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 protein phosphatase calcineurin is a signaling intermediate that induces the transformation of fast-twitch skeletal muscle fibers to a slow-twitch phenotype. This reprogramming of the skeletal muscle gene expression profile may have therapeutic applications for metabolic disease. Insulin-stimulated glucose uptake in skeletal muscle is both impaired in individuals with type II diabetes mellitus and positively correlated with the percentage of slow- versus fast-twitch muscle fibers. Using transgenic mice expressing activated calcineurin in skeletal muscle, we report that skeletal muscle reprogramming by calcineurin activation leads to improved insulin-stimulated 2-deoxyglucose uptake in extensor digitorum longus (EDL) muscles compared with wild-type mice, concomitant with increased protein expression of the insulin receptor, Akt, glucose transporter 4, and peroxisome proliferator-activated receptor-gamma co-activator 1. Transgenic mice exhibited elevated glycogen deposition, enhanced amino acid uptake, and increased fatty acid oxidation in EDL muscle. When fed a high-fat diet, transgenic mice maintained superior rates of insulin-stimulated glucose uptake in EDL muscle and were protected against diet-induced glucose intolerance. These results validate calcineurin as a target for enhancing insulin action in skeletal muscle.
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PMID:Skeletal muscle reprogramming by activation of calcineurin improves insulin action on metabolic pathways. 1294 59

The endothelium regulates vascular tone through the release of vasodilating and vasoconstricting substances. The most important of these vasodilating substances is nitric oxide (NO), which is also vascular protective and inhibits inflammation, oxidation, vascular smooth muscle cell proliferation, and migration. Damage to the endothelium causes endothelial dysfunction with impaired release of NO and loss of its antiatherogenic protection. Traditional risk factors for coronary artery disease, including diabetes, hypercholesterolemia, hypertension, and low levels of high-density lipoprotein cholesterol, are associated with endothelial dysfunction and thus promote the atherogenic process. More recently, insulin resistance in the absence of overt diabetes or the metabolic syndrome has been associated with endothelial dysfunction. This association provides evidence that the atherosclerotic process may actually begin earlier in the spectrum of insulin resistance, ultimately resulting in a progression of the metabolic syndrome to prediabetes and then to type 2 diabetes. Aggressive treatment of dyslipidemia and hypertension, even before the onset of type 2 diabetes, would appear prudent in decreasing the progression of the atherosclerotic process. The thiazolidinediones are peroxisome proliferator-activated receptor-gamma agonists that improve glucose and lipid metabolism. These agents have recently been shown to improve endothelial function in the early stages of insulin resistance. Results from ongoing trials with thiazolidinediones will reveal whether they will also reduce cardiovascular end points.
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PMID:Role of endothelial dysfunction in insulin resistance. 1295 22

Body size at birth is an indicator of the intrauterine environment. The effects of the Pro12Pro genotype and the 12Ala allele of the PPARgamma-2 gene on glucose and insulin metabolism in adult life depend on body size at birth. A low birth weight is associated with insulin resistance and type 2 diabetes. The peroxisome proliferator-activated receptor-gamma (PPARgammas) are also regulators of adipocyte differentiation, and the PPARgamma-2 gene could also contribute to the development of dyslipidemia. Therefore, the effects of the Pro12Ala polymorphisms of the PPARgamma-2 gene on lipid metabolism were measured in 476 elderly persons whose birth weight was known. The Ala12 allele was associated with increased serum total, low-density lipoprotein (LDL), and non-high-density lipoprotein (non-HDL) cholesterol concentrations but only among those who had birth weights below 3000 g. These interactions between the effects of the PPARgamma-2 gene on adult traits and the effects of birth weight may be interpreted as examples of gene-environmental interactions, which underlie plasticity during development.
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PMID:The effects of the Pro12Ala polymorphism of the PPARgamma-2 gene on lipid metabolism interact with body size at birth. 1297 43

