Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To see whether or not there is complement activation in patients with diabetes mellitus, we investigated the plasma concentrations of C4, C3, C4a, C3a and SC5b-9 in either juvenile or adult onset insulin-dependent (IDDM) and non-insulin-dependent (NIDDM) diabetic patients at least 2 years after diagnosis. C4, C3, SC5b-9 plasma levels were not significantly different in IDDM and NIDDM patients than in age-matched controls. Anaphylatoxin peptide conversion product C4a, but not C3a, was found significantly higher in adult-onset IDDM patients than in patients with juvenile onset IDDM, NIDDM patients and age-matched controls. Complement activation did not appear to be correlated with the metabolic control, nor the duration of disease nor the presence of circulating antibodies (including islet cells (ICA), insulin (IA), thyroid microsomal (TMA), and thyroglobulin (TGA)). Although there are many factors that may trigger complement activation, we found the highest levels of C4a in elderly subjects (both diabetics and control subjects) and particularly in those who had clinically detectable vascular complications.
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PMID:Complement activation in diabetes mellitus. 168 67

Prolonged hypoglycemia induced by acetohexamide (AH) in a patient with noninsulin dependent diabetes mellitus accompanied by primary hypothyroidism was presented. A 74-year-old man who had been treated with AH (500mg, daily) for diabetes mellitus since 1973 was admitted to our hospital in Oct. 1988 because of hypoglycemic coma. On admission, the level of blood glucose was 20mg/dl. Continuous intravenous administration of 10 per cent glucose solution led to improvement in the mental state on the second day. However, the level of blood glucose remained between 30 to 45mg/dl for four days after admission. On the fifth day, a fasting blood glucose level finally reached 75mg/dl. In a thyroid function test, the serum levels of thyroid hormone showed the following decreases: T3 68ng/dl, T4 2.8 micrograms/dl, free T4 0.3ng/dl, while basal TSH levels increased to 50.3 microU/ml. Since anti-thyroid microsomal antibody was positive and thyroid 99mTc-pertechnetate uptake was slightly elevated, the hypothyroidism in this patient was considered to be caused by chronic thyroiditis. Urinalysis was positive for protein. In a renal function test, the blood urea nitrogen was 26.7mg/dl and creatinine 1.7mg/dl, and creatinine clearance decreased to 22ml/min. After thyroid function returned to euthyroid, creatinine clearance improved (41 ml/min). To clarify the relationship between hypothyroidism and the metabolism of AH, the serum levels of AH and its metabolite hydroxyhexamide (HH) following oral administration of AH (500mg) were evaluated before and after thyroxine replacement therapy. The blood glucose level before therapy was lower than that after therapy, and hypoglycemic symptoms were observed early in the second and third morning after AH administration.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A case of acetohexamide-induced hypoglycemia: the influence of hypothyroidism on the metabolism of acetohexamide. 201 45

Addition of phenobarbital, an inducer of the liver mixed function oxidase system, to sulphonylurea regimen improves insulin sensitivity and intracellular glucose handling in patients with non-insulin dependent diabetes mellitus. The inducer also activates liver NADPH synthesis and its availability for mono-oxygenase reactions. In this study we further evaluated the mutual relationship between glucose and drug metabolism and the effect of sulphonylurea therapy by using genetically obese female mice. The mice were treated with glibenclamide, phenobarbital or both. Glibenclamide reduced blood glucose and plasma insulin levels indicating improved insulin sensitivity in the mice. Total glucose phosphorylating, delivering and NADPH generating enzyme activities were reduced together with decreased microsomal protein content and the amount of smooth endoplasmic reticulum in the liver. Phenobarbital had an opposite effect: the drug induced liver drug metabolism and increased hepatic glucose phosphorylating and NADPH generating enzyme activities. Treatment with glibenclamide seems to reduce serum immunoreactive insulin levels, microsomal enzyme function and NADPH generating enzyme activities in genetically obese mice.
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PMID:Reduced glucose-6-phosphorylase and NADPH generating enzyme activities associated with glibenclamide induced hypoglycemia and hypoinsulinemia in genetically obese mice. 217 90

