Apolipoprotein E (apo E), a component of VLDL, HDL and chylomicron remnants, is inherited at a single genetic locus with 3 common alleles (epsilon 2, epsilon 3 and epsilon 4). epsilon 2 homozygosity is found in 0-2% of healthy populations, but in 75-100% of subjects with type III hyperlipoproteinaemia, in whom an increased prevalence of glucose intolerance has previously been reported. The lipoprotein abnormality associated with diabetes mellitus has features in common with type III hyperlipoproteinaemia and both conditions lead to accelerated atherogenesis with a similar anatomical distribution. We have therefore examined the frequency of apo E genotypes in 120 subjects with insulin-treated diabetes mellitus (ITDM) and 107 healthy controls, and examined the effect of apo E polymorphism on lipoproteins in the diabetic group. As in the general population, the apo E phenotype in ITDM was a significant determinant of the total serum and LDL cholesterol concentrations which were lowest in patients possessing the epsilon 2 allele, intermediate in those homozygous for epsilon 3 and highest in those with an epsilon 4 allele. The observed gene frequencies of epsilon 2 (0.091), epsilon 3 (0.780) and epsilon 4 (0.130) were similar to those of the healthy control group and those in the general population. However, there was an unexpected increase (P less than 0.0002) in epsilon 2 homozygosity of 6.7% compared to a prevalence of 0.8% predicted both from the Hardy-Weinberg equilibrium and the 0.9% prevalence observed in the healthy control group. This suggests either that epsilon 2 homozygosity increases susceptibility to the development of ITDM or that the two conditions are genetically linked.(ABSTRACT TRUNCATED AT 250 WORDS)