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

Type V hyperlipemia is not very common. The series of 54 cases descrubed here is the largest reported to date. Our observations were recorded when lipidograms showed the presence of chylomicrons and a large pre-beta-lipoprotein spot in the serum of fasting subjects. Type V hyperlipemia was often combined with other metabolic syndromes such as diabetes, hyperuricemia or gout, or obesity. Chronic alcoholism was also noted in half our subjects, in whom hyperlipemia quickly regressed after alcohol consumption ceased. Ischemic arterial complications, chiefly coronary, were found in one third of our cases, and the vascular risks accompanying this type of hyperlipemia rose considerably in patients with high blood pressure. Various type of treatment were administered, but all subjects were put on a special diet, comprising either the elimination of alcoholic drinks only, or, in addition to this, reduced carbohydrate or calorie intake. As a rule, these measures resulted in a distinct regression of lipid anomalies. Clofibrate or derivatives proved effective in cases where hyperlipemia failed to respond to dietary measures.
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PMID:[Type V hyperlipemia. 54 cases (author's transl)]. 22 80

The effects of clofibrate treatment have been monitored in a double-blind cross-over study conducted in 16 male patients with coronary heart disease. Most had latent diabetes mellitus with elevated and delayed insulin release after i.v. glucose administration. Blood glucose and insulin levels were measured during repeated i.v. glucose tolerance tests in each patient and serum triglyceride and plasma fibrinogen were estimated at intervals. Clofibrate treatment significantly lowered fasting blood glucose levels (p less than 0.01) and improved the glucose tolerance (p less than 0.01). Fasting plasma insulin levels and those at 30 min after glucose loading were reduced (p less than 0.05). Serum triglycerides (p less than 0.01) and plasma fibrinogen levels (p less than 0.05) were lowered during the treatment period. The change in k-value (glucose utilization) did not correlate to changes in triglyceride or fibrinogen. This study confirms the beneficial effect of clofibrate therapy on abnormal glucose tolerance observed by other workers. It is suggested that clofibrate acts by reducing peripheral insulin resistance.
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PMID:The effect of clofibrate on glucose tolerance, insulin secretion, triglycerides and fibrinogen in patients with coronary heart disease. 32 58

Mitochondrial and peroxisomal fatty acid oxidation were compared in whole liver homogenates. Oxidation of 0.2 mM palmitoyl-CoA or oleate by mitochondria increased rapidly with increasing molar substrate:albumin ratios and became saturated at ratios below 3, while peroxisomal oxidation increased more slowly and continued to rise to reach maximal activity in the absence of albumin. Under the latter condition mitochondrial oxidation was severely depressed. In homogenates from normal liver peroxisomal oxidation was lower than mitochondrial oxidation at all ratios tested except when albumin was absent. In contrast with mitochondrial oxidation, peroxisomal oxidation did not produce ketones, was cyanide-insensitive, was not dependent on carnitine, and was not inhibited by (+)-octanoylcarnitine, malonyl-CoA and 4-pentenoate. Mitochondrial oxidation was inhibited by CoASH concentrations that were optimal for peroxisomal oxidation. In the presence of albumin, peroxisomal oxidation was stimulated by Triton X-100 but unaffected by freeze-thawing; both treatments suppressed mitochondrial oxidation. Clofibrate treatment increased mitochondrial and peroxisomal oxidation 2- and 6- to 8-fold, respectively. Peroxisomal oxidation remained unchanged in starvation and diabetes. Fatty acid oxidation was severely depressed by cyanide and (+)-octanoylcarnitine in hepatocytes from normal rats. Hepatocytes from clofibrate-treated rats, which displayed a 3- to 4-fold increase in fatty acid oxidation, were less inhibited by (+)-octanoylcarnitine. Hydrogen peroxide production was severalfold higher in hepatocytes from treated animals oxidizing fatty acids than in control hepatocytes. Assuming that all H2O2 produced during fatty acid oxidation was due to peroxisomal oxidation, it was calculated that the contribution of the peroxisomes to fatty acid oxidation was less than 10% both in cells from control and clofibrate-treated animals.
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PMID:Mitochondrial and peroxisomal fatty acid oxidation in liver homogenates and isolated hepatocytes from control and clofibrate-treated rats. 43 7

