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)

At least 90% of the 12 to 15 million persons with diabetes mellitus in the United States, half of whose condition remains undiagnosed, have type 2 diabetes. Type 2 diabetes is preceded by a long period of impaired glucose tolerance, a reversible metabolic state associated with increased prevalence of macrovascular complications. Thus, at the time of diagnosis, long-term complications have developed in almost one fourth of patients. Susceptibility to type 2 diabetes requires genetic (most likely polygenic) and acquired factors, and its pathogenesis involves an interplay of progressive insulin resistance and beta-cell failure. The ideal treatment of type 2 diabetes should reverse insulin resistance and beta-cell dysfunction in most treated patients and prevent, delay, or reverse long-term complications. Current strategies are aimed at amelioration of insulin resistance (diet, exercise, weight loss, and metformin and troglitazone therapy), augmentation of insulin supply (sulfonylurea and insulin therapy), or limitation of postprandial hyperglycemia (acarbose therapy). Future therapies probably will target (1) insulin resistance, using a multifaceted approach; (2) hepatic glucose production, using gluconeogenesis inhibitors; (3) excess nonesterified fatty acid production, using lipolysis inhibitors; and (4) fat oxidation, using carnitine palmitoyltransferase I and II inhibitors. Attempts also could be made to stimulate energy expenditure and increase nonoxidative glucose disposal by means of beta 3-adrenoceptor agonists. One promising strategy is an attack on multiple pathophysiological processes by combining antidiabetic agents with disparate mechanisms of action. Thus, we now have unprecedented resources for drug therapy for diabetes, with great opportunity for innovative combinations. It is hoped that these expanded choices will provide the tools necessary for a more efficient management of type 2 diabetes and prevention of its long-term complications.
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PMID:Pathophysiology of type 2 diabetes and modes of action of therapeutic interventions. 948 41

It is widely held that although obesity and type 2 diabetes are polygenic in origin, the primary defect causing both conditions is insulin resistance, which in turn gives rise to a constellation of other abnormalities, including hyperinsulinemia, dyslipidemia, glucose intolerance, and (in the genetically predisposed) frank hyperglycemia. Explored here is an alternative, albeit speculative, scenario in which hyperinsulinemia and insulin resistance arise either simultaneously or sequentially from some preexisting defect within the leptin signaling pathway. In either case, a central component of the model is that the breakdown of glucose homeostasis that is characteristic of the condition of obesity with type 2 diabetes is secondary to disturbances in lipid dynamics. The possibility is raised that abnormally high concentrations of malonyl-CoA in liver and skeletal muscle suppress the activity of mitochondrial carnitine palmitoyltransferase I and thus fatty acid oxidation in both sites. It is suggested that the buildup of fat within the muscle cell (caused in part by excessive delivery of VLDLs from the liver) interferes with glucose transport or metabolism or both, producing insulin resistance. Elevated circulating concentrations of fatty acids are also implicated in the etiology of type 2 diabetes by virtue of 1) their powerful acute insulinotropic effect, 2) their ability to exacerbate insulin resistance in muscle, and 3) their long-term detrimental action on pancreatic beta-cell function.
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PMID:Glucose-fatty acid interactions in health and disease. 949 60

