Endocrinology, Vol 132, 1671-1676, Copyright © 1993 by Endocrine Society

ARTICLES

The stimulatory effect of insulin on diacylglycerol generation in adipocyte membranes from ob/ob mice is impaired by growth hormone

R Towns, JL Kostyo, D Martin, SY Chou and MR Bennink
Department of Physiology, University of Michigan, Ann Arbor 48109.

Physiologically, the action of insulin on carbohydrate and lipid metabolism is opposed by several hormones, including glucocorticoids, glucagon, catecholamines, and pituitary GH. Perhaps least is known about the mechanism(s) involved in the antiinsulin action of GH. Since the generation of diacylglycerol (DAG) appears to be an early event in the insulin-signaling cascade, it was of interest to determine whether GH would interfere with this effect of insulin. Experiments were conducted to determine whether insulin would stimulate the generation of DAG in adipocytes of the obese (ob/ob) mouse, and whether this response could be blocked by the diabetogenic GH derivative S- carboxymethylated human GH (RCM-hGH). Isolated adipocytes of the ob/ob mouse were used for these studies, because unlike normal rodents, the ob/ob mouse responds predictably to the antiinsulin action of GH. Insulin produced a rapid biphasic increase in the amount of DAG in a crude membrane fraction of the adipocytes. The first peak in DAG mass occurred within 5 min of exposure of the cells to insulin, and the second peak occurred after 30 min. The first peak in DAG mass did not occur in adipocytes that had been incubated with pertussis toxin before exposure to insulin. Also, adipocytes isolated from ob/ob mice that had been treated with RCM-hGH failed to respond to insulin with an increase in DAG mass. RCM-hGH blocked both the first and second insulin-induced peaks in DAG mass within 6 h of its administration. This is the time at which ob/ob mouse adipocytes exhibit increased insulin resistance in response to RCM-hGH. Neither exposure to insulin nor treatment with RCM- hGH had any appreciable effect on the fatty acid composition of the DAG present in the adipocyte membranes. These findings are compatible with the idea that GH produces some defect in the insulin-signaling cascade that is proximal to the events that result in the generation of DAG in the adipocyte.