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)

The field of new lipid-lowering drug research is very active, with researchers, looking to make the currently available drugs more powerful and safer, and to develop new classes of drugs. Among the statins, development has gone the farthest for rosuvastatin and pitavastatin. Colesevelam is a new bile acid sequestrant with a better digestive tolerance. Among the new classes of drugs, the most promising molecules are the cholesterol absorption inhibitors--with ezetimibe as the first in line--and the PPAR-alpha and PPAR-gamma activators. Among the other classes, the acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors, microsomal triglyceride transfer protein (MTP) inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, and ileal bile acid transporter inhibitors, have to be mentioned. In most of the cases, those new compounds are being developed mainly as a combined treatment with statins. However, these combination therapies differ depending on the lipid abnormalities of the patient. The statin-ezitimibe and the statin-bile acid sequestrant combinations have been the most studied treatments in pure hypercholesterolaemia. On another hand, the statin-PPAR-alpha and -gamma activator combination were the first to be developed for patients with combined hyperlipidaemia or type 2 diabetes mellitus. However, the clinical benefit of ACAT or CETP inhibitors remains to be determined and the development of MTP inhibitors has been restricted so far, because of problems of digestive intolerance and hepatic steatosis. Finally, the discovery of new specific lipoprotein receptors, such as the ABCA1 and SRB1 receptors, means that we can work towards developing new potential targets for pharmacological intervention.
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PMID:[New antilipemics: prospects]. 1282 7

Nonalcoholic steatohepatitis (NASH), along with other forms of nonalcoholic fatty liver disease, is an increasingly common clinico-pathological syndrome. It is frequently associated with obesity, especially visceral fat, and type 2 diabetes, and is intimately related to markers of the insulin resistance syndrome. Both the prevalence and the severity of liver steatosis are related to body mass index, waist circumference, hyperinsulinaemia, hypertriglyceridemia and impaired glucose tolerance. The pathophysiology of NASH involves two steps: 1) insulin resistance, which causes steatosis; 2) and oxidative stress, which produces lipid peroxidation and activates inflammatory cytokines. The identification of subjects who may progress from fatty liver to NASH, and from NASH to fibrosis/cirrhosis is an important clinical challenge as well as the finding of appropriate therapy that could prevent such deleterious process. Substantial weight loss is accompanied by a marked attenuation of insulin resistance and related metabolic syndrome and, concomitantly, by an important regression of liver steatosis in most patients, although mild inflammation may be detected in some subjects. Thus, NASH may be considered as another disease of affluence, as is the insulin resistance syndrome and perhaps being part of it.
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PMID:Nonalcoholic steatohepatitis and insulin resistance: interface between gastroenterologists and endocrinologists. 1283 90

The current study was undertaken to examine metabolic and body composition correlates of fatty liver in type 2 diabetes mellitus (DM). Eighty-three men and women with type 2 DM [mean body mass index (BMI): 34 +/- 0.5 kg/m2] and without clinical or laboratory evidence of liver dysfunction had body composition assessments of fat mass (FM), visceral adipose tissue (VAT), liver and spleen computed tomography (CT) attenuation (ratio of liver to spleen), muscle CT attenuation, and thigh adiposity; these assessments were also performed in 12 lean and 15 obese nondiabetic volunteers. Insulin sensitivity was measured with a euglycemic insulin infusion (40 mU. m-2. min-1) combined with systemic indirect calorimetry to assess glucose and lipid oxidation, and with infusions of [2H2]glucose for assessment of endogenous glucose production. A majority of those with type 2 DM (63%) met CT criteria for fatty liver, compared with 20% of obese and none of the lean nondiabetic volunteers. Fatty liver was most strongly correlated with VAT (r = -0.57, P < 0.0001) and less strongly but significantly associated with BMI (r = -0.42, P < 0.001) and FM (r = -0.37, P < 0.001), but only weakly associated with subcutaneous adiposity (r = -0.29; P < 0.01). Fatty liver was also correlated with subfascial adiposity of skeletal muscle (r = -0.44; P < 0.01). Volunteers with type 2 DM and fatty liver were substantially more insulin resistant those with type 2 DM but without fatty liver (P < 0.001) and had higher levels of plasma free fatty acids (P < 0.01) and more severe dyslipidemia (P < 0.01), a pattern observed in both genders. Plasma levels of cytokines were increased in relation to fatty liver (r = -0.34; P < 0.01). In summary, fatty liver is relatively common in overweight and obese volunteers with type 2 DM and is an aspect of body composition related to severity of insulin resistance, dyslipidemia, and inflammatory markers.
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PMID:Fatty liver in type 2 diabetes mellitus: relation to regional adiposity, fatty acids, and insulin resistance. 1295 38

