Effects of insulin on the metabolic control of hepatic gluconeogenesis in vivo.
OBJECTIVE
Insulin represses the expression of gluconeogenic genes at the mRNA level, but the hormone appears to have only weak inhibitory effects in vivo. The aims of this study were 1) to determine the maximal physiologic effect of insulin, 2) to determine the relative importance of its effects on gluconeogenic regulatory sites, and 3) to correlate those changes with alterations at the cellular level.


METHODS
Conscious 60-h fasted canines were studied at three insulin levels (near basal, 4x, or 16x) during a 5-h euglycemic clamp. Pancreatic hormones were controlled using somatostatin with portal insulin and glucagon infusions. Glucose metabolism was assessed using the arteriovenous difference technique, and molecular signals were assessed.


RESULTS
Insulin reduced gluconeogenic flux to glucose-6-phosphate (G6P) but only at the near-maximal physiological level (16x basal). The effect was modest compared with its inhibitory effect on net hepatic glycogenolysis, occurred within 30 min, and was associated with a marked decrease in hepatic fat oxidation, increased liver fructose 2,6-bisphosphate level, and reductions in lactate, glycerol, and amino acid extraction. No further diminution in gluconeogenic flux to G6P occurred over the remaining 4.5 h of the study, despite a marked decrease in PEPCK content, suggesting poor control strength for this enzyme in gluconeogenic regulation in canines.


CONCLUSIONS
Gluconeogenic flux can be rapidly inhibited by high insulin levels in canines. Initially decreased hepatic lactate extraction is important, and later reduced gluconeogenic precursor availability plays a role. Changes in PEPCK appear to have little or no acute effect on gluconeogenic flux.
Edgerton
Dale S
DS
Vanderbilt University Medical Center, Nashville, Tennessee, USA. dale.edgerton@vanderbilt.edu
Ramnanan
Christopher J
CJ
Grueter
Carrie A
CA
Johnson
Kathryn M S
KM
Lautz
Margaret
M
Neal
Doss W
DW
Williams
Phillip E
PE
Cherrington
Alan D
AD
D000704:Analysis of Variance; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001706:Biopsy; D001786:Blood Glucose / Q000378:metabolism; D004285:Dogs; D005215:Fasting; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005260:Female; D005934:Glucagon / Q000378:metabolism; D005943:Gluconeogenesis / Q000502:physiology; D005947:Glucose / Q000008:administration & dosage / Q000378:metabolism; D015309:Glucose Clamp Technique; D007328:Insulin / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D019344:Lactic Acid / Q000097:blood / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D014851:Wakefulness
D015415:Biomarkers; D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D019344:Lactic Acid; D005934:Glucagon; D005947:Glucose