Family and genetic studies of indices of insulin sensitivity and insulin secretion in Pima Indians

Background The present analyses were conducted to examine the extent to whi ch insulin sensitivity and insulin secretion, assessed using simple indices derived from an oral glucose tolerance test, are influenced by genetic fac tors, and to assess whether these genetic factors overlap with those influe ncing susceptibility to type 2 diabetes in Pima Indians. Methods Indices calculated from fasting and 2-h post-load insulin (I-0, I-1 20) and glucose (G(0), G(120)) concentrations included insulin sensitivity index [ISI0 = 10(4)/(I-0.G(0))] and corrected insulin response {CIR120=I-12 0/[G(120).(G(120)-70mg/dl)]}. Heritability (h(2)) was determined using vari ance components methods in 1421 non-diabetic individuals from 446 sibships. Among 595 individuals in 186 sibships, genome-wide quantitative trait link age analyses of ISI0 and CIR120 were conducted and affected-sibling analyse s of diabetic siblings stratified by prediabetic measurements of ISI0 and C IR120 were also performed. Results Both ISI0 (h(2) = 0.37 +/-0.06) and CIR120 (h(2) = 0.25 +/-0.07) we re moderately heritable. Modest evidence for linkage with CIR120 (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 sib lings were stratified by CIR120, evidence for linkage in this region was st rongest (LOD = 1.5) among those with a low CIR120. Additional regions with modest evidence for linkage with ISI0 were observed on chromosomes 9p (LOD = 2.0) and 14p (LOD = 1.7). Conclusions The present analyses suggest that insulin sensitivity and insul in secretion are influenced by genetic factors in Pima Indians. The linkage analyses suggest that the putative diabetes-susceptibility gene on chromos ome Iq affects insulin secretion. Published in 2001 by John Wiley & Sons, L td.