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)

This paper reports on the effect of GCP-02, a dual activator of the peroxisome proliferator-activated receptors alpha/gamma (PPARalpha/gamma), on glucose and lipid metabolism in insulin-resistant obese mice induced by monosodium glutamate. The mice were divided into four groups on the basis of treatment: control group, rosiglitazone (positive control) (7 micromol/kg), and low- and high-dosage GCP-02 (7 micromol/kg and 3.5 micromol/kg, respectively). Drugs were given orally once a day for 19 days, and mice underwent testing for insulin tolerance, oral glucose tolerance and gluconeogenesis, and plasma cholesterol, triglyceride and free fatty acid levels. Mice were sacrificed, and body length and weight were measured; intraperitoneal adipose, heart and liver weighed; and plasma alanine aminotransferase (ALT) level and aspartate aminotransferase (AST) activity measured. Liver, soleus muscle and myocardium were assayed for glycogen, triglyceride and free fatty acid content and myocardia tested for superoxide dismutase (SOD) activity and malonaldehyde content. RT-PCR revealed expression of insulin receptor substrate 1 and 2 (IRS1, IRS2) and related genes in liver. GCP-02 had a more powerful effect than rosiglitazone on improving insulin sensitivity, ameliorating glucose tolerance, suppressing L-alanine-induced gluconeogenesis, and decreasing plasma levels of cholesterol, triglyceride and free fatty acid. It reduced body weight in control mice, significantly lowered hepatic content of glycogen, triglyceride and free fatty acid and myocardial content of triglyceride, and increased myocardial SOD activity. IRS2 mRNA was down-regulated in control mice but up-regulated by GCP-02. Thus, GCP-02 is a potential candidate for the prevention and therapy of diseases associated with insulin resistance such as type 2 diabetes mellitus and cardiovascular disease.
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PMID:Effect of GCP-02, a PPARalpha/gamma dual activator, on glucose and lipid metabolism in insulin-resistant mice. 1804 28

Advanced glycation endproducts (AGEs) are unavoidable byproducts of various metabolic pathways. They are formed by reactive metabolic intermediates such as methylglyoxal (MG), glyoxal, and 3-deoxyglucosone. These reactive intermediates bind to proteins, DNA, and other molecules and disrupt their structures and functions, which leads to different diseases such as vascular complications of diabetes, atherosclerosis, hypertension, Alzheimer's disease, and aging. In recent years, more compounds that prevent the formation of AGEs or degrade the existing AGEs have been produced and patented. They include: 1) aminoguanidine, 2) drugs used in the treatment of type 2 diabetes such as metformin and pioglitazone (patented), 3) angiotensin receptor blockers and angiotensin converting enzyme inhibitors, 4) pentoxyfylline (patented), 5) metal ion chelators desferoxamine and penicillamine, 6) antioxidants such as vitamin C or E, 7) amino group capping agents such as aspirin, 8) enzymes that cause deglycation of Amadori products, the Amadoriases, 9) compounds that mostly break alpha-dicarbonyl cross-links such as phenacylthiazolium bromide and its stable derivative ALT-711 (Alagebrium), and 10) derivatives of aryl ureido and aryl carboxaminido phenoxy isobutyric acids (patented). While some of these anti-AGE compounds are being used in clinical practice (such as metformin, pioglitazone, pentoxyfylline and aspirin) or tested in clinical trials (such as aminoguanidine and ALT-711), most of them are commonly used as experimental tools to investigate the role of AGEs in different disease conditions.
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PMID:Methylglyoxal and advanced glycation endproducts: new therapeutic horizons? 1822 Nov 7

Both elevated liver enzymes and a family history of diabetes mellitus (FHDM) are independent risk factors for type 2 diabetes. This study evaluates the epidemiological association between elevated liver enzymes and FHDM. Subjects included 3512 women workers without diabetes, hepatitis, a smoking habit, or a history of alcohol intake. Blood samples and personal data were collected from all subjects. Subjects with FHDM had a higher mean body mass index (BMI: 23.9kg/m(2) vs. 23.4kg/m(2); p=0.003). Laboratory testing also revealed higher mean fasting plasma glucose (FPG: 5.67mmol/L vs. 5.22mmol/L; p<0.001), asparate aminotransferase (AST: 20.0IU/L vs. 19.2IU/L; p=0.049), alanine aminotransferase (ALT: 18.4IU/L vs. 16.7IU/L; p=0.004), gamma-glutamyltranspeptidase (GGT: 24.1IU/L vs. 20.5IU/L; p<0.001), and triglycerides (TG: 1.09mmol/L vs. 1.00mmol/L; p=0.011) for FHDM subjects, when adjusted for age and BMI. Multiple linear regression analysis revealed that FHDM, age, BMI, FPG, and TG were correlated with GGT (p=0.004 for FHDM; p<0.001 for age, BMI, FPG, and TG). Elevated liver enzymes were associated with FHDM. In particular, elevated GGT was related to FHDM, independent of the other variables. Elevated liver enzymes, probably due to fat deposition in the liver, may play a role in increasing the risk of diabetes in individuals with FHDM.
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PMID:Elevated liver enzymes in women with a family history of diabetes. 1824 60

