Figure 4. Genetic architecture of rare, low frequency, and common variants associated with FI levels.

In this plot, the absolute values of the percent change in fasting insulin level due to rare monogenic mutations (diamonds) and common genetic variants (circles) are plotted against the minor allele frequency of the variant. The extremely rare monogenic mutations (above the dashed line to the left of the x axis) were observed in 2 to 18 individuals (3; 37–40; 47; 53; 54) with the height of the point indicating the percent change in fasting insulin levels of mutation carriers from 40 pmol/L, an estimate of population mean fasting insulin level. Mutations in INSR and AKT2 p.Arg274His cause compensatory hyperinsulinemia, individuals with TBC1D4 p.Arg363Ter show normal fasting insulin levels but postprandial hyperinsulinemia, and mutations in PTEN cause enhanced insulin sensitivity providing protection against type 2 diabetes. For common variants, the percent change in fasting insulin levels per insulin-increasing allele is plotted above the solid horizontal axis. These observations are from sequencing (6) and array-based GWAS (3). For several genes, the effects from rare mutations can be compared to the effects of common variants in or near the gene: PPARG (blue), TBC1D4 (green), PTEN (orange), and AKT2 (red). ^a Donohue syndrome: Biallelic loss-of-function mutations in INSR (54). ^b Rabson-Mendenhall syndrome: Biallelic loss-of-function mutations in INSR (54). ^c Post-pubertal severe IR: Heterozygous or homozygous loss-of-function mutations in INSR (54). ^d Loss of function PTEN mutations cause Cowden Syndrome in which carriers exhibit a lowered fasting insulin level (mean=29 pmol/l) compared to matched controls (3). ^e Carriers with the AKT2 p.Glu17Lys mutation were described with hypoinsulinemic hypoketotic hypoglycemia and hemihypertrophy with undetectable serum insulin (37; 38).