Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Atherosclerosis is a major complication of type 2 diabetes. The pathogenesis of this complication is poorly understood, but it clearly involves production in the vascular wall of macrophage (Mo) lipoprotein lipase (LPL). Mo LPL is increased in human diabetes. Peripheral factors dysregulated in diabetes, including glucose and free fatty acids (FAs), may contribute to this alteration. We previously reported that high glucose stimulates LPL production in both J774 murine and human Mo. In the present study, we evaluated the direct effect of FAs on murine Mo LPL expression and examined the involvement of peroxisome proliferator-activated receptors (PPARs) in this effect. J774 Mo were cultured for 24 h with 0.2 mmol/l unsaturated FAs (arachidonic [AA], eicosapentaenoic [EPA], and linoleic acids [LA]) and monounsaturated (oleic acid [OA]) and saturated FAs (palmitic acid [PA] and stearic acid [SA]) bound to 2% bovine serum albumin. At the end of this incubation period, Mo LPL mRNA expression, immunoreactive mass, activity, and synthetic rate were measured. Incubation of J774 cells with LA, PA, and SA significantly increased Mo LPL mRNA expression. In contrast, exposure of these cells to AA and EPA dramatically decreased this parameter. All FAs, with the exception of EPA and OA, increased extra- and intracellular LPL immunoreactive mass and activity. Intracellular LPL mass and activity paralleled extracellular LPL mass and activity in all FA-treated cells. In Mo exposed to AA, LA, and PA, an increase in Mo LPL synthetic rate was observed. To evaluate the role of PPARs in the modulatory effect of FAs on Mo LPL gene expression, DNA binding assays were performed. Results of these experiments demonstrate an enhanced binding of nuclear proteins extracted from all FA-treated Mo to the peroxisome proliferator-response element (PPRE) consensus sequence of the LPL promoter. PA-, SA-, and OA-stimulated binding activity was effectively diminished by immunoprecipitation of the nuclear proteins with anti-PPAR-alpha antibodies. In contrast, anti-PPAR-gamma antibodies only significantly decreased AA-induced binding activity. Overall, these results provide the first evidence for a direct regulatory effect of FAs on Mo LPL and suggest a potential role of PPARs in the regulation of Mo LPL gene expression by FAs.
Diabetes 2001 Mar
PMID:Direct regulatory effect of fatty acids on macrophage lipoprotein lipase: potential role of PPARs. 1124 88

The importance of the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma) in regulating insulin resistance and blood pressure has been demonstrated in families with loss of function mutations. Gain of function mutations has been associated with severe obesity. However, previous population studies of the common variant Pro12Ala have produced conflicting results. As it is likely that the natural ligands for this receptor may include fatty acids, we hypothesized that the effect of this common variant may be altered by the character of the diet, particularly the ratio of dietary polyunsaturated fat to saturated fat (P:S ratio). We studied 592 nondiabetic participants in an ongoing population-based cohort study who were genotyped for the Pro12Ala polymorphism in the PPAR gamma2 isoform. As the Ala homozygotes were uncommon (2.0%), all analyses were conducted comparing Pro homozygotes (79.1%) to Ala allele carriers. There was no difference in fasting insulin concentration or BMI between Ala allele carriers and Pro homozygotes. The fasting insulin concentration was negatively associated with the P:S ratio (P = 0.0119) after adjustment for age and sex, and a strong interaction was evident between the P:S ratio and the Pro12Ala polymorphism for both BMI (P = 0.0038) and fasting insulin (P = 0.0097). The data suggest that when the dietary P:S ratio is low, the BMI in Ala carriers is greater than that in Pro homozygotes, but when the dietary ratio is high, the opposite is seen. This gene-nutrient interaction emphasizes the difficulty of examining the effect of common polymorphisms in the absence of data on nongenetic exposures, and may explain the heterogeneity of findings in previous studies.
Diabetes 2001 Mar
PMID:Evidence for gene-nutrient interaction at the PPARgamma locus. 1124 92

