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)

Basal serum growth hormone and response of GH to GRF in 10 patients with noninsulin-dependent diabetes and in 10 control subjects were studied. The basal GH level in NIDDM was higher than that in control subjects. There was a significant difference. After an intravenous bolus of hGRF 1-29 NH2 with the dose of 1 microgram/kg body weight, GH (Peak level-basal level) decreased in NIDDM patients in comparing with control group (P < 0.05). These findings may suggest that the pituitary GH reserve is reduced in patients with NIDDM. There exists some defect in central GH control in diabetics with enhanced somatostatin secretion and abnormal sensitivity of the GH secretion cells to a variety of regulatory factors including GRF, glucose, amino-acids, free fat acid.
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PMID:[Blunted growth hormone response to hGRF 1-29 NH2 in patients with non-insulin-dependent diabetes mellitus]. 130 83

This study reports plasma levels of a specific nonenzymatic peroxidation product of arachidonic acid, esterified 8-epi-PGF2 alpha, from healthy- and NIDDM individuals as an index of oxidative stress in vivo. Plasma 8-epi-PGF2 alpha was isolated by solid-phase extraction on a C18 followed by an NH2 cartridge and analyzed by GC-MS/NICI as PFB-ester/TMS-ether derivative. We found that the average concentration of esterified 8-epi-PGF2 alpha among NIDDM subjects (0.93 +/- 0.07 nM, n = 39) was higher (P < 0.0001, Mann-Whitney test) than in healthy individuals (0.28 +/- 0.04 nM, n = 15). These data indicate that NIDDM is associated with increased plasma lipid peroxidation.
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PMID:Plasma 8-epi-PGF2 alpha levels are elevated in individuals with non-insulin dependent diabetes mellitus. 762 10

A suppressed growth hormone (GH) response to GH-releasing hormone (GHRH) in both lean and overweight type II diabetics has been reported. Pyridostigmine (PD), an acetylcholinesterase inhibitor, elicits GH secretion when administered alone and enhances the GH response to GHRH in normal subjects. The aim of our study was to evaluate the effect of PD on GHRH-stimulated GH secretion in both lean and obese type II diabetic patients. We studied 16 patients with type II diabetes mellitus (seven lean and nine obese). Eleven nondiabetic subjects (six lean and five obese) served as controls. Each subjects underwent treatment with (1) 120 mg PD orally or (2) 2 tablets of placebo orally, 60 minutes before intravenous (IV) injection of 100 micrograms GHRH-(1-29)NH2. We have found no significant differences in GH responses to GHRH between obese diabetics and obese controls. On the other hand, the absolute GH levels were significantly suppressed in lean type II diabetics compared with lean controls at 15 and 30 minutes after GHRH injection. Obese diabetic subjects had slightly but not significantly decreased GH responses to GHRH+PD compared with obese nondiabetic subjects (8.36 +/- 1.62 v 14.4 +/- 7.62 micrograms/L). Lean type II diabetics showed a blunted GH release after GHRH+PD compared with normal-weight healthy subjects (GH peaks, 15.77 +/- 2.17 v 40.88 +/- 6.17 micrograms/L, P < .05). PD enhanced significantly the GH response to GHRH in obese diabetics, obese controls, and non-obese controls (P < .05), but not in non-obese type II diabetics.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of pyridostigmine on the growth hormone response to growth hormone-releasing hormone in lean and obese type II Diabetic patients. 802 15

Insulin receptor substrate-1 (IRS-1) plays an important role in insulin-stimulated signaling mechanisms. Therefore, we investigated the frequency and clinical significance of variants in the coding region of this gene in patients with non-insulin-dependent diabetes (NIDDM). Initial screening included a population-based sample of 40 Finnish patients with typical NIDDM. Applying single strand conformation polymorphism analysis the following amino acid substitutions were found among the 40 NIDDM patients: Gly818-Arg, Ser892Gly, and Gly971Arg. The first two variants have not been previously reported. Additional samples of 72 patients with NIDDM and 104 healthy control subjects with completely normal oral glucose tolerance test and a negative family history of diabetes were screened. The most common polymorphism was the Gly971Arg substitution which was found in 11 (9.8%) of 112 NIDDM patients and in 9 (8.7%) of 104 control subjects. The Gly818Arg substitution was found in 2 (1.8%) of NIDDM patients and in 2 (1.9%) of control subjects, and the Ser892Gly substitution was found in 3 (2.7%) NIDDM patients and in 1 (1.0%) control subject. The Gly971Arg substitution was not associated with an impairment in insulin secretion capacity (estimated by insulin responses in an oral glucose tolerance test or by the hyperglycemic clamp) or insulin action (estimated by the euglycemic clamp). Of the three amino acid substitutions observed Ser892Gly is the most interesting one since it abolishes one of the potential serine phosphorylation sites (SPGE) which is located immediately NH2-terminal to the only SH2 binding site of growth factor receptor-bound protein (GRB2), and thus could potentially influence some aspects of signal transduction and metabolic response to insulin.
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PMID:Insulin receptor substrate-1 variants in non-insulin-dependent diabetes. 808 55

