Insulin resistance in Pima Indians appears to result from a post-receptor impairment of
insulin signal transduction that affects only some responses to
insulin. To identify the primary lesion responsible for
insulin resistance, we investigated the influence of
insulin on
ribosomal protein S6 kinase activities in skeletal muscle of
insulin-sensitive and
insulin-resistant nondiabetic Pima Indians during a 2-h hyperinsulinemic, euglycemic clamp. In sensitive subjects,
S6 kinase activity was transiently activated fivefold over basal activity by 45 min of
insulin infusion. Although basal activities in the two groups were similar, the response to
insulin was delayed and restricted to about threefold over basal in subjects resistant to
insulin. Two major
S6 kinase activities in extracts of human muscle were resolved by chromatography on
Mono Q. Peak 1, which accounted for basal activity owes to an
enzyme antigenically related to the 90-kD
S6 kinase II, a member of the rsk gene family. The major
insulin-stimulated
S6 kinase eluted as peak 2 and is antigenically related to a 70-kD
S6 kinase. Our results show that
insulin resistance impairs signaling to the 70-kD
S6 kinase.