Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Patients with diabetes mellitus are at increased risk of morbidity and mortality from macrovascular disease manifesting as coronary heart disease, cerebrovascular accidents, and peripheral vascular disease. Increased frequency of dyslipidemia, hyperglycemia, obesity, hypertension, and associated nephropathy may contribute to accelerated atherogenesis in diabetic patients. Therefore, besides intensive control of hyperglycemia, management of dyslipidemia, hypertension, and obesity should also be emphasized in diabetic patients. Those who smoke should be strongly encouraged to quit smoking. Besides attempts to achieve normal levels of plasma lipoproteins, consideration also should be given to normalization of compositional abnormalities of various lipoproteins in patients with diabetes mellitus. The therapeutic goals for cholesterol reduction should be lower in diabetic patients than nondiabetic subjects. The first step is to achieve good metabolic control of diabetes mellitus by diet, exercise, and weight reduction and, if needed, with sulfonylureas or insulin therapy. Because most of the patients with insulin-dependent diabetes mellitus achieve normal levels of plasma lipoproteins with intensive insulin therapy, lipid-lowering medications are rarely needed. In patients with non-insulin-dependent diabetes mellitus, however, dyslipidemia often persists despite good glycemic control. Lipid-lowering medications should be considered in such patients. Because nicotinic acid can cause marked deterioration in glycemic control, and bile acid-binding resins may accentuate hypertriglyceridemia, these agents are less desirable for use by diabetic patients. Inhibitors of hydroxymethylglutaryl coenzyme A reductase may be preferred in patients with elevated LDL cholesterol and mld hypertriglyceridemia. For diabetic patients with marked hypertriglyceridemia, however, fibric acid derivatives should be the drug of choice.
Diabetes 1992 Oct
PMID:Lipid-lowering therapy and macrovascular disease in diabetes mellitus. 152 29

The effects of streptozotocin-induced diabetes on the various forms of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCoA reductase), phosphorylated/dephosphorylated and thiolic/disulphide, were studied in rat liver. Animals were treated twice with 65 mg/kg intraperitoneally of streptozotocin to induce diabetes and sacrificed after 5 days. The relative amounts of the four possible forms of the enzyme were determined in control and diabetic rats. As determined from the total activity, and in agreement with previous reports, the enzyme protein was significantly decreased in streptozotocin-treated rats. However, the percentage of the active thiolic dephosphorylated form was higher in these animals than in controls, suggesting a response of the liver to the decrease both total and specific activity of HMGCoA reductase.
 ...
PMID:Diabetes-induced alteration of HMGCoA reductase forms in rat livers. 157 57

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

Mice made insulin deficient by the injection of streptozocin develop hyperglycemia and hypertriglyceridemia with triglyceride-rich, very-low-density lipoproteins (VLDLs). Thioglycolate-elicited peritoneal macrophages freshly isolated from insulin-deficient mice have increased activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase, which is reflected in a greater rate of cholesterol synthesis by these macrophages. In contrast, thioglycolate-elicited macrophages from control mice with diet-induced hypertriglyceridemia had normal levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. Cell surface receptors responsible for VLDL uptake are decreased in macrophages isolated from insulin-deficient mice, although receptors for acetylated low-density lipoproteins are not altered. Insulin treatment of insulin-deficient mice lowers plasma glucose and triglyceride concentrations. Additionally, insulin treatment returns the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase and the rate of cholesterol synthesis in thioglycolate-elicited macrophages to normal while increasing the number of receptors responsible for VLDL uptake. It is suggested that the increases in 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and the rate of cholesterol synthesis in macrophages isolated from insulin-deficient mice are secondary to the reduction in the number of receptors responsible for VLDL uptake induced by insulin deficiency. These alterations in the cholesterol metabolism of macrophages occurring with insulin deficiency may have important implications for the atherosclerotic process in diabetes mellitus.
Diabetes 1986 Jul
PMID:Insulin deficiency alters cellular cholesterol metabolism in murine macrophages. 352 17

