CHROMOSOMAL MAPPING AND MUTATIONAL ANALYSIS OF THE CODING REGION OF THE GLYCOGEN-SYNTHASE-KINASE-3-ALPHA AND BETA-ISOFORMS IN PATIENTS WITHNIDDM

Activation of glycogen synthesis in skeletal muscle in response to ins ulin results from the combined inactivation of glycogen synthase kinas e-3 (GSK-3) and activation of the protein phosphatase-1, changing the ratio between the inactive phosphorylated state of the glycogen syntha se to the active dephosphorylated state. In a search for genetic defec ts responsible for the decreased insulin stimulated glycogen synthesis seen in patients with non-insulin-dependent diabetes mellitus (NIDDM) and their glucose-tolerant first-degree relatives we have performed m utational analysis of the coding region of the 2 isoforms of GSK-3 alp ha and GSK-3 beta in 72 NIDDM patients and 12 control subjects. No str uctural changes were detected apart from a few silent mutations. Mappi ng of the GSK-3 alpha to chromosome 19q13.1-13.2 and the GSK-3 beta to chromosome 3q13.3-q21 outside known genetic loci linked to NIDDM furt her makes it unlikely that these genes are involved in the pathogenesi s of common forms of NIDDM.