1 Fourteen maturity onset diabetics showed improvement of glucose tolerance while on treatment with clofibrate. Fasting blood glucose levels were reduced by 20% after treatment for 14 and 28 days. 2 The effect was found to be independent of concurrent treatment with oral hypoglycaemic drugs. 3 Plasma insulin levels were also lower during clofibrate treatment. 4 Clofibrate may prove to be a useful adjunct to the treatment of maturity onset diabetes.
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PMID:Effect of clofibrate on glucose tolerance in maturity onset diabetes. 90 37

Platelet hypersensitivity has been documented in diabetes and angina pectoris and can be partially reversed in hyperbetalipoproteinemia by clofibrate. We therefore examined the effects of incubating another lipid-lowering agent, halofenate, with both normal platelets and platelets made hypersensitive in vitro by incorporation of 55 per cent excess cholesterol into their membranes. At therapeutic concentrations, halofenate caused a time- and dose-dependent inhibition of the aggregation of normal platelets by epinephrine. After 30 minutes' incubation at 37 degrees C., halofenate significantly inhibited the extent of aggregation by 88 per cent (p less than 0.01), whereas clofibrate inhibited aggregation by 44 per cent (p less than 0.01). Halofenate was a more potent inhibitor of platelets than clofibrate (p less than 0.01). The mean threshold concentration of epinephrine necessary for aggregation of normal platelets (4.2 muM) was not significatnly increased with clofibrate (10 muM) but was markedly elevated with halofenate (245 muM; p less than 0.001). Significant but less dramatic increases in threshold concentration of ADP and collagen were found with halofenate but no clofibrate. Cholesterol-rich platelets were 114-fold more sensitive to epinephrine and twofold more sensitive to ADP than normal platelets but after incubation with halofenate became even less sensitive than normal. Clofibrate inhibited the extent of aggregation of hypersensitive platelets but did not alter the threshold concentration of epinephrine necessary for aggregation. Thus, halofenate is more potent than clofibrate in reducing the sensitivity of normal platelets to aggregating agents in vitro and can completely reverse experimentally produced platelet hypersensitivity. These data suggest that halofenate might be useful in reversing increased platelet sensitivity in cardiovascular diseases.
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PMID:Halofenate: a potent inhibitor of normal and hypersensitive platelets. 95 86

Clofibrate 3 g/die for 10 consecutive days, significantly reduced arginine-induced IRI release in chemical diabetics and in normal controls, whether of normal body weight or obese. Blood glucose levels were not affected by clofibrate. In agreement with previous findings, it would appear that clofibrate, administered for short periods does not lead to a decrease in glucose tolerance. However, studies relating to the effect of chronic clofibrate administration in chemical diabetes are needed in order to be sure that prolonged inhibition of IRI secretion does not lead to overt diabetes.
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PMID:Inhibitory effect of clofibrate on arginine-induced insulin secretion in chemical diabetes. 102 Jun 7

A randomized double-blind study was performed to examine the effect of clofibrate on glucose tolerance in subjects with non-insulin-dependent diabetes mellitus (NIDDM). Clofibrate (1.5 g/day) or placebo was administered to 70 patients and an oral glucose tolerance test (OGTT) was performed before and 12 wk after treatment. Blood glucose levels were significantly improved in clofibrate-treated groups at all time points during OGTT, whereas there was no change in insulin levels. Improvement of fasting glucose levels required 8 wk of clofibrate treatment. Insulin binding to erythrocytes demonstrated no significant change in the clofibrate-treated subjects. These results suggest that clofibrate improves glucose tolerance in NIDDM subjects without a change in insulin receptors and that clofibrate increases insulin sensitivity through an unknown postreceptor mechanism.
Diabetes Care 1988 Jun
PMID:Improvement of glucose tolerance in NIDDM by clofibrate. Randomized double-blind study. 304 17