Previous studies with healthy volunteers and non-insulin-dependent diabetic (NIDDM) patients have shown a strong association between overall glucose metabolism and hepatic microsomal enzyme activity. In this study, the effects of 10-day oral administration of phenobarbital (PB), a potent inducer of the hepatic microsomal mixed-function oxidase system, on carbohydrate and lipid metabolism in the basal state and on glucose kinetics during submaximal hyperinsulinemic (5 mU.kg-1.min-1 insulin) clamps were investigated in nondiabetic rats and in rats made diabetic by the intravenous (IV) administration of either low-dose (40 mg/kg) or high-dose (55 mg/kg) streptozocin (STZ). In control rats receiving PB in drinking water (0.5 mg/mL), serum insulin and triglyceride levels were diminished without any change in glucose and cholesterol concentrations in the fed state. Administration of PB in drinking water (0.25 mg/mL) to both groups of diabetic rats decreased their water intake and serum triglyceride levels in the absence of an effect on glucose, insulin, and cholesterol concentrations in the fed state. However, fasting serum glucose levels and basal glucose turnover rates were lower in both groups of diabetic rats receiving PB. PB treatment increased the heparin-releasable lipoprotein lipase (LPL) activity of epididymal fat in both control and low-dose diabetic groups; this was not assessed in the high-dose diabetic group. Neither peripheral glucose utilization nor hepatic glucose production during submaximal insulin clamps was modified by PB treatment in nondiabetic rats. In contrast, PB administration enhanced insulin-mediated peripheral glucose utilization, as well as suppression of hepatic glucose production, in both low-dose and high-dose diabetic groups.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Phenobarbital treatment enhances insulin-mediated glucose metabolism and improves lipid metabolism in the diabetic rat. 813 83

While insulin is known to promote vascular smooth muscle (VSM) relaxation, it also enhances endothelin-1 (ET-1) secretion and action in conditions such as NIDDM and hypertension. We examined the effect of insulin pretreatment on intracellular free calcium ([Ca2+]i) responses to ET-1 in cultured aortic smooth muscle cells (ASMCs) isolated from Sprague-Dawley (SD) rats and measured ET(A) receptor characteristics and ET-1-evoked tension responses in aorta obtained from insulin-resistant, hyperinsulinemic Zucker-obese (ZO) and control Zucker-lean (ZL) rats. Pretreatment of rat ASMCs with insulin (10 nmol/l for 24 h) failed to affect basal [Ca2+]i levels but led to a significant increase in peak [Ca2+]i response (1.7-fold; P < 0.01) to ET-1. The responses to IRL-1620 (an ET(B) selective agonist), ANG II, and vasopressin remained unaffected. ET-1-evoked peak [Ca2+]i responses were significantly attenuated by the inclusion of the ET(A) antagonist, BQ123, in both groups. The ET(B) antagonist, BQ788, abolished [Ca2+]i responses to IRL-1620 but failed to affect the exaggerated [Ca2+]i responses to ET-1. Saturation binding studies revealed a twofold increase (P < 0.01) in maximal number of binding sites labeled by 125I-labeled ET-1 in insulin-pretreated cells and no significant differences in sites labeled by 125I-labeled IRL-1620 between control and treatment groups. Northern blot analysis revealed an increase in ET(A) mRNA levels after insulin pretreatment for 20 h, an effect that was blocked by genistein, actinomycin D, and cycloheximide. Maximal tension development to ET-1 was significantly greater (P < 0.01), and microsomal binding studies using [3H]BQ-123 revealed a twofold higher number of ET(A) specific binding sites (P < 0.01) in aorta from ZO rats compared with that of ZL rats. These data suggest that insulin exaggerates ET-1-evoked peak [Ca2+]i responses via increased vascular ET(A) receptor expression, which may contribute to enhanced vasoconstriction observed in hyperinsulinemic states.
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PMID:Insulin increases endothelin-1-evoked intracellular free calcium responses by increased ET(A) receptor expression in rat aortic smooth muscle cells. 960 72

The hyperlipidemia associated with obesity and type 2 diabetes is caused by an increase in hepatic triglyceride synthesis and secretion that is secondary to an increase in de novo lipogenesis, a decrease in fatty acid (FA) oxidation, and an increase in the flux of peripherally derived FA to the liver. The uptake of FA across the plasma membrane may be mediated by three distinct proteins--FA translocase (FAT), plasma membrane FA binding protein (FABP-pm), and FA transport protein (FATP)--that have recently been characterized. Acyl-CoA synthetase (ACS) enhances the uptake of FAs by catalyzing their activation to acyl-CoA esters for subsequent use in anabolic or catabolic pathways. In this study, we examine the mRNA levels of FAT, FABP-pm, FATP, and ACS in the liver and adipose tissue of genetically obese (ob/ob) mice and their control littermates. FAT mRNA levels were 15-fold higher in liver and 60-80% higher in adipose tissue of ob/ob mice. FABP-pm mRNA levels were twofold higher in liver and 50% higher in adipose tissue of ob/ob mice. FATP mRNA levels were not increased in liver or adipose tissue. ACS mRNA levels were higher in adipose tissue but remained unchanged in liver. However, the distribution of ACS activity associated with mitochondria and microsomes in liver was altered in ob/ob mice. In control littermates, 61% of ACS activity was associated with mitochondria and 39% with microsomes, whereas in ob/ob mice 34% of ACS activity was associated with mitochondria and 66% with microsomes; this distribution would make more FA available for esterification, rather than oxidation, in ob/ob mouse liver. Taken together, our results suggest that the upregulation of FAT and FABP-pm mRNAs may increase the uptake of FA in adipose tissue and liver in ob/ob mice, which, coupled with an increase in microsomal ACS activity in liver, will enhance the esterification of FA and support the increased triglyceride synthesis and VLDL production that characterizes obesity and type 2 diabetes.
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PMID:Regulation of putative fatty acid transporters and Acyl-CoA synthetase in liver and adipose tissue in ob/ob mice. 989 32

