Background: The present analyses were conducted to examine the extent to which insulin sensitivity and insulin secretion, assessed using simple indices derived from an oral glucose tolerance test, are influenced by genetic factors, and to assess whether these genetic factors overlap with those influencing susceptibility to type 2 diabetes in Pima Indians.
Methods: Indices calculated from fasting and 2-h post-load insulin (I(0), I(120)) and glucose (G(0), G(120)) concentrations included insulin sensitivity index [ISI(0)=10(4)/(I(0).G(0))] and corrected insulin response [CIR(120)=I(120)/[G(120).(G(120)-70 mg/dl)]]. Heritability (h(2)) was determined using variance components methods in 1421 non-diabetic individuals from 446 sibships. Among 595 individuals in 186 sibships, genome-wide quantitative trait linkage analyses of ISI(0) and CIR(120) were conducted and affected-sibling analyses of diabetic siblings stratified by prediabetic measurements of ISI(0) and CIR(120) were also performed.
Results: Both ISI(0) (h(2)=0.37+/-0.06) and CIR(120) (h(2)=0.25+/-0.07) were moderately heritable. Modest evidence for linkage with CIR(120) (logarithm of odds (LOD)=1.6) was observed on chromosome 1q in a region previously shown to have linkage with young-onset diabetes in Pimas. When diabetic siblings were stratified by CIR(120), evidence for linkage in this region was strongest (LOD=1.5) among those with a low CIR(120). Additional regions with modest evidence for linkage with ISI(0) were observed on chromosomes 9p (LOD=2.0) and 14p (LOD=1.7).
Conclusions: The present analyses suggest that insulin sensitivity and insulin secretion are influenced by genetic factors in Pima Indians. The linkage analyses suggest that the putative diabetes-susceptibility gene on chromosome 1q affects insulin secretion. Published in 2001 by John Wiley & Sons, Ltd.