UMLS:C0011860 - FACTA Search

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

GDM develops in 1-3% of all pregnancies. Women with GDM are characterized by a relatively diminished insulin secretion coupled with a pregnancy-induced insulin resistance primary located in skeletal muscle tissue. The cellular background for this insulin resistance is not known. The binding of insulin to its receptor and the subsequent activation of the insulin receptor tyrosine kinase have significant importance for the cellular effect of insulin. Thus, the pathogenesis to the insulin resistance was studied by investigating insulin receptor binding and tyrosine kinase activity in skeletal muscle biopsies from women with GDM and pregnant controls. No major abnormalities were found in GDM wherefore it is likely that the insulin resistance is caused by intracellular defects distal to the activation of the tyrosine kinase. Glucose tolerance returns to normal postpartum in the majority of women with GDM. However, previous studies, in populations quite different from a Danish population, have shown that women with previous GDM have a high risk of developing overt diabetes mellitus later in life. Hence, we aimed to investigate the prognosis of women with previous GDM with respect to subsequent development of diabetes and also to identify predictive factors for the development of overt diabets in these women. A follow-up study of diet treated GDM women diagnosed during 1978 to 1985 at the Rigshospital, Copenhagen was performed. Glucose tolerance was evaluated in 241 women (81% of the GDM population) 2-11 years after pregnancy. Abnormal glucose tolerance was found in 34.4% of the women (3.7% IDDM, 13.7% NIDDM, 17% IGT) in contrast to a control group where none had diabetes and 5.3% had IGT. Logistic regression analysis identified the following independent risk factors for later development of diabetes: a high fasting glucose level at diagnosis of GDM, a delivery more than 3 weeks before term, and an abnormal OGTT 2 months postpartum. Low insulin secretion at diagnosis of GDM was also an independent risk factor. The presence of ICA and GAD-autoantibodies in pregnancy was associated with later development of IDDM. In another study the following techniques: hyperinsulinaemic euglycaemic clamp, indirect calorimetry and tritiated glucose infusion were used to evaluate insulin sensitivity in glucose tolerant nonobese women with previous GDM and controls. A decreased insulin sensitivity due to a decreased non-oxidative glucose metabolism in skeletal muscle was found in women with previous GDM. Hence, the activity of three key enzymes in intracellular glucose metabolism (GS, HK and PFK) was studied in skeletal muscle biopsies obtained in the basal state and after 3 h hyperinsulinaemia, with the aim to identify the cellular defects causing the decreased insulin sensitivity. However, no abnormalities in enzyme activity was found. The same group of previous GDM women had a relatively reduced insulin secretion evaluated by the IVGTT. A longitudinal study of 91 GDM women showed a relatively reduced insulin secretion to oral glucose in pregnancy, postpartum as well as 5-11 years later. Thus the present review has shown that even nonobese glucose tolerant women with previous GDM are characterized by the metabolic profile of NIDDM i.e. insulin resistance and impaired insulin secretion. Hence, the combination of this finding together with the significantly increased risk for development of diabetes indicates that all women with previous GDM should have a regular assessment of their glucose tolerance in the years after pregnancy. The first OGTT should be performed around 2 months postpartum in order to diagnose women already diabetic and to identify women with the highest risk for later development of overt diabetes. Women with previous GDM comprise a target group for future intervention trials with the aim to prevent or delay development of NIDDM and IDDM.
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PMID:Gestational diabetes mellitus and subsequent development of overt diabetes mellitus. 985 Aug 11

Within the last 5 years chromium (Cr) has been shown to play a role in glucose intolerance, Type 2 diabetes mellitus (Type 2 DM), and gestational diabetes. In addition, diabetes and the neuropathy of a patient on home parenteral nutrition were alleviated when supplemental Cr was added to total parenteral nutrition (TPN) solutions. In a study conducted in China that has been supported by studies in the United States, supplemental Cr as Cr picolinate improved the blood glucose, insulin, cholesterol, and hemoglobin A1C in people with Type 2 DM in a dose dependent manner. Follow-up studies of > 1 year have confirmed these studies. The requirement for Cr is related to the degree of glucose intolerance: 200 microg/day of supplemental Cr is adequate to improve glucose variables of those who are mildly glucose intolerant. However, people with more overt impairments in glucose tolerance and diabetes usually require more than 200 microg/day. Daily intake of 8 microg of Cr per kg body weight was also more effective than 4 microg/kg in women with gestational diabetes. The mechanism of action of Cr involves increased insulin binding, increased insulin receptor number, and increased insulin receptor phosphorylation. In summary, supplemental Cr has been shown to have beneficial effects without any documented side effects on people with varying degrees of glucose intolerance ranging from mild glucose intolerance to overt Type 2 DM.
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PMID:Chromium, glucose intolerance and diabetes. 985 33

