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)

Exposing micro-dissected pancreatic islets of non-inbred ob/ob mice to 2-5 mM-alloxan for 10 min decreased the ability of the islets to accumulate Rb+. Rb+ accumulation in pieces of exocrine pancreas was unaffected by alloxan. When islets were treated with alloxan in the presence of 2-20 mM-D-glucose, the Rb+-accumulating ability was protected in a dose-dependent manner. The protective action of D-glucose was reproduced with 3-O-methyl-D-glucose but not with L-glucose or D-mannoheptulose; mannoheptulose prevented D-glucose from exerting its protective action. The inhibition of Rb+ accumulation was due to a decreased inward pumping, since alloxan did not affect Rb+ efflux from pre-loaded islets. The inhibitory effect of alloxan had a latency of about 1 min, as revealed by experiments with dispersed islet cells in suspension. Alloxan-treated islets showed only a marginal decrease in ATP and no change in glucose 6-phosphate concentration. Although alloxan slightly decreased the hydrolysis of ATP in a subcellular fraction enriched in plasma membranes, this effect could not be attributed to a ouabain-sensitive adenosine triphosphatase. The plasma membranes exhibited a K+-activated hydrolysis of p-nitrophenyl phosphate; this enzyme activity too was insensitive to alloxan. Glucose may protect the univalent-cation pump by preventing permeation of alloxan via a path coupled to the hexose-transport system. Inhibition of the pump may be fundamental to the induction of alloxan-diabetes.
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PMID:Alloxan cytotoxicity in vitro. Inhibition of rubidium ion pumping in pancreatic beta-cells. 19 15

The role of cyclic adenosine-3',5'-monophosphate (cAMP) for insulin secretion has been investigated. In isolated islets of Langerhans from the rat, glucose increases cAMP concomitant with insulin secretion. Stimulation of these two parameters is likewise reversible in parallel. The minimal and maximal concentrations of glucose eliciting cAMP and insulin responses are similar. Isomers and epimers of glucose influence insulin and cAMP in a parallel fashion as do sulfonylurea compounds (tolbutamide and glibenclamide). On the contrary, the time-dependent potentiation of glucose-induced insulin secretion is not accompanied by gross changes in cAMP. Reciprocally, in the absence of glucose islet cAMP can be markedly elevated by other agents (methyl xanthines, cholera toxin) without major insulin responses. The results indicate that metabolism of cAMP in the beta-cell is intimately linked to the glucose (and sulfonylurea) action on insulin secretion, although other factors influenced by the hexose are also necessary for the release process. The finding that the cAMP response is impaired in fasting, during the neonatal period and in diabetes mellitus (in the Chinese hamster) suggests an important role for the nucleotide in physiological and pathophysiological states characterized by decreased insulin release.
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PMID:Cyclic AMP and insulin release. 21 Jun 17

1. Effects of dietary composition, energy restriction, and diabetes on hexose absorption were examined by feeding male rats isoenergetic, semi-synthetic diets of differing carbohydrate and protein content. Diets were carbohydrate, (g/kg): 890 sucrose; carbohydrate-protien, 500 sucrose, 390 casein; or protein, 890 casein. An additional group was fed on commercial rat chow ad lib. 2. Hexose (3-O-methyl-D-glucose) absorption was measured by luminal perfusion of the entire small intestine in situ. Absorption by the total small intestine, i.e. absorption per rat, and absorption per g dry weight of mucosa (specific absorption) were calculated. 3. When semi-synthetic diets were fed at 210 kJ/d to normal animals absorption depended on composition of diets: carbohydrate enhanced or protein suppressed hexose absorption. Dietary carbohydrate as glucose, dextrimaltose or starch gave the same hexose absorption response as sucrose. 4. When diets of normal rats were restricted to 118 kJ/d, specific absorption was independent of dietary composition and was increased for all dietary groups to the level of the group fed on the carbohydrate diet at 210 kJ/d. 5. When diabetic rats were given 210 kJ/d, hexose specific absorption was the same for all diabetic groups independent of dietary composition and was equal to that of controls given carbohydrate, but greater than that of protein-fed controls. 6. Thus, when two of the three stimuli (i.e. carbohydrate diet plus energy restriction or diabetes) were combined, the effect was not additive, and the response of hexose specific absorption to diabetes and energy restriction was the same: absorption was independent of dietary composition and was stimulated relative to controls fed on diets containing protein. 7. The pattern of response of total small intestinal hexose absorption to the stimuli of dietary composition, energy restriction and diabetes was similar to that of specific absorption. 8. Compared with groups given semi-synthetic diets, rats eating commercial rat chow ad lib. (approximately 286 kJ/d) showed increased mucosal mass and decreased specific absorption, but total absorption was similar to that of the carbohydrate and carbohydrate-protein-fed groups. 9. In a separate study in control rats, specific and total intestinal absorption of L-leucine did not respond to dietary composition, i.e. level of protein fed.
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PMID:Effects of diet, energy restriction and diabetes on hexose transport in the rat. 46 35

