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Three mutant insulins in man.

S Shoelson, M Haneda, P Blix

    Nature
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    Researchers identified a unique insulin variant in patients with diabetes and insulin resistance. This abnormal insulin, [LeuB25]insulin, causes hyperglycemia despite normal insulin tolerance, indicating a new understanding of diabetes mellitus.

    Area of Science:

    • Biochemistry
    • Endocrinology
    • Genetics

    Background:

    • Structurally abnormal insulin variants can cause diabetes mellitus.
    • Previous identification of a patient with a specific insulin B chain substitution (leucine for phenylalanine at position 24 or 25) and associated diabetes.

    Purpose of the Study:

    • To identify and characterize insulin variants in patients presenting with hyperglycemia, hyperinsulinemia, and normal exogenous insulin tolerance.
    • To develop a reliable method for isolating and identifying insulin variants from human serum.

    Main Methods:

    • High-Performance Liquid Chromatography (HPLC) combined with radioimmunoassay for insulin variant isolation and identification.
    • Analysis of patient leukocyte DNA to identify genetic mutations in the insulin gene.

    Related Experiment Videos

    Main Results:

    • Three unrelated patients with diabetes mellitus, hyperinsulinemia, and normal insulin tolerance were identified.
    • All three patients were found to secrete structurally variant and chemically distinct insulins.
    • One identified insulin variant is [LeuB25]insulin, resulting from a leucine for phenylalanine substitution in the B chain.

    Conclusions:

    • The study confirms the existence of abnormal insulin variants causing diabetes mellitus.
    • A novel HPLC-radioimmunoassay method effectively identifies insulin variants in patient serum.
    • Identification of [LeuB25]insulin provides insight into the pathophysiology of specific diabetes mellitus cases.