Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin resistance syndromes are heterogeneous in either severity or mechanism. Many drugs have been shown to counteract various elements of insulin resistance. Some of them, by normalization of metabolic parameters, decrease insulin resistance induced by chronic hyperglycemia in diabetes. Insulin and, to some extent, sulfonylureas are in this group, but these drugs are not stricto sensu medication of insulin resistance. Some drugs sensitize peripheral tissues to the action of insulin. For instance, biguanides and thiazolidine-dione facilitate translocation to the membrane of glucose transporter in presence of insulin. Other compounds as vanadate or IGF-1 mimic some peripheral action of insulin. Finally, blockade of FFA oxidation by specific inhibitors (methylpalmoxyrate) can limit insulin resistance. In 1992, among these compounds, specific of insulin resistance, biguanides are mostly used. However, the efficacy of these drugs is moderate and limited to type 2 diabetes.
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PMID:Pharmacological approach in the treatment of insulin resistance. 130 17

The serum levels of 34K insulin-like growth factor (IGF)-binding protein were measured by RIA in 88 type 1 diabetic patients, 9 patients with type 2 diabetes, 7 patients with insulinoma, 19 normal subjects (all after an overnight fast), and 82 normal subjects after a breakfast meal. In addition, the effect of 2- to 3-h euglycemic steady state hyperinsulinemia on serum IGF-binding protein and IGF-1 levels was studied in some subjects in each of the fasted groups. Compared with normal subjects, the mean serum IGF-binding protein levels were 4-fold (P less than 0.001) higher in type I diabetic patients treated with conventional insulin injections, 2.5-fold (P less than 0.001) higher in those treated with continuous sc insulin infusion, and 2-fold (P less than 0.05) higher in patients with type 2 diabetes. In the patients with insulinoma, the mean IGF-binding protein level was 63% below normal (P less than 0.001), and it normalized after removal of the tumor. There was a slight negative correlation between the IGF-binding protein level and insulin dose in the diabetic patients (r = -0.22; P less than 0.05). In normal subjects, serum insulin concentrations were 2-fold higher (P less than 0.001) and the IGF-binding protein level was 29% lower after a meal (P less than 0.05) than in the fasting state. Serum IGF-I concentrations were virtually identical in the type 1 and 2 diabetic patients, insulinoma patients, and normal subjects. During steady state euglycemic hyperinsulinemia, the IGF-binding protein level fell by 40-70% in each group (P less than 0.001), whereas the IGF-I level declined (P less than 0.05) in the type 2 diabetic patients only. The decline of binding protein was closely related to the baseline level (r = 0.94; P less than 0.001). No correlation was found between serum IGF-I and binding protein levels in any group. In conclusion, 1) serum 34K IGF-binding protein levels are elevated in type 1 and 2 diabetic patients and decreased in patients with insulinoma; 2) the serum binding protein, but not IGF-I concentration is decreased by acute hyperinsulinemia; and 3) these data suggest that the serum insulin concentration plays a role in regulation of the serum 34K IGF-binding protein concentration.
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PMID:Insulin regulates the serum levels of low molecular weight insulin-like growth factor-binding protein. 244 29

Sera and their IgG from 10/104 diabetic patients (five with insulin-dependent and five with noninsulin-dependent diabetes, NIDDM), contained antibodies that bound 125I-labeled purified human insulin receptors. 9 of these 10 sera failed to inhibit insulin binding (to rat hepatocytes and human placental membranes), did not stimulate glucose oxidation (by isolated rat adipocytes), and did not bind human placental IGF-1 receptors. Only one serum (and its IgG) modestly inhibited insulin binding and stimulated glucose oxidation. We conclude (a) that sera from 9/104 diabetics (five insulin-dependent and four noninsulin-dependent) contained a newly identified species of IgG antiinsulin receptor autoantibodies (AIRA), which bound to the insulin receptor at a locus different from the insulin binding site and did not inhibit insulin binding; and (b) that only 1/104 diabetic sera contained low-titer "conventional" antiinsulin receptor autoantibodies that bound to the insulin receptor at or near the insulin binding site, inhibited insulin binding and caused a clinical condition, which was difficult to distinguish from typical NIDDM.
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PMID:Nonbinding inhibitory antiinsulin receptor antibodies. A new type of autoantibodies in human diabetes. 296 69