Peroxisome proliferator-activated receptor (PPAR)-alpha agonists lower circulating lipids, but the consequences for muscle lipid metabolism and insulin sensitivity are not clear. We investigated whether PPAR-alpha activation improves insulin sensitivity in insulin-resistant rats and compared the effects with PPAR-gamma activation. Three-week high fat-fed male Wistar rats were untreated or treated with the specific PPAR-alpha agonist WY14643 or the PPAR-gamma agonist pioglitazone (both 3 mg x kg(-1) x day(-1)) for the last 2 weeks of high-fat feeding. Like pioglitazone, WY14643 lowered basal plasma levels of glucose, triglycerides (-16% vs. untreated), and leptin (-52%), and also muscle triglyceride (-34%) and total long-chain acyl-CoAs (LCACoAs) (-41%) (P < 0.05). In contrast to pioglitazone, WY14643 substantially reduced visceral fat weight and total liver triglyceride content (P < 0.01) without increasing body weight gain. WY14643 and pioglitazone similarly enhanced whole-body insulin sensitivity (clamp glucose infusion rate increased 35 and 37% and glucose disposal 22 and 15%, respectively, vs. untreated). Both agents enhanced insulin-mediated muscle glucose metabolic index (Rg') and reduced muscle triglyceride and LCACoA accumulation (P < 0.05). Although pioglitazone had more potent effects than WY14643 on muscle insulin sensitization, this was associated with its greater effect to reduce muscle LCACoA accumulation. Overall insulin-mediated muscle Rg' was inversely correlated with the content of LCACoAs (r = -0.74, P = 0.001) and with plasma triglyceride levels (r = -0.77, P < 0.001). We conclude that even though WY14643 and pioglitazone, representing PPAR-alpha and PPAR-gamma activation, respectively, may alter muscle lipid supply by different mechanisms, both significantly improve muscle insulin action in the high fat-fed rat model of insulin resistance, and this effect is proportional to the degree to which they reduce muscle lipid accumulation.
Diabetes 2001 Feb
PMID:Peroxisome proliferator-activated receptor (PPAR)-alpha activation lowers muscle lipids and improves insulin sensitivity in high fat-fed rats: comparison with PPAR-gamma activation. 1127 55

In addition to their role in inflammation, cytokines like TNFalpha have been reported to regulate the adipose tissue function suggesting a role for these soluble mediators in metabolism. However, it is not known whether adipocytes have the capacity to secrete chemokines, a group of low molecular weight inflammatory mediators that control leukocyte migration into tissues. Here we show that primary cultures of human preadipocytes constitutively produce three chemokines, interleukin-8 (IL-8), macrophage inflammatory protein-1alpha (MIP-1alpha) and monocyte chemotactic protein-1 (MCP-1), while their level of expression is low in mature adipocytes. Upon TNFalpha treatment, the expression of all the three chemokines is upregulated in adipocytes differentiated in vitro. In addition, we describe the presence of seven different chemokine receptors, mainly in mature adipocytes, both in vitro and in human fat tissue sections. Prolonged stimulation of cultured human adipocytes with exogenous chemokines leads to a decrease in lipid content in association with the downregulation of PPARgamma mRNA expression. Moreover, chemokines positively control the secretion of leptin, a hormone that regulates appetite, by a post-transcriptional mechanism. These findings reveal a new role for chemokines in the regulation of adipose tissue and suggest a novel therapeutic basis for the treatment of obesity, diabetes and cachexia.
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PMID:Chemokines control fat accumulation and leptin secretion by cultured human adipocytes. 1132 18

Tumor necrosis factor (TNF)-alpha is one of the candidate mediators of insulin resistance associated with obesity, a major risk factor for the development of type 2 diabetes. The insulin resistance induced by TNF-alpha is antagonized by thiazolidinediones (TZDs), a new class of insulin-sensitizing drugs. The aim of the current study was to dissect the mechanism whereby pioglitazone, one of the TZDs, ameliorates TNF-alpha-induced insulin resistance in 3T3-L1 adipocytes. Pioglitazone restored insulin-stimulated 2-deoxyglucose (DOG) uptake, which was reduced by TNF-alpha, with concomitant restorations in tyrosine phosphorylation and protein levels of insulin receptor (IR) and insulin receptor substrate (IRS)-1, as well as association of the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase with IRS-1 and PI 3-kinase activity. Adenovirus-mediated gene transfer of either wild-type human peroxisome proliferator-activated receptor (PPAR)-gamma2 or a mutant carrying a replacement at the consensus mitogen-activated protein kinase phosphorylation site (hPPAR-gamma2-S112A) promoted adipogenesis of 3T3-L1 fibroblasts and restored TNF-alpha-induced decrease of triglyceride in adipocytes as effectively as pioglitazone. Overexpression of the PPAR-gamma proteins in TNF-alpha-treated adipocytes restored protein levels of IR/IRS-1, but did not improve insulin-stimulated tyrosine phosphorylation of IR/IRS-1 or insulin-stimulated 2-DOG uptake. These results indicate that the ability of pioglitazone to restore insulin-stimulated tyrosine phosphorylation of IR/IRS-1, which is necessary for amelioration of TNF-alpha-induced insulin resistance, may be independent of the adipogenic activity of PPAR-gamma that regulates protein levels of IR/IRS-1.
Diabetes 2001 May
PMID:Pioglitazone ameliorates tumor necrosis factor-alpha-induced insulin resistance by a mechanism independent of adipogenic activity of peroxisome proliferator--activated receptor-gamma. 1133 12