Rosiglitazone is an FDA-approved oral antidiabetic agent for the treatment of type 2 diabetes. This compound improves insulin sensitivity through the activation of the nuclear receptor, peroxisome proliferator-activated receptor-gamma (PPAR-gamma). In addition to sensitizing cells to insulin, the PPAR-gamma2 isoform appears to be critical for the regulation of osteoblast and adipocyte differentiation from common mesenchymal bone marrow progenitors. We have demonstrated previously that PPAR-gamma2 activated with rosiglitazone acts as a dominant inhibitor of osteoblastogenesis in murine bone marrow in vitro. Here, we show that in vivo, rosiglitazone administration results in significant bone loss. When rosiglitazone (20 microg/g body weight/d) was given to 6-month-old, nondiabetic C57BL/6 mice for 7 wk, a significant decrease in total body bone mineral density was observed. Analysis of bone microarchitecture, using micro-computed tomography, demonstrated a decrease in bone volume, trabecular width, and trabecular number and an increase in trabecular spacing. Histomorphometric analysis showed a decrease in bone formation rate, with a simultaneous increase in fat content in the bone marrow. Changes in bone morphology and structure were accompanied by changes in the expression of osteoblast- and adipocyte-specific marker genes; the expression of the osteoblast-specific genes Runx2/Cbfa1, Dlx5, and alpha1(I)collagen were decreased, whereas the expression of the adipocyte-specific fatty acid binding protein aP2, was increased. These in vivo data suggest that rosiglitazone therapy may pose a significant risk of adverse skeletal effects in humans.
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PMID:Bone is a target for the antidiabetic compound rosiglitazone. 1450 May 73

We tested the hypothesis that short-term treatment of mice with Type 2 diabetes mellitus (DM) with rosiglitazone (ROSI), an agonist of peroxisome proliferator-activated receptor-gamma, ameliorates the impaired coronary arteriolar dilation by reducing oxidative stress via a mechanism unrelated to its effect on hyperglycemia and hyperinsulinemia. Control and Type 2 DM (db/db) mice were treated with ROSI (3 mg x kg(-1) x day(-1)) for 7 days, which did not significantly affect their serum concentration of glucose and insulin. Compared with controls, in db/db mice serum levels of 8-isoprostane and dihydroethydine-detectable superoxide production in carotid arteries were significantly elevated and were reduced by ROSI treatment. In coronary arterioles (diameter, approximately 80 microm) isolated from db/db mice, the reduced dilations to ACh, the nitric oxide (NO) donor NONOate, and increases in flow were significantly augmented either by in vitro administration of apocynin, an inhibitor of NAD(P)H-oxidase, or by in vivo ROSI treatment, responses that were then significantly reduced by the NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester. In aortas of db/db mice, activity of SOD and catalase was reduced, whereas NAD(P)H oxidase activity was enhanced. ROSI treatment enhanced catalase and reduced NAD(P)H oxidase activity but did not affect the activity of SOD. These findings suggest that ROSI treatment enhances NO mediation of coronary arteriolar dilations due to the reduction of vascular NAD(P)H oxidase-derived superoxide production and enhancement of catalase activity. Thus, in addition to the previously revealed beneficial metabolic effects, the antioxidant action of rosiglitazone may protect coronary arteriolar function in Type 2 DM.
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PMID:PPARgamma activation, by reducing oxidative stress, increases NO bioavailability in coronary arterioles of mice with Type 2 diabetes. 1455 Oct 45

