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

An increased prevalence of cataract is associated with diabetes. Biochemical studies of diabetic lenses have revealed a variety of metabolic abnormalities including changes in the levels of electrolytes, glutathione, nucleotides and sugars. Similar biochemical changes have also been observed in cataracts associated with galactosaemia, suggesting that these sugar cataracts have a common biochemical aetiology. The common biochemical factor found to initiate both types of sugar cataract is the formation of sugar alcohols (polyols) from either glucose or galactose by the enzyme aldose reductase (alditol: NADP+ 1-oxidoreductase, EC 1.1.1.21). Increased intracellular levels of these polar alcohols have a hyperosmotic effect which leads to lens fibre swelling, vacuole formation and subsequent opacification. The process of sugar cataract formation in animals can be prevented by inhibiting aldose reductase.
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PMID:Diabetic and galactosaemic cataracts. 643 98

The activity of enzymes with a regulatory function in the pathways of glycolysis, gluconeogenesis and NADP-generation was investigated in 50 placentae from normal pregnancies and deliveries, 23 placentae from women with gestational diabetes, and 12 placentae from insulin-dependent patients. In placentae from the gestational diabetic group, the activity of pyruvate kinase and of NADPH-generating enzymes was raised and the activity of enzymes connected to glucogenesis was unchanged. These alterations were attributed to the oversupply of glucose and insulin to morphologically normal and well-oxygenated placental tissue. In the placentae from the insulin-dependent group, the activity of pyruvate kinase was reduced, the activity of NADPH-generating enzymes was enhanced and the activity of those related to the gluconeogenesis was unchanged. It is suggested that this pattern of enzyme changes reflects a reduction in the glycolytic capacity in these placentae, which may be due to inhibition by products of enhanced fatty acid oxidation in diabetes, amino acids and/or by long-term anoxia as a result of uteroplacental circulatory disturbances. The possible relation of reduced energy-forming capacity of the placenta in diabetes to its transport function is discussed.
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PMID:Changes in activity of enzymes related to glycolysis, gluconeogenesis and lipogenesis in placentae from diabetic women. 672 31

When isolated rat pancreatic islets are exposed to L-leucine (20 mM), the rate of NH4 production is close to the summed rates of L-[1-14C] leucine decarboxylation and alpha-ketoisocarproate production, whereas the rates of acetoacetate production and L-[U-14C]-leucine oxidation are compatible with conversion of each mole of the amino acid to one mole of acetoacetate and three moles of CO2. ATP content, ATP/ADP ratio, and adenylate charge are maintained at normal values by L-leucine, whereas the NADH/NAD+ ratio (but not the NADPH/NADP+ ratio) is significantly increased. The release of insulin evoked by L-leucine is potentiated by 2-ketoisovalerate, unaffected by L-valine, and inhibited by menadione. L-leucine mimicks the effect of D-glucose on 86Rb+ and 45Ca2+ handling by the islets. However, relative to its rate of oxidation, the insulinotropic effect of L-leucine is less marked than that of D-glucose. This may be due, in part at least, to a decrease in the oxidation of endogenous nutrients. It is concluded that the metabolic, cationic, and secretory effects of L-leucine in isolated islets are not incompatible with the fuel hypothesis for insulin release.
Diabetes 1980 Jun
PMID:The stimulus-secretion coupling of amino acid-induced insulin release: metabolism and cationic effects of leucine. 676 28