The suggestion of a role for the abnormally regulated growth hormone (GH) in the pathogenesis of diabetes mellitus (DM), implicates also the somatomedins, as mediators of some of GH actions. The present study was aimed at assessing the somatomedin response to exogenous GH administration in diabetes type II (NIDDM) subjects as well as its possible relationship with the degree of control of diabetes. Twenty-two subjects (seven controls and 15 NIDDM patients), matched for sex and age, underwent human GH infusion (0.1 U/kg b.w.) over a one-hour period (time 0 to 1 hour). Total somatomedins (SMs) were measured by human placental membrane radioreceptor assay (in which all SMs crossreact) and Somatomedin-C (SM-C) was determined by a specific RIA. Values were obtained from plasma samples at times 0, 1, 4, 6, and 24 hours. Glycosylated hemoglobin (HbA1a-c) measurements were done from blood samples obtained at time 0. The increase in SMs following GH infusion in NIDDM group was not significantly different from that of the controls. In contrast, the SM-C increase at time 6 and 24 hours were significantly higher than in controls (p less than 0.05 and p less than 0.01, respectively). No significant difference was found between SMs or SM-C response to GH infusion in patients with HbA1a-c greater than 10% vs. less than 10%. These results indicate an exaggerated and prolonged increase in SM-C synthesis following exogenous GH infusion in NIDDM subjects, apparently unrelated to the degree of control of diabetes.
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PMID:Exaggerated somatomedin-C response to human growth hormone infusion in patients with type II diabetes mellitus. 653 51

NIDDM is likely to have a major genetic component in view of the different prevalence between ethnic groups, the familial clustering, and the high concordance in monozygotic twins. Linkage analysis of extended pedigrees of patients with maturity-onset diabetes of the young (MODY) identified the glucokinase gene mutations. Specific phenotypes have also led to the discovery of the insulin gene mutations in patients with high insulin or proinsulin levels, to the insulin receptor mutations in patients with marked insulin resistance, and to the mutations in mitochondrial DNA associated with deafness and maternal inheritance. These four types of diabetogenic gene mutations account for only a minor proportion of NIDDM. Direct screening for mutations in candidate genes with single-strand conformation polymorphism or heteroduplex screening or with direct sequencing in the diabetic patients with the appropriate pathophysiological abnormality can be a successful strategy. Genetic diagnosis provides clear definite diagnosis and specific therapies, such as IGF-1 for the insulin receptor mutations and coenzyme Q10 for the mitochondrial gene mutations.
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PMID:[Genetic diagnosis of diabetes mellitus]. 778 64

A 58-year-old woman was admitted to our hospital for impaired consciousness, hyperglycemia and bitemporal hemianopsia. She was diagnosed as having NIDDM one year ago and was treated with diet and glibenclamide (1.25 mg/day) for 6 months. However, she stopped her medical treatment one month ago and then polydipsia and general fatigue were manifested. She was admitted to a hospital five days ago at which time hyperglycemia (405 mg/dl) and anemia (Hb8.0g/dl) were detected. She was transferred to our hospital for control of blood glucose and further examination of bitemporal hemianopsia. She showed typical acromegalic features including enlargement of the nose, lips and tongue, increased heel pad and acral growth. Conscious disturbance was cured by the infusion of saline and the administration of insulin. Endoscopy revealed an active gastric ulcer (A1). Endocrine data disclosed increased GH levels in plasma and urine, whereas plasma IGF-1 levels were low. Plasma GH paradoxically increased following the administration of TRH. A water deprivation test showed an impaired increase in urinary osmolarity, indicating partial central diabetes insipidus (DI). MRI with Gd-contrast revealed a macroadenoma which progressed toward suprasella. She was diagnosed as having acromegaly, partial DI and probable hyperosmolar hyperglycemic nonketotic diabetic pre-coma. Polyuria (5-101/day) due to partial DI was controlled by the administration of DDAVP (10 micrograms/day). The constant subcutaneous administration of octreotide (240 micrograms/day) resulted in normal plasma GH levels and a marked shrinkage of the pituitary tumor. The pituitary tumor was finally removed by the transsphenoidal approach following treatment with octreotide for 4 months. HE staining of the pituitary tumor showed atrophic and acidophilic cells surrounded by hyaloid connective tissue. After the surgery, plasma GH levels were normalized and complications were cured. In conclusion, this is a very rare case of acromegaly associated with diabetic pre-coma and partial DI, and effectively treated with constant subcutaneous infusion of octreotide.
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PMID:[Effective treatment with constant subcutaneous infusion of octreotide in a patient with acromegaly associated with diabetic pre-coma and diabetes insipidus]. 785 21

