Adaptation of Insulin Clearance to Metabolic Demand is a Key Determinant of Glucose Tolerance

With the development of insulin resistance (IR), there is a compensatory increase in the plasma insulin response to offset the defect in insulin action in order to maintain normal glucose tolerance. The insulin response is the result of two factors: insulin secretion and metabolic clearance rate of insulin (MCR_I).

T2DM subjects (104 NGT, 57 IGT, and 207), divided in non-obese and obese groups, received a euglycemic insulin-clamp (40 mU/m².min) and OGTT (75-grams) on separate days. MCR_I was calculated during the insulin-clamp performed with 3-3H-glucose and the OGTT and related to IR: peripheral (glucose uptake during insulin clamp), hepatic (basal EGPxFPI), and adipocyte (fasting FFAxFPI).

MCR_I during the insulin-clamp was reduced in obese versus non-obese NGT (0.60±0.03 vs 0.73±0.02 L/min.m², p<0.001), in non-obese IGT (0.62±0.02, p<0.004) and in non-obese T2DM (0.68±0.02, p<0.03). The MCR_I during the insulin-clamp was strongly and inversely correlated with IR (r=-0.52, p<0.0001). During OGTT the MCR_I suppressed within 15-30 minutes in NGT and IGT subjects and remained suppressed. In contrast, there was minimal suppression in T2DM.

In conclusion, the development of IR in obese subjects is associated with decline in MCR_I that represents a compensatory response to maintain normal glucose tolerance but is impaired in T2DM individuals.