Family history of type 2 diabetes increases the risk of both obesity and its complications: is type 2 diabetes a disease of inappropriate lipid storage?

Abstract

The aim of this study was to characterize diabetes risk in relation to amount and distribution of body fat (environmental factors) and genetic risk defined as having first-degree (FH1) or second-degree relatives with diabetes. We analysed the METSIM population of 10197 middle-aged, randomly selected men. At baseline, information about family history of diabetes was registered and all individuals underwent extensive phenotyping. A follow-up study was conducted after 6years. The metabolic consequences of increased visceral versus subcutaneous fat were characterized in a separate cohort of 158 healthy men (the Kuopio Cohort of the EUGENE2 study). At baseline, individuals with a family history of diabetes (FH+) had approximately a twofold increase in the prevalence of type 2 diabetes compared with individuals without a family history of the disease (FH-) (18.0% vs. 9.9%; P=1.3× 10(-31) ). FH1 individuals were more commonly overweight and obese compared with FH- (69.2% vs. 64.8%; P=1.3×10(-4) ) and, for a given body mass index, showed an increased risk profile for both type 2 diabetes and cardiovascular disease as well as a greater susceptibility to the negative consequences of increased body fat also when nonobese. Subgroup analyses indicated that the metabolic consequences were due primarily to increased ectopic/visceral fat rather than subcutaneous fat. The increased risk profile in FH+ individuals was not altered by adjusting for 43 major diabetes risk genes. Family history of type 2 diabetes (particularly FH1) is associated with both increased risk of becoming overweight/obese and with a greater susceptibility to the negative consequences of increasing body fat, probably as a consequence of an increased propensity to accumulate ectopic (nonsubcutaneous) fat.