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)

In non-insulin-dependent diabetes, site-specific defects of glucose metabolism in the pancreatic B-cell may account for a preferential alteration of its secretory response to the hexose. A novel therapeutic approach could thus be based on the use of non-glucidic nutrients that would bypass the metabolic defect in the islets of diabetic subjects. In this respect, the esters of mitochondrial dicarboxylic acids, such as succinic or glutamic acid, offer the advantage of being well transported into the islet cells and, hence, of stimulating efficiently both proinsulin biosynthesis and insulin release.
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PMID:[Current therapeutic approach to diabetes using esters of dicarboxylic mitochondrial metabolites]. 755 36

AICA riboside (0.1 to 1.0mM) caused a concentration-related increase of insulin output caused by D-glucose (5.6 to 20.0mM) in either rat isolated pancreatic islets or perfused pancreases. In the latter model, the rate of insulin release was further enhanced upon removal of AICA riboside from the perfusate. No insulinotropic action of AICA riboside was observed in the absence of D-glucose or at a low concentration (2.8mM) of the hexose. Preincubation of isolated islets for 30 min in the presence of AICA riboside (0.5 to 1.0mM) also enhanced insulin release recorded over 60 min incubation, in the absence of AICA riboside, but presence of either D-glucose (8.3mM), 2-ketoisocaproate (10.0mM), or the association of D-glucose (5.6 mM) and 2-ketoisocaproate (5.0 mM). The preincubation of the islets with AICA riboside failed, however, to augment the later secretory response to the association of L-leucine (10 mM) and either L-glutamine (10 mM) or L-asparagine (10 mM). In perfused pancreases exposed to 6 mM D-glucose, the presence of L-asparagine (10 mM) did not augment the insulinotropic action of AICA riboside. It is concluded that AICA riboside displays positive insulinotropic potential. However, the determinants of such an insulinotropic action remain to be elucidated.
Diabetes Res 1994
PMID:Insulinotropic action of AICA riboside. I. Insulin release by isolated islets and the perfused pancreas. 764 78

Hyperglycemia has been implicated in the pathogenesis of both micro- and macrovascular complications in diabetes. Little is known, however, about glucose transporters and their regulation in the vascular system. In this study, the regulation of glucose transporters by glucose was examined in cultured BAECs and BSMCs, and in human arterial smooth muscle cells. Both BAECs and BSMCs transported glucose via the facilitated diffusion transport system. Glucose-transport activity in vascular smooth muscle cells was inversely and reversibly regulated by glucose. Exposure of BSMCs and HSMCs to high glucose decreased Vmax for 2DG and 3-O-MG uptake, whereas Km remained unchanged. The hexose-transport system of BAECs exhibited lower 2DG and 3-O-MG uptake compared with BSMCs and showed little or no adaptation to changes in ambient glucose. Northern blot analysis demonstrated that GLUT1 mRNA levels in BAECs and BSMCs were unaffected by the concentration of glucose in the medium. GLUT2-5 mRNA could not be detected by Northern blot analysis. GLUT1 protein, quantified by Western blot analysis, was more abundant in BSMCs than in BAECs and was decreased by approximately 50% when medium glucose was elevated from 1.2 to 22 mM for 24 h. The alterations in the level of GLUT1 protein correlated with the changes observed in transport activity. These observations suggest differential regulation of glucose transporter in response to glucose between smooth muscle and endothelial cells. The sites of autoregulation may involve translational control and/or the stability of the protein in the smooth muscle cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1993 Jan
PMID:Differential regulation of glucose transport and transporters by glucose in vascular endothelial and smooth muscle cells. 767 4

Succinic acid monomethyl ester (SAM) was recently proposed as an insulinotropic tool in non-insulin-dependent diabetes mellitus. Three models were now used to investigate whether SAM protects the B-cell against the impairment of glucose-stimulated insulin release caused by either glucose deprivation or starvation. In the first model, preincubation of the islets for 180 min at low glucose concentration in the presence of SAM prevented the decrease in the secretory response to D-glucose otherwise observed during a subsequent incubation. In the second model, an impaired secretory response to D-glucose was observed after 3-day culture at low (2.8 or 5.6 mM) as distinct from high (11.1 mM) hexose concentration and the presence of SAM in the culture medium again protected against this anomaly. In the third model, the infusion of SAM for 3 days to starved rats restored the secretory potential of isolated islets to a level comparable to that otherwise found in fed rats. Thus, during glucose deprivation or starvation, SAM is indeed able to maintain B-cell responsiveness to D-glucose.
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PMID:SAM prevents impairment of glucose-stimulated insulin secretion caused by hexose deprivation or starvation. 773 55

