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

The effect of diabetes control on the activities of hydroxymethylglutaryl-CoA reductase (HMG-CoA reductase), cholesterol acyltransferase (ACAT), and phenol 2-monooxygenase, the major enzymes regulating cholesterol metabolism, was determined in alloxan-induced diabetic rabbits, and the results obtained were correlated with lipid and lipoprotein levels. Although intestinal HMG-CoA reductase activity was significantly increased (P less than 0.001) in poorly controlled compared with moderately controlled diabetic rabbits, there was a significant reduction in the activities of intestinal ACAT (P less than 0.01), hepatic HMG-CoA reductase (P less than 0.05) and ACAT (P less than 0.001), and phenol 2-monooxygenase (P less than 0.01). The poorly controlled animals were hypercholesterolemic (P less than 0.01), and this was reflected in the very-low-density and high-density lipoprotein fractions. Serum cholesterol levels in the nondiabetic and moderately controlled diabetic groups were similar. This increase in intestinal HMG-CoA reductase activity in the poorly controlled diabetic animals occurred in the absence of hyperphagia. Although abnormalities in cellular cholesterol metabolism could be partly responsible for the alterations in serum cholesterol levels in diabetes, the precise mechanisms underlying these enzymatic changes have yet to be elucidated.
Diabetes 1990 May
PMID:Cholesterol metabolism in alloxan-induced diabetic rabbits. 233 20

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

Coronary artery disease (CAD) is the leading cause of death among whites with non-insulin-dependent diabetes mellitus (NIDDM). Several risk factors--dyslipidemia induced by NIDDM, obesity, hypertension and hyperglycemia--likely contribute to accelerated atherosclerosis. The dyslipidemia in NIDDM is characterized by abnormalities in composition and metabolism of very low density lipoproteins, low-density lipoproteins (LDL) and high-density lipoproteins (HDL). However, because of the lack of long-term prospective epidemiologic studies, the relative importance of lipoprotein risk factors in the causation of CAD in diabetic patients is not clear. The World Health Organization Multinational Study of vascular disease in diabetics observed increased prevalence of CAD in diabetic populations with relatively high levels of plasma cholesterol and supports the concept that lowering cholesterol levels may significantly reduce coronary risk in NIDDM. To determine the effectiveness of lovastatin, an inhibitor of HMG CoA reductase, for lowering cholesterol levels, 16 patients with NIDDM and mild to moderate increases in plasma cholesterol were given lovastatin (20 mg twice daily) in a randomized, double-blind, placebo-controlled manner for 4 weeks. Compared with the placebo, lovastatin reduced concentrations of total cholesterol (233 +/- 10 vs 172 +/- 7 mg/dl [standard error of the mean], p less than 0.001), LDL cholesterol (140 +/- 9 vs 101 +/- 6 mg/dl, p less than 0.001), and LDL apolipoprotein-B (108 +/- 16 vs 80 +/- 16 mg/dl, p less than 0.001). Plasma triglycerides and very low density lipoprotein cholesterol levels also decreased by 31 and 42%, respectively. Although HDL cholesterol levels did not increase, the total cholesterol/HDL cholesterol ratio decreased significantly with lovastatin therapy. No adverse effects were noted and glycemic control was well-maintained.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Treatment of dyslipidemia in non-insulin-dependent diabetes mellitus with lovastatin. 305 23

Coronary heart disease is an important cause of death in patients with non-insulin-dependent diabetes mellitus (NIDDM) and is particularly common in diabetic populations that have relatively high levels of plasma cholesterol. To determine whether plasma cholesterol levels in patients with NIDDM could be reduced by drug therapy, we assessed the effect of lovastatin, a potent inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, in a randomized double-blind placebo-controlled manner in 16 white patients with NIDDM and mild to moderate elevations of plasma cholesterol. Lovastatin (20 mg twice daily) or a placebo was given for four weeks, during which blood glucose concentrations remained controlled. As compared with the placebo, lovastatin reduced total cholesterol by 26 percent, low-density lipoprotein (LDL) cholesterol by 28 percent, and LDL apolipoprotein B by 26 percent. Lovastatin therapy also reduced plasma triglycerides and very-low-density lipoprotein cholesterol by 31 percent and 42 percent, respectively. Although there was no change in the plasma level of high-density lipoprotein (HDL) cholesterol, the ratio of total cholesterol to HDL cholesterol fell by 29 percent. No side effects or abnormalities in serum values were noted during short-term lovastatin therapy. The beneficial effects of lovastatin on plasma lipid levels in patients with NIDDM could decrease the risk of the development of coronary heart disease.
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PMID:Lovastatin for lowering cholesterol levels in non-insulin-dependent diabetes mellitus. 342 5