We examined the relationship between glucose-induced insulin release and the intermediary metabolism of islets from fed and fasted rats. Isolated islets were perifused and insulin release measured in the effluent. At various times after switching islets from 2.4 to 8.6 or 14.5 mM glucose or from 2.4 to 14.5 and back to 2.4 mM glucose, islets were quickly frozen, freeze dried, and subsequently analyzed for tissue content of glucose-6-P, fructose-1,6-P2 plus triose-P, Pi, ATP, ADP, 5'-AMP, NADH, NADPH, total NAD, and total NADP using enzymatic fluorometric procedures. When islets from fed rats were exposed to high glucose, there were concomitant increases of insulin release and islet content of glucose-6-P, fructose-1,6-P2 plus triose-P, NADH, and NADPH. During stimulation Pi and 5'-AMP content fell markedly. The total adenine nucleotide content remained constant. Similar secretory and metabolic changes occurred when 1.5 mM Pi was added to the perifusion fluid. When glucose-stimulated islets were switched back to low glucose for 10 min, all substances but fructose-1,6-P2 plus triose-P, 5'-AMP, NADPH, and possibly ATP returned to the prestimulatory level. Starvation of rats for 3 days blocked the secretory response to 8.6 mM glucose. Fructose-1,6-P2 plus triose-P rose but it did not attain the level existing in islets from fed rats. The ratios (ATP)/(5'-AMP) and (ATP)/(Pi)(adp) increased to the values observed in glucose-stimulated islets of fed rats. The metabolic changes in islets from fed rats exposed to high glucose are consistent with an activation of glycolysis occurring concomitantly with stimulated rates of insulin release. This occurs despite the decrease of important activators of glycolysis--Pi and 5'-AMP. The enhanced glycolysis possibly results from P-fructokinase activation by increased fructose-6-P levels. Activation of glycolysis with 8.6 mM glucose was not as pronounced in islets from starved rats. Despite the different secretory response of islets from fet and fasted rats, the changes of phosphorylation state in the islets, in particular, Pi and 5'-AMP levels, were similar.
Diabetes 1980 Jan
PMID:Effects of glucose on insulin release and on intermediary metabolism of isolated perifused pancreatic islets from fed and fasted rats. 699 11

In isolated rat pancreatic islets, glucose (5.6, 11.1, and 16.7 mM) significantly increased reduced glutathione (GSH) and decreased oxidized glutathione (GSSG) levels in a dose-related manner. This was paralleled by a concomitant increase of NADPH and a decrease of NADP. The change of the GSH level occurred as quickly as one minute after addition of glucose. Exogenous insulin (200, 400, and 800 microU/ml) significantly decreased islet GSH levels in the presence of 5.6 and 16.7 mM glucose and significantly inhibited the insulin-releasing effect of the thiol reagent parachloromercuribenzoate (p-CMB) and tolbutamide. These data, together with earlier observations, suggest that GSH levels in pancreatic islets are increased by glucose and decreased by exogenous insulin via their effects on the pentose phosphate shunt and NADPH. Our results are compatible with the hypothesis that glucose and exogenous insulin, by modifying the redox state of the NADPH/NADP and GSH/GSSG systems, modulate the sensitivity of the beta-cell to the insulin-triggering actions of glucose, p-CMB, and tolbutamide.
Diabetes 1980 Oct
PMID:Islet glutathione and insulin release. 700 64

Oxidative decarboxylation is the first irreversible step in the degradation of leucine. The effect of streptozotocin diabetes on this reaction was studied in cell-free rat liver preparations, using [1-14C]alpha-ketoisocaproate as substrate. Diabetes increased the branched-chain ketoacid dehydrogenase (BCKD) activity (per g liver or per mg protein) of homogenates, but the ratios of homogenate BCKD activity to other mitochondrial markers remained unchanged. A cytosolic branched-chain ketoacid decarboxylase activity (15-22% of homogenate activity), which did not require NAD, CoA, or NADP, was also increased in diabetics. Insulin treatment of diabetics normalized enzyme activity in all fractions. The apparent Km of BCKD in homogenates was 43-45 microM; diabetes increased the apparent Vmax from 165 nmol x min-1 x g tissue-1 to 260 nmol x min-1 x g-1. In contrast, the Km for cytosolic alpha-ketoisocaproate decarboxylation was 270 microM in controls, and diabetes resulted in both a lower Km (210 microM) and a higher Vmax. Adrenalectomy did not affect activity in homogenates from controls, but partially reversed the diabetes-associated increase. Glucagon pretreatment of controls did not affect activity. In summary, distinct mitochondrial and cytosolic enzymes decarboxylate alpha-ketoisocaproate in liver. The increased hepatic capacity of diabetic rats to degrade the carbon skeleton of leucine is attributed mainly to a relative increase in mitochondrial mass.
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PMID:Effects of diabetes on oxidative decarboxylation of branched-chain keto acids. 743 56

