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)

Alloxan inactivated glucokinase in intact, isolated pancreatic islets incubated in vitro. Inactivation of glucokinase was antagonized by 30 mM glucose present during incubation of islets with alloxan. Glucokinase partially purified from transplantable insulinomas or rat liver was inactivated by alloxan with a half-maximal effect at 2-4 microM alloxan. Inactivation of purified glucokinase was antagonized by glucose, mannose, and 2-deoxyglucose in order of decreasing potency but not by 3-O-methylglucose. Glucose anomers at 6 and 14 mM were discriminated as protecting agents, with the alpha-anomer more effective than the beta-anomer. Glucokinase was not protected from alloxan inactivation by N-acetylglucosamine, indicating that the reactive site for alloxan is not the active site; therefore, glucose may protect glucokinase by inducing a conformational change. Glucokinase is thought to be the glucose sensor of the pancreatic beta-cell. The finding that glucokinase is inactivated by alloxan and protected by glucose with discrimination of its anomers similar to inhibition of glucose-stimulated insulin secretion by alloxan supports this hypothesis and appears to explain the mechanism for inhibition of hexose-stimulated insulin secretion by this agent and the unique role of glucose and mannose as protecting agents.
Diabetes 1986 Oct
PMID:Identification of glucokinase as an alloxan-sensitive glucose sensor of the pancreatic beta-cell. 353 Aug 46

Prior exposure of the endocrine pancreas to a high as distinct from low concentration of D-glucose is thought to result in either an increased (priming action) or decreased (glucotoxic action) responsiveness of the B-cell to a subsequent stimulation by the hexose. In order to investigate these phenomena in vitro, rat pancreatic islets were preincubated for 180 min at increasing concentrations of D-glucose in the absence or presence of extracellular Ca2+, and then stimulated with the hexose (16.7 mM) in the absence or presence of theophylline (1.4 mM). Under these conditions, a dose-related priming action of D-glucose was observed without evidence of any glucotoxic effect. The priming effect persisted when the islets were preincubated in the absence of Ca2+, although such a prior Ca2+ deprivation itself decreased the magnitude of the further secretory response to D-glucose. The presence of theophylline in the final incubation medium minimized but failed to abolish the priming action of D-glucose. It is proposed that Ca2+ and cyclic AMP availability may interfere with the priming action of D-glucose. Moreover, the present results suggest that a more stringent or more prolonged pretreatment of the islet cells may be required in order to allow for the occurrence of the postulated cytotoxic action of D-glucose upon the pancreatic B-cell.
Diabetes Res 1987 Jan
PMID:Interaction between D-glucose and Ca2+ in the priming of the pancreatic B-cell. 355 68

The possibility that glucose may directly regulate its rate of utilization in skeletal muscle was investigated in vitro with the rat soleus muscle. Preincubation of the muscles with varying glucose concentrations modulated the rate of glucose utilization through the glycolytic pathway during a subsequent incubation. At glucose concentrations below approximately 3.0 mM, utilization was maximal (26.8 +/- 2.4 and 87.5 +/- 4.8 nmol X g-1 X min-1 when assayed in the presence of 0.5 and 5.0 mM glucose, respectively). Preincubation with higher glucose concentrations (up to 20 mM) reduced the utilization by 40-60% in a biphasic manner: a rapid fall between 1 and 4 mM, followed by a gradual approximately 2% decrease per each millimolar increase of glucose. The effect of preexposure to glucose was not due to substrate dilution by the remaining glucose in the extracellular or intracellular space of the muscle. The uptake of the nonmetabolizable glucose analogues 3-O-methylglucose and 2-deoxyglucose was also modulated by extracellular glucose in a similar manner. Thus, the regulatory site seems to reside in the transport function of the hexose. The ATP content was very similar in muscles preexposed to 1.0 and 15.0 mM glucose for 3 h and therefore does not seem to be the mediator of the glucose effect. This substrate regulation of the rate of glucose transport and of the glycolytic flux may be operative in the in vivo glucose homeostatic system and may contribute to the reduced peripheral glucose utilization observed in diabetes.
Diabetes 1987 Sep
PMID:In vitro autoregulation of glucose utilization in rat soleus muscle. 360 97

3-O-methyl-D-glucose (which is not metabolized in isolated parenchymal cells) was used to characterize the hexose transport process in hepatocytes prepared from 24 h fasted rats. The Vmax and Km obtained were 161 +/- 12 nmol/mg dry wt./min and 39 +/- 4 mM respectively (Europe-Finner GN, 1984, Biosci. Rep. 4, 483-489). Streptozotocin-induced diabetes decreased the Km of the system by 50% to a value of 19 +/- 6 mM without causing any change in the Vmax. Short term insulin treatment of cells prepared from 24 h diabetic rats appeared to partially return the system to normal.
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PMID:The effect of streptozotocin-induced diabetes on hepatic hexose transport. 389 37

