Molecular characterization of insulin-mediated suppression of hepatic glucose production in vivo.
OBJECTIVE
Insulin-mediated suppression of hepatic glucose production (HGP) is associated with sensitive intracellular signaling and molecular inhibition of gluconeogenic (GNG) enzyme mRNA expression. We determined, for the first time, the time course and relevance (to metabolic flux) of these molecular events during physiological hyperinsulinemia in vivo in a large animal model.


METHODS
24 h fasted dogs were infused with somatostatin, while insulin (basal or 8 x basal) and glucagon (basal) were replaced intraportally. Euglycemia was maintained and glucose metabolism was assessed using tracer, (2)H(2)O, and arterio-venous difference techniques. Studies were terminated at different time points to evaluate insulin signaling and enzyme regulation in the liver.


RESULTS
Hyperinsulinemia reduced HGP due to a rapid transition from net glycogen breakdown to synthesis, which was associated with an increase in glycogen synthase and a decrease in glycogen phosphorylase activity. Thirty minutes of hyperinsulinemia resulted in an increase in phospho-FOXO1, a decrease in GNG enzyme mRNA expression, an increase in F2,6P(2), a decrease in fat oxidation, and a transient decrease in net GNG flux. Net GNG flux was restored to basal by 4 h, despite a substantial reduction in PEPCK protein, as gluconeogenically-derived carbon was redirected from lactate efflux to glycogen deposition.


CONCLUSIONS
In response to acute physiologic hyperinsulinemia, 1) HGP is suppressed primarily through modulation of glycogen metabolism; 2) a transient reduction in net GNG flux occurs and is explained by increased glycolysis resulting from increased F2,6P(2) and decreased fat oxidation; and 3) net GNG flux is not ultimately inhibited by the rise in insulin, despite eventual reduction in PEPCK protein, supporting the concept that PEPCK has poor control strength over the gluconeogenic pathway in vivo.
Ramnanan
Christopher J
CJ
Department of Molecular Physiology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA. chris.ramnanan@vanderbilt.edu
Edgerton
Dale S
DS
Rivera
Noelia
N
Irimia-Dominguez
Jose
J
Farmer
Ben
B
Neal
Doss W
DW
Lautz
Margaret
M
Donahue
E Patrick
EP
Meyer
Catalina M
CM
Roach
Peter J
PJ
Cherrington
Alan D
AD
D020155:3-Hydroxybutyric Acid / Q000097:blood; D000596:Amino Acids / Q000097:blood; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D004285:Dogs; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D005934:Glucagon / Q000097:blood / Q000494:pharmacology*; D005943:Gluconeogenesis / Q000187:drug effects*; D006019:Glycolysis; D006400:Hematocrit; D006854:Hydrocortisone / Q000097:blood; D006946:Hyperinsulinism / Q000378:metabolism; D007328:Insulin / Q000097:blood* / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008112:Liver Glycogen / Q000378:metabolism; D008297:Male; D013004:Somatostatin / Q000494:pharmacology
D000596:Amino Acids; D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D008112:Liver Glycogen; D013004:Somatostatin; D005934:Glucagon; D020155:3-Hydroxybutyric Acid; D006854:Hydrocortisone