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)

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

The effect of insulinopenic diabetes on the expression of glucose transporters in the small intestine was investigated. Enterocytes were sequentially isolated from jejunum and ileum of normal fed rats, streptozotocin-diabetic rats, and diabetic rats treated with insulin. Facilitative glucose transporter (GLUT) 2, GLUT5, and sodium-dependent glucose transporter 1 protein content was increased from 1.5- to 6-fold in enterocytes isolated from diabetic animals in both jejunum and ileum. Insulin was able to reverse the increase in transporter protein expression seen after induction of diabetes. There was a four- to eightfold increase in the amount of enterocyte glucose transporter mRNA after diabetes with greater changes in sodium-dependent glucose transporter 1 and GLUT2 than in GLUT5 levels. In situ hybridization showed that after the induction of diabetes there was new hybridization in lower villus and crypt enterocytes that was reversed by insulin treatment. Thus, the increase in total hexose transport caused by diabetes is due to a premature expression of hexose transporters by enterocytes along the crypt-villus axis, causing a cumulative increase in enterocyte transporter protein during maturation. These changes are likely to represent an adaptive response by the organism to increase nutrient absorption in a perceived state of tissue starvation. These adaptive changes may lead to exacerbation of hyperglycemia in uncontrolled diabetes.
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PMID:Small intestine hexose transport in experimental diabetes. Increased transporter mRNA and protein expression in enterocytes. 811 95

The metabolic, ionic, and secretory response to D-glucose was investigated in islets of adult rats either injected with streptozotocin during the neonatal period (STZ rats) or presenting with inherited diabetes (GK rats). At a high concentration of D-glucose (16.7 mM), the ATP/ADP ratio was lower in islets from STZ and GK than control rats. This coincided with an impaired response of perifused islets to a rise in D-glucose concentration in terms of stimulation of insulin release, suppression of effluent radioactivity from islets prelabeled with [2-3H]adenosine, reduction in 86Rb efflux, and induction of a phosphate flush in islets prelabeled with 32P(i). The ratio in either D-[5-3H]glucose utilization or D-[2-14C]glucose oxidation at high/low hexose concentration, as well as the paired ratio between D-[2-14C]glucose oxidation and D-[5-3H]glucose utilization in islets incubated at a high concentration of the hexose, was also lower in STZ and GK rats than in control rats. Such was not the case, however, from the oxidation of [2-14C]pyruvate. Instead, the latter 2-keto acid, when tested at a 5.0 mM concentration, improved more efficiently the overall oxidative response of the islets to a rise in D-glucose concentration in STZ and GK rats than in control animals. It is proposed, therefore, that in both STZ and GK rats, the B-cell secretory defect is primarily attributable to an anomaly in oxidative glycolysis. In islets exposed to a high concentration of D-glucose, this metabolic deficiency results in impaired ATP generation, altered closing of ATP-responsive K+ channels, and, hence, diminished insulin output.
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PMID:Metabolic, ionic, and secretory response to D-glucose in islets from rats with acquired or inherited non-insulin-dependent diabetes. 812 95

Insulin rapidly represses expression of the gene encoding the insulin-responsive glucose transporter (GLUT4) in 3T3-L1 mouse adipocytes. Upon exposure to the hormone the cellular level of GLUT4 mRNA falls (t1/2 approximately 2.5 hr) to 20-30% of its initial level within 10 hr. This is followed by a similar decrease in the level of GLUT4 protein. Down-regulation of GLUT4 mRNA is a result of both rapid repression of transcription of the GLUT4 gene and an increased rate of turnover of the GLUT4 message. As a consequence of prolonged exposure to insulin, 3T3-L1 adipocytes lose their capacity for acute stimulation of hexose uptake by insulin. These findings provide an explanation for the resistance of glucose uptake to insulin in adipose tissue observed in non-insulin-dependent (type 2) diabetes mellitus, particularly that associated with hyperinsulinemia and obesity.
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PMID:Insulin down-regulates expression of the insulin-responsive glucose transporter (GLUT4) gene: effects on transcription and mRNA turnover. 842 83