In type 2 diabetes mellitus, insulin secretory deficiency is an important process linking asymptomatic insulin resistance and diabetes. Fatty acids could play a role in the reduction of beta cell insulin secretion. On a short term basis (< 24 h), fatty acids stimulate glucose-dependent insulin secretion through an increase of ATP availability (due to acyl-CoA mitochondrial oxidation) and an extramitochondrial diacylglycerol and inositol tri phosphate (IP3) production (which stimulate insulin-containing granule exocytosis). Such effects were observed in human both in vitro and in vivo. By contrast, a chronic exposure (> 24 h) of beta cells to fatty acids leads to a reduction in glucose-dependent insulin secretion. Current explanation relies in the effect of fatty acids on beta cell gene expression through PPARs (peroxysome proliferator activated receptor). Thus, in rodents, fatty acids can increase the expression of carmitine palmitoyl transferase gene (CPT-1, the key enzyme involved in fatty acid internalization in mitochondria) while reducing the gene expression of acetyl carboxylase (this enzyme synthesis malonyl CoA, which inhibits fatty acid oxidation). Thus, a chronic exposure to fatty acids will preferentially distribute these nutrients towards mitochondria (as malonyl CoA is reduced and CPT-1 is increased), which in turn reduces their extramitochondrial metabolism as well as IP3 production that is needed for secretory granule exocytosis. Finally, in Zucker Fatty rat, diabetes is associated with a triglyceride accumulation in beta cells. This is correlated with a reduction in insulin secretion and an increase in cellular apoptosis phenomena. Thiazolidinediones prevent intracellular lipid accumulation and delay diabetes. The prevention of lipotoxicity could represent a new therapeutic strategy to preserve insulin secretion in type 2 diabetic patients.
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PMID:[Fatty acids and beta cells]. 1094 43

Studies in Zucker diabetic fatty rats have led to the concept that chronically elevated free fatty acid (FFA) levels can cause apoptosis of triglyceride-laden pancreatic beta-cells as a result of the formation of ceramides, which induce nitric oxide (NO)-dependent cell death. This "lipotoxicity" hypothesis could explain development of type 2 diabetes in obesity. The present study examines whether prolonged exposure to FFA affects survival of isolated normal rat beta-cells and whether the outcome is related to the occurrence of triglyceride accumulation. A dose-dependent cytotoxicity was detected at 5-100 nmol/l of unbound oleate and palmitate, with necrosis occurring within 48 h and an additional apoptosis during the subsequent 6 days of culture. At equimolar concentrations, the cytotoxicity of palmitate was higher than that of oleate but lower than that of its nonmetabolized analog bromopalmitate. FFA cytotoxicity was not suppressed by etomoxir (an inhibitor of mitochondrial carnitine palmitoyltransferase I) or by antioxidants; it was not associated with inducible NO synthase expression or NO formation. An inverse correlation was observed between the percentage of dead beta-cells on day 8 and their cellular triglyceride content on day 2. For equimolar concentrations of the tested FFA, oleate caused the lowest beta-cell toxicity and the highest cytoplasmic triglyceride accumulation. On the other hand, oleate exerted the highest toxicity in islet non-beta-cells, where no FFA-induced triglyceride accumulation was detected. In conditions without triglyceride accumulation, the lower FFA concentrations caused primarily apoptosis, both in islet beta-cells and non-beta-cells. It is concluded that FFAs can cause death of normal rat islet cells through an NO-independent mechanism. The ability of normal beta-cells to form and accumulate cytoplasmic triglycerides might serve as a cytoprotective mechanism against FFA-induced apoptosis by preventing a cellular rise in toxic free fatty acyl moieties. It is conceivable that this potential is lost or insufficient in cells with a prolonged triglyceride accumulation as may occur in vivo.
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PMID:Inverse relationship between cytotoxicity of free fatty acids in pancreatic islet cells and cellular triglyceride accumulation. 1147 37

Fatty acids may promote type 2 diabetes by altering insulin secretion from pancreatic beta cells, a process known as lipotoxicity. The underlying mechanisms are poorly understood. To test the hypothesis that peroxisome proliferator-activated receptor alpha (PPARalpha) has a direct effect on islet function, we treated INS-1 cells, an insulinoma cell line, with a PPARalpha adenovirus (AdPPARalpha) as well as the PPARalpha agonist clofibric acid. AdPPARalpha-infected INS-1 cells showed PPARalpha agonist- and fatty acid-dependent transactivation of a PPARalpha reporter gene. Treatment with either AdPPARalpha or clofibric acid increased both catalase activity (a marker of peroxisomal proliferation) and palmitate oxidation. AdPPARalpha induced carnitine-palmitoyl transferase-I (CPT-I) mRNA, but had no effect on insulin gene expression. AdPPARalpha treatment increased cellular triglyceride content but clofibric acid did not. Both AdPPARalpha and clofibric acid decreased basal and glucose-stimulated insulin secretion. Despite increasing fatty acid oxidation, AdPPARalpha did not increase cellular ATP content suggesting the stimulation of uncoupled respiration. Consistent with these observations, UCP2 expression doubled in PPARalpha-treated cells. Clofibric acid-induced suppression of glucose-simulated insulin secretion was prevented by the CPT-I inhibitor etomoxir. These data suggest that PPARalpha-stimulated fatty acid oxidation can impair beta cell function.
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PMID:PPARalpha suppresses insulin secretion and induces UCP2 in insulinoma cells. 1203 69

