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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of 3 months streptozotocin-induced diabetes mellitus on contraction and relaxation of aorta were examined in vitro. A further diabetic group was treated with a novel sulphonylnitromethane-based aldose reductase inhibitor for 3 months following diabetes induction. Diabetes resulted in reduced maximal tension production, particularly for responses to phenylephrine (p < 0.001) and serotonin (p < 0.001). However, with aldose reductase inhibitor treatment, responses were in the non-diabetic range. The ratio of maximum contractions to noradrenaline and phenylephrine were 28% elevated by diabetes (p < 0.01), which may suggest increased alpha 2-adrenoreceptor-mediated responses. Endothelium-independent relaxation to glyceryl trinitrate was unaffected by diabetes or treatment. By contrast, there were 38% deficits in endothelium-dependent relaxation to acetylcholine (p < 0.001) and Ca2+ ionophore A23187 (p < 0.001) with diabetes which were prevented by aldose reductase inhibitor treatment (p < 0.001). A 121% shift in the concentration giving a 50% maximum effect for acetylcholine towards lower sensitivity with diabetes (p < 0.001) was also largely corrected by treatment (p < 0.001). A non-diabetic group treated with aldose reductase inhibitor showed a 30% decrease in the 50% effective concentration for acetylcholine (p < 0.05). A 15% deficit in maximum relaxation to the ATP-sensitive K+ channel opener cromakalim for the diabetic group (p < 0.001) was prevented by aldose reductase inhibitor treatment (p < 0.01). We conclude that there are polyol pathway related abnormalities for contraction, some aspects of endothelium-independent relaxation, but particularly for endothelium-dependent relaxation in aorta from chronic streptozotocin-diabetic rats.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Impaired contraction and relaxation in aorta from streptozotocin-diabetic rats: role of polyol pathway. 147 11

Axonal transport is known to be impaired in peripheral nerve of experimentally diabetic rats. As axonal transport is dependent on the integrity of the neuronal cytoskeleton, we have studied the way in which rat brain and nerve cytoskeletal proteins are altered in experimental diabetes. Rats were made diabetic by injection of streptozotocin (STZ). Up to six weeks later, sciatic nerves, spinal cords, and brains were removed and used to prepare neurofilaments, microtubules, and a crude preparation of cytoskeletal proteins. The extent of nonenzymatic glycation of brain microtubule proteins and peripheral nerve tubulin was assessed by incubation with 3H-sodium borohydride followed by separation on two-dimensional polyacrylamide gels and affinity chromatography of the separated proteins. There was no difference in the nonenzymatic glycation of brain microtubule proteins from two-week diabetic and nondiabetic rats. Nor was the assembly of microtubule proteins into microtubules affected by the diabetic state. On the other hand, there was a significant increase in nonenzymatic glycation of sciatic nerve tubulin after 2 weeks of diabetes. We also identified an altered electrophoretic mobility of brain actin from a cytoskeletal protein preparation from brain of 2 week and 6 week diabetic rats. An additional novel polypeptide was demonstrated with a slightly more acidic isoelectric point than actin that could be immunostained with anti-actin antibodies. The same polypeptide could be produced by incubation of purified actin with glucose in vitro, thus identifying it as a product of nonenzymatic glycation. These results are discussed in relation to data from a clinical study of diabetic patients in which we identified increased glycation of platelet actin. STZ-diabetes also led to an increase in the phosphorylation of spinal cord neurofilament proteins in vivo during 6 weeks of diabetes. This hyperphosphorylation along with a reduced activity of a neurofilament-associated protein kinase led to a reduced incorporation of 32P into purified neurofilament proteins when they were incubated with 32P-ATP in vitro. Our combined data show a number of posttranslation modifications of neuronal cytoskeletal proteins that may contribute to the altered axonal transport and subsequent nerve dysfunction in experimental diabetes.
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PMID:Posttranslational modifications of nerve cytoskeletal proteins in experimental diabetes. 147 75

