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

Increased renal production of prostaglandins (PG) may contribute to the hyperfiltration that accompanies early diabetes. It was postulated that a putative metabolic abnormality of diabetes, ie, increased flux through the polyol pathway, stimulates renal PG production and that this phenomenon can be prevented by aldose-reductase inhibition. To test this hypothesis, the effects of polyol accumulation on urinary excretion rates (UER) of PGE2 and 6-keto-PGF1 alpha were studied, using the galactose-fed rat model. UER of PGE2 and 6-keto-PGF1 alpha were measured in three groups of weanling Wistar male rats. Group 1 was maintained on normal chow (n = 6), group 2 was fed chow supplemented with 30% galactose (n = 6), and group 3 received chow supplemented with 30% galactose and 0.7% sorbinil (n = 6). Ten 24-hour urine samples were obtained from each group between 151 and 240 days on the respective diets. UER of PGE2 (P less than .001) and 6-keto-PGF1 alpha (P less than .01) were higher in group 2 than in group 1. UER of PGE2 (NS) and 6-keto-PGF1 alpha (NS), respectively, were similar in groups 1 and 3. These data indicate that flux through the polyol pathway modulates the UER of PGE2 and 6-keto-PGF1 alpha. This phenomenon may contribute to the glomerular hyperfiltration of early diabetes.
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PMID:Increased urinary prostaglandin excretion in galactose-fed rats. 250 May 76

Previous studies have suggested a link between hyperfiltration and enhanced polyol pathway activity in the streptozotocin diabetic rat. In the present study we examined the relationship between glomerular sorbitol content, a measure of polyol pathway activity and glomerular filtration rate (GFR), as a function of plasma glucose and time after induction of diabetes. GFR is increased by 1 to 2 weeks in the untreated streptozotocin diabetic rat but falls to values equal to or below control by 2 months. Treatment of diabetic rats with a low dose of insulin to achieve moderate hyperglycemia results in the maintenance of elevated GFR for 2 months. Glomerular sorbitol content in the 1- to 2-week diabetic rats was not significantly different from values in glomeruli from control rats at 1 to 2 weeks but was 11-fold higher than control by 2 months in the untreated diabetic rat. Treatment of diabetic rats with insulin to achieve moderate hyperglycemia resulted in values for glomerular sorbitol content that were not different from control. Thus, elevated GFR was not associated with elevated glomerular sorbitol content in the 1- to 2-week diabetic rat and was dissociated from elevated glomerular sorbitol content in the 2-month diabetic rat. Treatment of 1- to 2-week diabetic rats with sorbinil prevented the rise in GFR observed at this time despite the fact that sorbitol content of glomeruli was not elevated. These results suggested that sorbinil was reducing GFR in the diabetic rat by a mechanism other than aldose-reductase inhibition. The synthesis of vasodilatory prostaglandins by isolated glomeruli and the activity of phospholipase A2 in the particulate cell fraction of glomerular homogenates is higher in 1- to 2-week diabetic rats compared with controls, a finding that may contribute to the elevated GFR in these rats.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Sorbinil suppresses glomerular prostaglandin production in the streptozotocin diabetic rat. 250 May 78

Streptozocin-induced diabetes significantly decreased acetohexamide reductase activity of 10,000 g supernatant of liver homogenates from both male and female rats. However, the decrease in activity from female rats was smaller than that from male rats, thereby eliminating the sex difference in the activity of the 10,000 g supernatant. In male rats, the diabetes markedly decreased acetohexamide reductase activity only in the microsomal fraction of liver homogenate, whereas in female rats, it decreased the activity only in the cytosolic fraction. These results indicate that the mechanism for the decreasing effect of the diabetes on reductive metabolism of acetohexamide in 10,000 g supernatant differs between male and female rats.
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PMID:Influence of streptozocin-induced diabetes on reductive metabolism of acetohexamide in rat liver. 256 46