The effect of peroxisome proliferator-activated receptor (PPAR)-alpha activators on the liver is well established, but the other effects on muscle and adipose tissue about lipid metabolism and insulin sensitivity are not clear. We investigated whether PPAR-alpha activation affects adiposity of skeletal muscle as well as adipose tissue and improves insulin sensitivity in spontaneous type 2 diabetes model, Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Thirty-three weeks of aged, 20 male OLETF rats were divided into two groups. Control group (n=10) was fed with chow and treatment group (n=10) with chow contained fenofibrate for 7 weeks. At the age of 40 weeks, all rats were examined with MRI, intravenous glucose tolerance test, and then sacrificed for measurement of fat mass and RNA analyses. The total fat (the sum of subcutaneous, mesenteric, epididymal, and retroperitoneal fat pads) measured by dissection was significantly reduced in treatment group. The signal intensity of muscular adiposity was significantly decreased in treatment group. The mRNA levels of FAT/CD36 and mitochondrial carnitine palmitoyltransferase I (M-CPT I) in liver were remarkably increased. Fasting plasma insulin and leptin levels, insulin response after intravenous glucose loading and homeostasis model assessment insulin resistance (HOMA(IR)) index were lowered in treatment group. Fenofibrate increase mitochondrial fatty acid beta-oxidation in liver but not in skeletal muscle and lower the plasma levels of triglyceride and free fatty acid. It might result in reduction of adiposity of truncal adipose tissue and skeletal muscle. We suggest that reduction of adiposity in trunk and skeletal muscle might improve insulin sensitivity.
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PMID:Fenofibrate lowers abdominal and skeletal adiposity and improves insulin sensitivity in OLETF rats. 1216 16

The adipocyte-derived cytokine, resistin, has been proposed as the link between obesity and type 2 diabetes mellitus in murine models. In humans, resistin is identical to FIZZ3 (found in inflammatory zone 3), which belongs to a family of proteins that appears to be involved in inflammatory processes. To study the mechanisms by which fibrates improve glucose homeostasis, we determined resistin mRNA levels by using relative quantitative reverse-transcriptase-polymerase chain reaction (RT-PCR) in omental white adipose tissue samples obtained from patients treated with placebo or fenofibrate (200 mg/d) for 8 weeks before elective cholecystectomy. Fenofibrate treatment reduced total plasma cholesterol and low-density lipoprotein (LDL)-cholesterol levels by 24% and 35%, respectively. Compared with placebo values, a 2.4-fold induction in resistin mRNA levels was observed in white adipose tissue of fenofibrate-treated patients, whereas no changes were observed in the mRNA levels of the well-known perosixome proliferator-activated receptor (PPAR) target genes CD36, acyl-CoA oxidase, and carnitine palmitoyltransferase. These findings indicate that resistin changes were not related to PPAR activation by fenofibrate. Interestingly, resistin mRNA levels showed a negative correlation with plasma cholesterol levels (r2 =.53, P =.039, n = 8), but not with triglyceride levels (r2 =.02, P =.73, n = 8). These results suggest that cholesterol regulates resistin expression in human white adipose tissue.
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PMID:Reductions in plasma cholesterol levels after fenofibrate treatment are negatively correlated with resistin expression in human adipose tissue. 1264 75