We propose new hypotheses for the mechanisms of streptozotocin (STZ) and alloxan inducing experimental diabetes in animals. STZ is transported into pancreatic beta cells through glucose transporter in the cell membranes and attacks mitochondria. Mitochondrial ATP generation is inhibited and the resulting high concentration of intracellular ADP causes its degradation providing hypoxanthine, a substrate of xanthine oxidase (XOD) whose activity is intrinsically very high in beta cells. Then, XOD-catalyzing reaction is proceeded as proved by increased formation of uric acid and O2- radicals are produced, but beta cells are inefficient to scavenge these radicals because of their extremely low activity of superoxide dismutase. On the other hand, STZ directly activates XOD and enhances O2- generation. Consequently, pancreatic beta cells are dually suffered from O2- radicals or probably hydroxyl radicals derived from the former when exposed to STZ. Allopurinol, an inhibitor of XOD, can protect animals from the diabetogenic effect of STZ. In pancreatic beta cells, alloxan anion radicals are generated from alloxan probably mediated by the action of microsomal cytochrome P-450 system. These radicals have long half-life and directly damage DNA in vitro. The widely accepted hypothesis that the cause of alloxan-induced diabetes is attributable to O2- radicals formed from alloxan is excluded, because alloxan itself shows a very potent scavenging effect to O2- radicals. Therefore alloxan anion radicals seem to be directly related to the incidence of diabetes by alloxan.
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PMID:[New hypotheses for the mechanisms of streptozotocin and alloxan inducing diabetes mellitus]. 148 45

DNA polymorphisms in the glucokinase gene have recently been shown to be tightly linked to early-onset non-insulin-dependent diabetes mellitus in approximately 80% of French families with this form of diabetes. We previously identified a nonsense mutation in exon 7 in one of these families and showed that it was the likely cause of glucose intolerance in this dominantly inherited disorder. Here we report the isolation and partial sequence of the human glucokinase gene and the identification of two missense mutations in exon 7, Thr-228----Met and Gly-261----Arg, that cosegregate with early-onset non-insulin-dependent diabetes mellitus. To assess the molecular mechanism by which mutations at these two sites may affect glucokinase activity, the crystal structure of the related yeast hexokinase B was used as a simple model for human beta-cell glucokinase. Computer-assisted modeling suggests that mutation of Thr-228 affects affinity for ATP and mutation of Gly-261 may alter glucose binding. The identification of mutations in glucokinase, a protein that plays an important role in hepatic and beta-cell glucose metabolism, indicates that early-onset non-insulin-dependent diabetes mellitus may be primarily a disorder of carbohydrate metabolism.
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PMID:Human glucokinase gene: isolation, characterization, and identification of two missense mutations linked to early-onset non-insulin-dependent (type 2) diabetes mellitus. 150 86

The changes in sensitivity of the rat duodenum to ATP were examined in preparations from control rats and from rats with streptozotocin (STZ)-induced diabetes. ATP was able to relax the duodenum of control animals in a concentration-dependent manner and this relaxation was significantly increased in STZ-diabetic rats. In preparations from diabetic rats, relaxation responses to ATP were greater than those of age-matched control groups. These results suggest that functional changes or degeneration of non-adrenergic, non-cholinergic nerves in the myenteric plexus may occur in STZ-diabetic rats, and that these alterations may result in the increased sensitivity of the relaxation of the duodenum to ATP.
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PMID:Abnormalities of the autonomic nervous system of the duodenum in streptozotocin-induced diabetic rats. 150 3