Abnormal plasma ascorbic acid (AA) and dehydroascorbic acid (DHAA) levels observed in diabetes may be correlated to a deficiency in the recycling of AA. Ascorbic acid and DHAA levels are altered in diabetic liver in the present study. In addition, a coupling of the hexose monophosphate (HMP) shunt by way of NADPH to glutathione reductase and subsequent DHAA reduction is demonstrated. Ascorbic acid production was assayed directly and by way of the HMPS pathway. Results indicate that AA production from DHAA via the HMPS pathway occurs, and is significantly decreased in diabetic liver. Glucose-6-phosphate dehydrogenase (G6PDH) activity is shown to be decreased in diabetic liver. Since G6PDH is essential in providing NADPH for the reduction of glutathione required for subsequent DHAA reduction, its decreased activity is consistent with altered levels of AA and DHAA observed in diabetic tissues.
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PMID:Enzymatic basis for altered ascorbic acid and dehydroascorbic acid levels in diabetes. 846 10

In islets from adult rats injected with streptozotocin during the neonatal period, both a nonmetabolized analog of L-leucine and 3-phenylpyruvate augmented 14CO2 output from islets either prelabeled with L-[U-14C]glutamine or exposed to D-[2-14C]glucose and D-[6-14C]glucose, in a manner qualitatively comparable to that found in islets from control rats. The islets of diabetic rats differed, however, from those of control rats by their unresponsiveness to both the L-leucine analog and a high concentration of D-glucose in terms of increasing 3HOH generation from [2-3H]glycerol, an impaired sparing action of the hexose upon 14CO2 output from islets prelabeled with [U-14C]palmitate, and, most importantly, by a decreased rate of D-[2-14C]glucose and D-[6-14C]glucose oxidation when either incubated at a high concentration of the hexose (16.7 mM) or stimulated by nonglucidic nutrient secretagogues at a low concentration of D-glucose (2.8 mM). In islet homogenates, the activity of glyceraldehyde phosphate dehydrogenase, glutamate decarboxylase, and NADP-malate dehydrogenase was lower in diabetic than control islets. Such was not the case for glutamate-alanine transaminase, glutamate-aspartate transaminase, or glutamate dehydrogenase. The neonatal injection of streptozotocin thus affected, in the adult rats, the activity of several islet enzymes. Nevertheless, the metabolic data suggest that an impaired circulation in the glycerol phosphate shuttle, as observed in response to stimulation of the islets by either a high concentration of D-glucose or nonglucidic nutrient secretagogues, represents an essential determinant of the preferential impairment of glucose-induced insulin release in this model of non-insulin-dependent diabetes.
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PMID:Metabolic response to nonglucidic nutrient secretagogues and enzymatic activities in pancreatic islets of adult rats after neonatal streptozotocin administration. 848 60

In perifused pancreatic islets from euglycemic rats, the secretory response to either glibenclamide or glimepiride (1.0 microM each) increases as a function of the concentration of D-glucose (2.8-16.7 mM) present in the perifusion medium. On the contrary, the sulfonylurea-induced increment in 45Ca efflux from prelabeled islets decreases at increasing concentrations of the hexose. Neither glibenclamide nor glimepiride affect D-glucose metabolism in isolated islets, as judged from the production of 3HOH from D-[5-3H]glucose or the generation of 14CO2, as well as 14C-labeled amino acids and acidic metabolites, from D-[3,4-14C]glucose, D-[2-14C]glucose and D-[6-14C]glucose. The insulinotropic action of the hypoglycemic sulfonylureas is not impaired in islets prepared from rats infused for 48 hr with a hypertonic solution of D-glucose. The dimethyl ester of succinic acid is more efficient than D-glucose in supporting the insulin-releasing effect of glibenclamide or glimepiride. Thus, although the insulinotropic action of hypoglycemic sulfonylureas appears unaffected in a model of B-cell glucotoxicity, a potentiation of their secretory effects might be expected, in non-insulin-dependent diabetes, from the combined administration of succinic acid methyl ester.
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PMID:Modulation of the insulinotropic action of glibenclamide and glimepiride by nutrient secretagogues in pancreatic islets from normoglycemic and hyperglycemic rats. 849 43