There is increasing evidence that type 2 diabetes mellitus and glucose intolerance are a cause, not just a consequence, of pancreatic cancer. We examined whether other factors that characterize the insulin resistance syndrome are also risk factors for pancreatic cancer in a prospective cohort study of 631,172 men and women (ages 45+ years) who received health insurance from the Korean Medical Insurance Corporation. The biennial medical evaluations from 1992 to 1995 provided the baseline information for this study. Relative risks (RR) were estimated using proportional hazards models adjusted for age, sex, smoking, and fasting serum glucose (after excluding the first 2 years of follow-up). There were 2,194 incident cases of pancreatic cancer diagnosed in the cohort over a median follow-up of 12 years. There was no evidence that pancreatic cancer risk was associated with total cholesterol, systolic blood pressure, WBC count, or body mass index. Abnormal levels of aspartate aminotransferase and alanine aminotransferase were both associated with a moderately increased risk of developing the disease (40+ versus <20; RR, 1.33; 95% CI, 1.14-1.55; P(trend) = 0.05 and RR, 1.34; 95% CI, 1.16-1.56; P(trend) = 0.02, respectively). Excluding 6 years of follow-up reduced this RR (95% CI) for aspartate aminotransferase to 1.22 (1.01-1.49), but even after excluding 10 years follow-up the RR (95% CI) for alanine aminotransferase was unchanged [1.36 (1.01-1.83)]. Although fasting serum glucose has been found previously to be associated with pancreatic cancer risk in this cohort, most other factors that characterize insulin resistance syndrome were not associated with pancreatic cancer risk. The association with elevated liver enzyme levels is a novel finding that warrants further investigation.
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PMID:Pancreatic cancer and factors associated with the insulin resistance syndrome in the Korean cancer prevention study. 1826 20

An asymptomatic 70-year-old Hispanic woman with type 2 diabetes was found in 2004 to have an AST of 132 U/L, ALT 146 U/L, alkaline phosphatase 1107 U/L, total serum bilirubin 3.5 mg/dL, and albumin 2.9 g/dL. Viral hepatitis testing was negative. Serum IgG, IgA, and IgM were all elevated, antimitochondrial antibody was weakly positive, and antinuclear antibody was negative. Liver biopsy was reported to show "evolving cirrhosis with marked lymphoid hyperplasia." Although the indication was nowhere stated, she was prescribed ursodeoxycholic acid 500 mg b.i.d, on which her biochemical tests initially improved. One year later she developed itching and jaundice. Imaging studies revealed multiple gallstones. An MRCP was suggestive of cirrhosis with a questionable common bile duct stricture, and she underwent ERCP with removal of gallbladder and common bile duct stones and placement of a biliary stent. A periampullary mass, which proved to be a somatostatinoma, was excised in 2006 via an open laparotomy, at which the stent was removed and a second liver biopsy performed. It was reported as showing chronic active hepatitis, activity stage 2, and fibrosis grade 3 with bridging. Her subsequent course was complicated by recurrent bleeding from small bowel arteriovenous malformations. Seen for the first time at Columbia University Medical Center in January 2007, she complained of continuing pruritus. AST was 69 U/L, ALT 43 U/L, alkaline phosphatase 491 U/L, and total bilirubin 3.3 mg/dL. Serum albumin was 2.6 g/dL. Antinuclear antibodies, negative in 2004, were now positive at 1:320, and antimitochondrial M2 antibodies were strongly positive. Serum IgG and IgA, but NOT IgM, were elevated. Review of her outside liver biopsies revealed features of primary biliary cirrhosis (PBC) in the first, and of both PBC and autoimmune hepatitis (AIH) in the second. The patient exhibits an overlap syndrome, in which both histologic and serologic features of AIH evolved in a setting initially most suggestive of PBC alone. The phenomenon of autoimmune overlap syndromes is discussed.
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PMID:Evolution from primary biliary cirrhosis to primary biliary cirrhosis/autoimmune hepatitis overlap syndrome. 1829 83