Biosynthetic regulation of renal glomerular heparan sulfate-proteoglycans by various aldohexoses (mannose, glucose, and galactose) was investigated. Isolated kidneys were perfused for 5 hr with medium containing [35S]sulfate, to label sulfated proteoglycans, or [35S]methionine, to label total glomerular proteins. All the hexoses, above 10 mM concentration, caused a significant decrease in the de novo synthesis of [35S]sulfate-labeled proteoglycans. The relative effectiveness of the hexoses was as follows: mannose much greater than glucose greater than galactose. The proteoglycans were of relatively lower molecular weights and exhibited reduced charge-density characteristics. Autoradiographic studies revealed a 2- to 3-fold decrease of grain density over the glomerular basement membrane and mesangial compartments, and immunoprecipitable heparan sulfate-proteoglycans were similarly decreased 2- to 3-fold. There was no significant decrease in the total [35S]methionine-labeled glomerular proteins or immunoprecipitable type IV collagen and laminin. Cellular ATP levels were dramatically reduced in all groups, and the maximal depletion was caused by mannose. Addition of ATP (0.1-1.0 mM) to the perfusion medium resulted in the normalization of the de novo synthesis and of the biochemical characteristics of heparan sulfate-proteoglycans. The relevance of decreased de novo synthesis of proteoglycans due to the depletion of ATP in hyperglycemic states is discussed in terms of increased glomerular permeability to plasma proteins, as seen in diabetes mellitus.
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PMID:Biosynthetic regulation of proteoglycans by aldohexoses and ATP. 152 71

Normal and streptozotocin diabetic female Wistar rats were given normal diets with the following additions: 0, or 12,500 iu/kg food vitamin A (retinyl palmitate). At the end of 6 weeks, the rats were examined for weight gain or loss, general body condition, and cataracts. At sacrifice, blood was collected for measurement of serum glucose. gamma-Crystallin levels were determined in aqueous and vitreous humours using a radioimmunoassay. One lens (the right) was homogenized in 8 M guanidinium chloride for ATP analysis. In normal rats, gamma-crystallin was detected in both aqueous and vitreous humours, with a greater concentration found in the vitreous. Diabetes caused a 4-5 fold increase in gamma-crystallin in both aqueous and vitreous humours. Diabetes also led to a significant loss of body weight, and decrease in lens ATP levels. Addition of vitamin A to the diet resulted in reduction in gamma-crystallin leakage into the aqueous and vitreous humours. Vitamin A at 12,500 iu/kg food resulted in an increase in lens ATP for the diabetic rats. Neither streptozotocin diabetes nor vitamin A in the diet appeared to affect the weight of the lenses after 6 weeks. It is suggested that childhood vitamin A deficiency leading to latent fiber cell damage may be an important factor contributing to the high incidence of cataracts in the third world.
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PMID:Modelling cortical cataractogenesis. XII: Supplemental vitamin A treatment reduces gamma-crystallin leakage from lenses in diabetic rats. 153 87

To examine the mechanisms of hyperglycemia-induced insulin resistance, eight insulin-dependent (type I) diabetic men were studied twice, after 24 h of hyperglycemia (mean blood glucose 20.0 +/- 0.3 mM, i.v. glucose) and after 24 h of normoglycemia (7.1 +/- 0.4 mM, saline) while receiving identical diets and insulin doses. Whole-body and forearm glucose uptake were determined during a 300-min insulin infusion (serum free insulin 359 +/- 22 and 373 +/- 29 pM, after hyper- and normoglycemia, respectively). Muscle biopsies were taken before and at the end of the 300-min insulin infusion. Plasma glucose levels were maintained constant during the 300-min period by keeping glucose for 150 min at 16.7 +/- 0.1 mM after 24-h hyperglycemia and increasing it to 16.5 +/- 0.1 mM after normoglycemia and by allowing it thereafter to decrease in both studies to normoglycemia. During the normoglycemic period (240-300 min), total glucose uptake (25.0 +/- 2.8 vs. 33.8 +/- 3.9 mumol.kg-1 body wt.min-1, P less than 0.05) was 26% lower, forearm glucose uptake (11 +/- 4 vs. 18 +/- 3 mumol.kg-1 forearm.min-1, P less than 0.05) was 35% lower, and nonoxidative glucose disposal (8.9 +/- 2.2 vs. 19.4 +/- 3.3 mumol.kg-1 body wt-1min-1, P less than 0.01) was 54% lower after 24 h of hyper- and normoglycemia, respectively. Glucose oxidation rates were similar. Basal muscle glycogen content was similar after 24 h of hyperglycemia (234 +/- 23 mmol/kg dry muscle) and normoglycemia (238 +/- 22 mmol/kg dry muscle). Insulin increased muscle glycogen to 273 +/- 22 mmol/kg dry muscle after 24 h of hyperglycemia and to 296 +/- 33 mmol/kg dry muscle after normoglycemia (P less than 0.05 vs. 0 min for both). Muscle ATP, free glucose, glucose-6-phosphate, and fructose-6-phosphate concentrations were similar after both 24-h treatment periods and did not change in response to insulin. We conclude that a marked decrease in whole-body, muscle, and nonoxidative glucose disposal can be induced by hyperglycemia alone.
Diabetes 1992 May
PMID:Mechanisms of hyperglycemia-induced insulin resistance in whole body and skeletal muscle of type I diabetic patients. 156 26

