In a patient with serum insulin consisting predominantly of an abnormal form that elutes before normal insulin as well as a small amount of normal insulin (616214), Shoelson et al. (1983) concluded that the insulin variant had a substitution of serine for phenylalanine at position 24 of the B chain. The authors designated the variant 'insulin Los Angeles.'
In a patient with mild diabetes, marked fasting hyperinsulinemia, and a reduced fasting C-peptide:insulin molar ratio, Haneda et al. (1983, 1984) found that one insulin gene had a point mutation at position 24 of the B chain resulting in substitution of serine for phenylalanine. The patient had abnormal circulating insulin molecules that could be distinguished from each other and from normal insulin. The patient responded normally to exogenous insulin. Five additional family members of both sexes in 3 generations were affected.
Hua et al. (1993) pointed out that among vertebrate insulins phe(B24) is invariant, and in crystal structures the aromatic ring appears to anchor the putative receptor-binding surface through long-range packing interactions in the hydrophobic core. In 1 analog, namely, gly(B24)-insulin, partial unfolding of the B chain has been observed with paradoxical retention of near-native bioactivity. Hua et al. (1993) demonstrated that, contrariwise, in ser(B24)-insulin, near-native structure is restored despite significant loss of function. To their knowledge, this was the first structural study of a diabetes-associated mutant insulin and the findings supported the hypothesis that insulin undergoes a change in conformation on receptor binding.
