METABOLIC CONSEQUENCES OF A FAMILY HISTORY OF NIDDM (THE BOTNIA STUDY) - EVIDENCE FOR SEX-SPECIFIC PARENTAL EFFECTS

Although a strong genetic susceptibility has been established for NIDD M and a maternal transmission of the disease predominates in some popu lations, a relationship between parental diabetes status and metabolic abnormalities in nondiabetic offspring has not been shown in humans. To address this question, we studied 2,152 first-degree relatives of p atients with NIDDM (FH+) and 528 age- and weight-matched spouses witho ut a family history of NIDDM (FH-) in Western Finland (the Botnia stud y). A subset of the subjects underwent a euglycemic insulin clamp comb ined with indirect calorimetry to measure insulin sensitivity and ener gy expenditure. Despite similar amounts of total body fat, persons wit h a family history of NIDDM had a greater waist-to-hip ratio (WHR) tha n spouses without a family history of diabetes (P < 0.003). They also had a decreased resting metabolic rate (P = 0.005), but this differenc e disappeared when adjusted for the difference in WHR. Insulin-stimula ted glucose metabolism (P = 0.002), particularly nonoxidative glucose metabolism (P = 0.009), was reduced in FH+ compared with FH- subjects, and this difference remained after adjustment for WHR. A parental his tory of NIDDM influenced the insulin response to the oral glucose load , with male offspring of diabetic mothers showing the lowest insulin v alues (P = 0.011). Moreover, a parental effect was also observed on HD L and HDL(2) cholesterol concentrations with female offspring of diabe tic mothers showing lower values than female offspring of diabetic fat hers (both P < 0.002). We conclude that abdominal obesity, insulin res istance, and decreased resting metabolic rate are characteristic featu res of first-degree relatives of patients with NIDDM and that the decr ease in resting metabolic rate is partially related to the degree of a bdominal obesity. A sex-specific paternal effect was observed on insul in and HDL cholesterol concentrations. Therefore, one has to consider the possibility of unprecedented maternal or paternal inheritance of d ifferent NIDDM phenotypes.