In vivo age-related changes in membrane fluidity of erythrocytes were investigated by a spin label method after fractionation of the cells by discontinuous density gradient centrifugation. Membrane fluidity was lower in older than in younger erythrocytes in both the normal and diabetic subjects. Cells from diabetic subjects showed a significantly lower level of membrane fluidity for all three age groups (younger, middle and older) than the corresponding cells from normal subjects. The magnitude of progression in the decrease in membrane fluidity in erythrocytes did not differ significantly between both groups of subjects. Both erythrocyte ATP and acetylcholinesterase activity declined, while glycosylated hemoglobin (HbA1c) increased with cell age in both groups of subjects. The HbA1c level in each corresponding fraction was higher in diabetic subjects than normal subjects, but was not correlated with membrane fluidity in either group. Neither the ATP level nor acetylcholinesterase activity in each corresponding fraction differed between groups. Membrane fluidity was significantly correlated with acetylcholinesterase activity in both normal and diabetic subjects. Our results indicate that decreased erythrocyte membrane fluidity in diabetic patients does not form gradually during their life span but develops soon after the cells enter the circulation or during their maturation in the bone marrow.
Diabetes Res Clin Pract 1992 Apr
PMID:Lowered membrane fluidity of younger erythrocytes in diabetes. 157 26

Pancreatic islet glucokinase (ATP:D-hexose-6-phosphotransferase) cDNAs were isolated from a human islet cDNA library in lambda-gt11. One clone (hlGLK2), 2723 bp plus additional poly(A) residues, appeared to be full length because its size was consistent with a single 2.9-kb glucokinase mRNA on Northern-blot analysis of islet RNA. This cDNA contained an open reading frame of 1395 bp from an ATG codon at position 459, encoding a predicted protein of 465 amino acids (52,000 M(r)). Comparison of the nucleotide sequences of the human islet glucokinase cDNA with that of the recently isolated human liver glucokinase cDNA revealed that the two cDNAs differed completely on their 5'-ends, followed by an identical 2204-bp overlap extending to the 3'-ends. The 5'-ends of islet and liver glucokinase cDNAs predicted proteins that differ by 15 NH2-terminal residues. The overall sequence identity (70%) between the first exons of the human islet and rat islet cDNAs suggested that the islet promoter regions, like the liver promoter regions, have been conserved through evolution. Thus, NH2-terminal differences for human liver and islet enzymes might be explained by use of alternate promoters between the two tissues, analogous to the NH2-terminal differences of the rat liver and rat islet enzymes. If so, this relationship predicts important tissue-specific regulatory functions of these regions. Variations in the glucokinase gene are likely to occur in humans. Isolation of a human islet glucokinase cDNA has provided the sequence necessary to determine whether these variants are important determinants in the genetic predisposition for diabetes mellitus.
Diabetes 1992 Jul
PMID:Human islet glucokinase gene. Isolation and sequence analysis of full-length cDNA. 161 94


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