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)

Infusion of somatostatin, an inhibitor of glucagon secretion, in insulin-dependent diabetics resulted in a 75-100% reduction in the blood-glucose rise after oral glucose administration, but did not improve intravenous glucose tolerance. Somatostatin reduced blood-xylose levels by 50-90% after ingestion of this pentose and delayed the peak increment in blood-xylose by 1-2 h. Similar effects on blood-xylose levels and a 30% reduction in splanchnic blood-flow were observed in normal subjects during infusion of somatostatin. Glucagon administration (3 ng per kg per min) or intraduodenal administration of xylose did not reverse somatostatin's effect on xylose tolerance. Somatostatin reduces postprandial hyperglycaemia in diabetes primarily by decreasing and/or delaying carbohydrate absorption rather than enhancing carbohydrate disposal. This effect may be mediated, in part, but a reduction in splanchnic blood-flow. These findings indicate that postprandial hyperglycaemia in diabetes is due primarily to insulin deficiency rather than glucagon excess.
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PMID:Influence of somatostatin on carbohydrate disposal and absorption in diabetes mellitus. 6 40

Both alloxan and streptozotocin produce beta-cell necrosis in the rat. Previous studies have shown protection against alloxan toxicity by D-glucose, D-mannose, and the nonmetabolized analogue 3-0-methyl-D-glucose and removal of this protective effect by D-mannoheptulose. The effect of several agents (i.v. infusion) against the beta-cell toxic effect of streptozotocin (60 mg./kg. i.v. in 24-hour-fasted 200-gm. male rats) was studied. Protection was determined by plasma glucose concentrations 24 and 48 hours later and, in certain experiments, by histologic examination of the islets. D-glucose and D-mannose provided no protection. Similarly, D-galactose, D-fructose, alpha-methyl-D-glucoside, D-L-glyceraldehyde, D-xylose, and D-glucosamine had no effect. However, 3-0-methyl-D-glucose administered immediately before streptozotocin resulted in progressive inhibition of beta-cell toxicity with complete protection at 0.83 mMoles per rat. The protective effect of 3-0-methyl-D-glucose was not altered by mannoheptulose. 2-Deoxy-D-glucose, which has no effect against alloxan, provided nearly complete protection against streptozotocin at 2.2 mMoles per rat. The effects of 3-0-methyl-D-glucose and 2-deoxy-D-glucose were additive and were not altered by glucose. Furthermore, the 3-0-methyl-D-glucose as well as 2-deoxy-D-glucose protective effects were still present, albeit attenuated, when these agents were given following the administration of streptozotocin. This is in contrast to alloxan, against which 3-0-methyl-D-glucose provides protection only when given before alloxan. 3-0-Methyl-D-glucose is the only carbohydrate protective against both streptozotocin and alloxan in the rat. However, several silent differences seem to exist between the mechanisms of beta-cytotoxic effects of these two diabetogenic compounds.
Diabetes 1976 Jul
PMID:Studies on streptozotocin diabetes. 13 82

The effect of an ovine corticotropin-releasing factor (oCRF) bolus administered intravenously at the onset of glucose ingestion during oral glucose tolerance tests (OGTTs) was evaluated in conscious lean (FA/FA) and genetically obese (fa/fa) rats. When the amount of oCRF was purposely small to not stimulate the hypothalamo-pituitary-adrenal (HPA) axis, it normalized the glucose intolerance of genetically obese rats as tested during OGTTs and decreased their insulin output, whereas it had no effect in lean rats. In obese rats, plasma xylose levels measured after the ingestion of a xylose load were unaltered by the intravenous oCRF bolus, indicating that the beneficial effect of oCRF on glucose intolerance of fa/fa rats was unlikely to be dependent on glucose absorption. When the intravenous bolus of oCRF was doubled at the onset of OGTTs, it stimulated the HPA axis and produced a worsening of glucose intolerance in obese rats together with an increase in their insulin response. Again, it had no effect in lean rats. The abnormal intravenous glucose tolerance of obese rats was unaffected by the administration of an oCRF bolus: This is in keeping with previous data showing that bypassing the oral cavity fails to elicit several sensory reflexes that markedly influence subsequent glucose clearance. It has been suggested that obese rats may have deficient oropharyngeal reflexes that could be reactivated by the oCRF bolus, thereby being responsible for the normalization of their impaired OGTT, which lies in the hepatic glucose production process.
Diabetes 1992 Apr
PMID:Beneficial effect of intravenous bolus of corticotropin-releasing factor on glucose intolerance of genetically obese (fa/fa) rats. 160 74

