The Influence of Adiponectin Gene Polymorphism on the Rosiglitazone Response in Patients With Type 2 Diabetes

Abstract

OBJECTIVE -The aim of this study was to examine the effects of rosiglitazone on adiponectin and plasma glucose levels in relation with common adiponectin gene (ACDC) polymorphisms.RESEARCH DESIGN AND METHODS -A total of 166 patients with type 2 diabetes were treated with rosiglitazone (4 mg/day) for 12 weeks without changing any of their previous medications. In all, single nucleotide polymorphism (SNP)45 and SNP276 of ACDC were examined.RESULTS -Regarding SNP45, there was a smaller reduction in the fasting plasma glucose (FPG) level and the HbA 1c value in the carriers of the GG genotype than in the carriers of the other genotypes (P ϭ 0.031 and 0.013, respectively). There was a smaller increase in the serum adiponectin concentration for the GG genotype than for the other genotypes (P ϭ 0.003). Regarding SNP276, there was less reduction in the FPG level for the GG genotype than for the other genotypes (P ϭ 0.001). In the haplotype analysis, the reductions in the FPG and HbA 1c levels were smaller for the GG homozygote haplotype than for the other haplotypes (P ϭ 0.001 and 0.001, respectively). The increase in the plasma adiponectin concentration for the GG homozygote haplotype was smaller than that of the other haplotypes (P ϭ 0.003).CONCLUSIONS -These data suggest that genetic variations in the adiponectin gene can affect the rosiglitazone treatment response of the circulating adiponectin level and blood glucose control in type 2 diabetic patients. Diabetes Care 28:1139 -1144, 2005A diponectin is a circulating protein secreted by adipocytes and is associated with the development of insulin resistance and atherosclerosis (1,2). Serum adiponectin concentrations are lower in patients with type 2 diabetes, obesity, and coronary heart disease than in healthy subjects (3,4). This molecule is known to be a potent insulin sensitizer. Thiazolidinediones lower the blood glucose level primarily by activating the peroxisome proliferator-activated receptor (PPAR)-␥, which then improves insulin sensitivity (5). The synthetic PPAR-␥ agonist, rosiglitazone, is reported to increase the serum adiponectin level in type 2 diabetes (6).Adiponectin is encoded by ACDC, which is located on chromosome 3q27 (7,8). Studies of ACDC mutations have revealed 16 single nucleotide polymorphisms (SNPs) (9). Among them Ϫ11377, ϩ45, and ϩ276 have been reported to be associated with type 2 diabetes, circulating adiponectin levels, and insulin resistance in a Japanese population (10,11). However, previous studies on the association between ACDC SNPs, type 2 diabetes, and adiponectin levels have shown that the specific SNPs associated with this process differ according to both the study and the ethnic population. The aim of this study was to examine the association between SNPs in ACDC and the response to rosiglitazone. In addition, this study also investigated the PPAR responsive element (PPRE) polymorphism in the ACDC promoter. RESEARCH DESIGN ANDMETHODS -A total of 166 patients were treated with rosiglitazone (4 mg/ day) during a 12-week treatme...

LPIN1 genetic variation is associated with rosiglitazone response in type 2 diabetic patients

“…Multiple regression results showed that the rs10192566 genetic effect remained signifi cantly associated with rosiglitazone response (defi ned by a greater than 15% decrease in HbA1c levels after 12 weeks) after adjustment for age, gender, initial body weight gain, baseline FPG, and HOMA-IR [odds ratio (OR) 2.21, P = 0.013] ( Table 6). This genetic effect of LPIN1 became stronger when regression analysis included previously reported gene loci (adiponectin and PPAR-c, OR = 3.39, P = 0.004) [9,10].…”

“…* P-values reflect differences between the CC and CG+GG genotypes assessed by t-test. 9 P-value assessed by chi-square test. Bonferroni correction was made to control the effects of multiple comparisons.…”

“…Only lipin b increased with PPAR-c activator treatment [6], which is a possible mechanism of insulin-sensitizing action and increasing body weight in TZD treatment. We ex tended our previous studies [9,10] to investigate the association of rosiglitazone response to LPIN1 gene variations in 261 patients with T2DM. Similar to the results of previous studies, rs1163809, rs10192566, and rs2278513 were in nearly complete linkage disequilibrium [7].…”

“…DNA was ex tracted from blood as previously described [9,11]. Several single nucleotide polymorphisms (SNPs) reported and among them, six at the LPIN1 locus were genotyped: rs11693809, rs10192566, rs2278513, rs2577262, rs2716610, and rs1050800.…”

“…These studies implicate a role for LPIN1 genetic variation in glucose homeostasis and lipid metabolism. We have previously reported that genetic variations in adiponectin, PPAR-c2, and perilipin affect rosiglitazone response in patients with type 2 diabetes (T2DM) [9][10][11]. In this study, we ex tended our previous study cohort and evaluated the effects of LPIN1 polymorphisms on rosiglitazone response in T2DM.…”