Insulin inhibits glucose production by a direct effect in diabetic depancreatized dogs during euglycemia.
In our previous studies in nondiabetic dogs and humans, insulin suppressed glucose production (GP) by both an indirect extrahepatic and a direct hepatic effect. However, insulin had no direct effect on GP in diabetic depancreatized dogs under conditions of moderate hyperglycemia. The present study was designed to investigate whether insulin can inhibit GP by a direct effect in this model under conditions of euglycemia. Depancreatized dogs were made euglycemic (approximately 6 mmol/l), rather than moderately hyperglycemic (approximately 10 mmol/l) as in our previous studies, by basal portal insulin infusion. After approximately 100 min of euglycemia, a hyperinsulinemic euglycemic clamp was performed by giving an additional infusion of insulin either portally (POR) or peripherally at about one-half the rate (1/2 PER) to match the peripheral venous insulin concentrations. The greater hepatic insulin load in POR resulted in greater suppression of GP (from 16.5 +/- 1.8 to 12.2 +/- 1.6 micromol. kg(-1). min(-1)) than 1/2 PER (from 17.8 +/- 1.9 to 15.6 +/- 2.0 micromol. kg(-1). min(-1), P < 0.001 vs. POR), consistent with insulin having a direct hepatic effect in suppressing GP. We conclude that the direct effect of insulin to inhibit GP is present in diabetic depancreatized dogs under conditions of acutely induced euglycemia. These results suggest that, in diabetes, the prevailing glycemic level is a determinant of the balance between insulin's direct and indirect effects on GP.
Gupta
Neehar
N
Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Sandhu
Harmanjit
H
Goh
Tracy
T
Shah
Keyur
K
Wiesenthal
Stephanie R
SR
Yoshii
Hidenori
H
Chong
Victor
V
Lam
Tony K T
TK
Haber
C Andrew
CA
Williams
Wendy
W
Tchipashvili
Vaja
V
Giacca
Adria
A
D000818:Animals; D001786:Blood Glucose / Q000096:biosynthesis*; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000378:metabolism*; D004285:Dogs; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D015309:Glucose Clamp Technique; D006943:Hyperglycemia / Q000188:drug therapy / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010179:Pancreas / Q000601:surgery
D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D007328:Insulin