Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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

The free amino acid content of diaphragm muscles of control and diabetic rats was studied 5 days after the injection of streptozotocin. Muscles were prepared for analysis either immediately after sacrifice or following incubation in balanced salt solution containing 5.5 mM glucose, with or without an electron acceptor, 0.02 mM methylene blue. Diaphragms of diabetic rats contained significantly more free taurine, glutamate, and branched chain amino acids than the controls at sacrifice, and significantly less glutamine, serine, asparagine, lysine, arginine, histidine, threonine, citrulline, and carnosine. Alanine decreased in plasma of diabetic rats but not in diaphragms before incubation. Hemidiaphragms of diabetic rats produced less alanine and more glutamate during incubation than controls. After incubation they contained less than half as much alanine and glutamine and twice as much glutamate than the controls, having released approximately 40% less alanine and 25% more glutamate into the medium than the controls. Glutamine release was not significantly different between the two groups. Methylene blue increased the free alanine content in the tissue water as well as alanine release by control and by diabetic muscles; the glutamate content of muscles decreased concomitantly. The effects of methylene blue were greater in the diabetic group. Branched chain amino acid release by diabetic muscles decreased during incubation with methylene blue. Muscles of diabetic rats contained more alpha-ketoglutarate than the controls after incubation with or without methylene blue. Methylene blue increased the alpha-ketoglutarate content of muscles and its release into the medium, the effect being greater in diabetics than in controls. Hemidiaphragms from diabetic rats released less pyruvate during incubation than controls, while lactate release by the two groups was not significantly different. Incubation with methylene blue caused a marked increase in pyruvate release by diabetic muscles, and a lesser stimulation in controls; lactate release increased in both groups. After incubation the lactate/pyruvate ratio in muscles was lower in the methylene blue treated group. The in vitro effect of 0.02 mM phenazine methosulfate on alanine production was similar to that of methylene blue. The data is compatible with the hypothesis that the NADH/NAD ratio may exert a restraining effect on alanine production and release by muscle. The progressive increase in this ratio may play a role in the eventual deceleration of gluconeogenesis during a prolonged fast and may restrain this process in uncompensated diabetes.
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PMID:The effect of diabetes and the redox potential on amino acid content and release by isolated rat hemidiaphragms. 738 25

Diabetes is known to cause impaired endothelium-dependent relaxation of blood vessels. The purpose of this study was to determine whether this endothelial dysfunction is a permanent defect or is reversible after acute arginine supplementation in vitro or by surgical intervention in vivo using syngeneic pancreatic islet transplantation. Lewis rats were injected with streptozotocin to induce diabetes and were studied either 8 or 12 weeks later. Another group received syngeneic islets via intraportal injection at 8 weeks of diabetes and were allowed to become euglycemic for 4 weeks before study. Thoracic aortic rings were tethered in isolated muscle baths, contracted with a submaximal concentration of norepinephrine, and challenged with either the endothelium-dependent vasodilator acetylcholine or the endothelium-independent vasodilator nitroglycerin. Relaxation to acetylcholine (but not nitroglycerin) was reduced in both 8- and 12-week diabetic rings compared with age-matched control rings. Preincubation of diabetic rings in vitro with L-arginine (but not D-arginine) restored relaxation to acetylcholine to normal to rings from 8-week but not 12-week diabetic animals. Plasma basic amino acids (arginine, lysine, and histidine) were reduced by diabetes, whereas other neutral or acidic amino acids were unchanged (phenylalanine, proline, and glutamate), reduced (serine, cysteine, threonine, tyrosine, tryptophan, and aspartate), or elevated (isoleucine, leucine, and valine). Islet transplantation restored to normal the changes in plasma amino acids. Elevation in blood glucose and total glycosylated hemoglobin in diabetic animals was normalized after islet transplantation. Furthermore, islet transplantation completely restored the defective endothelium-dependent relaxation to acetylcholine in diabetic rings.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1995 Sep
PMID:Syngeneic pancreatic islet transplantation reverses endothelial dysfunction in experimental diabetes. 765 36

