Does the −11377 promoter variant of APM1 gene contribute to the genetic risk for Type 2 diabetes mellitus in Japanese families?

Excerpt

To the Editor: Although the physiopathological bases of Type 2 diabetes mellitus are well established, with an important role of generalized insulin resistance hitting key organs for glucose homeostasis—like muscle, liver and beta-cell—little is known about its molecular determinants and about the genetic factors involved in the transition between obesity and Type 2 diabetes. A considerable amount of evidence has suggested that a polymorphism in fat-expressed PPAR-γ, the major thiazolidinedione target, could contribute, even modestly, to the genetic risk for Type 2 diabetes [1]. In contrast, genome wide scans presented evidence of linkage between a region of chromosome 3q27, the metabolic syndrome and Type 2 diabetes in American and French Caucasian subjects [2], and also with coronary heart disease in Indo-Mauritians [3]. We recently replicated the linkage with diabetes in Japanese Type 2 diabetic families [4]. A strong positional candidate gene located on 3q27 is APM1, which encodes for the adipocyte complement related protein (Acrp30, also named adiponectin) which is specifically expressed in differentiated adipocytes. It was recently shown that its proteolytically-cleaved product (gAcrp30) lowers glucose concentrations through fatty acid oxidation without variations of insulin and glucagon concentrations, and prevents the development of high-fat diet induced obesity [5]. Furthermore, decreased expression of adiponectin correlates with insulin resistance in mouse models of obesity or lipoatrophy, and physiological doses of adiponectin decrease insulin resistance in these mice by lowering triglyceride content in muscle and liver [5]. In human, hypoadiponectinaemia was reported in obese and Type 2 diabetic subjects, and adiponectin concentrations are closely associated with insulin sensitivity in different ethnic groups [6]. We have recently shown that sequence variations in APM1 gene are associated with circulating adiponectin concentrations and modulate the risk for insulin resistance and diabetes in French Caucasians [7]. A previous study has also suggested a large heritability for plasma adiponectin concentrations in humans [8]. …