Using 31P-nuclear magnetic resonance spectroscopy, we have identified elevated concentrations of sedoheptulose-7-phosphate (S-7-P) in lenses from three animal models of hyperglycemia: streptozotocin-induced diabetic rats, galactose-fed rats, and xylose-fed rats. This observation provides a unique and independent confirmation of the activation of the hexose monophosphate shunt (HMPS) pathway in the hyperglycemic lens in vivo. While the elevation in concentration of S-7-P was very dramatic, the other HMPS metabolites in these tissues were below the threshold of detection, as expected for the HMPS pathway near equilibrium. In terms of nonenzymatic glycation, these results suggest that the only HMPS metabolite of importance in the hyperglycemic rat lens is S-7-P. Although in the diabetic lens its role appears to be relatively minor, in the galactosemic lens this compound may be an important contributor to the increased production of advanced glycosylation end products.
Diabetes 1995 Jul
PMID:31P-nuclear magnetic resonance evidence of an activated hexose-monophosphate shunt in hyperglycemic rat lenses in vivo. 778 49

A decreased insulin response, preferentially to glucose, has been considered a hallmark of non-insulin dependent diabetes mellitus (Type 2) in humans. Syndromes resembling human diabetes occur spontaneously in many animal species and can also be induced by treating animals with drugs or viruses, excising their pancreases or manipulating their diet. Among these models, rat diabetes induced by neonatal streptozotocin administration (n-STZ models) has been first recognized as an adequate tool to study the long-term consequences of a gradually reduced beta-cell mass. More recently, the GK (Goto Kakisaki) Wistar rat has become available and is now considered as a promising spontaneous rat model of non-insulin dependent diabetes. We and others have found that defects in insulin secretion and action develop in the n-STZ and the GK models, which in many ways resemble those described in human non-insulin dependent diabetes. This review is aimed to sum up with a comparative approach, the informations so far collected in the n-STZ and GK models concerning the cellular mechanisms leading to the desensitization of their beta-cells to glucose. Taken together, the data reinforce the view that the impairment of glucose-induced insulin release in n-STZ and GK rats is clearly related to a defect in oxidative glycolysis. This leads to a severe decrease in the mitochondrial oxidative catabolism of glucose-derived pyruvate. Its coincides with a lower ATP/ADP ratio in glucose-stimulated islets and a subsequent alteration of ionic events tightly coupled to the fuel function of the hexose in islet cells, i.e. the decrease in K+ conductance.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Glucose refractoriness of pancreatic beta-cells in rat models of non-insulin dependent diabetes. 780 48

Facilitative hexose transporter expression was compared in rat and human testes. In rat testis, only GLUT1 and GLUT3 proteins were expressed. By contrast, human testis expressed GLUT1 and GLUT3 in addition to GLUT5. Immunocytochemical studies showed that GLUT3 was expressed in all cells of the seminiferous epithelium of rat testis, including sperm. In human testis, GLUT3 was expressed exclusively in cells juxtaposed to the lumen of the seminiferous tubule and ejaculate sperm, a pattern of expression that was identical to that of GLUT5. Induction of insulinopenic diabetes mellitus in the rat did not alter the levels or the distribution of GLUT3 protein or mRNA in the testis. Moreover insulin treatment of the diabetic rats did not produce changes in GLUT3 mRNA or protein levels. The results show that rat and human testis express the high-affinity glucose transporter GLUT3, which allows for the efficient uptake of glucose. In addition, the testis may be protected from changes in glucose transporter expression in experimental diabetes.
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PMID:GLUT3 glucose transporter isoform in rat testis: localization, effect of diabetes mellitus, and comparison to human testis. 781 Jul 57