To determine whether the carbohydrate content of serum proteins is related to overall glycemic control, we studied serum protein-bound hexose and glycosylated hemoglobin [HbA1(a+b+c)] in 37 ambulant diabetic patients and 32 nondiabetic controls. Protein-bound hexose was correlated with HbA1(a+b+c) in the diabetic patients (r = 0.36, P less than 0.025). The mean protein-bound hexose level of the diabetic patients was greater than that of the controls (190.8 versus 174.7 mg/dl, P less than 0.01), but diabetic patients with HbA1(a+b+c) less than 12% had a mean protein-bound hexose similar to the controls. In nine of the diabetic patients, mean protein-bound hexose and HbA1(a+b+c) were significantly reduced during a period of intensive outpatient care, while two major serum glycoproteins, haptoglobins and alpha-1-antitrypsin, were unchanged. Our findings support the hypothesis that increased glycosylation of serum proteins may occur in diabetes mellitus; this abnormality in serum protein-bound hexose may be corrected by close attention to overall glycemic control.
Diabetes 1979 Nov
PMID:Serum protein-bound hexose in diabetes: the effect of glycemic control. 48 38

A preferential impairment of the pancreatic B cell secretory response to D-glucose occurs in adult rats injected with streptozotocin during the neonatal period. Three possible explanations for such a preferential defect were investigated in the present study. First, the time course for 3-O-methyl-D-glucose uptake by islets suggested that the anomaly in hexose transport was mainly attributable to a decrease in the space accessible to the D-glucose analog commensurate with the decrease in B cell mass, rather than to a delayed equilibration of hexose concentration across the B cell plasma membrane. Second, the activity of glucose-6-phosphatase was found to be equally low in islets from diabetic and control rats, ruling out the futile cycling between D-glucose and D-glucose 6-phosphate as a cause for the preferential alteration of the secretory response to the hexose. Third, the activity of flavine adenine dinucleotide-linked glycerophosphate dehydrogenase was found to be decreased to a greater relative extent than the B cell mass. This coincided with an impaired generation of 3HOH from L-[2-3H] glycerol in intact islets. It is proposed, therefore, that an altered circulation in the glycerol phosphate shuttle may play a major role in the impaired process of glucose-stimulated insulin release in this model of noninsulin-dependent diabetes.
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PMID:Enzymic and metabolic anomalies in islets of diabetic rats: relationship to B cell mass. 131 52

In spontaneously diabetic BB rats, the effect of chronically maintained blood glucose levels on the degree of energy failure and brain pH change during an ischemic insult, and on subsequent recovery after reperfusion, was studied with in vivo 31P magnetic resonance spectroscopy. Short duration forebrain ischemia (10-min carotid occlusion plus hypotension of 50 mmHg) was induced in diabetic and nondiabetic male BB rats whose blood glucose levels were maintained with insulin. Spectra were obtained in 1-min blocks before, during, and for 1 h after ischemia. Before ischemia, hypoglycemic (blood glucose less than 3 mM) diabetic rats had an increased Pi peak intensity, with no significant pH change, compared with other groups. During ischemia, the rate and extent of hydrolysis of high-energy phosphate metabolites (as measured by an increase in Pi) decreased, and the severity of tissue acidosis increased as preischemia blood glucose concentration increased. Among hyperglycemic BB rats, similar ischemia-induced changes were found for subgroups with blood glucose levels of 13.7 +/- 1.2 and 20.3 +/- 0.6 mM, in keeping with the known decrease in hexose binding sites associated with chronic hyperglycemia. Decline in PCr level during ischemia was not significantly different between groups. With reperfusion, both Pi and pH values rapidly returned to preischemia values. PCr levels, however, did not recover in hyperglycemic diabetic animals, with the degree of residual impairment dependent on the preischemia glucose level. Results suggest that optimal management of diabetes may lessen the degree of injury within the ischemic penumbra in diabetic patients who suffer a stroke.
Diabetes 1992 Oct
PMID:Forebrain ischemia in diabetic and nondiabetic BB rats studied with 31P magnetic resonance spectroscopy. 139 7