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

Almost two decades of research have greatly increased our knowledge in the complex field of metabolic aberrations in polycystic ovary syndrome, but still many problems remain unsolved. The statistical association between insulin levels and androgens originally put the focus on possible direct cause-and-effect relationships between these factors. Indeed there is evidence that insulin may affect ovarian functions in multiple ways, presumably in some cases causing anovulation and hyperandrogenism. Clearly, insulin may increase biologically active testosterone through reducing SHBG levels. Conversely, major increases in androgen levels may induce muscular changes leading to reduced insulin-mediated glucose uptake. There are suggestions of increased steroidogenesis in both ovarian and adrenal pathways, with the net result of increased androgen production. There are also findings supporting increased corticosteroid production, which could contribute to insulin resistance directly or through promoting accumulation of abdominal fat, a typical feature of over-weight women with PCOS. Free fatty acids, released in great amounts from abdominal fat, may induce insulin resistance. Insulin resistance may also be due to a primary aberration in the insulin receptor. Putatively increased serine phosphorylation may cause both impairment of the insulin signal and increased 17,20 lyase activity, thus suggesting a common cause for insulin resistance and increased androgen production. There are also findings supporting a high prevalence of beta-cell dysfunction in PCOS, ranging from increased insulin secretion, not explained by insulin resistance or BMI, to failing beta-cell function, mainly in obese women during progress to glucose intolerance and NIDDM. Recent genetic findings also support a multifactorial genesis to PCOS, notably with positive findings both in genes regulating steroidogenesis and insulin secretion. It is suggested that PCOS is the result of "thrifty" genes, providing advantages in times of shortage of nutrition such as muscular strength, moderate abdominal fatness and decreased insulin sensitivity, i.e. an anabolic, energy saving constitution. However, when this constitution is exposed to unlimited food supplies and modern sedentary life style a full-blown PCOS with insulin resistance and infertility is triggered, presumably via several mechanisms, which follow a logical amplification system between two basic anabolic hormones, insulin and testosterone.
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PMID:Polycystic ovary syndrome and insulin resistance: thrifty genes struggling with over-feeding and sedentary life style? 985 13

1. We investigated whether JTT-501 (4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl]-3,5-isoxa zolidinedione) would improve insulin resistance in genetic (Zucker fatty rats) and non-genetic (high-fat fed rats) rodent models of obesity. 2. JTT-501 (10-100 mg kg(-1) day(-1)) was administered orally to Zucker fatty rats for 7-21 days. In the high-fat fed rat model, JTT-501 (100 mg kg(-1) day(-1) was administered orally for 7 days. In both models, JTT-501 improved metabolic abnormalities by enhancing insulin action during the glucose tolerance test and the euglycaemic-hyperinsulinaemic clamp study. In ex vivo assays, JTT-501 ameliorated the impaired insulin-sensitive glucose oxidation and lipid synthesis in peripheral tissues. Furthermore, JTT-501 enhanced insulin receptor autophosphorylation in hindlimb muscle. 3. JTT-501 reduced serum leptin concentrations in both models, but did not affect body weight or epididymal fat weight. 4. Our observations indicate that JTT-501 improves the metabolic abnormalities in both genetic and non-genetic insulin-resistant models by enhancing insulin action in peripheral tissues. These effects of JTT-501 are due, at least in part, to enhanced insulin receptor autophosphorylation. In addition, JTT-501 is able to reduce serum leptin concentrations in hyperleptinaemia of the insulin-resistant model. We expect JTT-501 to show promise for treating non-insulin dependent diabetes mellitus patients with insulin resistance.
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PMID:JTT-501, a novel oral antidiabetic agent, improves insulin resistance in genetic and non-genetic insulin-resistant models. 988 66