The adenosine analogue formycin A is phosphorylated to its triphosphate ester in a sequence of reactions catalyzed by adenosine kinase and adenylate kinase. Formycin A triphosphate is an ATP analogue that is currently used to probe for ATP binding sites. Considering the key role ascribed to ATP in the coupling of metabolic to cationic events in the process of glucose-stimulated insulin release, we investigated whether formycin A displays insulinotropic action in rat pancreatic islets. Formycin A (10 microM to 1.0 mM) caused a concentration-related increase of insulin release evoked by 8.3 mM D-glucose and prevented the fall in insulin output otherwise observed over two successive incubations of 90 min each. Formycin A (1.0 mM) also augmented insulin secretion at low (5.6 mM) and high (16.7 mM) concentrations of D-glucose. At the low hexose concentration, the secretory response to formycin A was comparable to that evoked by either glibenclamide or glipizide. At higher concentrations of D-glucose, however, formycin A was more potent than the hypoglycemic sulfonylureas in enhancing insulin output. These findings support the role of ATP in glucose-stimulated insulin release and, therefore, suggest that ATP mimetics represent a new class of insulinotropic agents that have potential utility in the treatment of non-insulin-dependent diabetes mellitus.
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PMID:Insulinotropic action of formycin A. 785 78

We wished to determine whether the elevated glucose cycling (GC) between glucose and glucose-6-phosphate (G<-->G6P) in diabetes can be reversed with acute insulin treatment. In six insulin-deprived, anesthetized, depancreatized dogs, insulin was infused for 6-9 h at a starting dose of 45-150 pmol.kg-1.min-1 to normalize plasma glucose from 23.9 +/- 1.4 to 5.0 +/- 0.4 mmol/l and gradually decreased to and maintained at a basal rate (1.7 +/- 1.0 pmol.kg-1.min-1) during the last 3 h. GC, measured with [2-3H]- and [6-3H]glucose, fell markedly from 15.3 +/- 2.7 and normalized at 1.3 +/- 0.6 mumol.kg-1.min-1 (P < 0.001). This occurred because total hepatic glucose output fell much more (from 41.2 +/- 3.1 to 11.6 +/- 1.2) than did glucose production (from 25.9 +/- 1.9 to 10.3 +/- 1.0 mumol.kg-1.min-1) (both P < 0.01). Freeze-clamped liver biopsies were taken at timed intervals for measurements of hepatic enzymes and substrates. The elevated hepatic hexose-6-phosphate levels decreased with insulin infusion (151 +/- 24 vs. 71 +/- 13 nmol/g, P < 0.01). Maximal activities of glucose-6-phosphatase (G6Pase) (from 17.6 +/- 0.8 to 19.6 +/- 2.6 U/g) and glucokinase (from 1.1 +/- 0.2 to 1.0 +/- 0.2 U/g) did not change. Insulin infusion resulted in a threefold increase (P < 0.05) in the activity of glycogen synthase (active form), but had no effect on hepatic glycogen content.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1994 Nov
PMID:Importance of substrate changes in the decrease of hepatic glucose cycling during insulin infusion and declining glycemia in the depancreatized dog. 792 1

Recent evidence suggests that pioglitazone, a thiazolidinedione hypoglycemic agent, acts by increasing insulin responsiveness at the peripheral level. We studied the effect of pioglitazone (1 to 50 micrograms/mL) on the glucose transporter and glucose transport in BC3H-1 cells, a continuously cultured skeletal muscle cell line lacking the myoD transcription factor required for cell fusion. Glucose-fed cells (25 mmol/L) responded to insulin with a more than twofold increase in 2-deoxyglucose (2-DOG) uptake as compared with baseline. Treating these cells with pioglitazone alone for 24 hours resulted in a dose-dependent increase in hexose uptake, reaching twofold at 50 micrograms/mL. Combining long-term pioglitazone (10 micrograms/mL for 24 hours) and short-term insulin treatment resulted in an additive effect on 2-DOG uptake over a wide range of insulin concentrations (0.1 to 100 nmol/L) without the desensitization to 2-DOG uptake seen in other systems following long-term insulin administration. To determine the basis of the increased glucose uptake response, the level of specific mRNA and immunoreactive glucose transporter protein was determined. Northern and Western blot studies on glucose-treated cells (25 mmol/L) showed that glucose transporter mRNA and protein increased in parallel following treatment with either pioglitazone or insulin alone. The combination of insulin with pioglitazone resulted in an additive stimulation of glucose transporter mRNA and protein. In summary, pioglitazone stimulates hexose uptake both independently and in combination with insulin in BC3H-1 myocytes. These effects are largely accounted for by increases in glucose transporter mRNA and protein, indicating its potential efficacy in the treatment of non-insulin-dependent diabetes mellitus (NIDDM).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of glucose transport by pioglitazone in cultured muscle cells. 805 51


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