Cultured neuroblastoma, cerebral microvessel endothelial, and retinoblastoma cells were used to examine the mechanism of acute inhibition by D-glucose of myo-inositol uptake. Acute exposure of the cells to 30 mM D-glucose caused a significant decrease in Na(+)-dependent myo-inositol uptake in all three cell types. The effect of D-glucose to acutely inhibit myo-inositol uptake was dependent on the extracellular glucose concentration and was not reversed by sorbinil. 2-Deoxy-D-glucose (30 mM), 3-O-methyl-D-glucose (30 mM), and cytochalasin B (100 microM) did not acutely inhibit myo-inositol uptake. These data suggest that the hydroxyl groups on carbons 2 and 3 of D-glucose, which in a Haworth projection appear trans to each other, are important for inhibitory activity. Other monosaccharides (30 mM) having a similar 2,3-trans-diol configuration, L-glucose, D- and L-fucose, D- and L-galactose, D- and L-xylose, and D-arabinose, all to varying degrees significantly inhibited myo-inositol uptake. In all cases, the L-isomers were more potent inhibitors of myo-inositol uptake than the corresponding D-isomers. Monosaccharides (30 mM) having hydroxyl groups on carbons 2 and 3 in a cis configuration, D-mannose, L-rhamnose, D-allose, and D-ribose, did not acutely inhibit myo-inositol uptake. Replacing the hydroxyl group with a fluorine on carbons 2 or 3 of D-glucose negated its inhibitory activity of myo-inositol uptake. In contrast, replacing the hydroxyl group with a fluorine on carbon 6 of D-glucose did not block its inhibition of myo-inositol uptake.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1991 Aug
PMID:Trans-hydroxyl group configuration on carbons 2 and 3 of glucose. Responsible for acute inhibition of myo-inositol transport? 186 May 53

Phosphorylcholine (P-choline) is a precursor of the phospholipids in the lens membrane. A human lens normally contains approx. 1 mM P-choline but this is significantly lowered in some cataractous lenses. A normal rat lens contains a very high concentration (11 mM). We found that rat lens P-choline was depleted drastically when the lenses were exposed to hyperglycemic conditions either in culture, with galactose or xylose, or in vivo by streptozotocin-induced diabetes. The lens P-choline level was measured by fractionating the organic phosphates in the lens homogenate using an ion exchange column, or by quantitating the P-choline 31P NMR intensity in intact lenses. The results of both the chemical method and the noninvasive method agreed remarkably well. Besides the change in P-choline, the choline influx was also drastically reduced both in lenses from diabetic rats and in lenses incubated with 30 mM xylose. In addition, the ATP concentration was greatly diminished under similar conditions. The changes in P-choline, choline, and ATP could all be prevented in the presence of an aldose reductase inhibitor (ARI). It is thus concluded that these changes in phospholipid precursors may result from lenticular membrane defects caused by hyperglycemic stress. The effect of the lowered precursors on lipid biosynthesis was observed, and surprisingly showed a more rapid phospholipid-biosynthesis in the 2-week diabetic rat lens than in the 3-day diabetic rat lens.
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PMID:The effect of an aldose reductase inhibitor on lens phosphorylcholine under hyperglycemic conditions: biochemical and NMR studies. 249 85

Aldose reductase has been found in several tissues involved in the various complications of long-term diabetes. Since the loss of intramural pericytes is typical of early microangiopathy of the diabetic retina, the presence of aldose reductase and its activity were investigated in pericytes cultured from capillaries of human retinas. Verification that contaminating cells had been removed was made on the basis of the pericytes' distinctive appearance in culture, inability to internalize acetylated-low-density lipoprotein, and immunoreactivity for muscle actin. Using pure cultures of human pericytes, the presence of aldose reductase was demonstrated immunohistochemically with antibodies directed against human placental aldose reductase, and aldose reductase activity was shown biochemically by monitoring the accumulating of xylitol in cells incubated with xylose. Xylitol accumulation was inhibited by the inclusion of an aldose reductase inhibitor in the xylose-containing medium.
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PMID:Aldose reductase and polyol in cultured pericytes of human retinal capillaries. 249 86

Aldose reductase (AR) is implicated in some of the disabling complications of diabetes, including neuropathy, retinopathy and cataracts. Our studies are aimed at further clarifying the role of AR in diabetes and facilitating the design of new classes of potent, specific AR inhibitors by gaining an understanding of the protein structure of AR. To this end, we have determined the complete protein sequence of rat lens AR using cDNA analysis and primer extension of mRNA. By comparing protein sequences, we have found that the structural relatedness (41% to 57%) among the vertebrate proteins, aldose reductase, aldehyde reductase, prostaglandin F synthase and the frog lens protein rho-crystallin can now be extended to prokaryotes by the inclusion of Corynebacterium 2,5-diketo-D-gluconate reductase. This more distantly related protein shares 30-40% identity with the vertebrate enzymes. Sequence alignments reveal that 18% of the amino acids are completely conserved in all members of the superfamily, many of them in clusters, suggesting that they mark important structural features such as the nucleotide binding site and substrate binding site. rho-Crystallin, which is structurally related to this superfamily of NADPH-dependent reductases, does not appear to reduce PGH2, PGD2, xylose or glyceraldehyde to any appreciable extent. It does, however, bind NADPH.
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PMID:A superfamily of NADPH-dependent reductases in eukaryotes and prokaryotes. 250 40