Conjugated linoleic acid (CLA) isomers have a number of beneficial health effects, as shown in biomedical studies with animal models. Previously, we reported that a mixture of CLA isomers improved glucose tolerance in ZDF rats and activated peroxisome proliferator-activated receptor (PPAR)-gamma response elements in vitro. Here, our aim was to elucidate the effect(s) of specific CLA isomers on whole-body glucose tolerance, insulin action in skeletal muscle, and expression of genes important in glucose and lipid metabolism. ZDF rats were fed either a control diet (CON), one of two CLA supplemented diets (1.5% CLA) containing differing isoforms of CLA (47% c9,t11; 47.9% c10,t12, 50:50; or 91% c9,t11, c9,t11 isomers), or were pair-fed CON diet to match the intake of 50:50. The 50:50 diet reduced adiposity and improved glucose tolerance compared with all other ZDF treatments. Insulin-stimulated glucose transport and glycogen synthase activity in skeletal muscle were improved with 50:50 compared with all other treatments. Neither phosphatidlyinositol 3-kinase activity nor Akt activity in muscle was affected by treatment. Uncoupling protein 2 in muscle and adipose tissue was upregulated by c9,t11 and 50:50 compared with ZDF controls. PPAR-gamma mRNA was downregulated in liver of c9,t11 and pair-fed ZDF rats. Thus, the improved glucose tolerance in 50:50 rats is attributable to, at least in part, improved insulin action in muscle, and CLA effects cannot be explained simply by reduced food intake.
Diabetes 2001 May
PMID:Isomer-specific antidiabetic properties of conjugated linoleic acid. Improved glucose tolerance, skeletal muscle insulin action, and UCP-2 gene expression. 1133 20

Type 2 diabetes mellitus is characterised by impaired insulin secretion, diminished peripheral insulin action and increased hepatic glucose production. Clinical trials have indicated that near-normal glucose control may reduce the risk for microvascular and - to a lesser extent - macrovascular complications in Type 2 diabetic patients. Thiazolidinediones improve insulin action by activating a nuclear receptor, PPARgamma. Therefore, these drugs are often referred to as 'insulin sensitisers'. Rosiglitazone is the second compound of this group. Clinical studies with rosiglitazone have shown that it is effective in lowering blood glucose levels in Type 2 diabetic patients treated with either diet alone, sulphonylurea or metformin. Preliminary studies suggest that rosiglitazone also improves glycaemic control in insulin-treated patients while even slightly decreasing insulin dose. The magnitude of the effects is, however, moderate. In diet-treated patients, the reduction of HbA1c levels amounted on average 0.5 - 1.5% and addition to existing sulphonylurea therapy decreased HbA1c by 1.0 - 1.2%. The clinical relevance of additional beneficial effects, i.e., on blood pressure and microalbuminuria, needs to be determined further. Rosiglitazone does not cause hypoglycaemia or gastrointestinal side effects. There is however some concern related to fluid retention, which seems to be an effect of all PPARgamma agonists. In patients treated with rosiglitazone, no severe hepatotoxic side effects have been noticed until now. In the treatment of our patients with Type 2 diabetes, drugs like rosiglitazone which directly reduce insulin resistance are very welcome but more data on its combined use with insulin are needed. Additional studies will also explore its long-term effects in sparing beta-cell function and reducing diabetes-related complications and atherosclerosis.
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PMID:Rosiglitazone. 1133 99