The etiology of insulin resistance during diabetic ketoacidosis is still poorly understood. Changes in insulin receptor binding and the existence of postreceptor alterations have been proposed. In an attempt to clarify the role of low pH and ketone bodies in the insulin resistance, we examined the effectiveness of insulin during and after 48 h of exposure of cultured 3T3-L1 adipocytes to low pH and ketoacids. In the "acute" stage, lowering of physiologic pH (pH 7.4) to pH 6.9 induced a decrease in insulin binding (50%), which was due to a decrease in the rate of association. Concomitantly, the insulin sensitivity was decreased (ninefold). The basal hexose uptake and insulin responsiveness were only slightly decreased at low pH. Beta-hydroxybutyrate partially counteracted the effect of low pH on insulin binding and sensitivity in a dose-dependent fashion (ED50: 10 mM). The binding-enhancing effect of ketoacids was more pronounced at low pH than at physiologic pH and absent at optimum pH (pH 8.0). After 48 h of exposure of the cells to pH 6.9, insulin binding and insulin sensitivity (measured at physiologic pH) were similar as in cells cultured at pH 7.4. The insulin response, however, was substantially impaired (40%), due to an increase in basal hexose uptake as well as a decrease in maximal insulin-stimulated uptake. These postbinding alterations induced by low pH could be reversed by culturing the cells at physiologic pH for another 48 h. Prolonged exposure to ketoacids did not affect the insulin effectiveness.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1985 Aug
PMID:Low pH and ketoacids induce insulin receptor binding and postbinding alterations in cultured 3T3 adipocytes. 392 64

Enzymatic assays were modified to permit sensitive and highly reproducible simultaneous measurements of D-mannose and D-glucose in biological fluids during weeks 34-40 of human pregnancy. Plasma mannose and glucose averaged 9.8 +/- 0.4 (+/- SEM) and 790 +/- 16 micrograms/ml, respectively, after an overnight fast in pregnant women (n = 22) with normal carbohydrate metabolism. Significantly higher plasma mannose levels were found, despite only minor increases in plasma glucose, in pregnant women with relatively well controlled diabetes mellitus after an overnight fast (16.9 +/- 0.6 micrograms/ml mannose; 883 +/- 29 micrograms/ml glucose; n = 31) or 3-4 h after breakfast (15.7 +/- 1.2 micrograms/ml mannose; 1159 +/- 101 micrograms/ml glucose; n = 19). Plasma mannose correlated significantly with plasma glucose in the women with diabetes mellitus, particularly after an overnight fast. Samples of amniotic fluid were also obtained from the gravida with diabetes mellitus to provide some index of simultaneous relationships in utero. Amniotic fluid mannose and glucose averaged 5.9 +/- 0.4 and 302 +/- 24 micrograms/ml, respectively, after an overnight fast and 6.7 +/- 1.3 and 459 +/- 84 micrograms/ml 3-4 h after breakfast. In amniotic fluid, as in plasma, the concurrent levels of mannose and glucose conformed to relatively fixed relationships. Thus, both fetus and mother appear to be exposed to readily demonstrable amounts of mannose during late gestation and the absolute as well as relative abundance of mannose may be increased coincident with faulty maternal glucoregulation. However, since mannose did not exceed 3% of the concurrent concentration of glucose in any instance, it does not seem likely that endogenous levels of circulating mannose can modify glucose utilization appreciably by competing with glucose for phosphorylation via hexokinase and subsequent intracellular processing.
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PMID:Relationships between glucose and mannose during late gestation in normal pregnancy and pregnancy complicated by diabetes mellitus: concurrent concentrations in maternal plasma and amniotic fluid. 395 33

1. The content of citrate in ;freeze-clamped' livers from starved and alloxan-diabetic rats was measured by using the specific citrate assay method of Gruber & Moellering (1966). 2. The content of citrate fell progressively during a period of 48hr. starvation to reach a plateau value that is 50% of the value for livers from fed rats. Some possible explanations for the conflicting reports of changes in hepatic citrate content during starvation are discussed. 3. The hepatic contents of ATP, pyruvate, lactate, glycogen and the hexose phosphates were decreased during starvation, whereas those of acetyl-CoA and AMP were increased. 4. Acute alloxan-diabetes produced similar changes in the contents of these metabolic intermediates. 5. The effects of starvation and diabetes on the citrate and acetyl-CoA contents are discussed in relation to control of gluconeogenesis, fatty acid synthesis and the activity of citrate synthase.
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PMID:The effects of starvation and alloxan-diabetes on the contents of citrate and other metabolic intermediates in rat liver. 565 Mar 65