Human low-density lipoprotein (LDL) was glucosylated by incubation in vitro with glucose (20-80 mM) with or without addition of cyanoborohydride. The incorporation of covalently bound glucose was linear over time, and amino acid analysis showed the presence of glucosyllysine residues. The glucosylated LDL (glc LDL) moved more rapidly than normal LDL on agarose electrophoresis. The rate of degradation of 125I-labeled glucosylated LDL (glc LDL) by cultured human fibroblasts was reduced compared with that of native I-LDL, the difference increasing with extent of glucosylation. Effects were seen with blockage of as few as 6-15% of the LDL lysine residues; high-affinity degradation was completely lost when one-third of the lysine residues were blocked. Conjugation of LDL with glucose-6-phosphate also blocked high-affinity uptake and degradation. Whereas native LDL uptake inhibited the activity of beta-hydroxy-beta-methylglutaryl coenzyme A reductase and stimulated acyl coenzyme A:cholesterol acyltransferase activity, glc LDL had no effects on these enzymes. The fractional catabolic rate of glc LDL in guinea pigs was reduced. Degradation of glc LDL by mouse peritoneal macrophages was not significantly faster than that of native LDL. Finally, the presence of glc LDL in human plasma was demonstrated. Preliminary data show that 1.3% of lysine residues in normal LDL and 2-5.3% of lysines in diabetic LDL were glucosylated. Since, like other plasma proteins, LDL undergoes glucosylation in diabetes, its turnover and sites of catabolism may differ from normal and this may be relevant to the accelerated atherosclerosis of diabetes.
Diabetes 1982 Apr
PMID:Nonenzymatic glucosylation of low-density lipoprotein alters its biologic activity. 681 75

Cholesterol synthesis rate, as determined by 3-hydroxy-3-methylglutaryl coenzyme A reductase activity, is characterized in the major organs of genetically diabetic mice. Both C57BL/Ks db+/db+ and C57BL/6 ob+/ob+ mice are hyperinsulinemic and insulin-resistant. These animals demonstrate loss of the circadian rhythm of hepatic reductase activity and a tendency for increased intestinal activity. As a result, proportionally more endogenous cholesterol synthesis occurs in intestinal mucosa than liver in genetically diabetic animals. Thus, the alterations in activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase which are observed in animal models of diabetes are the result of diminished insulin effect rather than insulin level.
 ...
PMID:Hepatic and intestinal 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in genetically diabetic mice. 687 Aug 77

Human drug interaction studies in vivo are conducted when in vitro and/or animal interactions suggest clinical relevance. Studies in vitro have indicated that the new, entirely synthetic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor fluvastatin affects the metabolism of the nonsteroidal anti-inflammatory drug diclofenac and the oral hypoglycemic tolbutamide. Diclofenac and tolbutamide are both model substrates of the CYP2C isozymes, suggesting that this enzyme could be involved in the underlying mechanism of interaction. The concomitant use of lipid-lowering drugs with oral hypoglycemic agents has been recommended in patients with non-insulin-dependent diabetes mellitus (NIDDM). Therefore, 2 studies were initiated to explore potential pharmacokinetic and pharmacodynamic interactions between fluvastatin, simvastatin, or placebo and the oral hypoglycemic agents tolbutamide (study I) and glyburide (study II), each in 16 healthy subjects. These compounds were selected because of a demonstrated in vitro interaction with tolbutamide and widespread clinical use of glyburide. A further study (study III) was conducted to investigate the potential pharmacokinetic and pharmacodynamic interactions between fluvastatin and glyburide under therapeutic conditions in 32 patients with NIDDM. Single and multiple coadministration of fluvastatin 40 mg or simvastatin 20 mg increased the mean maximum plasma concentration and area under the concentration-time curve of glyburide by about 20%. The pharmacokinetics of tolbutamide were influenced to only a minor extent. Fluvastatin concentration-time profiles were unaffected by tolbutamide or glyburide coadministration. However, the pharmacokinetic interactions between fluvastatin or simvastatin and tolbutamide and glyburide were not associated with clinically relevant changes in blood glucose and insulin concentrations and, therefore, are not considered to be relevant in therapeutic practice.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Lack of interaction between fluvastatin and oral hypoglycemic agents in healthy subjects and in patients with non-insulin-dependent diabetes mellitus. 760 92