In a prospective study 150 newly detected maturity onset-diabetics were randomized in 2 biostatistically comparable groups and underwent a treatment of different intensity. While the patients of the control group were treated according to the routine method used up to now in the dispensary for diabetics, in the intervention group an intensifying of the therapy took place, taking particular into consideration the body weight as well as the carbohydrate and fat metabolism. The decrease of body weight achieved by dietary intensive care proved to be the decisive factor for the tendency towards normalisation of glucose tolerance, hyperlipoproteinaemia and IRI-secretion, which could be registered in the intervention group after 2 years of observation. Following the preceding strong phase of diet, by Biguanides and Clofibrate a further significant improvement of the carbohydrate and fat metabolism could not be achieved. The decisive reserve in the treatment of obese maturity onset-diabetes could be seen in a permanent and continuous reduction of body weight. The results of this treatment depend highly on an intensive education as well as on frequent control of the patients' metabolism and their cooperation.
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PMID:[Intensified therapy of newly detected maturity onset diabetes]. 698 92

The high-Km glucose transporter, GLUT-2, and the high-Km hexokinase of beta cells, glucokinase (GK), are required for glucose-stimulated insulin secretion (GSIS). GLUT-2 expression in beta cells of Zucker diabetic fatty (ZDF) rats is profoundly reduced at the onset of beta-cell dysfunction of diabetes. Because ZDF rats are homozygous for a mutation in their leptin receptor (OB-R) gene and are therefore leptin-insensitive, we expressed the wild-type OB-R gene in diabetic islets by infusing a recombinant adenovirus (AdCMV-OB-Rb) to determine whether this reversed the abnormalities. Leptin induced a rise in phosphorylated STAT3, indicating that the transferred wild-type OB-R was functional. GLUT-2 protein rose 17-fold in AdCMV-OB-Rb-treated ZDF islets without leptin, and leptin caused no further rise. GK protein rose 7-fold without and 12-fold with leptin. Preproinsulin mRNA increased 64% without leptin and rose no further with leptin, but leptin was required to restore GSIS. Clofibrate and 9-cis-retinoic acid, the partner ligands for binding to peroxisome proliferator-activator receptor alpha (PPARalpha) and retinoid X receptor, up-regulated GLUT-2 expression in islets of normal rats, but not in ZDF rats, in which PPARalpha is very low. Because the fat content of islets of diabetic ZDF rats remains high unless they are treated with leptin, it appears that restoration of GSIS requires normalization of intracellular nutrient homeostasis, whereas up-regulation of GLUT-2 and GK is leptin-independent, requiring only high expression of OB-Rb.
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PMID:Overexpression of leptin receptors in pancreatic islets of Zucker diabetic fatty rats restores GLUT-2, glucokinase, and glucose-stimulated insulin secretion. 975 66

CYP2E1 and CYP4A11 are cytochrome P450 enzymes that are regulated by physiological conditions including diabetes and fasting. In addition, the xenochemical clofibrate has been reported to induce both rodent CYP2E1 and CYP4A. These findings suggest similar modes of regulation. Also in common to both enzymes is the ability to metabolize fatty acids such as laurate and arachidonic acid. Here, we used primary cultures of human hepatocytes to determine if certain xenochemicals could regulate CYP2E1 and CYP4A11. Ethanol significantly (p < 0.05) increased expression of CYP2E1 mRNA by 216 +/- 32% of control, but did not alter CYP4A11 mRNA accumulation (145 +/- 22% of control). In contrast, hepatocytes exposed to ethanol exhibited only a slight elevation in CYP2E1 protein (122 +/- 13% of control) and a negligible effect on CYP4A11 protein. Clofibrate significantly (p < 0.05) enhanced both CYP4A11 mRNA and protein by 239 +/- 30% and 154 +/- 10% of control, respectively, but did not increase CYP2E1. Because rodent CYP4A is reportedly regulated by fatty acids through peroxisome proliferator activated receptor alpha (PPARalpha) and CYP2E1 is induced by high fat diets, we examined the effects of a medium chain fatty acid, palmitate on CYP2E1 mRNA content. Palmitic acid significantly (p < 0.05) increased CYP2E1 mRNA to 326 +/- 57% of control. Collectively, results presented here identify agents that enhance CYP2E1 and CYP4A11 at the transcription level and suggest that fatty acids may represent a similar mode of regulation for these P450 enzymes. The lack of induction of CYP2E1 protein by ethanol in human hepatocytes indicates that for certain P450 enzymes, isolated hepatocytes may not be an adequate tool for predicting in vivo responses.
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PMID:Regulation of CYP2E1 by ethanol and palmitic acid and CYP4A11 by clofibrate in primary cultures of human hepatocytes. 1505 2


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