Evidence for an autosomal recessive gene regulating the persistence of the insulin response to glucose in man

The significance of genetic factors for insulin release after glucose infusion was studied in 155 nuclear families of which 59 were control families and 96 had been ascertained through a parent with onset of diabetes after 30 years of age. Fasting insulin and glucose as well as three principal components of the insulin and glucose curves were submitted to path analysis and complex segregation analysis. The three principal components were considered to reflect the magnitude, the degree of response and the persistence of the curves. The genetic heritability of the insulin variables varied between 0.47-0.93 and that of the glucose variables between 0.20-0.54. There were considerable intergenerational differences in the genetic heritability for the persistence of the glucose curve and for the degree of response and persistence of the insulin curve. The cultural heritability was found to be of minor importance, while the non-transmitted sibling environment was large. There was significant evidence for a major locus for the persistence of the insulin curve. The best fit was for a completely recessive autosomal gene with the gene frequency 0.21. The phenotype distribution of this variable showed significant kurtosis which could simulate a major locus. However, the significant evidence for such a locus remained after an analysis using partial quantitation. The diabetics were significantly different from the non-diabetics for all the variables studied, but a complete discrimination between the diabetics and non-diabetics could not be obtained. There was no significant difference between the children of the diabetics and non-diabetics for any of the variables studied.