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Diabetes 52:1935-1942, 2003
© 2003 by the American Diabetes Association, Inc.

Insulin-Stimulated Protein Kinase C {lambda}/{zeta} Activity Is Reduced in Skeletal Muscle of Humans With Obesity and Type 2 Diabetes

Reversal With Weight Reduction

Young-Bum Kim1, Ko Kotani1, Theodore P. Ciaraldi2,3, Robert R. Henry2,3, and Barbara B. Kahn1

1 Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, Massachusetts
2 Veterans Affairs San Diego Healthcare System (9111G), San Diego, California
3 Department of Medicine, University of California, La Jolla, California

In humans with obesity or type 2 diabetes, insulin target tissues are resistant to many actions of insulin. The atypical protein kinase C (PKC) isoforms {lambda} and {zeta} are downstream of phosphatidylinositol-3 kinase (PI3K) and are required for maximal insulin stimulation of glucose uptake. Phosphoinositide-dependent protein kinase-1 (PDK-1), also downstream of PI3K, mediates activation of atypical PKC isoforms and Akt. To determine whether impaired PKC{lambda}/{zeta} or PDK-1 activation plays a role in the pathogenesis of insulin resistance, we measured the activities of PKC{lambda}/{zeta} and PDK-1 in vastus lateralis muscle of lean, obese, and obese/type 2 diabetic humans. Biopsies were taken after an overnight fast and after a 3-h hyperinsulinemic-euglycemic clamp. Obese subjects were also studied after weight loss on a very-low-calorie diet. Insulin-stimulated glucose disposal rate is reduced 26% in obese subjects and 62% in diabetic subjects (both comparisons P < 0.001). Insulin-stimulated insulin receptor substrate (IRS)-1 tyrosine phosphorylation and PI3K activity are impaired 40–50% in diabetic subjects compared with lean or obese subjects. Insulin stimulates PKC{lambda}/{zeta} activity ~2.3-fold in lean subjects; the increment above basal is reduced 57% in obese and 65% in diabetic subjects. PKC{lambda}/{zeta} protein amount is decreased 46% in diabetic subjects but is normal in obese nondiabetic subjects, indicating impaired insulin action on PKC{lambda}/{zeta}. Importantly, weight loss in obese subjects normalizes PKC{lambda}/{zeta} activation and increases IRS-1 phosphorylation and PI3K activity. Insulin also stimulates PDK-1 activity approximately twofold with no impairment in obese or diabetic subjects. In contrast to our previous data on Akt, reduced insulin-stimulated PKC{lambda}/{zeta} activity could play a role in the pathogenesis of insulin resistance in muscle of obese and type 2 diabetic subjects.

Address correspondence and reprint requests to Barbara B. Kahn, Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, 99 Brookline Ave., Boston, MA 02215. E-mail: bkahn{at}caregroup.harvard.edu


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