Patients with diabetes mellitus have an increased risk for coronary artery disease due to hyperglycemia, hypertension, dyslipidemia, and other risk factors. The diabetic dyslipidemia in these patients is characterized by moderately high levels of (1) serum cholesterol and triglycerides; (2) small, dense low-density lipoprotein (LDL) particles; and (3) low high-density lipoprotein (HDL) cho-lesterol concentrations. Recent clinical trials have demonstrated the benefits of cholesterol-lowering therapy in both diabetic and nondiabetic patients, thus supporting aggressive treatment of diabetic dyslipidemia for coronary artery disease prevention. A 3-step approach is recommended for the treatment of diabetic dyslipidemia. First, modification of diet and lifestyle, including decreased intakes of cholesterol, cholesterol-raising fats, and total energy, and increased physical activity should be advised. Second, good glycemic control should be achieved with diet and hypoglycemic drugs, if needed. Third, lipid-lowering drugs should be used, if necessary. Non-HDL cholesterol levels, which include both very-low-density lipoprotein (VLDL) and LDL cholesterol, should be the target of cholesterol-lowering therapy. The use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (the "statins") has become the first-line drug therapy for diabetic dyslipidemia. Bile acid sequestrants are effective cholesterol-lowering agents in normotriglyceridemic patients with non-insulin-dependent diabetes mellitus (NIDDM). Patients with severe hypertriglyceridemia may require fibric acids or n-3 polyunsaturated fatty acids. Nicotinic acid worsens hyperglycemia; therefore, it should be avoided in most cases. The efficacy and safety of estrogen-replacement therapy in postmenopausal women with diabetes needs to be determined. The combination of two lipid-lowering agents may be appropriate for some NIDDM patients but should be used judiciously.
 ...
PMID:Treatment of diabetic dyslipidemia. 952 14

The aim of this in vitro study was to investigate the effect of troglitazone, a new oral antidiabetic agent, on LDL catabolism. HepG2 cells, which are cells from a well-differentiated cell line of hepatoma cells, were cultured and used to study LDL catabolism. Different concentrations of troglitazone, all within the therapeutic range for humans, were incubated in culture medium with 125I-labeled LDL to measure cell-associated and degraded 125I-LDL. Troglitazone increased cell-associated and degraded 125I-LDL by approximately 30%. We also investigated if this effect occurred through a LDL receptor-mediated pathway or a non-LDL receptor pathway. By using dextran sulfate, a substance known to release bound LDL from its receptor, we found that troglitazone upregulated LDL receptor activity by approximately 35%. In addition, we found that troglitazone increased the expression of the LDL receptor mRNA. The effect of troglitazone was comparable with that of a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, fluvastatin, with troglitazone having an upregulatory effect similar to that of fluvastatin. Insulin within human physiological concentrations also increased LDL receptor activity. We found that troglitazone and insulin had an additive effect on LDL catabolism. Also, the effect of troglitazone on LDL catabolism was studied in the presence of cyclosporine, an immunosuppressant drug that reduces LDL catabolism mainly by decreasing LDL receptor activity. The results showed that troglitazone can compensate for the reduced LDL receptor activity induced by cyclosporine, but that cyclosporine had a residual effect on the action of troglitazone. Thus troglitazone enhanced LDL binding, cell association, and degradation by increasing LDL receptor mRNA expression, with a subsequent increase in LDL receptor activity.
Diabetes 1998 Aug
PMID:Troglitazone upregulates LDL receptor activity in HepG2 cells. 970 16

The increased risk of coronary artery disease in subjects with diabetes mellitus can be partially explained by the lipoprotein abnormalities associated with diabetes mellitus. Hypertriglyceridemia and low levels of high-density lipoprotein are the most common lipid abnormalities. In type 1 diabetes mellitus, these abnormalities can usually be reversed with glycemic control. In contrast, in type 2 diabetes mellitus, although lipid values improve, abnormalities commonly persist even after optimal glycemic control has been achieved. Screening for dyslipidemia is recommended in subjects with diabetes mellitus. A goal of low-density lipoprotein cholesterol of less than 130 mg/dL and triglycerides lower than 200 mg/dL should be sought. Several secondary prevention trials, which included subjects with diabetes, have demonstrated the effectiveness of lowering low-density lipoprotein cholesterol in preventing death from coronary artery disease. The benefit of lowering triglycerides is less clear. Initial approaches to lowering the levels of lipids in subjects with diabetes mellitus should include glycemic control, diet, weight loss, and exercise. When goals are not met, the most common drugs used are hydroxymethylglutaryl coenzyme A reductase inhibitors or fibrates.
 ...
PMID:Hyperlipidemia and diabetes mellitus. 978 48


1 2 3 4 5 6 7 Next >>