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

Dysfunction of the pancreatic beta cell is an important defect in the pathogenesis of type 2 diabetes, although its exact relationship to the insulin resistance is unclear. To determine whether insulin signaling has a functional role in the beta cell we have used the Cre-loxP system to specifically inactivate the insulin receptor gene in the beta cells. The resultant mice exhibit a selective loss of insulin secretion in response to glucose and a progressive impairment of glucose tolerance. These data indicate an important functional role for the insulin receptor in glucose sensing by the pancreatic beta cell and suggest that defects in insulin signaling at the level of the beta cell may contribute to the observed alterations in insulin secretion in type 2 diabetes.
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PMID:Tissue-specific knockout of the insulin receptor in pancreatic beta cells creates an insulin secretory defect similar to that in type 2 diabetes. 1002 99

Protein tyrosine phosphatase-1B (PTP-1B) has been implicated in the negative regulation of insulin signaling. Disruption of the mouse homolog of the gene encoding PTP-1B yielded healthy mice that, in the fed state, had blood glucose concentrations that were slightly lower and concentrations of circulating insulin that were one-half those of their PTP-1B+/+ littermates. The enhanced insulin sensitivity of the PTP-1B-/- mice was also evident in glucose and insulin tolerance tests. The PTP-1B-/- mice showed increased phosphorylation of the insulin receptor in liver and muscle tissue after insulin injection in comparison to PTP-1B+/+ mice. On a high-fat diet, the PTP-1B-/- and PTP-1B+/- mice were resistant to weight gain and remained insulin sensitive, whereas the PTP-1B+/+ mice rapidly gained weight and became insulin resistant. These results demonstrate that PTP-1B has a major role in modulating both insulin sensitivity and fuel metabolism, thereby establishing it as a potential therapeutic target in the treatment of type 2 diabetes and obesity.
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PMID:Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. 1020 63

The skeletal muscle activity of protein tyrosine phosphates 1B (PTP1B), a modulator of insulin and IGF-1 signaling, is reduced in obese nondiabetic subjects and in subjects with type 2 diabetes in comparison with leaner, nondiabetic controls. PTP1B mRNA, like many other signaling molecules, including the insulin receptor, is alternatively spliced. Since we have shown that the ratio of the insulin receptor splice variants is modulated by insulin in vitro and is related to insulin levels in vivo, we hypothesized that the relative ratios of the alternatively spliced PTP1B mRNA might also vary in humans in proportion to the degree of hyperinsulinemia. This was tested in 21 nondiabetic Pima Indians, a population at increased risk for obesity and type 2 diabetes. The relative ratio of the PTP1B splice variants was quantified using RT-PCR of total RNA extracted from fractionated monocytes. The ratio of the splice variants was positively correlated with fasting plasma insulin concentration (r = 0.757; P = 0.0001), 2-h plasma insulin concentration following an oral glucose tolerance test (r = 0.614; P = 0.01, n = 16), and percentage of body fat (r = 0.746; P = 0.0001). These data indicate that variability in the ratio of the two splice variants is due, in part, to in vivo levels of chronic hyperinsulinemia. This simple, noninvasive assay is therefore a potential biomarker for chronic hyperinsulinemia, similar to the HbAlc assay in use to monitor glucose management in diabetic patients.
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PMID:Insulin-inducible changes in the relative ratio of PTP1B splice variants. 1006 87

We have analyzed the association of variants in the genes for amylin, insulin receptor, insulin receptor substrate-1 (IRS-1), and coagulation factor V with type 2 diabetes mellitus. Random samples of subjects with type 2 diabetes and controls were taken from two population-based studies, the Hoorn and Rotterdam studies, to reduce the risk of artifactual associations. No association was found for variants in the genes for amylin, IRS-1, and coagulation factor V, nor was there any evidence for epistatic interactions between these gene variants. A significant difference in the frequency of the Arg972 allele of the IRS-1 gene was observed between control subjects from Hoorn and Rotterdam (9.4% vs. 18.6%; P < 0.05). The insulin receptor Met985 variant was found at frequencies of 4.4% and 1.8%, respectively, in type 2 diabetic (n = 433) and normoglycemic patients (n = 799; P < 0.02). Inclusion of data from two other studies yielded a summarized odds ratio of 1.87 (95% confidence interval, 1.06-3.29; P = 0.03). We conclude that the association between the Met985 variant in the insulin receptor gene and type 2 diabetes, which we previously reported in the Rotterdam study, is supported by thejoint analysis with a second population-based study and other studies. The large regional differences in allele frequency of the Arg972 allele of IRS-1 gene makes genetic association studies of this gene less reliable.
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PMID:Prevalence of variants in candidate genes for type 2 diabetes mellitus in The Netherlands: the Rotterdam study and the Hoorn study. 1008 86

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