Androgen biosynthesis requires 3beta-hydroxysteroid dehydrogenase type II (3betaHSDII) and the 17alpha-hydroxylase and 17,20-lyase activities of cytochrome P450c17. Thiazolidinedione and biguanide drugs, which are used to increase insulin sensitivity in type 2 diabetes, lower serum androgen concentrations in women with polycystic ovary syndrome. However, it is unclear whether this is secondary to increased insulin sensitivity or to direct effects on steroidogenesis. To investigate potential actions of these drugs on P450c17 and 3betaHSDII, we used "humanized yeast" that express these steroidogenic enzymes in microsomal environments. The biguanide metformin had no effect on either enzyme, whereas the thiazolidinedione troglitazone inhibited 3betaHSDII (K(I) = 25.4 +/- 5.1 microm) and both activities of P450c17 (K(I) for 17alpha-hydroxylase, 8.4 +/- 0.6 microm; K(I) for 17,20-lyase, 5.3 +/- 0.7 microm). The action of troglitazone on P450c17 was competitive, but it was mainly a noncompetitive inhibitor of 3betaHSDII. The thiazolidinediones rosiglitazone and pioglitazone exerted direct but weaker inhibitory effects on both P450c17 and 3betaHSDII. These differential effects of the thiazolidinediones do not correlate with their effects on insulin sensitivity, suggesting that distinct regions of the thiazolidinedione molecule mediate these two actions. Thus, thiazolidinediones inhibit two key enzymes in human androgen synthesis contributing to their androgen-lowering effects, whereas metformin affects androgen synthesis indirectly, probably by lowering circulating insulin concentrations.
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PMID:Thiazolidinediones but not metformin directly inhibit the steroidogenic enzymes P450c17 and 3beta -hydroxysteroid dehydrogenase. 1127 97

The definable causes of nonalcoholic steatohepatitis (NASH) include jejunoileal bypass surgery (JIB), other causes of rapid and profound weight loss in obese subjects, total parenteral nutrition, drugs, industrial toxins, copper toxicity, and disorders characterized by extreme insulin resistance. However, the etiopathogenesis in most cases of NASH appears multifactorial. Obesity, type 2 diabetes, and hypertriglyceridemia are often associated with hepatic steatosis, and although this does not invariably lead to NASH, the fatty liver is vulnerable to hepatocellular injury initiated by reactive oxygen species (ROS). It is critical to understand not only the triggers for hepatitis (injury and inflammation) in NASH but also how this is perpetuated as chronic liver disease. The present focus is on whether the biochemical processes that generate oxidative stress lead to hepatocyte injury and secondary recruitment of inflammation or whether inflammation is the primary mediator of liver cell injury. Insulin resistance is a reproducible pathogenic factor in NASH. It favors accumulation of free fatty acids in the liver and predisposes to oxidative stress by stimulating microsomal lipid peroxidases and by the direct effects of high insulin levels in decreasing mitochondrial beta-oxidation. CYP2E1 is normally suppressed by insulin but is invariably increased in the livers of patients with NASH. In rodent dietary models of steatohepatitis, CYP2E1 is the catalyst of microsomal lipid peroxidation, while in Cyp 2e1 nullizygous mice, CYP4A proteins are induced and function as alternative microsomal lipid peroxidases. Other studies implicate activation of peroxisome proliferator-activated receptor-alpha (PPAR alpha) as leading to NASH; PPAR alpha is a transcription factor that governs both microsomal (via CYP4A) and peroxisomal (beta-oxidation) pathways of lipid oxidation and ultimately production of ROS. Increased lipid peroxidation is a crucial difference between the livers of rodents with experimental NASH and those of ob/ob genetically obese mice that have uncomplicated steatosis. Administration of endotoxin, through the release of tumor necrosis factor-alpha (TNF-alpha), provokes liver inflammation with hepatocyte injury in the steatotic liver. This may be particularly relevant in JIB and has been suggested as a pathogenic mechanism in primary NASH. It has been proposed that inheriting one or more copies of the hemochromatosis gene, C282Y, promotes fibrotic progression in NASH because of increased hepatic iron deposition, but recent studies have failed to confirm this. The relationship between the severity of hepatitis in NASH and progression to cirrhosis implies that products of the inflammatory infiltrate play a role in fibrogenesis. In summary, NASH can be regarded as the hepatic consequence of the metabolic syndrome (or syndrome X). Attention should now shift from steatosis, a generally benign process that is less evident in the advanced stages of cirrhosis, to the mechanisms for hepatocellular injury, inflammation, and hepatic fibrosis. In particular, the genetic, molecular, and cellular factors that ordain and moderate fibrosis in the context of steatohepatitis will be of greatest relevance to effective therapy and clinical outcome.
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PMID:Etiopathogenesis of nonalcoholic steatohepatitis. 1129 94