The fraction of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase in the dephosphorylated (active) form in rat liver in vivo was measured after various experimental treatments of animals. Intraperitoneal injection of glucose (to raise serum insulin concentrations) into rats 4 h into the light phase (L-4) resulted in a transient (30 min) increase in the expressed (E)/total (T) activity ratio of HMG-CoA reductase without any change in total activity (obtained after complete dephosphorylation of the enzyme). Conversely, intravenous injection of guinea-pig anti-insulin serum into rats 4 h into the dark phase (D-4) significantly depressed the E/T ratio within 20 min. Intravenous injection of glucagon into normal rats at this time point did not affect the degree of phosphorylation of the enzyme, in spite of a 10-fold increase in hepatic cyclic AMP concentration induced by the hormone treatment. A 3-fold increase in the concentration of the cyclic nucleotide induced by adrenaline infusion was similarly ineffective in inducing any change in expressed or total activities of hepatic HMG-CoA reductase. However, when insulin secretion was inhibited, either by the induction of streptozotocin-diabetes or by simultaneous infusion of somatostatin, glucagon treatment was able to depress the expressed activity of HMG-CoA reductase (i.e. it increased the phosphorylation of the enzyme). Therefore insulin appears to have a dominant role in the regulation of the phosphorylation state of hepatic HMG-CoA reductase. In apparent corroboration of this suggestion, short-term 4 h food deprivation of animals before D-4 resulted in a marked decrease in the E/T activity ratio of reductase, which was not affected further by an additional 8 h starvation. By contrast, the total activity of the enzyme was not significantly affected by 4 h starvation, but was markedly diminished after 12 or 24 h starvation. Longer-term starvation also produced a chronic increase in the degree of phosphorylation of the enzyme. These results are discussed in relation to the role of reversible phosphorylation in the control of hepatic HMG-CoA reductase activity in vivo.
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PMID:Acute effects of starvation and treatment of rats with anti-insulin serum, glucagon and catecholamines on the state of phosphorylation of hepatic 3-hydroxy-3-methylglutaryl-CoA reductase in vivo. 288 48

Previous studies have demonstrated that cholesterol synthesis is increased twofold in the small intestines of rats with streptozotocin-induced diabetes. The purpose of the present study was to determine the effect of adding glucose or fructose to standard rat chow on cholesterol synthesis in control and diabetic rats. In control rats a 25% glucose or fructose diet fed for 21 days markedly inhibited hepatic cholesterol synthesis in the liver. In contrast, in diabetic animals only fructose inhibited hepatic cholesterol synthesis. In both control and diabetic animals the addition of these simple sugars to the diet did not markedly alter extrahepatic cholesterol synthesis. The enhancement of small intestinal cholesterol synthesis observed in diabetic animals was present regardless of the dietary manipulations. Further studies demonstrated that the addition of smaller concentrations of fructose (10%) to standard rat chow decreased hepatic cholesterol synthesis in both control and diabetic rats. Similarly the addition of fructose to the diet of control and diabetics for a period as short as 2 days was also sufficient to inhibit hepatic cholesterol synthesis. In both control and diabetic animals, fructose feeding decreased hepatic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity but did not alter the percentage of HMG-CoA reductase in the active form. Finally, the intestinal hypertrophy and stimulation of intestinal cholesterogenesis that are characteristic of streptozotocin-induced diabetes occurred when either glucose or fructose was the sole caloric source.
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PMID:Effect of glucose or fructose feeding on cholesterol synthesis in diabetic animals. 293 18

This study measured the ouabain-sensitive and ouabain-resistant adenosine triphosphatase activity in homogenates of the sciatic nerves and of pooled fourth and fifth lumbar dorsal root ganglia from rats fed 20% galactose or made diabetic with streptozotocin for either 4 or 8 weeks. Diabetes caused reductions in both fractions of sciatic nerve adenosine triphosphatase activity. After 8 weeks the ouabain-sensitive fraction was 54% of control (p less than 0.05) and the ouabain-resistant fraction was 57% of control (p less than 0.05). Galactose feeding more than doubled the ouabain-sensitive adenosine triphosphatase activity in the sciatic nerve (225% of control after 4 weeks, 215% of control after 8 weeks of galactose feeding, both p less than 0.01) and produced a progressive increase in the ouabain-resistant fraction (119% of control at 4 weeks (p less than 0.05) and 176% of control at 8 weeks (p less than 0.01)). In a group of rats fed galactose for 5 days, sciatic nerve ouabain-sensitive adenosine triphosphatase activity was 165% of control. Treatment with the aldose-reductase inhibitors tolrestat, ponalrestat or sorbinil prevented accumulation of polyol and depletion of myo-inositol in the sciatic nerves, indicating effective inhibition of aldose reductase. These drugs prevented completely the effect of galactose on the sciatic nerve adenosine triphosphatase activity, but had no significant effect on the reduction in adenosine triphosphatase activity in the sciatic nerves of diabetic rats. In the dorsal root ganglia galactose feeding had no measurable effect on the adenosine triphosphatase activity. Diabetes caused a modest numerical reduction in the ouabain-sensitive activity only.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Adenosine triphosphatase in nerves and ganglia of rats with streptozotocin-induced diabetes or galactosaemia; effects of aldose reductase inhibition. 297 Sep 84

