Analysis of the Relationship Between the Pro12Ala Variant in the PPAR-γ2 Gene and the Response Rate to Therapy With Pioglitazone in Patients With Type 2 Diabetes

Blüher, Matthias; Lübben, G.; Paschke, Ralf

doi:10.2337/diacare.26.3.825

Cited by 104 publications

(82 citation statements)

References 36 publications

(49 reference statements)

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“…Addition of the Pro12Ala polymorphism to the logistic regression analysis model, including as confounding factors age, sex, BMI, degree of metabolic control, age at diagnosis, and duration of diabetes, did not change the association of the Arg 972 IRS-1 variant with secondary failure to sulfonylurea (2.0 [1.38 -3.86], P ϭ 0.038). These results extend previous data showing that the Pro12Ala polymorphism in PPAR-␥ does not affect the therapeutic response to pioglitazone (31) and indicate that this common variant is unlikely to be responsible for secondary failure to oral hypoglycemic agents.…”

Section: Discussionsupporting

confidence: 80%

The Arg972 Variant in Insulin Receptor Substrate-1 Is Associated With an Increased Risk of Secondary Failure to Sulfonylurea in Patients With Type 2 Diabetes

et al. 2004

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OBJECTIVE -The aim of this study was to investigate whether diabetic patients carrying the Arg 972 insulin receptor substrate-1 (IRS-1) variant are at increased risk for secondary failure to sulfonylurea. RESEARCH DESIGN AND METHODS -A total of 477 unrelatedCaucasian type 2 diabetic patients were recruited according to the following criteria: onset of diabetes after age 35 years, absence of ketonuria at diagnosis, and anti-GAD Ϫ antibody. Type 2 diabetes was diagnosed according to the American Diabetes Association criteria. Patients with secondary sulfonylurea failure were defined as those requiring insulin due to uncontrolled hyperglycemia (fasting plasma glucose Ͼ300 mg/dl) despite sulfonylurea-metformin combined therapy, appropriate diet, and absence of any conditions causing hyperglycemia.RESULTS -Of the total patients, 53 (11.1%) were heterozygous for the Arg 972 IRS-1 variant, 1 (0.2%) was homozygous, and the remainder (88.7%) were homozygous for the wild-type allele. The genotype frequency of the Arg 972 IRS-1 variant was 8.7% among diabetic patients well controlled with oral therapy and 16.7% among patients with secondary failure to sulfonylurea (odds ratio 2.1 [95% CI 1.18 -3.70], P ϭ 0.01). Adjustment for age, sex, BMI, metabolic control, age at diagnosis, duration of diabetes, and Pro12Ala polymorphism of peroxisome proliferatoractivated receptor-␥2 gene in a logistic regression analysis with secondary failure to sulfonylurea as a dependent variable did not change this association (2.0 [1.38 -3.86], P ϭ 0.038).CONCLUSIONS -These data demonstrate that the Arg 972 IRS-1 variant is associated with increased risk for secondary failure to sulfonylurea, thus representing a potential example of pharmacogenetics in type 2 diabetes. Diabetes Care 27:1394 -1398, 2004T ype 2 diabetes is a progressive disorder, and maintenance of good metabolic control has been demonstrated to reduce the risk of its associated long-term vascular complications and a delay in their onset (1). It has been estimated that each year 5-7% of diabetic patients treated with sulfonylurea convert to insulin treatment progressively as sulfonylurea fails (2,3). This clinical phenomenon has been termed secondary failure to sulfonylurea. Secondary failure to sulfonylurea has been variably attributed to change in body weight, lack of adequate diet regimen, young age at diagnosis, deterioration of insulin sensitivity or presence of anti-islet cell and anti-GAD antibodies (3,4). However, the U.K. Prospective Diabetes Study has demonstrated that the progressive deterioration of glycemic control in type 2 diabetic patients was associated with declining of pancreatic ␤-cell function despite either conventional treatment with dietary modification or intensive monotherapy treatment (1,3). A progressive deterioration of insulin secretion has been confirmed in smaller studies, and ␤-cell homeostatic model assessment has been demonstrated to be a better predictor of the insulinrequiring stage in type 2 diabetes than clinical indexes such as duration of di...

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Section: Discussionsupporting

confidence: 80%

The Arg972 Variant in Insulin Receptor Substrate-1 Is Associated With an Increased Risk of Secondary Failure to Sulfonylurea in Patients With Type 2 Diabetes

et al. 2004

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“…A gain-of-function p.Pro115Gln variant is associated with obesity and insulin resistance 93,94) . A silent c.161C T (1431C T: rs3856806) polymorphism in exon 6 of the PPAR gene was investigated in several studies.…”

Section: Other Ppar Gene Variantsmentioning

confidence: 99%

Retinoid X Receptor Heterodimer Variants and Cardiovascular Risk Factors

Nohara

Kobayashi

Mabuchi

2009

JAT

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Nuclear receptors are transcription factors that can be activated by specific ligands. Recent progress has shown that retinoid X receptor (RXR) and its heterodimerization partners, including peroxisome proliferator-activated receptors, regulate many important genes involved in energy homeostasis and atherosclerosis, and should be promising therapeutic targets of metabolic syndrome. RXR heterodimers regulate a number of complex cellular processes, and genetic studies of RXR heterodimers have provided important clinical information in addition to knowledge gained from basic research. Genetic variants of RXR heterodimers were screened and investigated, and some variants were shown to have a considerable impact on metabolic disorders, including phenotypic components of familial combined hyperlipidemia. The combined efforts of basic and clinical science regarding nuclear receptors have achieved significant progress in unraveling the inextricably linked control system of energy expenditure, lipid and glucose homeostasis, inflammation, and atherosclerosis. This review summarizes the current understanding regarding RXR heterodimers based on their human genetic variants, which will provide new clues to uncover the background of multifactorial disease, such as metabolic syndrome or familial combined hyperlipidemia.

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“…Response to thiazolidinedione therapy has been associated with PPARG (peroxisome proliferator-activated receptor-gamma) variation [90,91], though not by all studies [92][93][94]. Literature on the impact of the KCNJ11 risk variant E23K on treatment response to sulfonylureas is similarly controversial.…”

Section: Discussionmentioning

confidence: 99%

Genetic variants affecting incretin sensitivity and incretin secretion

et al. 2010

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Recent genome-wide association studies identified several novel risk genes for type 2 diabetes. The majority of these type 2 diabetes risk variants confer impaired pancreatic beta cell function. Though the molecular mechanisms by which common genetic variation within these loci affects beta cell function are not completely understood, risk variants may alter glucose-stimulated insulin secretion, proinsulin conversion, and incretin signals. In humans, the incretin effect is mediated by the secretion and insulinotropic action of two peptide hormones, glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1. This review article aims to give an overview of the type 2 diabetes risk loci that were found to associate with incretin secretion or incretin action, paying special attention to the potential underlying mechanisms.

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Analysis of the Relationship Between the Pro12Ala Variant in the PPAR-γ2 Gene and the Response Rate to Therapy With Pioglitazone in Patients With Type 2 Diabetes

Cited by 104 publications

References 36 publications

The Arg972 Variant in Insulin Receptor Substrate-1 Is Associated With an Increased Risk of Secondary Failure to Sulfonylurea in Patients With Type 2 Diabetes

The Arg972 Variant in Insulin Receptor Substrate-1 Is Associated With an Increased Risk of Secondary Failure to Sulfonylurea in Patients With Type 2 Diabetes

Retinoid X Receptor Heterodimer Variants and Cardiovascular Risk Factors

Genetic variants affecting incretin sensitivity and incretin secretion

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