N-Myristoyltransferase is the enzyme that catalyses the transfer of myristate from myristoyl-CoA to the NH2-terminal glycine residue of a number of protein of diverse functions. Many of the known myristoylated proteins are important in signal transduction. We have compared the activity of rat liver N-myristoyltransferase from lean and obese (fa/fa) Zucker rats (a model for non-insulin dependent diabetes mellitus, NIDDM). N-myristoyltransferase activity isolated from the particulate fraction of obese (fa/fa) Zucker rat liver was approximately 4.7-fold lower than the corresponding activity observed in either the controls or the vanadate-treated obese rat livers. This pattern was only observed in the particulate fraction; the homogenate and soluble N-myristoyltransferase activities were not significantly different to the control activities. N-myristoyltransferase activity isolated from the brain of the four groups showed no significant variations. These results, and previous work [King, M. J., Pugazhenthi, S., Khandelwal, R. L. and Sharma, R. K. (1993) Biochim. Biophys. Acta. 1165, 259-262], would indicate that the rat liver particulate N-myristoyltransferase activity appears to be inversely proportional to the level of plasma insulin, implicating insulin in the control of N-myristoylation. The specific activity of the particulate liver N-myristoyltransferase was approximately 10-fold higher than that of the soluble liver N-myristoyltransferase, raising the possibility that N-myristoyltransferase exists in 2 populations, with the active form of N-myristoyltransferase residing in the membranous fraction. This situation could provide a system whereby N-myristoylation is regulated by the translocation of N-myristoyltransferase from the cytosol to its active site in the membranes.
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PMID:Membrane-associated N-myristoyltransferase activity is reduced in obese (fa/fa) Zucker rat liver. 824 Mar 41

N-Myristoyltransferase (NMT) catalyses the transfer of myristate from myristoyl-CoA to the NH2-terminal glycine residue of several proteins and are important in signal transduction. STZ-induced diabetes (an animal model for insulin-dependent diabetes mellitus, IDDM) resulted in a 2-fold increase in rat liver NMT activity as compared with control animals. In obese Zucker (fa/fa) rats (an animal model for non-insulin dependent diabetes mellitus, NIDDM) there was a approximately 4.7-fold lower liver particulate NMT activity as compared with the control lean rat livers. Administration of sodium orthovanadate to the diabetic rats normalised liver NMT activity. These results would indicate that the rat liver particulate N-myristoyltransferase activity appears to be inversely proportional to the level of plasma insulin, implicating insulin in the control of N-myristoylation.
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PMID:In vivo modulation of N-myristoyltransferase activity by orthovanadate. 892 31

The insulin-like growth factors (IGFs) are transported by a family of high-affinity binding proteins (IGFBPs) that protect IGFs from degradation, limit their binding to IGF receptors, and modulate IGF actions. The six classical IGFBPs have been believed to have no affinity for insulin. We now demonstrate that IGFBP-7/mac25, a newly identified member of the IGFBP superfamily that binds IGFs specifically with low affinity is a high-affinity insulin binding protein. IGFBP-7 blocks insulin binding to the insulin receptor and thereby inhibiting the earliest steps in insulin action, such as autophosphorylation of the insulin receptor beta subunit and phosphorylation of IRS-1, indicating that IGFBP-7 is a functional insulin-binding protein. The affinity of other IGFBPs for insulin can be enhanced by modifications that disrupt disulfide bonds or remove the conserved COOH terminus. Like IGFBP-7, an NH2-terminal fragment of IGFBP-3 (IGFBP-3((1-87))), also binds insulin with high affinity and blocks insulin action. IGFBPs with enhanced affinity for insulin might contribute to the insulin resistance of pregnancy, type II diabetes mellitus, and other pathological conditions.
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PMID:Inhibition of insulin receptor activation by insulin-like growth factor binding proteins. 938 10