In response to insulin, several proteins are phosphorylated on tyrosine and on serine/threonine residues. Decreased phosphorylation of signaling peptides by a defective insulin receptor kinase may be a cause of insulin resistance. Accordingly, inhibition of the appropriate phosphatases might increase the phosphorylation state of these signaling peptides and thereby elicit increased glucose transport. The purpose of this study was to examine the effect of the serine/threonine phosphatase inhibitor okadaic acid and the tyrosine phosphatase inhibitors phenylarsine oxide and vanadate on 2-deoxyglucose transport in insulin-resistant human skeletal muscle. All three phosphatase inhibitors stimulated 2-deoxyglucose transport in insulin-resistant skeletal muscle. These data suggest that these compounds have bypassed a defect in at least one of the signaling pathways leading to glucose transport. Furthermore, maximal transport rates induced by the simultaneous presence of insulin and phosphatase inhibitor in insulin-resistant muscle were equal to insulin-stimulated rates in lean control subjects. However, both vanadate alone and vanadate plus insulin stimulated 2-deoxyglucose transport significantly more in insulin-sensitive tissue than in insulin-resistant tissue. These results demonstrate that although vanadate is able to stimulate glucose transport in insulin-resistant muscle, it is not able to normalize transport to the same rate achieved in insulin-sensitive muscle.
Diabetes 1995 Jun
PMID:Okadaic acid, vanadate, and phenylarsine oxide stimulate 2-deoxyglucose transport in insulin-resistant human skeletal muscle. 778 33

We have recently identified a new member of the Ras/GTPase superfamily termed Rad which has unique sequence features and is overexpressed in the skeletal muscle of humans with type II diabetes (Reynet, C., and Kahn, C. R. (1993) Science, 262, 1441-1444). When expressed in bacteria as a glutathione S-transferase fusion protein, Rad bound [alpha-32P]GTP quickly and saturably. Binding was specific for guanine nucleotides and displayed unique magnesium dependence such that both GTP and GDP binding were optimal at relatively high Mg2+ concentrations (1-10 mM). Rad had low intrinsic GTPase activity which was greatly enhanced by a GTPase-activating protein (GAP) activity present in various tissues and cell lines. Several known GAPs had no stimulatory effect toward Rad. Conversion of Ser to Asn at position 66 in Rad (equivalent to position 12 in Ras) resulted in a total loss of GTP binding. Mutation of Pro61 (equivalent to Gly12 in Ras) or Gln109 (equivalent to Gln61 in Ras) had no effect on Rad GTPase activity, whereas creation of a double mutation at these positions resulted in exceptionally high intrinsic GTPase activity. In vitro, Rad was phosphorylated by the catalytic subunit of cAMP-dependent protein kinase (PK). Phosphopeptide mapping indicated two PKA phosphorylation sites near the COOH terminus. Rad also co-precipitated a serine/threonine kinase activity from extracts of various tissues and cell lines which catalyzed phosphorylation on Rad but was not inhibited by PKA inhibitor. Thus, Rad is a GTP-binding protein and a GTPase which has some structure/function similarities to Ras, but displays unique features. Rad may also be phosphorylated on serine/threonine residues by PKA and other kinases, as well as regulated by its own GAP which is present in many tissues and cell types.
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PMID:Characterization of Rad, a new member of Ras/GTPase superfamily, and its regulation by a unique GTPase-activating protein (GAP)-like activity. 787 54

Glut2, the facilitative glucose transporter isoform expressed in pancreatic beta cells, is believed to play a role in glucose-stimulated insulin secretion. Two polymorphisms that result in amino acid substitutions have been reported in the human Glut2 gene (Tanizawa, Y., Riggs, A. C., Chiu, K. C., Janssen, R. C., Bell, D. S. H., Go, R. P. C., Roseman, J. M., Acton, R. T., and Permutt, M. A. (1994) Diabetologia 37, 420-427). A threonine 110-->isoleucine substitution was present at equal frequency in diabetic and control populations, and a valine 197-->isoleucine substitution was discovered in a single allele of a patient with non-insulin-dependent diabetes. The effect of these amino acid changes on glucose transport activity was tested by expression of the mutant proteins in Xenopus oocytes. The polymorphism at threonine 110 had no effect on the expression of Glut2 protein or the uptake of 2-deoxyglucose. Remarkably, however, the highly conservative valine 197-->isoleucine amino acid change abolished transport activity of the Glut2 transporter expressed in Xenopus oocytes. This represents the first known dysfunctional mutation in a human facilitative glucose transporter protein. The presence of this mutation in a diabetic patient suggests that defects in Glut2 expression may be causally involved in the pathogenesis of non-insulin-dependent diabetes.
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PMID:A mutation in the Glut2 glucose transporter gene of a diabetic patient abolishes transport activity. 802 28