Individuals with non-insulin dependent or insulin-dependent diabetes mellitus present insulin resistance in peripheral tissues. This is reflected in a subnormal whole body insulin-dependent glucose utilization, largely dependent on skeletal muscle. Glucose transport across the cell membrane of this tissue is rate limiting in the utilization of the hexose. Therefore, it is possible that a defect exists in insulin-dependent glucose transport in skeletal muscle in diabetic states. This review focuses on two questions: is there a defect at the level of glucose transporters in skeletal muscle of diabetic animal models, and is this a consequence of abnormal insulin or glucose levels? The latter question arises from the fact that these parameters usually vary inversely to each other. Glucose transport into skeletal muscle occurs by two membrane proteins, the GLUT1 and GLUT4 gene products. By subcellular fractionation and Western blotting with isoform-specific antibodies, it was determined that isolated plasma membranes (PM) contain GLUT4 and GLUT1 proteins at a molar ratio of 3.5:1 and that an intracellular fraction (internal membranes; IM) different from sarcoplasmic reticulum contains only GLUT4 transporters. The IM furnishes transporters to the PM in response to insulin. Both transporter isoforms bind cytochalasin B in a D-glucose-protectable fashion. In streptozocin-induced diabetes of the rat with normal fasting insulin levels and marked hyperglycemia, the number of cytochalasin B-binding sites and of GLUT4 proteins diminishes in the PM whereas the GLUT1 proteins increase to a new ratio of about 1.5:1 GLUT4:GLUT1. In the IM, the levels of GLUT4 protein drop, as does the cellular GLUT4 mRNA. To investigate if these changes are associated with hyperglycemia, glucose levels were corrected back to normal values for a 24-h period with sc injections of phlorizin to block proximal tubule glucose reabsorption. This treatment restored cytochalasin B binding, restored GLUT4 and GLUT1 values back to normal levels in the PM, and partly restored cytochalasin B binding but not GLUT4 levels in the IM, consistent with only a partial recovery of GLUT4 mRNA. It is concluded that GLUT4 protein in the PM correlates inversely whereas GLUT1 protein correlates directly with glycemia. It is proposed that the decrease in GLUT4 levels is a protective mechanism, sparing skeletal muscle from gaining glucose and experiencing diabetic complications, albeit at the expense of becoming insulin resistant.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effects of hyperglycemia on glucose transporters of the muscle: use of the renal glucose reabsorption inhibitor phlorizin to control glycemia. 148 48

The effects of the oral hypoglycemic drug metformin on glucose and amino acid transporter activity and subcellular localization of GLUT1 and GLUT4 glucose transporters were tested in cultured L6 myotubes. In muscle cells preexposed to maximal doses of metformin (2 mM, for 16 h), 2-deoxyglucose uptake was stimulated by over 2-fold from 5.9 +/- 0.3 to 13.3 +/- 0.5 pmol/min.mg protein. Uptake of the nonmetabolizable amino acid analog methylaminoisobutyrate was unaffected by treatment with the drug under identical conditions. Extracellular calcium was required to preserve the full response to the biguanide. Exposure of muscle cells to insulin in the presence of metformin resulted in further activation of 2-deoxyglucose transport. The latter effect was additive to the maximum effect of metformin, suggesting that the biguanide stimulates hexose uptake into muscle cells by an insulin-independent mechanism. Glucose transporter number quantified by performing studies of D-glucose-protectable binding of cytochalasin-B in plasma membranes (PM) and internal membranes (IM) prepared from L6 myotubes revealed that a 16-h treatment with 800 microM metformin significantly elevated glucose transporter number in the PM (by 47%), with an equivalent decrement in glucose transporter number (47%) in the IM. Western blot analysis using antisera reactive with the GLUT1 and GLUT4 isoforms of glucose transporters showed that metformin caused a reduction in GLUT1 content in the IM fraction and a concomitant increase in the PM. Unlike insulin, metformin treatment had no effect on the subcellular distribution of GLUT4. We propose that the molecular basis of metformin action in skeletal muscle involves the subcellular redistribution of GLUT1 proteins from an intracellular compartment to the plasma membrane. Such a recruitment process may form an integral part of the mechanism by which the drug stimulates glucose uptake (and utilization) in skeletal muscle and facilitates lowering of blood glucose in the management of type II diabetes.
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PMID:Cellular mechanism of metformin action involves glucose transporter translocation from an intracellular pool to the plasma membrane in L6 muscle cells. 150 58

