulin secretion and prevents mealtime glucose spikes throughout the day and to evaluate the results of ongoing research into its potential role in delaying the progression to overt diabetes and reducing its complications and mortality.
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PMID:A review of nateglinide in the management of patients with type 2 diabetes. 1820 Aug


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