The discovery of antidiabetic agents that inhibit hepatic glucose production is a popular and potentially fruitful research area for the pharmaceutical research community. Metformin, a marketed agent with this mechanism of action, is widely used for the treatment of type 2 diabetes, however, more efficacious agents are sought. A number of promising proteins are being targeted for modulation by new compounds, including the glucagon receptor, glycogen phosphorylase, glucocorticoid receptor, 11 beta-hydroxysteroid dehydrogenase-1, fructose-1,6-bisphosphatase, carnitine palmitoyltransferase-1, glycogen synthase kinase-3, glucose-6-phosphate T1 translocase and the A2B receptor. Compounds designed to work against these targets are at the early clinical or preclinical phase of study. Glucagon receptor antagonists, glycogen phosphorylase inhibitors, 11 beta-hydroxysteroid dehydrogenase-1 inhibitors, carnitine palmitoyltransferase-1 inhibitors and fructose-1,6-bisphosphatase inhibitors are, or have been, clinically evaluated. Preclinical studies against the other targets have yielded compounds that demonstrate efficacy in diabetic animal models and clinical activity will continue.
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PMID:Pharmacological regulation of hepatic glucose production. 1280 81

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 importance of elevated levels of fatty acids in the pathogenesis of the deteriorated beta-cell function present in type 2 diabetes has been established. Long-term exposure of the beta-cell to high levels of fatty acids causes enhanced insulin secretion at low glucose (basal insulin release), while glucose-stimulated insulin secretion (GSIS) is decreased or unchanged. We have previously demonstrated that the spatial configuration of fatty acids (cis and trans isomers) is of importance for the acute impact on the beta-cell function. In this study we aimed to elucidate whether the spatial configuration also influenced beta-cell function after long-term exposure. Thus, we compared the effect of 3 days culture of INS-1 cells with cis (cis C 18:1-11) and trans vaccenic acid (trans C 18:1-11), as well as oleic (cis C 18:1-9) and elaidic acid (trans C 18:1-9), on basal and glucose-stimulated insulin release. All fatty acids tested increased basal insulin release; however, a significantly lower basal insulin release was demonstrated for cells cultured with 0.3 to 0.4 mmol/L trans vaccenic acid compared to equimolar levels of the cis isomer. GSIS was not changed by cis or trans vaccenic acid or by oleic acid, whereas it was stimulated by 0.3 to 0.4 mmol/L elaidic acid. The mechanisms behind the fatty acid-induced changes in the beta cells have been linked to changes in glucose and fatty acid oxidation. We demonstrated an increased fatty acid oxidation in beta cells after long-term exposure to all of the tested fatty acids. Interestingly, both trans isomers (trans vaccenic and elaidic acid) induced higher fatty acid oxidation than the cis isomers (cis vaccenic and oleic acid, respectively). No changes in glucose oxidation were found when INS-1 cells were cultured with either of the fatty acids. The increased fatty acid oxidation was associated with an increased content of carnitine palmitoyltransferase I (CPT-I) mRNA, but no difference in the content of CPT-I mRNA to the different fatty acids was found. Insulin mRNA expression in beta cells was not affected by the fatty acids. In conclusion, we have demonstrated that the pathological changes in insulin secretion from INS-1 cells to long-term culture with elevated levels of fatty acids are more pronounced for the cis (cis vaccenic acid and oleic acid) rather than the trans isomers (trans vaccenic acid and elaidic acid). We suggest that this, at least in part, may be explained by a lower fatty acid oxidation in cells cultured with the cis compared to the trans fatty acid isomers. Apparently, the difference in fatty acid oxidation was not caused by an increased induction of CPT-I mRNA, nor by changes in glucose oxidation or insulin mRNA in beta cells chronically exposed to the fatty acids.
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PMID:Long-Term exposure of INS-1 cells to cis and trans fatty acids influences insulin release and fatty acid oxidation differentially. 1533 78


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