The acetohexamide reductase activity in 10000 x g supernatant fluids of kidney homogenates was significantly higher in male than in female rats. Although difference in activity of acetohexamide reductase in the cytosol between the sexes was not observed, the activity in the microsomes was considerably higher in male than in female rats. These findings indicate that the microsomal enzyme plays an important role in the sex difference of acetohexamide reduction by 10000 x g supernatant fluids of kidney homogenates. The sensitivities to inhibitors of microsomal acetohexamide reductase were different from those of cytosolic acetohexamide reductase. Furthermore, streptozotocin-induced diabetes significantly decreased acetohexamide reductase activity only in the kidney microsomes of male rats, resulting in the abolishment of the sex difference of acetohexamide reduction by 10000 x g supernatant fluids of kidney homogenates.
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PMID:Metabolic reduction of acetohexamide in rat kidney: sex difference and effect of streptozotocin-induced diabetes. 297 93

Slowing of nerve conduction, a hallmark of both experimental and human diabetic neuropathy, is improved or corrected by aldose reductase inhibitors such as sorbinil. Animal experiments suggest that a myo-inositol-related defect in nerve sodium-potassium adenosine triphosphatase (ATPase) is responsible for the acute reversible slowing of nerve conduction in diabetes mellitus. This myo-inositol-related defect is at present viewed as a cyclic metabolic defect. Aldose reductase inhibitors have been shown to restore to normal both the myo-inositol content and the sodium-potassium ATPase activity of nerve. This suggests that the acute effects of aldose-reductase inhibitors on nerve conduction in both diabetic animals and human patients may be modified by the correction of an underlying myo-inositol-related defect of nerve sodium-potassium ATPase. Furthermore, this myo-inositol-related defect may contribute to other biochemical, functional and structural abnormalities of diabetic peripheral neuropathy.
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PMID:Sorbitol, myo-inositol and sodium-potassium ATPase in diabetic peripheral nerve. 302 50

Hyperfiltration is a very characteristic feature in insulin-dependent diabetes. Hyperfiltration is to some extent associated with long-term glycemic control but the correlation is not very strong. Long-term hyperfiltration may play a role in the genesis of late diabetic nephropathy, but it is difficult to distinguish effects of hyperfiltration per se from effects of poor metabolic control. Long-term hyperfiltration without diabetes does not produce nephropathy. It is hypothesized that IDDM patients who do not show considerable hyperfiltration in spite of poor metabolic control may be those who are to some extent protected against late diabetic nephropathy, but other mechanisms may also be involved in the renal protection of these patients, who survive long-term diabetes without nephropathy. On the other hand, those with poor metabolic control combined with hyperfiltration are likely to develop nephropathy. In addition, it is suggested that the metabolic aberrations in diabetes, with the subsequent changes in the biochemistry of the glomerular wall, are permissive and absolutely required for the development of diabetic nephropathy. Of note, diabetic glomerulopathy in NIDDM occurs without significant hyperfiltration and extreme hyperfiltration in the one-kidney-model (without diabetes) does not produce nephropathy. Nonglycemic modalities of intervention, resulting in reduced hyperfiltration, e.g., low-protein diet or administration of somatostatin analogues, deserves interest as new potential ways of preventing or postponing diabetic nephropathy. Also intervention with aldose-reductase inhibitors may be an important therapeutic modality for those patients in whom good metabolic control is not obtainable. It is now well-established that antihypertensive treatment, including ACE-inhibition, reduces rate of decline in GFR in patients with already established nephropathy. In addition, protein excretion is diminished in IDDM patients with incipient diabetic nephropathy by antihypertensive treatment where GFR is well-preserved during treatment. No data are available for NIDDM.
Diabetes Metab Rev 1988 Aug
PMID:Comparative renal pathophysiology relevant to IDDM and NIDDM patients. 306 56

The water content of the sural nerve of diabetic patients was quantitatively defined by magnetic resonance proton imaging as a putative reflection of activity of the aldose-reductase pathway. Thirty-nine patients were evaluated, comparing group A, symptomatic diabetic men with sensory neuropathy; group B, similarly symptomatic diabetic men treated with aldose-reductase inhibition; group C, neurologically asymptomatic diabetic men; and group D, control nondiabetic men. Marked increase in hydration of the sural nerve was seen in more than half of the symptomatic diabetic patients. Two of 11 neurologically asymptomatic diabetics had increased nerve hydration, suggesting a presymptomatic alteration of the nerve. Symptomatic diabetics treated with aldose-reductase inhibitors had normal nerve water levels. Increased level of peripheral nerve water represents a new finding in diabetes mellitus. It seems to be related to aldose-reductase activity, involved in the development of neuropathy, and similar to events that occur in other target tissue in human diabetes.
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PMID:Diabetic neuropathy. Structural analysis of nerve hydration by magnetic resonance spectroscopy. 314 35


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