The expressed and total activities of HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) reductase (EC 1.1.1.34) were measured in microsomal fractions prepared from cold-clamped liver samples [Easom & Zammit (1984) Biochem. J. 220, 733-738] from control or insulin-treated diabetic animals. Streptozotocin-induced diabetes resulted in a marked decrease in total activity of HMG-CoA reductase and in the fraction of the enzyme in the active form, but appreciable effects were only observed in the liver of animals in which the blood glucose was above 20 mM. Intravenous infusion of insulin into diabetic rats resulted in a rapid (less than 20 min) and total dephosphorylation of the enzyme in vivo without any change in total activity. Longer-term (4 h) treatment with insulin (injected intraperitoneally) produced a rapid increase in expressed/total HMG-CoA reductase activity ratio to about 90%, followed, after a lag of 2-3 h, by a 5-6-fold increase in total activity. These observations are discussed with respect to the possible role of insulin in generating and maintaining the respective diurnal rhythms in total and in expressed/total HMG-CoA reductase activity ratio observed for normal animals in vivo [Easom & Zammit (1984) Biochem. J. 220, 739-745].
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PMID:Effects of diabetes on the expressed and total activities of 3-hydroxy-3-methylglutaryl-CoA reductase in rat liver in vivo. Reversal by insulin treatment. 390 28

The activities of beta-Hydroxy-beta-methylglutaryl CoA reductase (HMG CoA reductase), Acyl CoA: Cholesterol-O-acyltransferase (ACAT) and cholesterol 7 alpha-hydroxylase, the major enzymes involved in cholesterol metabolism, were determined in diabetic and non-diabetic rats after vagotomy and compared with those of sham-operated controls. Hepatic cholesterol levels and serum lipid profiles were also examined. In the non-diabetic animals vagotomy produced a significant increase in HMG CoA reductase (the rate limiting enzyme of cholesterol biosynthesis), and ACAT (the enzyme responsible for intracellular esterification) activities, while the activity of cholesterol 7 alpha-hydroxylase (which catalyses the rate determining step of bile acid biosynthesis) was significantly decreased. These rats had higher levels of free and esterified cholesterol in the liver and serum cholesterol levels were also increased in comparison with sham-operated animals. Vagotomized diabetic rats had similar HMG CoA reductase activity, but significantly reduced ACAT and reduced cholesterol 7 alpha-hydroxylase activity in comparison with sham-operated diabetic rats. There were significant alterations in hepatic and serum cholesterol fractions in both normal and diabetic rats after vagotomy. The results suggest that vagotomy leads to an increased rate of cholesterol synthesis and a decreased rate of cholesterol utilization, thus providing a possible mechanism for excessive cholesterol accumulation. These results are discussed in relation to alterations in cholesterol metabolism found in diabetic autonomic neuropathy.
Diabetes Res 1985 Nov
PMID:Cholesterol metabolism: regulatory effects of the vagus in the normal and diabetic animal. 407