Oxidative ring opening of troglitazone (TGZ)(1) a thiazolidine 2,4-dione derivative used for the treatment of type II diabetes mellitus, leads to the formation of a quinone metabolite. The formation of TGZ quinone was shown to be NADPH dependent and to require active microsomal enzymes. Quinone formation was not affected by co-incubation with catalase or sodium azide and was partially inhibited (25%) by superoxide dismutase (SOD). Kinetic analysis of TGZ quinone formation in human liver microsomes implied single enzyme involvement. CYP3A isoforms were characterized as the primary enzymes involved in quinone formation by several lines of evidence including: (a) troleandomycin and ketoconazole almost completely inhibited microsomal quinone formation when SOD was present, whereas other CYP inhibitors had minimal effects (<20%); (b) TGZ quinone formation was highly correlated with regard to both contents (r(2): 0.9374) and activities (r(2): 0.7951) of CYP3A4 in human liver microsomes (HLM); (c) baculovirus insect cell-expressed human CYP3A4 was able to catalyze TGZ quinone formation at a higher capacity (V(max)/K(m)) than other human CYPs with the relative contribution of CYP3A4 in HLM estimated to be 20-fold higher than that of other CYPs; (d) TGZ quinone formation was increased by 350% in liver microsomes from rats pretreated with dexamethasone (DEX); and (e) plasma concentrations of TGZ quinone were increased by 260-680% in rats pretreated with DEX. The chemical nature of the quinone metabolite suggests an atypical CYP reaction consistent with a one-electron oxidation mechanism where an intermediate phenoxy radical combines with ferryl oxygen to subsequently form the quinone metabolite.
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PMID:Troglitazone quinone formation catalyzed by human and rat CYP3A: an atypical CYP oxidation reaction. 1138 77

Secondary hyperlipidemia is a major cardiovascular risk factor in individuals with type 2 diabetes. Increased hepatic production of apolipoprotein B (apoB)-containing lipoproteins contributes to the elevated plasma levels, but the mechanism is poorly understood. Recent results have established that microsomal triglyceride transfer protein (MTP) is rate limiting for the assembly and secretion of apoB-containing lipoproteins. To better understand the mechanism of type 2 diabetes-associated hyperlipidemia, we quantified hepatic MTP mRNA levels, hepatic microsomal triglyceride transfer activity, and in vivo triglyceride secretion from the liver in two diabetic mouse models. Obese diabetic (ob/ob) mice had 45% higher (P = 0.006) hepatic MTP mRNA levels, 54% higher (P < 0.0001) microsomal triglyceride transfer activity, and 70% higher (P < 0.0001) in vivo triglyceride secretion rates compared with ob/+ control mice. In contrast, in lean streptozotocin-treated diabetic mice, hepatic MTP mRNA levels were unchanged, whereas microsomal triglyceride transfer activity and in vivo triglyceride secretion rates were marginally decreased. These studies suggest that obesity-induced type 2 diabetes in mice confers increases in hepatic MTP expression and secretion of triglyceride-rich lipoproteins. High blood glucose and altered hepatic expression of sterol regulatory element binding protein genes play a minor role in this diabetic response.
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PMID:Hepatic expression of microsomal triglyceride transfer protein and in vivo secretion of triglyceride-rich lipoproteins are increased in obese diabetic mice. 1191 50


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