Counterregulatory response to hypoglycemia differs according to the insulin delivery route, but does not affect glucose production in normal humans

The magnitude of the counterregulatory response to insulin-induced hypoglyc emia is primarily determined by the degree of hypoglycemia. We examined whe ther the route of acute insulin delivery (portal or peripheral venous) is a lso important in determining the magnitude of the counterregulatory respons e to hypoglycemia in nine healthy nondiabetic men. Pancreatic insulin secre tion, stimulated by an iv tolbutamide infusion (portal insulin study), was matched with an exogenous insulin infusion into the peripheral vein 4-6 wee ks later (peripheral insulin study). Each study consisted of a 150-min base line tracer equilibration period, a 180-min euglycemic hyperinsulinemic (po rtal or peripheral insulin delivery) period, a 60-min hypoglycemic period i n which insulin secretion diminished during tolbutamide or was reduced duri ng exogenous insulin, and a 30-min recovery period. Peripheral venous gluco se concentrations were well matched in the portal and peripheral studies du ring euglycemia and hypoglycemia (glucose nadir, 2.9 +/- 0.1 mmol/L in the portal and 2.7 +/- 0.1 mmol/L in the peripheral; mean +/- SEM; P = NS), and insulin concentrations were about 1.5-fold higher throughout the experimen t in the peripheral us. the portal insulin study due to the first pass extr action of insulin in the portal study. There was a much greater increment ( P < 0.0001) in FFA in the portal vs. the peripheral study (area under the c urve: portal, 19.5 +/- 3.9 mmol/L.90 min; peripheral, 3.3 +/- 11 mmol/L.90 min), whereas plasma glucagon and GH were higher in the peripheral study (P = 0.01 for glucagon; P = 0.015 for GH). There was no significant differenc e between studies in epinephrine and norepinephrine responses to hypoglycem ia or stimulation of endogenous glucose production (area under the curve: p ortal, 636 +/- 103 mu mol/kg.90 min; peripheral, 705 +/- 69 mu mol/kg.90 mi n; P = NS). In summary, we have shown that the glucagon, GH, and FFA respon ses to hypoglycemia during insulin dissipation are affected by the route of insulin delivery and are not controlled exclusively by the nadir blood glu cose level. The clinical importance of these observations in diabetic subje cts as they relate to route of insulin delivery (portal or peripheral) duri ng insulin dissipation remains to be determined.