Nonalcoholic fatty liver disease (NAFLD) is frequently associated with type 2 diabetes mellitus, obesity, and dyslipidemia. We tested the hypothesis that there may be an association between NAFLD and insulin resistance (IR); and its correlation with glucose tolerance status of subjects who aren't known patients with diabetes. One hundred and seventy-six consecutive patients with elevated serum aminotransferase levels and bright liver were evaluated. Sixty-two patients were excluded from the study. Age, gender, height, weight, body mass index, waist circumferences, and family history of diabetes were recorded. Fasting plasma glucose, insulin, lipid profile were measured. A standard oral glucose tolerance test (OGTT) was performed and the index of IR was calculated according to the HOMA method. Patients with a normal glucose tolerance formed group 1 (64 patients) and patients with impaired or diabetic glucose tolerance group 2 (50 patients). Age, female sex, family history of type 2 diabetes, fasting insulin, fasting plasma glucose and HOMA-R index were statistically significantly different between the groups. Although the subjects in the study are not known patients with diabetes, the prevalence of impaired or diabetic glucose tolerance was prominent. In conclusion, performing OGTT in cases with nonalcoholic fatty liver disease may be useful for early screening of diabetes mellitus.
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PMID:Association of nonalcoholic fatty liver disease with insulin resistance: is OGTT indicated in nonalcoholic fatty liver disease? 1820 1

Obesity plays a central role in the development of insulin resistance and type 2 diabetes. We therefore examined the effects of a modified form of ciliary neurotrophic factor [Axokine, which is hereafter referred to as ciliary neurotrophic factor (CNTF)Ax15], which uses a leptin-like mechanism to reduce body weight, in the db/db murine model of type 2 diabetes. In previous studies, weight loss produced by CNTF treatment could largely be attributed to its effects on food intake. In contrast, CNTFAx15 treatment of db/db mice caused significantly greater weight loss and marked improvements in diabetic parameters (e.g., levels of glucose, insulin, triglyceride, cholesterol, and nonesterified free fatty acids) than could be accounted for by reduced caloric intake alone. These beneficial effects, above and beyond those seen in animals controlled for either food restriction or body weight, correlated with the ability of CNTFAx15 to increase metabolic rate and energy expenditure and reduce hepatic steatosis while enhancing hepatic responsiveness to insulin. The hepatic effects were linked to rapid alterations in hepatic gene expression, most notably reduced expression of stearoyl-CoA desaturase 1, a rate-limiting enzyme in the synthesis of complex lipids that is also markedly suppressed by leptin in ob/ob mice. These observations further link the mechanisms of CNTF and leptin action, and they suggest important, beneficial effects for CNTF in diabetes that may be distinct from its ability to decrease food intake; instead, these effects may be more related to its influence on energy expenditure and hepatic gene expression.
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PMID:Ciliary neurotrophic factor improves diabetic parameters and hepatic steatosis and increases basal metabolic rate in db/db mice. 1461 Feb 76

Past studies of the relation between hepatitis C virus (HCV) infection and type 2 diabetes conflict. The authors aimed to elucidate the relation by using a large community-based sample with a wide range of liver conditions. Between October 1997 and February 1998, 2,327 consecutive subjects (aged > or =35 years) were enrolled at the public health facility in Taiwan. Blood sugar, hepatitis B surface antigen, and antibody for HCV (anti-HCV) were tested. Abdominal sonography was performed on viral-hepatitis-positive subjects. In univariate analysis, older age, lower educational levels, sedentary work, body mass index of > or 25 kg/m2, and anti-HCV positivity were significantly associated with type 2 diabetes (p<0.05), but smoking, alcohol consumption, gender, and hepatitis B surface antigen status were not. In multivariate logistic regression, anti-HCV positivity was strongly associated with type 2 diabetes in subjects aged 35-49 years (odds ratio (OR)=3.3, 95% confidence interval (CI): 1.4, 8.0) and 50-64-years (OR=1.6, 95% CI: 1.1, 2.5). Sonographic evidence of fatty liver (OR=2.4, 95% CI: 1.2, 4.8) and chronic liver disease (OR=2.0, 95% CI: 1.0, 4.2) in anti-HCV-positive subjects was moderately associated with type 2 diabetes after age and gender adjustment. Data suggest that HCV infection is moderately associated with type 2 diabetes; the association was strongest for subjects aged 35-49 years and increased with severity of the liver condition.
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PMID:Community-based study of hepatitis C virus infection and type 2 diabetes: an association affected by age and hepatitis severity status. 1465