Ragaglitazar is a novel dual peroxisome proliferator-activated receptor (PPAR) alpha and gamma agonist intended to restore insulin sensitivity and correct diabetic dyslipidemia. These studies assessed single-dose pharmacokinetics and tolerability of ragaglitazar in healthy subjects, as well as multiple-dose pharmacokinetics, pharmacodynamics, and tolerability of ragaglitazar in healthy subjects and in patients with type 2 diabetes. Healthy subjects received a single oral dose (1-120 mg), and healthy subjects and type 2 diabetic patients received a loading dose and thereafter once-daily doses (0.5-16 mg) of ragaglitazar for 6 and 20 days, respectively. Ragaglitazar was rapidly absorbed (tmax: 1.5-1.7 h), with mean AUC0-24 h and Cmax proportional to dose after single and multiple dosing; t1/2 was 80 hours following a single dose and 104 hours in healthy subjects and 122 hours in patients after multiple dosing. Administration of 4 mg ragaglitazar to patients (n = 4) for 21 days resulted in mean decreases from baseline in fasting levels of plasma glucose (18%), C-peptide (18%), fructosamine (6%), triglycerides (36%), free fatty acids (49%), total cholesterol (11%), low-density lipoprotein (LDL) cholesterol (21%), and very low-density lipoprotein (VLDL) cholesterol (15%), as well as an increase in high-density lipoprotein (HDL) cholesterol (33%). Overall, ragaglitazar was well tolerated; with multiple dosing, there was a higher incidence of adverse events for patients that, at the highest dose level (16 mg), included peripheral edema and anemia.
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PMID:Ragaglitazar: the pharmacokinetics, pharmacodynamics, and tolerability of a novel dual PPAR alpha and gamma agonist in healthy subjects and patients with type 2 diabetes. 1455 Nov 79

Thiazolidinediones address underlying causes of type 2 diabetes, although their mechanism of action is not clearly understood. The compounds are thought to function as direct activators of the nuclear receptor PPARgamma (peroxisome proliferator-activated receptor-gamma), although pioglitazone, the weaker agonist of the two thiazolidinediones now in clinical use, seems to have more useful effects on circulating lipids. We have used tritiated pioglitazone and a photoaffinity cross-linker to identify a novel binding site in mitochondria. A saturable binding site for [3H]pioglitazone was solubilized from the membranes with CHAPS and migrated as a large complex by size exclusion chromatography. The binding correlated with a <17-kDa protein (m17), marked by a photoaffinity cross-linker, in both subcellular location and selectivity of competition by analogs. The protein was isolated and identified by mass spectrometry analysis and NH2-terminal sequencing. Three synthetic peptides with potential antigenic properties were synthesized from the predicted nontransmembrane sequence to generate antibodies in rabbits. Western blots show that this protein, which we have termed "mitoNEET," is located in the mitochondrial fraction of rodent brain, liver, and skeletal muscle, showing the identical subcellular location and migration on SDS-PAGE as the protein cross-linked specifically by the thiazolidinedione photoprobe. The protein exists in low levels in preadipocytes, and expression increases exponentially in differentiated adipocytes. The synthetic protein bound to solid phase associated with a complex of solubilized mitochondrial proteins, including the trifunctional beta-oxidation protein. It is possible that thiazolidinedione modification of the function of the mitochondrial target may contribute to lipid lowering and/or antidiabetic actions.
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PMID:Identification of a novel mitochondrial protein ("mitoNEET") cross-linked specifically by a thiazolidinedione photoprobe. 1457 Jul 2

In this study, the association of the Pro12Ala peroxisome proliferator-activated receptor gamma2 (PPARgamma2) polymorphism with atherosclerosis was examined in a Japanese Type 2 diabetic population. PPARgamma has been identified as a key regulator of adipogenesis. Recently, some studies reported that the Pro12Ala polymorphism was associated with resistance to Type 2 diabetes. It is well-known that Type 2 diabetes is closely related with disorder of lipid metabolism as well as impaired glucose homeostasis, resulting in atherosclerosis. We aimed to evaluate the association between carriers of the Pro12Ala PPARgamma2 mutation and clinical profiles concerning atherosclerosis besides plasma glucose and lipid concentrations. Screening for the mutation was performed using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method among 154 Type 2 diabetic patients. The homozygotes of the Pro12 allele were 143 (93%), the heterozygotes of the Pro12 and Ala12 allele were 11 (7%) and the homozygote of the Ala12 allele was not detected. The group with the Ala12 allele had a significantly lower value of carotid artery intima-media thickness (IMT) than that without it, although there was no difference between two groups in sex, age or other clinical variables we examined. The Pro12Ala PPARgamma2 polymorphism may be associated with carotid artery IMT values in Type 2 diabetes mellitus.
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PMID:The association of Pro12Ala polymorphism in PPARgamma2 with lower carotid artery IMT in Japanese. 1458 Nov 58