Plasma IGF-1 was measured in 38 diabetic pregnant women (DPW) and in 12 non diabetic pregnant women (NDPW) during the 1st, 2nd and 3rd trimester of pregnancy. IGF-1 was measured in the cord blood of 24 infants of diabetic mothers (IDDM) and IGF-1 in 11 infants of non diabetic mothers (NIDDM). A progressive and significant (p < 0.0001) increase of IGF-1 values was found throughout the pregnancy both in DPW and NDPW IGF-1 (149 +/- 18 ng/ml vs 181 +/- 14 ng/ml, 184 +/- 17 ng/ml vs 232 +/- 25 ng/ml, 279 +/- 20 ng/ml vs 325 +/- 17 ng/ml). Furthermore IGF-1 decreased significantly soon after delivery in both groups of women. In type 1 diabetic pregnant women IGF-1 values were significantly lower than the controlled non diabetic patients. IGF-1 in the cord blood was significantly higher in IDDM than in NIDDM 86 +/- 7 ng/ml and 62 +/- 7 ng/ml respectively (p < 0.03). In addition, DPW plasma levels IGF-1 were positively correlated with the weight of the placenta (r = 0.233, p < 0.03) and negatively correlated with the diabetes duration (r = 0.412, p < 0.05). No correlations were found between IGF-1 cord blood concentrations and gestational age, birth weight and length, but there was a significant correlation with weight percentile (r = 0.846, p < 0.001). No correlation was found between maternal IGF-1 plasma levels and other parameters like insulin need, weight gain, metabolic control and time of delivery.
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PMID:IGF-1 levels in diabetic pregnant women and their infants. 954 66

1. Using whole-cell and cell-attached recording configurations, the effects of insulin on leptin activation of ATP-sensitive K+ (KATP) channels were examined in the CRI-G1 insulinoma cell line. 2. Whole-cell recordings demonstrated that the leptin-induced hyperpolarization and increased potassium conductance are completely occluded by prior exposure to insulin (1-50 nM). In cell-attached recordings, insulin prevented leptin activation of tolbutamide-sensitive KATP channels. Furthermore, insulin (50 nM) slowly and completely reversed the effects of leptin (10 nM), an action not attributable to direct inhibition of KATP channels per se. 3. Low concentrations of insulin-like growth factor-1 (IGF-1; 10-100 nM) failed to prevent leptin activation of KATP channels, although higher concentrations (1 microM) did inhibit leptin actions. 4. The action of insulin was specific for leptin, as the hyperglycaemic agent diazoxide activated KATP channels following prior exposure to insulin. 5. Wortmannin (1-10 nM) and LY 294002 (10 microM) prevented leptin activation of KATP channels, indicating an involvement of phosphoinositide 3-kinase (PI 3-kinase). 6. In conclusion, leptin activation of KATP channels is counter-regulated by insulin in the CRI-G1 insulinoma cell line. This feedback mechanism may be important in the local integration of hormonal signals which regulate insulin secretion and in alterations of metabolic homeostasis associated with obesity and non-insulin dependent diabetes mellitus (NIDDM).
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PMID:Insulin occludes leptin activation of ATP-sensitive K+ channels in rat CRI-G1 insulin secreting cells. 971 53

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

Insulin receptor substrate-2 (IRS-2) belongs to a family of cytoplasmic adaptor proteins, which link insulin, IGF-1, and cytokine receptor tyrosine kinases to signaling pathways regulating metabolism, growth, and differentiation (1-3). IRS-2-deficient mice display all characteristics of type 2 diabetes, suggesting that dysfunction of the IRS-2 gene may contribute to the pathogenesis of human type 2 diabetes (4). Based on its progesterone inducibility, we have recently cloned and sequenced a full-length human IRS-2 cDNA containing an open reading frame (ORF) of 4,014 bp and 5'- and 3'-untranslated regions (UTRs) of 516 and 2,466 bp (5). Although the IRS-2 gene has previously been thought to lack introns within the coding region (6,7), the amino acid sequence predicted from our cDNA sequence differed at its very COOH-terminal end from an IRS-2 protein sequence derived from genomic IRS-2 sequences. Therefore, we carefully analyzed the genomic structure of the IRS-2 gene and found that the IRS-2 gene contains an intron that disrupts the ORF. Characterization of promoter and 5'-flanking regions of IRS-2 by sequencing, reporter gene assays, and chromatin structure analysis suggests that elements conferring progesterone inducibility are not located immediately upstream of the gene promoter.
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PMID:Human insulin receptor substrate-2: gene organization and promoter characterization. 1048 Jun 23


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