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Diabetes Pathophysiology
The Role of Insulin in the Regulation of PEPCK and Gluconeogenesis In Vivo
Christopher J Ramnanan, PhD,
1
Dale S Edgerton, PhD
2
and Alan D Cherrington, PhD
3
1. Post-doctoral Fellow; 2. Research Assistant Professor; 3. Professor, Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine
Abstract
The regulation of gluconeogenesis by insulin is complex and can involve insulin-mediated events in the liver, as well as in several non-hepatic
tissues. Given the complexity of this regulation, it is no surprise that there is considerable debate regarding insulin’s ability to regulate the
rate of gluconeogenic formation of glucose-6-phosphate (GNG flux to G6P) in vivo. Conventional ‘textbook’ teaching (based on in vitro
studies of rat liver) depicts that insulin can inhibit this pathway by suppressing the transcription of the enzyme phosphoenolpyruvate
carboxykinase (PEPCK). PEPCK is widely considered to be a ‘rate-limiting’ enzyme with high control strength. Additionally, recent data in
rodents have led to the conclusion that hyperinsulinemia in the brain can inhibit GNG flux to G6P, likely through transcriptional regulation of
PEPCK. Recent data from the authors’ lab have confirmed that the molecular regulation of PEPCK messenger RNA (mRNA) and protein by
insulin is conserved in large animals. Acute physiological hyperinsulinemia does not alter gluconeogenic formation of G6P, however, despite
substantial reductions in PEPCK protein. This indicates that PEPCK has poor regulatory control over the pathway in vivo. A physiological rise
in insulin suppresses hepatic glucose production by inhibiting glycogenolysis and promoting glycogen synthesis, stimulating glycolytic flux,
and redirecting gluconeogenically derived carbon to glycogen. This review documents the relevant ways in which insulin can regulate GNG
flux to G6P in vivo.
Keywords
Hepatic glucose production (HGP), insulin, hyperinsulinemia, gluconeogenesis, glycogenolysis, glucose-6-phosphate (G6P), GNG flux to G6P,
glycolysis, phosphoenolpyruvate carboxykinase (PEPCK), lipolysis, free fatty acids (FFAs)
Disclosure: The authors have no conflicts of interest to declare.
Acknowledgements: Work from the authors’ laboratory discussed herein has been supported by National Institutes of Health (NIH) grants R37 DK18243 and P60 DK020593 and an
American Diabetes Association Mentor-Based Fellowship to Alan D Cherrington, PhD.
Received: November 17, 2009 Accepted: December 7, 2009
Correspondence: Alan D Cherrington, PhD, Vanderbilt University School of Medicine, Department of Molecular Physiology, 710 Robinson Research Building, 2200 Pierce Avenue,
Nashville, TN 37232. E: alan.cherrington@vanderbilt.edu
The regulation of hepatic glucose production (HGP) by insulin is critical explained by a profound inhibition of glycogenolytic flux, but little (if
for the maintenance of desirable blood glucose concentrations.
1
HGP any) modification of flux through the gluconeogenic pathway.
1,10–14
The
reflects the sum of gluconeogenesis (the synthesis and release of purpose of this review is to examine the ways by which insulin brings
glucose from non-carbohydrate precursors) and glycogenolysis about its effects on the gluconeogenic pathway in vivo and to address
(glucose released from the breakdown of hepatic glycogen). An acute discrepancies in the literature concerning sensitivity of the pathway to
rise in portal vein insulin (such as occurs in response to feeding) the hormone in the whole animal.
causes the rapid suppression of HGP derived from both gluconeogenic
and glycogenolytic sources. Standard textbook teaching, based on Potential Regulatory Loci for Insulin’s Effects on
data culled largely from experiments on isolated hepatocytes, liver GNG Flux to G6P
slices, and perfused livers from rats, posits that the gluconeogenic There are three sources that feed into the glucose-6-phosphate (G6P)
pathway is inhibited by insulin via rapid and profound transcriptional pool within the hepatocyte:
regulation of the ‘rate-limiting’ gluconeogenic enzymes.
2–6
Recent data
in rodents are in line with this dogma and in addition suggest that G6P formed via glucokinase-mediated phosphorylation of glucose
hyperinsulinemia in the brain is sufficient to markedly inhibit flux taken up from circulation;
through the gluconeogenic pathway by downregulating gluconeogenic G6P derived from the breakdown of glycogen; and
gene expression.
7–9
By contrast, the exquisite sensitivity of HGP to G6P synthesized from three-carbon precursors (lactate, glycerol and
physiological hyperinsulinemia in humans and dogs in vivo is clearly certain amino acids) via the gluconeogenic pathway (GNG flux to G6P).
34 © TOUCH BRIEFINGS 2009
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