title: Familiality of metabolic abnormalities is dependent on age at onset and phenotype of the type 2 diabetic proband.
abstract: To determine the impact of a family history of the common form of type 2 diabetes and the phenotype of the proband on anthropometric and metabolic variables in normoglycemic first-degree relatives, we studied 2,100 first-degree relatives of patients with the common form of type 2 diabetes (FH+) and 388 subjects without a family history of diabetes (FH-). All subjects participated in an oral glucose tolerance test to allow measurement of insulin secretion [30-min incremental insulin/glucose (I/G 30)] and insulin sensitivity [homeostasis model assessment (HOMA) of insulin resistance (IR)]. A subset participated in a euglycemic clamp (n = 75) and an intravenous glucose tolerance test (n = 300). To study the effect of a particular phenotype of the proband, insulin secretion and sensitivity were also compared between first-degree relatives of diabetic probands with high and low waist-to-hip ratio (WHR) and probands with early and late onset of diabetes. FH+ subjects were more insulin resistant, as seen from a higher HOMA-IR index (P = 0.006) and a lower rate of insulin-stimulated glucose uptake (P = 0.001) and had more features of the metabolic syndrome (P = 0.02, P = 0.0002) compared with FH- subjects. Insulin secretion adjusted for insulin resistance (disposition index, DI) was also lower in the FH+ vs. FH- subjects (P = 0.04). Relatives of diabetic probands with a high WHR had reduced insulin-mediated glucose uptake compared with relatives of probands with a low WHR (P = 0.04). Relatives of diabetic patients with age at onset <44 yr had higher HOMA IR (P < 0.005) and lower DI (P < 0.005) than relatives of patients with age at onset >65 yr (highest quartile). We conclude that early age at onset of type 2 diabetes and abdominal obesity have a significant influence on the metabolic phenotype in the nondiabetic first-degree relative.
authors.affiliation: Wallenberg Laboratory, Department of Endocrinology, Lund University, S-20502 Malmo, Sweden.
authors.forename: D
authors.initials: D
authors.lastname: Tripathy
authors.forename: E
authors.initials: E
authors.lastname: Lindholm
authors.forename: B
authors.initials: B
authors.lastname: Isomaa
authors.forename: C
authors.initials: C
authors.lastname: Saloranta
authors.forename: T
authors.initials: T
authors.lastname: Tuomi
authors.forename: L
authors.initials: L
authors.lastname: Groop
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D015992:Body Mass Index; D015897:Comorbidity; D003920:Diabetes Mellitus / Q000453:epidemiology / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology* / Q000235:genetics*; D005260:Female; D005387:Finland / Q000453:epidemiology; D020022:Genetic Predisposition to Disease / Q000453:epidemiology* / Q000235:genetics*; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D008297:Male; D024821:Metabolic Syndrome / Q000453:epidemiology* / Q000235:genetics*; D008875:Middle Aged; D009765:Obesity; D010641:Phenotype; D013548:Sweden / Q000453:epidemiology