The finding of a reduced
insulin-stimulated
glucose uptake and
glycogen synthesis in the skeletal muscle of
glucose-tolerant first-degree relatives of patients with
NIDDM, as well as in cultured fibroblasts and skeletal muscle cells isolated from
NIDDM patients, has been interpreted as evidence for a genetic involvement in the disease. The mode of inheritance of the common forms of
NIDDM is as yet unclear, but the prevailing hypothesis supports a polygenic model. In the present study, we tested the hypothesis that the putative inheritable defects of
insulin-stimulated muscle
glycogen synthesis might be caused by genetic variability in the genes encoding
proteins shown by biochemical evidence to be involved in
insulin-stimulated
glycogen synthesis in skeletal muscle. In 70
insulin-resistant Danish
NIDDM patients, mutational analysis by reverse transcription-polymerase chain reaction-single strand conformation polymorphism-heteroduplex analysis was performed on genomic
DNA or skeletal muscle-derived cDNAs encoding
glycogenin,
protein phosphatase inhibitor-1, phophatase targeting to
glycogen,
protein kinase B-alpha and -beta, and the
phosphoinositide-dependent
protein kinase-1. Although a number of silent variants were identified in some of the examined genes, we found no evidence for the hypothesis that the defective
insulin-stimulated
glycogen synthesis in skeletal muscle in
NIDDM is caused by structural changes in the genes encoding the known components of the
insulin-sensitive
glycogen synthesis pathway of skeletal muscle.