1. The metabolism of [U-(14)C]glucose by the isolated diaphragm muscle of normal rats, rats rendered diabetic with streptozotocin and rats with transitory insulin deficiency after an injection of anti-insulin serum was studied. 2. The incorporation of [(14)C]glucose into glycogen and oligosaccharides was significantly decreased in the diabetic diaphragm muscle and in the muscle from rats treated with anti-insulin serum. 3. Neither diabetes nor transitory insulin deficiency influenced the oxidation of glucose, or the formation of lactate and hexose phosphate esters from glucose. 4. Insulin fully restored the incorporation of glucose into glycogen and maltotetraose in the diabetic muscle, but the incorporation into oligosaccharides, although increased in the presence of insulin, was significantly lower than the values obtained with normal diaphragm in the presence of insulin.
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PMID:The metabolism of glucose in diaphragm muscle from normal rats, from streptozotocin-treated diabetic rats and from rats treated with anti-insulin serum. 570 83

Arterial (A) and renal venous (RV) concentrations and net splanchnic exchange of glucose, fructose, lactate, pyruvate, glycerol, and alanine were studied in the basal state and during a 135-min intravenous infusion of fructose at 2 mmol/min in healthy subjects after a 60-h fast. After 45 min of the fructose infusion, somatostatin (9 microgram/min) was infused for 60 min to induce hypoglucagonemia. Fructose infusion resulted in a net uptake of this hexose by the kidney as well as the splanchnic bed. Estimated renal uptake of fructose could account for the disposal of 20% of the administered fructose load while splanchnic uptake accounted for 38%. The fructose infusion resulted in a rise in blood glucose of 0.9 mmol/L, a 35% increase in net glucose output from the splanchnic bed, and a consistent net output of glucose from the kidney (A-RV = -0.17 +/- 0.05 mmol/L as compared with 0 +/- 0.03 in the basal state, P less than 0.02). Net glucose release from the kidney could account for 55% of the net renal uptake of fructose. The fructose infusion also resulted in a marked change in renal lactate balance from a net uptake in the basal state (A - RV = 0.05 +/- 0.01 mmol/L) to a net output during fructose administration (A - RV = -0.10 +/- 0.04). Administration of somatostatin resulted in a fall in arterial glucagon levels and a 35% decrease in splanchnic glucose output but failed to alter the arterial-renal venous difference for glucose observed during the fructose infusion. We conclude that in 60-h fasted man: (a) intravenous infusion of fructose results in a net uptake of this hexose by the kidney as well as the liver, (b) this uptake is accompanied by stimulation of renal as well as hepatic glucose production and renal production of lactate, and (c) hypoglucagonemia inhibits splanchnic but not renal glucose output during fructose infusion. These data indicate that the kidney is an important site of fructose disposal and that glucose and lactate are end products of renal fructose metabolism.
Diabetes 1982 Jun
PMID:Role of the kidney in the metabolism of fructose in 60-hour fasted humans. 613 22

To study the glycosylation of glomerular basement membrane collagen (GBMC) in diabetes, kidneys were obtained at autopsy from 5 patients with insulin-requiring diabetes of long duration and diabetic complications, and from 5 control subjects. Glomeruli were prepared by sieving and collagen was isolated by limited pepsin proteolysis followed by salt precipitations. Amino acid analyses of the collagen preparations, after acid hydrolysis, indicated a composition consistent with that of type IV collagen. No differences in the relative contents of various amino acids, and in particular, 3-hydroxyproline, 4-hydroxyproline and hydroxylysine, were noted between diabetic and control samples. Non-enzymatic glucosylation was assessed by measuring hexose in ketoamine linkage with thiobarbituric acid after conversion to 5-hydroxymethylfurfural. In 4 of the 5 patients studied, glucosylation values exceeded the mean +2 S.D. of the controls; in the fifth subject glucosylation was in the high normal range. No correlation between the severity of diabetes and hexose content of GBMC was noted, however. In further studies, enzymatic glycosylation of GBMC was assayed after alkaline hydrolysis by separation of glucosylgalactosyl-O-hydroxylysine, galactosyl-O-hydroxylysine, and unsubstituted hydroxylysine in an amino acid analyzer. No differences in the relative contents of hydroxylysine-O-glycosides were evident between diabetic and control GBMC. The results suggest that non-enzymatic glucosylation, but not glycosylation catalyzed by collagen glucosyl and galactosyl transferases, is increased in diabetes. The increased carbohydrate content of collagen may lead to decreased turnover and/or excessive accumulations of basement membrane collagen thus contributing to the vascular complications of diabetes.
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PMID:Glycosylation of human glomerular basement membrane collagen: increased content of hexose in ketoamine linkage and unaltered hydroxylysine-O-glycosides in patients with diabetes. 621 60


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