Effect of insulin-like growth factor-I (IGF-I) on protein metabolism was investigated in burned rats receiving TPN. Twenty-six male SD rats were divided into two groups. IGF-I was administered to group IGF (IGF-I group, n = 14), but not to group C (Control group, n = 12). Loss of body weight after burn in group IGF was significantly lower than group C (p < 0.01). Cumulative nitrogen balance for 2 postburn days in group IGF was significantly higher than group C (p < 0.01). Rate of whole body protein turnover, synthesis and breakdown increased significantly in group IGF compared with group C. On the other hand, blood glucose was decreased significantly in group IGF (p < 0.05). Water balance made no significant difference between two groups. In group IGF, weight of the spleen, kidney, small intestine and colon increased significantly. Fractional synthesis rate and protein content of mucosa of the small intestine were significantly higher in group IGF than group C. From the histological point of view, mucosal layer was thickened and hyperplastic. Catabolism and surgical diabetes are caused in the surgical stress, and the administration of IGF-I are thought to be effective for improvement of those conditions. And IGF-I has the most remarkable effect on the small intestine of all organs studied in our experiment.
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PMID:[Effects of insulin-like growth factor-I in burned rats]. 770 46

Sorbitol (aldose reductase) pathway flux in diabetes perturbs intracellular metabolism by two putative mechanisms: reciprocal osmoregulatory depletion of other organic osmolytes e.g., myo-inositol, and alterations in NADPH/NADP+ and/or NADH/NAD+. The "osmolyte" and "redox" hypotheses predict secondary elevations in CDP-diglyceride, the rate-limiting precursor for phosphatidylinositol synthesis, but through different mechanisms: the "osmolyte" hypothesis via depletion of intracellular myo-inositol (the cosubstrate for phosphatidylinositol-synthase) and the "redox" hypothesis through enhanced de novo synthesis from triose phosphates. The osmolyte hypothesis predicts diminished phosphoinositide-derived arachidonyl-diacylglycerol, while the redox hypothesis predicts increased total diacylglycerol and phosphatidic acid. In high aldose reductase expressing retinal pigment epithelial cells, glucose-induced, aldose reductase inhibitor-sensitive CDP-diglyceride accumulation and inhibition of 32P-incorporation into phosphatidylinositol paralleled myo-inositol depletion (but not cytoplasmic redox, that was unaffected by glucose) and depletion of arachidonyl-diacylglycerol. 3 mM pyruvate added to the culture medium left cellular redox unaltered, but stimulated Na(+)-dependent myo-inositol uptake, accumulation, and incorporation into phosphatidylinositol. These results favor myo-inositol depletion rather than altered redox as the primary cause of glucose-induced aldose reductase-related defects in phospholipid metabolism in cultured retinal pigment epithelial cells.
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PMID:Effects of glucose on sorbitol pathway activation, cellular redox, and metabolism of myo-inositol, phosphoinositide, and diacylglycerol in cultured human retinal pigment epithelial cells. 820 Oct 9

