INSULIN-RESPONSE TO AN INTRAVENOUS GLUCOSE-LOAD DURING DEVELOPMENT OFOBESITY IN GOLD THIOGLUCOSE-INJECTED MICE

The insulin secretory response to an intravenous glucose load was exam ined in chronically catheterized, conscious mice 2, 5, and 10 wk after induction of obesity by a single injection of gold thioglucose. At 2 wk after administration of gold thioglucose, a significant increase in both the insulinemia and incremental area under the curve of insulin release after intravenous glucose were observed (incremental area unde r the curve for 2-wk control mice, 852 +/- 54 min/pM; incremental area under the curve for 2-wk GTG-injected mice, 1140 +/- 114 min/pM; P < 0.05). At this stage, no significant difference existed in the glucose tolerance or body weight of control and gold thioglucose-injected mic e. By 5 wk, the gold thioglucose-injected mice were approximately 33% heavier than their lean controls and showed a marked glucose intoleran ce. This was accompanied by overt hyperinsulinemia in both the basal s tate and also in response to an intravenous glucose bolus as indicated by the increase in the incremental area under the curve of insulin (5 -wk control mice, 816 +/- 114 min/pM; 5-wk gold thioglucose-injected m ice, 1374 +/- 156 min/pM; P < 0.05). At 10 wk after gold thioglucose a dministration, body weight and the degree of glucose intolerance were increased. Although 10-wk gold thioglucose-injected mice showed basal hyperinsulinemia, an intravenous glucose bolus elicited a smaller insu lin secretory response than that observed in the age-matched lean cont rol animals (10-wk control mice, 672 +/- 54 min/pM; 10-wk gold-thioglu cose-injected mice 186 +/- 42 min/pM; P < 0.05). Thus, during the earl y stages of gold thioglucose-induced obesity, a marked increase in ins ulin secretion in response to an intravenous glucose load occurs, but as the animals become chronically hyperinsulinemic and hyperglycemic, the insulin secretory response to intravenous glucose decreases, possi bly indicating glucose toxicity of the pancreas. The increase in insul in secretion observed in 2-wk gold thioglucose-injected animals may be an important abnormality in the initiation of obesity responsible for the onset of the hyperlipogenesis and insulin resistance in this anim al model.