The kidneys of streptozotocin (STZ)-diabetic rats are resistant to certain toxic effects of the antineoplastic drug cisplatin. The mechanism is unknown. This study used the galactosemic rat model to test the hypothesis that the apparent diabetes-induced protection is due to changes in the kidney secondary to chronically elevated hexose concentrations. Galactosemic rats are normoinsulinemic and are free from many of the multiple biochemical abnormalities seen in STZ diabetics. The experiments compared renal cortical platinum (Pt) and blood urea nitrogen (BUN) levels after intraperitoneal injection of 5 mg/kg of cisplatin in galactosemic, STZ-diabetic, and age-matched nondiabetic Sprague-Dawley rats. Nephrotoxicity was defined as a BUN concentration ratio (after to before cisplatin) > 2.5. The results demonstrate that the kidneys of both galactosemic and STZ-diabetic rats became resistant to cisplatin-induced elevation of BUN and, further, that the development of the protection was related to the duration of the diabetic state. Although the protective effect developed more slowly in the galactosemic rats, the attenuation of the rise in BUN was ultimately comparable to that seen in STZ diabetics. Renal cortex [Pt] after cisplatin injection was significantly lower in galactosemics and STZ diabetics compared with age-matched nondiabetics, with the order nondiabetics > galactosemics > STZ diabetics. It was noted, however, that renal Pt accumulation was maximally depressed within 4 weeks of experimental diabetes, whereas the BUN ratio continued to decline with increasing duration of both galactosemia and STZ diabetes. Thus, reduced renal Pt accumulation cannot by itself explain the progressive attenuation of the toxicity. The results support the hypothesis and suggest that the galactosemic rat will be a useful model for mechanistic study of diabetes-induced protection from cisplatin nephrotoxicity.
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PMID:Reduced renal accumulation and toxicity of cisplatin in experimental galactosemia. 851 46

The histological lesions of diabetic micro-angiopathy have a long latency, but vascular cell function may be affected at early stages of the process. Rats with experimental galactosaemia develop a diabetic-like retinopathy in the absence of other metabolic abnormalities characteristic of diabetes mellitus; basement membrane thickening is measurable in their retinal vessels after 7 months of galactose feeding. To examine the course of biosynthetic changes relevant to the process, retinal expression of collagen IV and fibronectin were compared in rats fed a 30% galactose diet or a control diet for 5 or 9 weeks. Total retinal RNA was studied by reverse transcription-polymerase chain reaction; the fibronectin primers encompassed the alternatively spliced EIIIA exon. The levels of alpha 1 (IV) collagen and fibronectin mRNAs were measured relative to an internal standard (beta-actin mRNA). The proportion of EIIIA+ to EIIIA- fibronectin transcripts was similar in the retinas of control and galactose-fed rats, which, however, showed increased levels of both fibronectin and collagen IV mRNAs in the presence of unchanged beta-actin mRNA levels. An upward trend was detected by 5 weeks of galactose feeding; and after 9 weeks the fibronectin/actin ratio was 1.2 +/- 0.3 vs 0.8 +/- 0.2 in controls (p = 0.015) and the collagen IV/actin ratio was 1.3 +/- 0.3 vs 0.9 +/- 0.2 in controls (p = 0.04). Thus, hyperhexosaemia of a few weeks' duration is a perturbation sufficient to increase the synthesis of basement membrane components in the retina. The search for additional early biosynthetic changes should assist in reconstructing the pathogenesis of hexose-induced retinal microangiopathy.
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PMID:Early biosynthetic changes in the diabetic-like retinopathy of galactose-fed rats. 878 71

We investigated whether low density lipoprotein (LDL) under oxidative stress might induce the release of fructose, glucose-6-phosphate and fructose-6-phosphate from perivascular cells, and also whether these substances might accelerate the formation of advanced glycation end products (AGE) from proteins in vitro. When vascular smooth muscle cells were incubated with LDL in Ham's F10 at 37 degrees C for 48 h. release of all these substances was increased dose-dependently by oxidized LDL. Fructose release was increased in a dose-dependent manner by glucose. Indomethacin (20 microM) significantly (P < 0.01) suppressed the release of fructose (25.4 +/- 15.7% of control) and hexose phosphates (29.4 +/- 4.0) with the inhibition of release of lactate dehydrogenase (35.5 +/- 4.9) as well as probucol, whereas an aldose reductase inhibitor, epalrestat, significantly (P < 0.001) inhibited only the fructose release (0.9 +/- 0.8). Release of fructose and hexose phosphates from vascular endothelial cells was also induced by oxidized LDL. AGE immunoreactivities and AGE-related fluorescence formed from proteins and glucose were significantly increased (P < 0.001) in the presence of small amounts of the cellular glucose metabolites (6.6%) with glucose (93.4%). These data suggest that release of potent AGE initiators, fructose and hexose phosphates, from perivascular cells induced by oxidized LDL may be an important phenomenon for vascular complications.
Diabetes Res Clin Pract 1996 Mar
PMID:Release of fructose and hexose phosphates from perivascular cells induced by low density lipoprotein and acceleration of protein glycation in vitro. 879 96


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