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A 58-yr-old obese white Caucasian male type 2 diabetic, entered into the UK Prospective Diabetes Study, was found to have raised fasting total proinsulin levels 708 pmol/L−1 (normal range, 3–16 pmol/L−1) and normal specific plasma insulin level 29 pmol/L−1 (normal range, 21–75 pmol/L−1). Immunoreactive plasma insulin, measured by RIA, was 503 pmol/L−1. DNA was extracted, the insulin gene amplified by the PCR, and by direct sequencing, a novel point mutation, G1552C, was identified, which resulted in the substitution of proline (CCT) for arginine (CGT) at position 65. This prevented cleavage of the C-peptide A-chain dibasic cleavage site (lys-arg) by the processing protease in the pancreatic β-cells. The plasma proinsulin and insulin levels were in accord with expression of both the wild-type and the mutant alleles. The G1552C mutation was not linked with diabetes, because it was present in a 37-yr-old nondiabetic daughter and not in a 35-yr-old daughter who had had gestational diabetes.

A Novel Point Mutation in the Insulin Gene Giving Rise to Hyperproinsulinemia*