The TAP1 and TAP2 genes, located in the HLA class II region, encode subunits of a peptide transporter. Both genes display limited genetic variability; four different nucleotide substitutions have been found in the TAP2 gene. Here studies on linkage disequilibrium between TAP2 variants and HLA class II alleles are reported, in an attempt to evaluate whether TAP2 variants are associated with insulin-dependent diabetes mellitus (IDDM). As reported previously, a significant decrease of homozygosity for TAP2 alleles encoding alanine at residue 665 (665 Ala) and glutamine at 687 (687 Gln) paralleled by an increase in homozygosity for TAP2 alleles encoding threonine at residue 665 (665 Thr) and a stop codon at 687 (687 Stop), was found in both Finnish and Norwegian IDDM patients compared to random controls. However, a strong linkage disequilibrium between these TAP2 polymorphisms and given HLA-DR and -DQ genes was observed among healthy controls. The frequent 665 Thr and 687 Stop variants were in linkage disequilibrium both with the DR4-DQ8 and the DR3-DQ2 haplotypes, haplotypes which are strongly associated with IDDM. In contrast, the DR1-DQ5 and DR13-DQ6 (e.g. DQB1*0603) haplotypes, which are decreased among IDDM patients, were associated with the 665 Ala and 687 Gln variants. Thus, when DR- and DQ-matched patients and controls were compared, associations of the investigated TAP2 variants and IDDM were no longer detectable. These data, therefore, indicate that the associations previously found between certain TAP2 variants and IDDM are secondary to a primary association between this disease and particular DQ alpha beta heterodimers.
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PMID:Linkage disequilibrium between TAP2 variants and HLA class II alleles; no primary association between TAP2 variants and insulin-dependent diabetes mellitus. 847 1

Insulin elicits an array of biologic responses. Insulin exerts a regulatory role in almost all cells of the body and is the primary hormone responsible for signaling the storage and utilization of basic nutrients. On the molecular level, the actions of insulin are initiated by binding of insulin to the insulin receptor. Interaction of the alpha and beta subunits of the receptor results in tyrosine kinase activity, which is integral to the initiation of cascades of phosphorylation/dephosphorylation reactions that mediate a large number of the actions of insulin. Insulin-receptor substrate 1 may be central to phosphorylation reactions through a role in serine and threonine kinase activity. Insulin action may also involve the generation of low-molecular-weight mediators capable of modulating intracellular enzymes. The regulation of glucose transport is a primary feature of the physiologic role of insulin and is performed by a family of glucose-transporter proteins with different characteristics. One mechanism by which insulin exerts its effect on glucose transport is the stimulation of the translocation of the glucose transporter to the plasma membrane. Degradation of insulin occurs through diverse mechanisms at numerous sites in the body. Reversal of the insulin signal at the cellular level may be accomplished by a class of enzymes termed phosphotyrosine phosphatases, which may play a role in certain pathophysiologic states. Important roles for insulin-receptor kinase, glucose transporters, insulin-receptor substrate 1, and various intracellular enzymes in the actions of insulin have been demonstrated; nonetheless, the formulation of potential therapeutic strategies directed at particular stages of the insulin action cascade will require further elucidation of its components.
J Diabetes Complications
PMID:Molecular determinants of insulin action. 851 61

The endothelial response to kinin stimulation is the result of a series of complex intracellular reactions involving changes in the intracellular concentration of free calcium ([Ca2+]i) and intracellular pH, enhanced phosphorylation of several proteins via the activation of at least four distinct families of protein kinases, and activation of membrane ion transport systems. Some of the more recent developments in this field suggest that endothelial tyrosine kinases and tyrosine phosphatases as well as serine/threonine phosphatases are also activated in response to bradykinin. In addition, the finding that the mitogen-activated protein kinase (MAP kinase) pathway was tyrosine phosphorylated, and presumably activated, in endothelial cells after an increase in [Ca2+]i has wideranging implications for these cells. Indeed, MAP kinase recognizes many different substrates in the cell, including growth factor receptors, microtubule-associated proteins, specific serine-threonine protein kinases, phospholipase A2, and transcription factors. Further recent studies of interest have underscored the role of endothelium-derived hyperpolarizing factor in addition to nitric oxide and prostacyclin in the coronary vasculature. Indeed, this mediator, which seems to be an endothelium-derived, cytochrome P450-derived metabolite of arachidonic acid, would now appear to represent a substantial constitutive component of the vasodilator response to bradykinin.
Diabetes 1996 Jan
PMID:Molecular responses of endothelial tissue to kinins. 852 5