Proglucagon contains the sequence of two glucagon-like peptides, GLP-1 and GLP-2, secreted from enteroendocrine cells of the small and large intestine. GLP-1 lowers blood glucose in both NIDDM and IDDM patients and may be therapeutically useful for treatment of patients with diabetes. GLP-1 regulates blood glucose via stimulation of glucose-dependent insulin secretion, inhibition of gastric emptying, and inhibition of glucagon secretion. GLP-1 may also regulate glycogen synthesis in adipose tissue and muscle; however, the mechanism for these peripheral effects remains unclear. GLP-1 is produced in the brain, and intracerebroventricular GLP-1 in rodents is a potent inhibitor of food and water intake. The short duration of action of GLP-1 may be accounted for in part by the enzyme dipeptidyl peptidase 4 (DPP-IV), which cleaves GLP-1 at the NH2-terminus; hence GLP-1 analogs or the lizard peptide exendin-4 that are resistant to DPP-IV cleavage may be more potent GLP-1 molecules in vivo. GLP-2 has recently been shown to display intestinal growth factor activity in rodents, raising the possibility that GLP-2 may be therapeutically useful for enhancement of mucosal regeneration in patients with intestinal disease. This review discusses recent advances in our understanding of the biological activity of the glucagon-like peptides.
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PMID:Glucagon-like peptides. 951 8

The homeodomain transcription factor insulin promoter factor-1 (IPF-1) is required for development of the pancreas and also mediates glucose-responsive stimulation of insulin gene transcription. Earlier we described a human subject with pancreatic agenesis attributable to homozygosity for a cytosine deletion in codon 63 of the IPF-1 gene (Pro63fsdelC). Pro63fsdelC resulted in the premature truncation of an IPF-1 protein which lacked the homeodomain required for DNA binding and nuclear localization. Subsequently, we linked the heterozygous state of this mutation with type 2 diabetes mellitus in the extended family of the pancreatic agenesis proband. In the course of expressing the mutant IPF-1 protein in eukaryotic cells, we detected a second IPF-1 isoform, recognized by COOH- but not NH2-terminal-specific antisera. This isoform localizes to the nucleus and retains DNA-binding functions. We provide evidence that internal translation initiating at an out-of-frame AUG accounts for the appearance of this protein. The reading frame crosses over to the wild-type IPF-1 reading frame at the site of the point deletion just carboxy proximal to the transactivation domain. Thus, the single mutated allele results in the translation of two IPF-1 isoproteins, one of which consists of the NH2-terminal transactivation domain and is sequestered in the cytoplasm and the second of which contains the COOH-terminal DNA-binding domain, but lacks the transactivation domain. Further, the COOH-terminal mutant IPF-1 isoform does not activate transcription and inhibits the transactivation functions of wild-type IPF-1. This circumstance suggests that the mechanism of diabetes in these individuals may be due not only to reduced gene dosage, but also to a dominant negative inhibition of transcription of the insulin gene and other beta cell-specific genes regulated by the mutant IPF-1.
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PMID:Insulin promoter factor-1 gene mutation linked to early-onset type 2 diabetes mellitus directs expression of a dominant negative isoprotein. 964 77

The hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide (GLP)-1 act on the pancreas to potentiate glucose-induced insulin secretion (enteroinsular axis). These hormones (incretins) are rapidly hydrolyzed by the circulating enzyme dipeptidyl peptidase IV (DP IV) into biologically inactive NH2-terminally truncated fragments. This study describes the effect of inhibiting endogenous DP IV with a specific DP IV inhibitor, isoleucine thiazolidide (Ile-thiazolidide), on glucose tolerance and insulin secretion in the obese Zucker rat. In initial studies, the specificity of Ile-thiazolidide as an inhibitor of incretin degradation was determined using matrix-assisted laser desorption/ionization-time of flight mass spectrometry. These results showed that inhibiting DP IV activity with Ile-thiazolidide blocked the formation of NH2-terminally truncated GIP and GLP-1. Oral administration of Ile-thiazolidide resulted in rapid inhibition of circulating DP IV levels by 65% in obese and lean Zucker rats. Suppression of DP IV levels enhanced insulin secretion in both phenotypes with the most dramatic effect occurring in obese animals (150% increase in integrated insulin response vs. 27% increase in lean animals). Ile-thiazolidide treatment improved glucose tolerance in both phenotypes and restored glucose tolerance to near-normal levels in obese animals. This was attributed to the glucose-lowering actions of increasing the circulating half-lives of the endogenously released incretins GIP and, particularly, GLP-1. This study suggests that drug manipulation of plasma incretin activity by inhibiting the enzyme DP IV is a valid therapeutic approach for lowering glucose levels in NIDDM and other disorders involving glucose intolerance.
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PMID:Improved glucose tolerance in Zucker fatty rats by oral administration of the dipeptidyl peptidase IV inhibitor isoleucine thiazolidide. 970 25


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