Wersternized diet, containing high fat diet intake combined with high consumption of softdrinks, is accused with the emerge of modern epidemic obesity and diabesity. Therefore, we aimed to study the effect of this diet combination on the homeostasis of glucose, lipids, and some adipohormones in rats and to simulate the metabolic perturbations induced by the unhealthy Westernized diet intake, leading to the development of type 2 diabetes. To achieve this, we divided male Wistar rats (80-120 g) into two main groups: the first was fed commercial normal fat diet and the second received an in-house-prepared high-fat diet (HFD), combined with fructose in drinking water for a period of 6 weeks, followed by a subdiabetogenic dose of streptozotocin (STZ) (35 mg/kg) to produce frank hyperglycemia. The effect of this diet alone or after 2 weeks of treatment with rosiglitazone or glimepiride on glucose homeostasis, lipid profile, and levels of resistin and leptin was studied. The HFD/fructose/STZ diet elevated fasting plasma glucose, fructosamine, insulin, and homeostasis model assessment (HOMA) index, as well as serum triglycerides (TGs), total cholesterol (TC), and low-density lipoprotein cholesterol, with a decrease in high-density lipoprotein cholesterol. Hepatic TG and TC levels, as well as serum activities of aspartate transaminase (AST), alanine transaminase (ALT), and lactate dehydrogenase (LDH), were increased, suggesting a diet-induced hepatic steatosis, beside the increased levels of serum resistin and leptin. Rosiglitazone corrected the altered parameters measured, except for liver TGs; similarly, glimepiride reinstated the inverted parameters but raised insulin level and, consequently, the HOMA index. These results show that this diet could be used to induce an effect that mimics human type 2 diabetes with its metabolic disturbances and is suitable for screening the antidiabetic agents used for management of this disease.
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PMID:Westernized-like-diet-fed rats: effect on glucose homeostasis, lipid profile, and adipocyte hormones and their modulation by rosiglitazone and glimepiride. 1840 27

Increased alanine aminotransferase (ALT) activity is associated with insulin resistance and the development of type 2 diabetes. The aim of this study was to characterize the modulation of cytosolic ALT expression in liver of gilthead sea bream (Sparus aurata) under conditions associated with increased gluconeogenesis and in streptozotocin (STZ)-treated fish. RT- and RACE-PCR assays allowed us to isolate a novel ALT isozyme (cALT2) generated from alternative splicing of cALT gene in S. aurata. HEK293 cells transfected with constructs expressing cALT2 as a C-terminal fusion with the enhanced green fluorescent protein allowed us to demonstrate that cALT2 is cytosolic. To unravel the molecular functions of cALT1 and cALT2 in liver of S. aurata, we examined tissue distribution, kinetic characterization of piscine cALT isozymes expressed in Saccharomyces cerevisiae, and regulation of hepatic cALT1 and cALT2 expression in various metabolic conditions. Kinetic analysis indicates that cALT2 is more efficient in catalysing the conversion of l-alanine to pyruvate than cALT1. Starvation increased cALT2 expression and decreased cALT1 mRNA in liver. Opposite effects were found in regularly fed fish at postprandial time 4-8h, and 6h after treatment with glucose or insulin. From these results we conclude that increased cALT2 expression occurred in liver under gluconeogenic conditions, while cALT1 was predominant during postprandial utilization of dietary nutrients. Since up-regulation of hepatic cALT2 expression occurred in STZ-induced diabetic S. aurata, increased hepatic cALT2 expression may be a promising marker in the prognosis of diabetes.
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PMID:A novel alternatively spliced transcript of cytosolic alanine aminotransferase gene associated with enhanced gluconeogenesis in liver of Sparus aurata. 1858 94