Genotypic abnormalities of the renin-ANG system have been suggested as a risk factor for the development of diabetic nephropathy. Cleavage of angiotensinogen is the rate-limiting step in the activation of the renin-ANG system. The TT genotype of a polymorphism encoding threonine instead of methionine (M235T) has been associated not only with increased plasma angiotensinogen concentration but also with essential hypertension. In addition, a polymorphism in the angiotensinogen gene substituting methionine for threonine (T174M) has been associated with hypertension in nondiabetic populations. We studied the relationship between these polymorphisms in the angiotensinogen gene in IDDM patients with diabetic nephropathy (121 men, 74 women, age 40.9 +/- 10 years, diabetes duration 27 +/- 8 years). There was no difference in M235T genotype distribution between IDDM patients with diabetic nephropathy and those with normoalbuminuria: 73/97/25 (37/50/13%) vs. 67/95/23 (36/52/12%) had MM/MT/TT genotypes, respectively. No difference in distribution of T174M genotypes between nephropathic and normoalbuminuric IDDM patients was observed either: 148/44/1 (77/23/0.5%) vs. 141/42/2 (76/23/1%) had TT/TM/MM genotypes, respectively. In patients with nephropathy, systolic blood pressure was higher (161 +/- 22 mmHg [mean +/- SD]) in patients carrying TT genotype of the M235T angiotensinogen polymorphism as compared with patients with MM or MT genotypes (150 +/- 23 mmHg; P = 0.03). We conclude that neither the M235T nor the T174M polymorphism in the angiotensinogen gene contributes to genetic susceptibility to diabetic nephropathy in white IDDM patients, whereas the TT genotype of the M235T is associated with elevated blood pressure in patients with diabetic nephropathy.
Diabetes 1996 Mar
PMID:Angiotensinogen gene polymorphisms in IDDM patients with diabetic nephropathy. 859 44

The allele 235T (a threonine in place of a methionine at position 235) of angiotensinogen has been found to be associated with a predisposition to essential hypertension. We investigated whether this allele also confers increased susceptibility to nephropathy in patients with insulin-dependent diabetes mellitus (IDDM). A group of 380 patients who had had IDDM for 15 to 20 years were genotyped at the angiotensinogen 235 locus. Included were 75 patients with normoalbuminuria (albumin excretion rate < 30 micrograms/min), two series of patients with microalbuminuria (n = 30 and n = 136), and two series with overt proteinuria (n = 41 and n = 98). Allele 235T frequency was higher among cases with microalbuminuria (0.41 in the two series combined) or overt proteinuria (0.40) than in the normoalbuminuria group (0.36). However, this difference was not statistically significant with this sample size (chi 2 = 1.2, P = NS with 2 df). Under a recessive model, allele 235T homozygotes had a 1.6-fold risk of developing nephropathy relative to carriers of other genotypes, but this value was not significantly different from 1(95% CI = 0.8 to 3.5). The strength of the association did not improve after stratification by degree of glycemic control. With respect to the hypertension in these IDDM patients, no association with allele 235T was found. Allele 235T frequencies in normotensive and hypertensive individuals were 0.363 and 0.353, respectively, among normoalbuminuric IDDM individuals (chi 2 = 0.01, P = NS) and 0.411 and 0.414 among microalbuminuric IDDM subjects (chi 2 = 0.0, P = NS). We conclude that the angiotensinogen polymorphism M235T might influence susceptibility to nephropathy in insulin-dependent diabetes, but its effect, if any, is rather small and independent of hypertension.
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PMID:Angiotensinogen polymorphism M235T, hypertension, and nephropathy in insulin-dependent diabetes. 862 Dec 7


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