Patients with Type 2 (non-insulin-dependent) diabetes mellitus and a strong family history of the disease may represent a sub-group where genetic factors play a preeminent role in transmission of the disease. A defect in the liver/islet cell glucose transporter (GluT 2) could explain many of the pathophysiological features of the disease. In order to test the hypothesis that genetic variation at the GluT 2 locus contributes genetic susceptibility to Type 2 diabetes, 60 unrelated Caucasian diabetic patients with at least one affected sibling were genotyped for a Taq 1 restriction fragment length polymorphism marker. Hybridisation with a cDNA GluT 2 probe identified two alleles of sizes 13 kilobase (T1) and 19 kilobase (T2). The allele frequencies in the diabetic group with a family history were significantly different from those in a racially-matched control population of 122 subjects with no personal or family history of the disease (diabetic patients T1 = 0.96, T2 = 0.04, control subjects T1 = 0.89, T2 = 0.11, p less than 0.03). However, when the study was repeated with 54 diabetic patients with indeterminate family history, statistical significance was not reached although the allele frequencies showed a similar trend. The findings of this study support the hypothesis that a genetic variant of the liver/islet cell glucose transporter may contribute to familial susceptibility in Type 2 diabetes.