A Polymorphism in the AMPKα2 Subunit Gene Is Associated With Insulin Resistance and Type 2 Diabetes in the Japanese Population

Abstract

AMP-activated protein kinase (AMPK) acts as a fuel gauge for glucose and lipid metabolism. The gene encoding the ␣2 isoform of the catalytic subunit of AMPK (PRKAA2) is located at one of the Japanese type 2 diabetes loci mapped by our previous genome scan (1p36-32). PRKAA2 is, therefore, a good candidate gene for insulin resistance and type 2 diabetes. We screened all nine exons, their exon-intron boundaries, and the 5 and 3 flanking regions of PRKAA2 to identify single nucleotide polymorphisms (SNPs), and we genotyped 192 type 2 diabetic patients and 272 nondiabetic subjects to assess possible associations between genotypes or haplotypes and type 2 diabetes. None of the 10 SNPs genotyped was associated with type 2 diabetes, but the haplotype analysis, consisting of six representative SNPs, revealed one haplotype, with the A (minor) allele for rs2051040 and a major allele for the other five SNPs, to be associated with type 2 diabetes (P ‫؍‬ 0.009). This finding was confirmed in two larger replication samples (657 case and 360 control subjects, P ‫؍‬ 0.021; and 356 case and 192 control subjects from the same area in Japan, P ‫؍‬ 0.007) and a significant P value was obtained in the joint haplotype analysis of all samples (1,205 case and 824 control subjects, P ‫؍‬ 0.0001). Furthermore, insulin resistance was associated with rs2051040 in nondiabetic subjects, and those with the A (minor) allele had a higher homeostasis model assessment of insulin resistance index than those who did not (initial control subjects [n ‫؍‬ 272], P ‫؍‬ 0.002; and joint replication control subjects [n ‫؍‬ 552], P ‫؍‬ 0.037). We speculate that the PRKAA2 gene influences insulin resistance and susceptibility to type 2 diabetes in the Japanese population. Diabetes 55:919 -923, 2006 I nsulin resistance has been well demonstrated to be a fundamental element in the etiology of type 2 diabetes. The molecular mechanisms and genetic factors involved in insulin resistance have been extensively investigated. AMP-activated protein kinase (AMPK) is an enzyme that is activated by physiological and pharmacological stimuli, including muscle contraction (1), the antidiabetic agent metformin (2), and adipokines, such as leptin (3) or adiponectin (4). It is a heterotrimeric protein composed of a catalytic subunit (␣) and two regulatory subunits (␤ and ␥). The catalytic subunit ␣ has two isoforms (␣1 and ␣2), and while the ␣1 subunit isoform is ubiquitously expressed, the ␣2 subunit isoform, PRKAA2, is predominantly found in skeletal muscle and liver. Activation of AMPK in skeletal muscle leads to increased glucose uptake and enhanced insulin sensitivity (5), whereas in the liver AMPK activation inhibits glucose production (6). These characteristics of AMPK make this enzyme one of the key regulators of insulin sensitivity and glucose homeostasis. While AMPK␣1 Ϫ/Ϫ mice have no apparent metabolic defects, AMPK␣2Ϫ/Ϫ mice exhibit insulin resistance (7). Moreover, PRKAA2 is located on 1p36-32 (8), which is reportedly linked to type 2 diabetes in the Japanese popu...

Associations of variations in the MRF2/ARID5B gene with susceptibility to type 2 diabetes in the Japanese population

“…The individuals in control group 2 were recruited from those undergoing routine health check-ups at the Hiroshima Atomic Bomb Casualty Council Health Management Center (Hiroshima, Japan) on the basis of: (1)450 years of old, (2) with hemoglobin A1c (HbA1c) values o6.2% and (3) having no family histories of T2D in the first-or second-degree relatives. 16,17 The above criteria were chosen to detect differences between patients and the community-based health subjects with the aim of enhancing the power of the analyses. All participants were of full Japanese ethnicity.…”

AMP-Activated Protein Kinase in the Heart

“…Case-control studies suggested an association between polymorphisms in the ␣2 subunit gene (PRKAA2) and glucose tolerance and blood cholesterol levels. 32,33 Whether these polymorphisms alter AMPK activities, or indicate the consequences of another gene, is unclear. In contrast, Mendelian disorders have been characterized that reflect mutations only in the ␥2 subunit gene (PRKAG2).…”

Role of AMP-activated protein kinase gamma 3 genetic variability in glucose and lipid metabolism in non-diabetic whites

“…While large-scale testing and haplotype analysis of the genes encoding protein kinase, AMP-activated, alpha 2 non-catalytic subunit (PRKAA2), protein kinase, AMP-activated, beta 1 non-catalytic subunit (PRKAB1) and protein kinase, AMPactivated, beta 2 non-catalytic subunit (PRKAB2) did not reveal any significant association with type 2 diabetes or insulin sensitivity in a Canadian and Scandinavian population [12], PRKAA2 variance was shown to correlate with insulin resistance and susceptibility to type 2 diabetes in a Japanese study [13] and with serum lipids in healthy white women [14]. In a Chinese population, two polymorphisms in the protein kinase, AMP-activated, gamma 2 noncatalytic subunit gene (PRKAG2) were associated with higher concentrations of serum triacylglycerol and total cholesterol, with risk of type 2 diabetes tending to be higher in single nucleotide polymorphism (SNP) carriers [15].…”