In normal individuals, insulin regulates lipoprotein metabolism. It increases hepatic triglycerides (TG) secretion and makes VLDL and chylomicrons post prandial removal easy by stimulating adipose tissue lipoprotein lipase (LPL). Insulin activity and cholesterol rich lipoprotein is more complicated: by its action on VLDL and chylomicrons turn-over, it influences LDL and HDL formation. It regulates cellular cholesterol pool at different levels: stimulation of LDL receptor, but also of HMG CoA reductase. Controlling LCAT, in participates in cholesterol removal by HDL. In insulin dependent diabetes, lack of adipose tissue LPL stimulation augments triglycerid-rich lipoproteins, by slowing their catabolism, resulting in a weak increase of LDL and a lowering of HDL. In non insulin dependent diabetes with hyperinsulinism, VLDL are elevated because of insulin stimulation of triglycerid hepatic production. LDL are increasing. HDL status remains discussed: HDL cholesterol is low but HDL triglycerid is high, there is no known disturbance of apo A level. In the two types of diabetes, although mechanism is different, perturbation of lipoprotein metabolism may account for the atherogenicity of this disorders.
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PMID:[Insulin and the metabolism of lipoproteins]. 634 30

In the past history of the pharmaceutical industry, secondary metabolites have been screened almost exclusively for antimicrobial activities. This biased and narrow view has severely limited the potential application of microbial metabolites. Fortunately, this situation is changing and we are now entering into a new era in which microbial metabolites are being applied to diseases heretofore only subjected to synthetic compounds. This new approach is the application of microbial secondary metabolites to diseases that are not caused by other bacteria or fungi. For years, major drugs such as hypotensive and anti-inflammatory agents that are used for non-infectious diseases have been strictly synthetic products. Similarly, major therapeutics for parasitic diseases in animals (for example, coccidiostats and anthelminthics) resulted strictly from screens of chemically synthesized compounds followed by molecular modification. However, today fermentation products such as monensin and lasalocid dominate the coccidiostat market. The avermectins, another group of streptomycete products, have high activity against helminths and arthropods. Indeed, their activity appears to be an order of magnitude greater than previously discovered anthelminthic agents, the vast majority of which are synthetic compounds. Umezawa's group in Japan has isolated many microbial products with important pharmacological activities by screening with simple enzymic assays. There is much interest in a natural inhibitor of intestinal glucosidase, which is produced by an actinomycete of the genus Actinoplanes. The aim is to decrease hyperglycaemia and triacylglycerol synthesis in adipose tissue, liver and the intestinal wall of patients with diabetes, obesity and type IV hyperlipidaemia. Another natural compound of interest is mevinolin, a fungal product which acts as a cholesterol-lowering agent in animals. Mevinolin is produced by Aspergillus terreus. In its hydroxyacid form (mevinolinic acid), mevinolin is a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase from liver. It is clear that, although the microbe has contributed greatly to the benefit of mankind, we have merely scratched the surface of the potential of microbial activity.
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PMID:A new era of exploitation of microbial metabolites. 640 Apr 79

There is experimental evidence to suggest that hypercholesterolaemia may play a pathogenetic role in progressive glomerular injury. We investigated the effect of cholesterol-lowering therapy on the progression of diabetic nephropathy in 34 patients with non-insulin-dependent diabetes mellitus. Patients were randomly assigned in a single-blind fashion to treatment with either lovastatin, an HMG CoA reductase inhibitor (n = 16; mean dose 30.0 +/- 12.6 mg/day) or placebo (n = 18) for 2 years. Renal function was assessed by serially measuring the serum creatinine, glomerular filtration rate (using Cr51-EDTA), and 24-h urinary protein excretion. Lovastatin treatment was associated with significant reductions in total cholesterol (p < 0.001), LDL-cholesterol (p < 0.001) and apo B (p < 0.01), the reductions at 24 months being 26, 30 and 18%, respectively. Beneficial effects on serum triglyceride, HDL-cholesterol and apo A1 levels were also observed. Lp(a) showed no significant change in both groups. Glomerular filtration rate deteriorated significantly in the placebo group after 24 months (p < 0.025) but showed no significant change in the lovastatin-treated patients. The increase in serum creatinine was statistically significant (p < 0.02) in placebo-treated patients at 12 and 24 months, and in the lovastatin group after 24 months. Twenty-four hour urinary protein excretion increased in both groups (p < 0.05). Lovastatin treatment was not associated with significant elevations in liver or muscle enzymes. We conclude that effective normalisation of hypercholesterolaemia may retard the progression of diabetic nephropathy.
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PMID:Cholesterol-lowering therapy may retard the progression of diabetic nephropathy. 748 45


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