At 3-4 degrees C, the transport of 3-O-methyl-D-glucose (30 mM) was severely impaired in islets prepared from adult rats injected with streptozotocin during the neonatal period. However, at 37 degrees C, the first and second phase of glucose-stimulated insulin release were decreased to the same relative extent in perifused islets of diabetic, as compared to control, animals. Moreover, the time-related increase in the oxidative response of the islets to 16.7 mM D-glucose was less pronounced in diabetic than control rats. The activity of the mitochondrial FAD-linked glycerophosphate dehydrogenase in islet homogenates of diabetic rats only represented one-fifth of that found in control rats, whereas the activity of the cytosolic NAD-glycerophosphate dehydrogenase was comparable in both types of rats. This coincided with the fact that a rise in D-glucose concentration from 2.8 to 16.7 mM failed to increase significantly L-[2-3H]glycerol conversion to 3HOH in islets from diabetic rats, in contrast to the situation found in control animals. The activity of 2-ketoglutarate dehydrogenase in islet homogenates when expressed per microgram protein was not different in control and diabetic rats. Likewise, the ratio between D-[6-14C]glucose oxidation and D-[3,4-14C]glucose oxidation and the capacity of either a non-metabolized analog of L-leucine or 3-phenylpyruvate to preferentially stimulated D-[6-14C]glucose oxidation relative to D-[5-3H]glucose utilization were both unaffected in islets from diabetic rats. These findings argue against the existence of a primary defect in the Krebs cycle of diabetic rats. It is proposed that, despite an obvious alteration of the hexose transport system in the islet cells of diabetic rats, the preferential impairment of the B-cell secretory response to D-glucose, as distinct from other secretagogues, in this model of non-insulin-dependent diabetes is mainly attributable to the low activity of FAD-linked glycerophosphate dehydrogenase, resulting in a decreased metabolic flow through the glycerol phosphate shuttle and a reduced rate of aerobic glycolysis.
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PMID:Study of hexose transport, glycerol phosphate shuttle and Krebs cycle in islets of adult rats injected with streptozotocin during the neonatal period. 153 53

Carbohydrate administration rapidly regulates hepatic mRNA-S14 content. Both sucrose and fructose but not glucose increase the transcription of hepatic mRNA-S14 in vivo. In primary hepatocyte cultures, mRNA-S14 transcription responds to either fructose or glucose. To test the hypothesis that the difference in hexose response is due to differences in cellular metabolism, we studied the regulation of this gene with a transient transfection assay system in Chinese hamster ovary (CHO) cells, hamster pancreatic beta-cells (HIT), and primary hepatocytes. In HIT cells, glucose stimulation of the expression vector pS14CAT (5 kilobases [kb]) containing 4.9 kb of 5'-flanking DNA was threefold greater than fructose. Glucose also gave a fourfold greater response at 27.5 mM than at 2.2 mM. In CHO cells, pS14CAT (5 kb) showed a twofold greater response to fructose than to glucose. The differential response to the hexoses in the two cell lines is a result of cell-specific metabolism. Without glucose in the media, both CHO and HIT cells used pyruvate for energy. However, glucose addition to CHO cells enhances glycolysis and hexose shunt pathway activity while inhibiting pyruvate oxidation and S14 gene transcription. In contrast, addition of glucose to HIT cells leads to enhanced tricarboxylic acid cycle activity to oxidize pyruvate and an associated stimulation of S14 transcription. We confirmed these conclusions in primary hepatocyte cultures. Addition of 27.5 mM glucose led to a twofold increase in endogenous mRNA-S14 accumulation, a twofold increase in transfected pS14LUC (5 kb) activity, and a parallel twofold increase in pyruvate oxidation.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1992 Mar
PMID:Cell-specific carbohydrate metabolism regulates S14 gene transcription. 155 93


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