Liver steatosis is a common human disease, most often caused by long-term alcohol consumption. Non-alcoholic steatohepatitis (NASH) is characterized by similar histopathological features to those observed in alcoholic liver disease, but occurs in the absence of significant alcohol consumption. Several aetiological factors contribute to NASH: obesity, type 2 diabetes mellitus, hyperlipidaemia, pregnancy, different chemical intoxications, parenteral nutrition, jejeuno-ileal bypass, chronic inflammatory bowel disease, nutritional protein deficiency and congenital metabolic disorders. Biochemically, oxidative stress and lipid peroxidation and their ensuing damage are implicated in the pathogenesis of NASH and alcoholic steatohepatitis (probably resulting from free fatty acids in the mitochondria, and induction of the cytochrome P450 isoform CYP2E1 in hepatocytes and Kupffer's cells). This paper deals with the pathomechanisms, clinical findings and currently available therapies for NASH. The potential use of metadoxine in the treatment of NASH is also discussed.
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PMID:A new approach to drug therapy in non-alcoholic steatohepatitis (NASH). 1470 19

Obesity and its attendant disorders, such as type 2 diabetes, are global health problems. We previously reported that C75, an inhibitor of fatty acid synthase (FAS) and stimulator of carnitine palmitoyltransferase I (CPT I), caused anorexia and profound weight loss in lean and genetically obese mice. To approximate human obesity, we utilized a chronic C75 treatment model for diet-induced obese (DIO) mice. Chronic C75 treatment decreased food consumption and increased energy expenditure due to increased fatty acid oxidation in both DIO and lean mice. There was a substantial loss of adipose tissue and resolution of hepatic steatosis in C75-treated DIO mice. Analysis of changes in the expression of hypothalamic neuropeptides demonstrated that the reduced food consumption in C75-treated DIO mice was accompanied by an increase in cocaine and amphetamine-related transcript expression but not by changes in neuropeptide Y such as seen with acute C75 treatment of lean mice. Inhibition of FAS and stimulation of CPT I provide a means to achieve stable, sustained weight loss in DIO mice.
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PMID:Chronic C75 treatment of diet-induced obese mice increases fat oxidation and reduces food intake to reduce adipose mass. 1473 2

The ability of insulin to stimulate glucose disposal varies more than six-fold in apparently healthy individuals. The one third of the population that is most insulin resistant is at greatly increased risk to develop cardiovascular disease (CVD), type 2 diabetes, hypertension, stroke, nonalcoholic fatty liver disease, polycystic ovary disease, and certain forms of cancer. Between 25-35% of the variability in insulin action is related to being overweight. The importance of the adverse effects of excess adiposity is apparent in light of the evidence that more than half of the adult population in the United States is classified as being overweight/obese, as defined by a body mass index greater than 25.0 kg/m(2). The current epidemic of overweight/obesity is most-likely related to a combination of increased caloric intake and decreased energy expenditure. In either instance, the fact that CVD risk is increased as individuals gain weight emphasizes the gravity of the health care dilemma posed by the explosive increase in the prevalence of overweight/obesity in the population at large. Given the enormity of the problem, it is necessary to differentiate between the CVD risk related to obesity per se, as distinct from the fact that the prevalence of insulin resistance and compensatory hyperinsulinemia are increased in overweight/obese individuals. Although the majority of individuals in the general population that can be considered insulin resistant are also overweight/obese, not all overweight/obese persons are insulin resistant. Furthermore, the cluster of abnormalities associated with insulin resistance - namely, glucose intolerance, hyperinsulinemia, dyslipidemia, and elevated plasma C-reactive protein concentrations -- is limited to the subset of overweight/obese individuals that are also insulin resistant. Of greater clinical relevance is the fact that significant improvement in these metabolic abnormalities following weight loss is seen only in the subset of overweight/obese individuals that are also insulin resistant. In view of the large number of overweight/obese subjects at potential risk to be insulin resistant/hyperinsulinemic (and at increased CVD risk), and the difficulty in achieving weight loss, it seems essential to identify those overweight/obese individuals who are also insulin resistant and will benefit the most from weight loss, then target this population for the most-intensive efforts to bring about weight loss.
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PMID:Obesity, insulin resistance, and cardiovascular disease. 1474 3

In the liver, insulin controls both lipid and glucose metabolism through its cell surface receptor and intracellular mediators such as phosphatidylinositol 3-kinase and serine-threonine kinase AKT. The insulin signaling pathway is further modulated by protein tyrosine phosphatase or lipid phosphatase. Here, we investigated the function of phosphatase and tension homologue deleted on chromosome 10 (PTEN), a negative regulator of the phosphatidylinositol 3-kinase/AKT pathway, by targeted deletion of Pten in murine liver. Deletion of Pten in the liver resulted in increased fatty acid synthesis, accompanied by hepatomegaly and fatty liver phenotype. Interestingly, Pten liver-specific deletion causes enhanced liver insulin action with improved systemic glucose tolerance. Thus, deletion of Pten in the liver may provide a valuable model that permits the study of the metabolic actions of insulin signaling in the liver, and PTEN may be a promising target for therapeutic intervention for type 2 diabetes.
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PMID:Liver-specific deletion of negative regulator Pten results in fatty liver and insulin hypersensitivity [corrected]. 1476 18


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