Molecular characterization of insulin-mediated suppression of hepatic glucose production in vivo

Christopher J. Ramnanan, Dale S. Edgerton, Noelia Rivera, Jose Irimia-Dominguez, Ben Farmer, Doss W. Neal, Margaret Lautz, E. Patrick Donahue, Catalina M. Meyer, Peter Roach, Alan D. Cherrington

Research output: Contribution to journalArticle

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Abstract

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. RESEARCH DESIGN AND METHODS - 24 h fasted dogs were infused with somatostatin, while insulin (basal or 8x basal) and glucagon (basal) were replaced intraportally. Euglycemia was maintained and glucose metabolism was assessed using tracer, 2H2O, 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 F2,6P2, 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 F2,6P2 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.

Original languageEnglish
Pages (from-to)1302-1311
Number of pages10
JournalDiabetes
Volume59
Issue number6
DOIs
StatePublished - Jun 2010

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Hyperinsulinism
Glycogen
Insulin
Glucose
Liver
Enzymes
Fats
Glycogen Phosphorylase
Glycogen Synthase
Messenger RNA
Glycolysis
Somatostatin
Glucagon
Lactic Acid
Proteins
Research Design
Carbon
Animal Models
Dogs

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Ramnanan, C. J., Edgerton, D. S., Rivera, N., Irimia-Dominguez, J., Farmer, B., Neal, D. W., ... Cherrington, A. D. (2010). Molecular characterization of insulin-mediated suppression of hepatic glucose production in vivo. Diabetes, 59(6), 1302-1311. https://doi.org/10.2337/db09-1625

Molecular characterization of insulin-mediated suppression of hepatic glucose production in vivo. / Ramnanan, Christopher J.; Edgerton, Dale S.; Rivera, Noelia; Irimia-Dominguez, Jose; Farmer, Ben; Neal, Doss W.; Lautz, Margaret; Donahue, E. Patrick; Meyer, Catalina M.; Roach, Peter; Cherrington, Alan D.

In: Diabetes, Vol. 59, No. 6, 06.2010, p. 1302-1311.

Research output: Contribution to journalArticle

Ramnanan, CJ, Edgerton, DS, Rivera, N, Irimia-Dominguez, J, Farmer, B, Neal, DW, Lautz, M, Donahue, EP, Meyer, CM, Roach, P & Cherrington, AD 2010, 'Molecular characterization of insulin-mediated suppression of hepatic glucose production in vivo', Diabetes, vol. 59, no. 6, pp. 1302-1311. https://doi.org/10.2337/db09-1625
Ramnanan CJ, Edgerton DS, Rivera N, Irimia-Dominguez J, Farmer B, Neal DW et al. Molecular characterization of insulin-mediated suppression of hepatic glucose production in vivo. Diabetes. 2010 Jun;59(6):1302-1311. https://doi.org/10.2337/db09-1625
Ramnanan, Christopher J. ; Edgerton, Dale S. ; Rivera, Noelia ; Irimia-Dominguez, Jose ; Farmer, Ben ; Neal, Doss W. ; Lautz, Margaret ; Donahue, E. Patrick ; Meyer, Catalina M. ; Roach, Peter ; Cherrington, Alan D. / Molecular characterization of insulin-mediated suppression of hepatic glucose production in vivo. In: Diabetes. 2010 ; Vol. 59, No. 6. pp. 1302-1311.
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AU - Neal, Doss W.

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