Diabetes is associated with a high level of mortality due to cardiovascular disease resulting from accelerated coronary artery atherosclerosis. A current focus for investigation of atherosclerotic mechanisms is the vascular endothelium since physical or functional injury may represent an initiating step for atherogenesis. Thiazolidinediones (TZDs) are the newest class of drugs for the treatment of insulin resistance and its metabolic consequences; they are peroxisome proliferator-activating receptor (PPAR)-gamma ligands that act as insulin-sensitizing agents. We are interested in the contribution of direct vascular actions to the clinical utility of these agents. We investigated the effect troglitazone and rosiglitazone on endothelial cell proliferation in low- and high-glucose media and further explored their action on the ubiquitous membrane transport system, the Na/H exchanger (NHE), which has been implicated in regulating the growth of vascular cells. Experiments were conducted in cultured bovine aortic endothelial cells (BAECs). Cell proliferation was assessed by cell counting, and NHE activity was determined in cells loaded with the pH-sensitive fluorescent dye, 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein, acetoxymethyl ester (BCECF-AM). Troglitazone caused a dose-dependent inhibition of endothelial cell proliferation with approximately 50% inhibition at 10 microM. Troglitazone inhibited endothelial cell proliferation with similar potency under low- (5 mM) and high-glucose (25 mM) concentrations. Rosiglitazone had no significant effect on endothelial cell proliferation at concentrations of up to 100 microM under low- or high-glucose concentrations. The NHE inhibitor, 3-metlylsulfonyl-4-piperidinobenzoyl guanidine (HOE 694), caused dose dependent inhibition of BAEC proliferation, which was independent of the media glucose concentration. Acute exposure of cells to troglitazone (10 microM) and rosiglitazone (30 microM) during recovery from acidosis showed slight but significant (P<.05) inhibition of NHE activity by troglitazone, but no significant (P>.05) effect by rosiglitazone. Exposure of cells to either drug for 24 h revealed no chronic regulation of NHE activity. Our data demonstrate that troglitazone has similar actions in endothelial cells as in vascular smooth muscle. The absence of rosiglitazone effects, a more potent PPAR-gamma activator, suggests that the observed actions of troglitazone may be at least partially independent of PPAR-gamma. The effects of troglitazone and rosiglitazone on endothelial cell proliferation and NHE activity, although contrasting, are consistent with a central signalling role of this transporter in cell proliferation.
J Diabetes Complications
PMID:Troglitazone, but not rosiglitazone, inhibits Na/H exchange activity and proliferation of macrovascular endothelial cells. 1135 80

Variation in the peroxisome proliferator-activated receptor gamma (PPAR gamma) gene may play a role in the development of type 2 diabetes mellitus. Therefore we investigated the association between the P12A and c1431t polymorphisms in the PPAR gamma gene and type 2 diabetes. The incidence of the P12A polymorphism was determined by PCR-RFLP and the c1431t by single-strand conformation polymorphism analysis in 219 patients with, and 429 without type 2 diabetes. The frequency of the A allele of P12A polymorphism was 0.16 and the t allele of c1431t polymorphism, 0.13 in patients with type 2 diabetes, and 0.13 and 0.12 respectively in subjects without diabetes 3.2% of patients with and 1.4% without type 2 diabetes were A12A. Since the polymorphisms are not linked the association of the 9 possible genotypes with type 2 diabetes was determined. All patients with genotype A12A/c1431c had type 2 diabetes (n = 3, p = 0.038). There was no association between A12A/t1431t and diabetes. DNA sequencing revealed no additional mutations in the coding region of the PPAR gamma gene in genotypes A12A/c1431c or A12A/t1431t. The associations found between polymorphisms in the PPAR gamma gene and type 2 diabetes suggest that either the A12 isofrom is functional leading to a predisposition to type 2 diabetes in homozygotes or that there is a third, unknown mutation linked to the A12/c1431 haplotype which is responsible.
Exp Clin Endocrinol Diabetes 2001
PMID:Association between the P12A and c1431t polymorphisms in the peroxisome proliferator activated receptor gamma (PPAR gamma) gene and type 2 diabetes. 1140 97

Takeda has a relatively long history in diabetes research. Pioglitazone, a thiazolidinedione derivative, was developed from our basic research on diabetic animal models in the 1960s and our chemical research on lipid-lowering agents in the 1970s. Pioglitazone reduced plasma glucose, triglyceride and insulin levels in obese-diabetic animal models with insulin resistance in liver and/or peripheral tissues, but did not decrease normoglycemia in normal rats and aged dogs or hyperglycemia in insulin-deficient streptozocin-induced diabetic rats and impaired-insulin-secretory Goto-Kakizaki rats. The ED50 of plasma glucose-lowering action was 0.5 mg/kg/day in Wistar fatty rats. These findings clearly indicate that pioglitazone works in animals with insulin resistance and has a quite different mechanism from sulfonylureas and insulin itself. Although the exact mechanism of pioglitazone still remains obscure, pioglitazone normalized abnormalities in the cellular signal transduction of insulin. These effects seem to be due to the inhibitory action of pioglitazone on TNF-alpha production, which is one of the factors responsible for insulin resistance. Pioglitazone is a potent agonist for the peroxisome proliferator-activated receptor, (PPAR)-gamma, that is related to differentiation of adipocytes, and the relationship between TNF-alpha production and PPAR-gamma has been reported. Therefore, the agonistic activity of pioglitazone on PPAR-gamma may be involved in the mechanism of reduction of insulin resistance. The clinical data clearly demonstrated that pioglitazone, at clinical doses of 15-45 mg/day, decreased plasma glucose, HbA1c and triglyceride, increased plasma HDL-cholesterol, but did not alter total cholesterol and LDL-cholesterol levels. These findings suggest that pioglitazone has a benefit for prevention of cardiovascular diseases in addition to diabetic complications.
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PMID:[Insulin resistance-reducing effect of a new thiazolidinedione derivative, pioglitazone]. 1141 43


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