The peroxisome proliferator-activated receptor gamma2 (PPARgamma2) Pro12Ala polymorphism has been associated with a decreased risk of type 2 diabetes and a lower albumin excretion rate (AER) in patients with established diabetes. We performed a case-control study aiming to evaluate the association between the Pro12Ala polymorphism and diabetic nephropathy. Genomic DNA was obtained from 104 type 2 diabetic patients (case subjects) with chronic renal insufficiency (78 on dialysis and 26 with proteinuria [AER >or=200 microg/min] and serum creatinine >or=2.0 mg/dl) and 212 normoalbuminuric patients (AER <20 microg/min) with known diabetes duration >or=10 years (control subjects). The genotypic distribution of the PPARgamma2 Pro12Ala polymorphism in these diabetic patients was in Hardy-Weinberg equilibrium, and the Ala allele frequency was 9%. The frequency of Ala carriers (Ala/Ala or Ala/Pro) was 20.3% in control subjects and 10.6% in case subjects (P = 0.031). The odds ratio of having diabetic nephropathy for Ala carriers was 0.465 (95% CI 0.229-0.945; P = 0.034). Carriers of the Ala allele were not different from noncarriers (Pro/Pro) regarding sex (38.9 vs. 44.1% males) or ethnicity (77.4 vs. 71.7% white) distribution, age (61 +/- 10 vs. 61 +/- 10 years), known diabetes duration (17 +/- 7 vs. 16 +/- 7 years), BMI (27 +/- 4 vs. 28 +/- 5 kg/m(2)), fasting plasma glucose (184 +/- 81 vs. 176 +/- 72 mg/dl), HbA(1c) (6.7 +/- 2.3 vs. 6.9 +/- 2.4%; high-performance liquid chromatography reference range: 2.7-4.3%), and systolic (145 +/- 27 vs. 0.144 +/- 24 mmHg) or diastolic (87 +/- 14 vs. 85 +/- 14 mmHg) blood pressure, respectively. In conclusion, the presence of the Ala allele may confer protection from diabetic nephropathy in patients with type 2 diabetes.
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PMID:The human peroxisome proliferator-activated receptor gamma2 (PPARgamma2) Pro12Ala polymorphism is associated with decreased risk of diabetic nephropathy in patients with type 2 diabetes. 1463 65

Despite many advances in cardiology, atherosclerosis remains a major medical problem. This is especially the case for individuals with insulin resistance and type 2 diabetes mellitus. Atherosclerotic lesions can develop as early as the second decade of life and progress into clinical disease over time. Atherosclerosis is a complex disorder, involving many cell types and circulating mediators and resulting in an inflammatory state. The control of transcription of inflammatory mediators via ligands for peroxisome proliferator-activated receptor-gamma, such as thiazolidinediones (TZDs), has been raised as a possible mechanism for improving atherosclerosis. Results of studies performed in vitro and in animal models suggest that TZDs may increase cholesterol efflux from macrophages, decrease cytokine expression, and limit chemokine levels. Such effects may underlie the decreases in atherosclerosis seen in mouse models of atherosclerosis after TZD treatment. The direct actions of the TZDs on atherosclerosis may couple with their effects on metabolic parameters through increased insulin sensitivity. Ongoing clinical trials evaluating cardiovascular end points with TZD therapy should provide insight into these possibilities.
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PMID:The vascular biology of atherosclerosis. 1467 67


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