Glucose and lipid metabolism in relation to novel polymorphisms in the 5′-AMP-activated protein kinase γ2 gene in Chinese

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Abstract

The 5′-AMP-activated protein kinase (AMPK) behaves as a fuel sensor in glucose and lipid metabolism. We sequenced exon 1 and flanking regions of the gene encoding for the γ2 subunit of AMPK (AMPKγ2) and identified two novel common polymorphisms at position −26 and IVS1 + 43. We then studied these two polymorphisms in relation to plasma glucose, insulin resistance, β-cell function, and serum lipids in 290 Han Chinese undergoing an oral glucose tolerance test and a frequently sampled intravenous glucose tolerance test. The −26C/T and IVS1 + 43C/T polymorphisms were in tight linkage disequilibrium (P = 0.0002). In adjusted categorical analyses, the −26TT genotype tended to be associated with a higher risk of type 2 diabetes (odds ratio 4.52, P = 0.07). The adjusted continuous analyses were confirmatory. −26TT subjects, compared with −26C allele carriers, had higher concentrations of plasma glucose, both fasting (7.3 vs. 6.1 mmol/L, P = 0.02) and after oral glucose loading (area under the curve for glucose, 1984 vs. 1596 min mmol/L, P = 0.002), and had lower acute insulin response to glucose (143 vs. 404, P = 0.0005) and disposition index (151 vs. 459, P = 0.008). In further adjusted analyses, we observed that IVS1 + 43TT subjects, compared with IVS1 + 43C allele carriers, had significantly higher serum concentrations of triglycerides (4.20 vs. 2.00 mmol/L, P < 0.0001) and total cholesterol (5.88 vs. 4.99 mmol/L, P = 0.01). In conclusion, in Chinese, the AMPKγ2 polymorphisms might be associated with glucose and lipid metabolism.

Introduction

Several recent studies indicate that 5′-AMP-activated protein kinase (AMPK), a metabolic master switch, may play a major role in glucose and lipid metabolism [1], [2], [3], [4]. AMPK can be activated physiologically by exercise and pharmacologically by 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) [5]. In lean as well as insulin-resistant obese rats, AMPK activation with AICAR leads to a pronounced decline in blood glucose [6], [7], [8], by increasing glucose uptake in skeletal muscle [6], [8], [9] and by decreasing hepatic glucose production [6], [8]. The effect of activated AMPK on insulin secretion is disputed. In vivo studies in rats consistently show that AICAR administration decreases plasma insulin concentration [6], [7], [8]. However, an in vitro study in isolated rat islets revealed that AICAR stimulated insulin release at low (3.3 mM) and submaximal (5.5 mM) concentrations of glucose, but inhibited release at a saturating glucose concentration (16.7 mM) [10]. AMPK activation may also reduce serum triglycerides, and cholesterol [6], [7], [8], by decreasing synthesis of fatty acid, triglycerides, and sterols and by increasing fatty acid oxidation and ketogenesis [2], [9].

AMPK is a heterotrimeric protein, that consists of a catalytic subunit (α1 or α2) and two regulatory subunits (β1 or β2 and γ1, γ2 or γ3) [11]. In humans, these subunits are encoded by separate genes [11]. The AMPKγ2 gene (PRKAG2) has been localized to chromosome 7q35-36 [12]. Several groups recently reported that functional mutations in human AMPKγ2 subunit gene caused a novel myocardial metabolic storage disease [13], [14], [15], [16], [17]. In pigs, the genes encoding AMPKγ subunits had been mapped to the regions of quantitative trait loci for meat quality [18], [19], and their mutations influence the glycogen content in the muscle and the meat quality [20], [21]. We hypothesized that genetic polymorphisms in AMPKγ2 might be associated with glucose and lipid metabolism in humans. We searched the AMPKγ2 gene for polymorphisms that cause amino acid substitution in the database (www.ncbi.nlm.nih.gov/SNP/), finding an A  T variation at position 16 in exon 1 leading to methionine  leucine substitution at amino acid position 6 (Met6Leu, rs17173294). We then sequenced exon 1 and flanking regions of the AMPKγ2 gene in a sample of 40 unrelated Chinese. We did not detect the Met6Leu substitution, but identified two novel single nucleotide polymorphisms (SNPs).

The present study reports the results of a genetic association study on two novel AMPKγ2 polymorphisms in relation to fasting and postprandial plasma glucose, insulin resistance, β-cell function, and serum lipids in Chinese.

Section snippets

Subjects and study design

For inclusion in the present study, we considered consecutive patients, who were referred to the specialized outpatient clinic for obesity in the Ruijin Hospital (Shanghai), and underwent an oral glucose tolerance test (OGTT) and an insulin-modified frequently sampled intravenous glucose tolerance test (FSIGT). Our study also included healthy volunteers in whom the results of OGTT and FSIGT were obtained. All subjects were unrelated Han Chinese living in the Shanghai region, and gave informed

Results

The characteristics of the 290 participants are shown in Table 1. Body mass index and age were the major determinants of the OGTT- and FSIGT-derived indexes for insulin sensitivity and β-cell function. Body mass index significantly (P < 0.0001 for all) and independently explained 14, 13, 16, and 4% of the variance of HOMA insulin resistance index, HOMA β-cell function, SI, and AIRG, respectively. For age, the corresponding proportions were 2% (P = 0.006), 10% (P < 0.0001), 1% (P = 0.13), and 33% (P < 

Discussion

We have identified two novel polymorphisms in the AMPKγ2 gene (−26C/T and IVS1 + 43C/T) showing tight linkage disequilibrium. The −26TT genotype was associated with higher concentrations of fasting and postprandial plasma glucose and accordingly was more prevalent among subjects with type 2 diabetes mellitus. The lower acute insulin response to glucose suggests that the −26TT genotype may be associated with abnormal β-cell function. In addition, we report that the IVS1 + 43TT genotype is associated

Acknowledgments

We are very grateful to Dr. Zachary T. Bloomgarden from Department of Endocrinology, Mount Sinai School of Medicine and Medical Center, New York, USA for critical reading. The present study would not have been possible without the participation of the patients and healthy volunteers. This research was supported by grants from National Natural Science Foundation of China (No. 30270625) and the E-Institute of Shanghai Universities (No. E03007).

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