Streptozotocin diabetes induces a 4-fold increase in the maximal velocity of inner medullary aldose reductase as determined in vitro but increases sorbitol synthesis in intact inner medullary collecting duct (IMCD) cells only 1.3-fold. In order to resolve this discrepancy we investigated the importance of intracellular factors in controlling the role of cellular sorbitol synthesis. These factors include glucose concentration, sorbitol concentration, the activity of the NADPH-regenerating pentose phosphate pathway, intracellular NADP and NADPH content, and intracellular reduced (GSH) and oxidized glutathione (GSSG). It was found that the apparent Km of cellular sorbitol production for glucose was identical in control and diabetic rats (56 +/- 18 vs. 59 +/- 14 mmol/l D-glucose), whereas Vmax increased by 31% in diabetes. In inner medullary collecting duct cells of diabetic rats containing 146 +/- 5 mumol sorbitol/g protein, sorbitol synthesis was slightly lower (-15%), compared to cells which had been sorbitol-depleted prior to the experiment (87 +/- 4 mumol sorbitol/g protein). However, no inhibitory effect of sorbitol (up to 200 mmol/l) was observed on aldose reductase activity in vitro. In diabetic rats the content of NADPH was about 32% lower than in the control rats (3.8 +/- 0.3 vs. 5.6 +/- 0.4 mumol/g protein) and the ratio of NADPH/NADP was decreased from 25.6 +/- 5.1 to 8.6 +/- 1.7. In homogenates of the inner medulla the activity of 6-phospho-gluconate dehydrogenase (EC 1.1.1.43) was identical in both experimental groups, so the pentose phosphate shunt seems to be unaltered. GSH content in diabetic rats was also diminished (4.02 +/- 0.67 mumol/g protein vs. 7.41 +/- 0.5 mumol/g protein) and the GSH/GSSG ratio fell from 92.6 to 57.4. In enzyme tests in vitro an apparent Km of 7.3 +/- 1.9 mumol/l of the aldose reductase for NADPH was found; NADP acted as competitive inhibitor with an apparent K(i) of 183 +/- 31 mumol/l. Aldose reductase activity was also found to be strongly inhibited by the SH-group reagent p-chloromercurybenzoesulfonate (apparent K(i) = 0.85 x 10(-6) mol/l). Combining the results obtained on the properties of the aldose reductase in vitro and the observation made in the intact cells, the investigators suggest that the decrease in NADPH/NADP ratio, as well as changes in the redox state in the cells of diabetic animals, can play a significant role in the control of sorbitol synthesis.
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PMID:Control of sorbitol metabolism in renal inner medulla of diabetic rats: regulation by substrate, cosubstrate and products of the aldose reductase reaction. 824 Dec 88

Peptide-chain initiation is inhibited in fast-twitch skeletal muscle, but not heart, of diabetic rats. We have investigated mechanisms that might maintain eukaryotic initiation factor (eIF)-2B activity, preventing loss of efficiency of protein synthesis in heart of diabetic rats but not in fast-twitch skeletal muscle. There was no change in the amount or phosphorylation state of eIF-2 in skeletal or cardiac muscle during diabetes. In contrast, eIF-2B activity was decreased in fast-twitch but not slow-twitch muscle from diabetic animals. NADP+ inhibited partially purified eIF-2B in vitro, but addition of equimolar NADPH reversed the inhibition. The NADPH-to-NADP+ ratio was unchanged in fast-twitch muscle after induction of diabetes but was increased in heart of diabetic rats, suggesting that NADPH also prevents inhibition of eIF-2B in vivo. The activity of casein kinase II, which can phosphorylate and activate eIF-2B in vitro, was significantly lower in extracts of fast-twitch, but not cardiac muscle, of diabetic rats compared with controls. The results presented here demonstrate that changes in eIF-2 alpha phosphorylation are not responsible for the effect of diabetes on eIF-2B activity in fast-twitch skeletal muscle. Modulation of casein kinase II activity may be a factor in the regulation of protein synthesis in muscle during acute diabetes. The activity of eIF-2B in heart might be maintained by the increased NADPH/NADP+.
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PMID:Regulation of eukaryotic initiation factor-2B activity in muscle of diabetic rats. 843 Jul 78


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