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?

J Intern Med. 2015 May;277(5):540-51. doi: 10.1111/joim.12289. Epub 2014 Aug 1.


Objectives: 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.

Design: We analysed the METSIM population of 10 197 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 6 years. 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).

Results: 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.

Conclusions: 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.

Keywords: diabetes; family history; genetics; insulin resistance; insulin secretion; obesity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Body Fat Distribution
  • Cross-Sectional Studies
  • Diabetes Mellitus, Type 2 / etiology*
  • Diabetes Mellitus, Type 2 / pathology
  • Humans
  • Insulin / metabolism
  • Insulin Resistance / physiology
  • Insulin Secretion
  • Intra-Abdominal Fat / pathology
  • Lipid Metabolism Disorders / etiology*
  • Lipid Metabolism Disorders / pathology
  • Male
  • Middle Aged
  • Obesity / etiology
  • Obesity / pathology
  • Overweight / etiology*
  • Overweight / pathology
  • Pedigree
  • Risk Factors
  • Subcutaneous Fat / pathology
  • Waist Circumference


  • Insulin