A NEW METHOD FOR COMPARING PORTAL AND PERIPHERAL VENOUS INSULIN DELIVERY IN HUMANS - TOLBUTAMIDE VERSUS INSULIN INFUSION

We describe a new noninvasive method for comparing insulin secreted ac utely by the pancreas us. a matched peripheral venous insulin infusion in humans. An intravenous tolbutamide infusion algorithm was develope d that produced sustained steady rates of portal insulin secretion ove r 5 h in 11 healthy young men. Plasma glucose levels were maintained i n the euglycemic range by adjusting the rate of an iv dextrose (20%) i nfusion. The pancreatic insulin secretory rate was calculated from per ipheral C-peptide levels by deconvolution using standard parameters fo r a two-compartment mathematical model for C-peptide distribution and metabolism. On a subsequent occasion in the same subject, exogenous in sulin was infused peripherally at a rate that matched the earlier tolb utamide-induced pancreatic insulin secretory rate, and euglycemia was maintained with a variable 20% dextrose infusion. The assumption that tolbutamide, when used in this fashion, has no independeninsulin-like or insulin-potentiating effect at either low or high levels of periphe ral insulinemia, does not affect insulin clearance, and does not suppr ess peripheral glucagon levels was validated in four patients with ins ulin-dependent diabetes mellitus. Mean peripheral immunoreactive insul in was significantly higher in the insulin infusion study than in the tolbutamide study (286 +/- 31 vs. 156 +/- 21 pmol/L; P = 0.0001). The dextrose infusion rates required to maintain euglycemia were also high er in the insulin infusion study (0.44 +/- 0.03 vs. 0.32 +/- 0.03 mmol /kg.min; P = 0.003). The MCR of insulin was greater in the tolbutamide infusion us. the exogenous insulin infusion study (32.6 +/- 2.9 vs. 1 9.8 +/- 2.2 ml/kg.min; P = 0.0003), probably due to the hepatic first pass effect on insulin clearance when insulin is delivered by the port al route. This noninvasive method can be used in future studies to exa mine the relative importance of direct hepatic us, peripheral effects of insulin in controlling hepatic glucose and lipid production.