Nondiabetic, young offspring of noninsulin-dependent diabetic (NIDDM) patients manifest insulin insensitivity. The pathophysiologic implications of the insulin insensitivity are uncertain since such subjects are usually normoglycemic. We have, therefore, studied isotopically the glucose turnover fluxes (D(3-3H) glucose technique) during postabsorptive state and after a physiological solid mixed meal ingestion for 240 min in 13 nondiabetic offspring and eight age-, sex- and weight-matched controls. Mean fasting serum glucose (84 +/- 3 vs. 78 +/- 2 mg/dl) and insulin (13.9 +/- 1.5 vs. 5.3 +/- 0.8 microU/ml) were significantly (p less than 0.05) greater in the offspring vs. controls. After the mixed meal ingestion, both serum glucose and insulin levels rose to significantly higher levels throughout the study period in the offspring vs. controls. Basal (2.04 +/- 0.73 vs. 1.84 +/- 0.76 ng/ml) and peak (5.72 +/- 0.65 vs. 6.47 +/- 0.40 ng/ml) serum c-peptide levels were not significantly different between the offspring and controls, respectively. Mean basal hepatic glucose output was significantly (p less than 0.05) higher in the offspring vs. controls (79 +/- 6 vs. 66 +/- 6 mg/m2.min). Following the mixed meal ingestion, the total splanchnic glucose appearance was significantly greater and qualitatively different in the offspring vs. controls. This occurred in the presence of identical intestinal carbohydrate absorption rates in both groups as assessed by simultaneous D-xylose test. Despite higher serum insulin levels, basal and post-meal metabolic clearance rates of glucose were similar in the two groups. We conclude that in nondiabetic offspring, greater basal and post-meal serum glucose and insulin levels occur.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes Res 1989 Sep
PMID:Defective insulin-mediated splanchnic glucose regulation and glucose clearance: early glucose homeostatic defects in nondiabetic, young offspring of patients with noninsulin-dependent diabetes mellitus. 269 5

To assess the pharmacologic properties and possible use in the treatment of diabetes mellitus of a recently developed analogue somatostatin (L-363,586), the analogue (2, 5, 10 or 40 micrograms/hr), somatostatin (200 micrograms/hr), or placebo were infused intravenously for 5 hours in 6 insulin-dependent diabetic subjects who were given a standard meal containing xylose. The metabolic clearance rate of the analogue (approximately 300 ml/min) was 1/6 that previously reported for somatostatin (approximately 2000 ml/min) and its half-life was approximately 20 times as great as that reported for somatostatin (45 vs 2 min). At a dose of 10 micrograms/hr, the analogue produced suppression of plasma glucagon, growth hormone, glucose, xylose and triglyceride responses to meal ingestion which were comparable to those observed when somatostatin was infused at a rate of 200 micrograms/hr. We conclude that L-363,586 is a long-acting and potent analogue of somatostatin, which has the potential for use as an adjunct to insulin in the treatment of diabetes mellitus.
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PMID:Efficacy, pharmacokinetics and tolerability of a somatostatin analogue (L-363,586) in insulin-dependent diabetes mellitus. 287 69

Alloxan diabetes increased 3-O-methylglucose transport rates in rat red blood cells (RBC) at temperatures below 30 degrees C and decreased them above 30 degrees C. Preincubation of RBC from control rats with 20 mM glucose, 3-O-methylglucose, 2-deoxyglucose or xylose greatly elevated transport at 14 degrees C by increasing Vmax. The effect was slight at 40 degrees C. Preincubation with glucose or deoxyglucose alone caused a 50% depression of transport rates at 40 degrees C as a result of a rise in the Km, which is similar to findings in cells from alloxan-diabetic rats. Measurement of intracellular glucose metabolites suggested inhibition of glycolysis in cells from diabetic rats and a positive correlation between the level of intracellular hexose monophosphates and transport inhibition. Membrane fatty-acid and cholesterol composition and membrane lipid-ordering as monitored by electron paramagnetic resonance were not altered by alloxan diabetes. It is concluded that intracellular sugar and sugar metabolism alter the temperature dependence of glucose transport kinetics. Glucose metabolism can feed back to inhibit transport by increasing the transport Km at physiological temperatures only.
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PMID:Temperature dependence of glucose transport in erythrocytes from normal and alloxan-diabetic rats. 334 33


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