title: Paradoxical insulin-induced increase in gluconeogenesis in response to prolonged hypoglycemia in conscious dogs.
abstract: The aim of this study was to determine the effects of differing insulin concentrations on the gluconeogenic response to equivalent prolonged hypoglycemia. Insulin was infused intraportally, for 3 h, into normal 18-h fasted conscious dogs at 2 (lower, n = 6) or 8 mU.kg-1.min-1 (high, n = 7) on separate occasions. This resulted in steady-state arterial insulin levels of 80 +/- 8 and 610 +/- 55 microU/ml, respectively. Glucose was infused during high dose to maintain the hypoglycemic plateau (50 +/- 1 mg/dl) equivalent to lower. Epinephrine (806 +/- 180 vs. 2,589 +/- 260 pg/ml), norepinephrine (303 +/- 55 vs. 535 +/- 60 pg/ml), cortisol (5.8 +/- 1.2 vs. 12.1 +/- 1.5 micrograms/dl), and pancreatic polypeptide (598 +/- 250 vs. 1,198 +/- 150 pg/ml) were all increased (P < 0.05) in the presence of high-dose insulin. Net hepatic glucose production increased significantly from 2.2 +/- 0.3 to 3.8 +/- 0.5 mg.kg-1.min-1 (P < 0.05) during high-dose infusion but remained at basal levels (2.3 +/- 0.4 mg.kg-1.min-1) during lower-dose insulin. During the 3rd h of hypoglycemia, gluconeogenesis accounted for between 42 and 100% of glucose production during high-dose infusion but only 22-52% during lower-dose insulin. Intrahepatic gluconeogenic efficiency, however, increased similarly during both protocols. Lipolysis, as indicated by arterial blood glycerol levels, increased by a greater amount during high- compared with lower-dose insulin infusion. Six hyperinsulinemic euglycemic control experiments (2 or 8 mU.kg-1.min-1, n = 3 in each) provided baseline data. Gluconeogenesis remained similar to basal levels, but lipolysis was significantly suppressed during both series of hyperinsulinemic euglycemic studies. In summary, these data suggest that 1) the important counterregulatory processes of gluconeogenesis and lipolysis can be significantly increased during prolonged hypoglycemia despite an eightfold increase in circulating insulin levels and 2) the amplified gluconeogenic rate present during the hypoglycemic high-dose insulin infusions was caused by enhanced substrate delivery to the liver rather than an increase in intrahepatic gluconeogenic efficiency.
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232.
authors.forename: S N
authors.initials: SN
authors.lastname: Davis
authors.forename: R
authors.initials: R
authors.lastname: Dobbins
authors.forename: C
authors.initials: C
authors.lastname: Tarumi
authors.forename: J
authors.initials: J
authors.lastname: Jacobs
authors.forename: D
authors.initials: D
authors.lastname: Neal
authors.forename: A D
authors.initials: AD
authors.lastname: Cherrington
mesh_terms: D000818:Animals; D001158:Arteries; D004285:Dogs; D004837:Epinephrine / Q000097:blood; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D005943:Gluconeogenesis / Q000187:drug effects*; D005947:Glucose / Q000008:administration & dosage; D005990:Glycerol / Q000097:blood; D006854:Hydrocortisone / Q000097:blood; D007003:Hypoglycemia / Q000378:metabolism*; D007328:Insulin / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D007657:Ketone Bodies / Q000097:blood; D007773:Lactates / Q000097:blood; D019344:Lactic Acid; D008066:Lipolysis / Q000187:drug effects; D008099:Liver / Q000098:blood supply / Q000378:metabolism; D008297:Male; D009638:Norepinephrine / Q000097:blood; D010191:Pancreatic Polypeptide / Q000097:blood
chemical_list: D005230:Fatty Acids, Nonesterified; D007328:Insulin; D007657:Ketone Bodies; D007773:Lactates; D019344:Lactic Acid; D010191:Pancreatic Polypeptide; D005947:Glucose; D005990:Glycerol; D006854:Hydrocortisone; D009638:Norepinephrine; D004837:Epinephrine