ABNORMAL ACTIVATION OF GLYCOGEN-SYNTHESIS IN FIBROBLASTS FROM NIDDM SUBJECTS - EVIDENCE FOR AN ABNORMALITY SPECIFIC TO GLUCOSE-METABOLISM

To determine whether the tendency for NIDDM to run in families could relate to genetically determined defects in insulin stimulation of glycogen synthesis, skin fibroblasts from subjects with a strong family history of NIDDM were studied. Fibroblasts from nondiabetic subjects without any family history of NIDDM were studied as control subjects. The cells were studied after 7-16 passages in culture. Rates of glycogen synthesis were lower in fibroblasts from NIDDM subjects both basally and with maximal insulin stimulation (0.77 +/- 0.11 vs. 0.46 +/- 0.04 pmol . well-1 . h-1 [P < 0.02] and 1.49 +/- 0.26 vs. 0.69 +/- 0.05 pmol . well-1 . h-1 [P < 0.01]). Rates of glycogen synthesis were stimulated 1.9 +/- 0.24 old above basal in the control cells and 1.5 +/- 0.1-fold above basal in the NIDDM cells (P < 0.02). Rates of [H-3]thymidine uptake were similar in control and NIDDM fibroblasts (basal, 28.3 +/- 2.8 vs. 39.2 +/- 8.0; maximum, 50.9 +/- 7.2 vs. 69.3 +/- 16.9 dpm x 10(-3) , respectively). Rates of uptake increased similarly in control and NIDDM cells by 1.8 +/- 0.1- and 1.7 +/- 0.1-fold above basal. Maximum specific fibroblast insulin binding was similar for control and NIDDM subjects (194.0 +/- 29.2 vs. 176.1 24.9 fmol I-125-labeled insulin bound/mg protein respectively). The tyrosine kinase activity of insulin receptors isolated from the control and NIDDM fibroblasts was similar (basal, 135 +/- 30 vs. 149 +/- 33; submaximal, 153 +/- 28 vs. 155 +/- 30; and maximal insulin, 191 +/- 45 vs. 213 +/- 48 dpm - mg protein-1 . min-1). The observed abnormality was thus distal to the insulin receptor and did not involve all aspects of insulin signaling. These data provide evidence for a genetic influence on insulin control of glycogen synthesis in people with a strong family history of NIDDM.