Non-alcoholic fatty liver disease (NAFLD) covers a wide spectrum of liver pathology--from steatosis alone, through the necroinflammatory disorder of non-alcoholic steatohepatitis (NASH) to cirrhosis and liver cancer. NAFLD/NASH is mostly related with visceral adiposity, obesity, type 2 diabetes melitus (DM t.2) and metabolic syndrome. Pathogenetic concepts of NAFLD include overnutrition and underactivity, insulin resistance (IR) and genetic factor. The prevalence of NAFLD has been estimated to be 17-33% in some countries, NASH may be present in about 1/3 of such cases, while 20-25% of NASH cases could progress to cirrhosis. NAFLD is now recognized as one of the most frequent reason of liver tests elevation without clinical symptoms. Insulin resistance is considering as having a central role in NAFLD pathogenesis. In hepatocytes, IR is related to hyperglycaemia and hyperinsulinaemia, formation of advanced glycation end-products, increased free fatty acids and their metabolites, oxidative stress and altered profiles of adipocytokines. Early stages of fatty liver are clinically silent and include elevation of ALT and GGTP, hyperechogenic liver in USG and/or hepatomegaly. Among clinical symptoms, abdominal discomfort is relatively common as well as chronic fatigue. NAFLD/NASH is not a benign disease, progressive liver biopsy have shown histological progression of fibrosis in 32%, the estimated rate of cirrhosis development is 20% and a liver--related death is 12% over 10 years. No treatment has scientifically proved to ameliorate NAFLD or to avoid its progression. The various therapeutic alternatives are aimed at interfering with the risk factors involved in the pathogenesis of the disorder in order to prevent the progression to end-stage liver disease. The most important therapeutic measure is increasing insulin sensitivity by an attempt to change a lifestyle mostly by dieting and physical activity in order to loose weight. The most used agent is metformin, the others are under controlled trials or their effectiveness is low. NASH is not a common indication for liver transplantation because of the older age distribution of patients and high prevalence of comorbidity, related to metabolic syndrome. Recurence of NASH in the grafted liver is also a relatively frequent complication.
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PMID:[Non-alcoholic fatty liver disease--new view]. 1870 46

Insulin resistance is a major feature of type 2 diabetes mellitus, obesity and nonalcoholic fatty liver disease (NAFLD). Several studies pointed out the possible role of increased leptin in NAFLD in humans. The aim of this study is to determine the effect of metformin on plasma leptin levels in obese patients with type 2 diabetes mellitus and NAFLD compared with lifestyle interventions. Thirty-four obese patients with newly diagnosed type 2 diabetes mellitus were prospectively followed for 6 months. All patients had ultrasonographic evidence of NAFLD at baseline. The patients were randomized into two groups: group 1 (n = 15) followed lifestyle changes only and group 2 (n = 19) received metformin (1,700 mg/day). At the end of treatment, BMI, WHR, HbA1c, fasting glucose, leptin, HOMA-IR, alanine aminotransferase values decreased in both groups. No significant difference in the end-points was observed between two groups. Only in group 2, LDL decreased and HDL increased significantly. Liver echogenity decreased significantly at the end of study in both groups. The percentage of patients who no longer had evidence of NAFLD was not significantly different between the groups (20% of patients on lifestyle intervention vs. 16% of patients on metformin). The data demonstrate that, metformin and lifestyle interventions equally affected the plasma leptin levels, BMI and degree of NAFLD in obese patients with type 2 diabetes mellitus. In addition, the effects of metformin on the variables were not found to be mediated by leptin.
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PMID:The effect of metformin on leptin in obese patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease. 1883 53

To investigate how liver disease alter the serum glycated proteins as markers of diabetic control, we studied serum GA, A1c and especially GA/A1c ratio in 255 patients having over 35IU/L in ALT(transaminase) compared with those of 829 type 2 diabetes mellitus (DM) in cross sectional manner. 255 patients with liver diseases were divided into 69 patients with biopsy proven liver cirrhosis (LC), 66 patients with chronic hepatitis(CH) and 120 patients with fatty liver(FL) diagnosed by abdominal echography. The mean GA/A1c ratio (+/-SD) was significantly higher (p<0.0001) in LC group(3.71+/-1.03) than the other groups (3.03+/-0.45 for CH, 3.05+/-0.42 for DM), while the mean GA/A1c ratio in FL group was significantly lower(2.74+/-0.31) (p<0.0001)) than that of DM groups. In LC group the GA/A1c ratio increased significantly depending upon serum albumin and/or platelet reductions. The GA/A1c ratio was significantly correlated with the other laboratory data such as serum albumin, cholinesterase, total cholesterol levels and weakly correlated with serum hemoglobin level. We also followed the serum levels of GA and A1c and the GA/A1c ratio during about 13 months (5 times blood collections) in 18 patients enrolled in this study. Resultantly the coefficient of variation of GA/A1c ratio was the smaller than the others(GA, A1c). The ROC curve of GA/A1c ratio for LC versus FL group was the most reliable between four groups and the cut-off value for LC versus FL was 2.94. Theses results suggest that GA/A1c ratio could be an useful marker for different diagnosis when facing patients with abnormal serum ALT level in a clinical setting.
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PMID:[Relationship between glycated albumin (GA) and glycated hemoglobin (A1c) in 255 patients with liver diseases using cross-sectional laboratory data]. 1897 54


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