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Diabetes Publish Ahead of Print published online ahead of print March 23, 2007
DOI: 10.2337/db06-1776
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Original Research

Contribution of Hepatic and Extra-Hepatic Insulin Resistance to the Pathogenesis of Impaired Fasting Glucose: Role of Increased Rates of Gluconeogenesis

Gerlies Bock, MD1, Elizabeth Chittilapilly, MD1, Rita Basu, MD1, Gianna Toffolo, PhD1, Claudio Cobelli, PhD1, Visvanathan Chandramouli, PhD1, Bernard R. Landau, MD, PhD1, and Robert A. Rizza, MD1

1Division of Endocrinology, Diabetes, Metabolism & Nutrition, Mayo Clinic College of Medicine, Rochester, MN

Correspondence: rizza.robert{at}mayo.edu

Key Words: Prediabetes • fasting hyperglycemia • endogenous glucose production • gluconeogenesis • glycogenolysis

Objective:: To determine the contribution of hepatic insulin resistance to the pathogenesis of impaired fasting glucose (IFG).

Research Design and Methods:: Endogenous glucose production (EGP) and glucose disposal were measured in 31 subjects with IFG and 28 subjects with normal fasting glucose (NFG) after an overnight fast and during a clamp when endogenous secretion was inhibited with somatostatin and insulin infused at rates that approximated portal insulin concentrations present in IFG subjects after an overnight fast (~80 pmol/l; "pre-prandial") or within thirty minutes of eating (~300 pmol/l; "prandial").

Results:: Despite higher (p<0.001) insulin and C-peptide concentrations and visceral fat (p<0.05), fasting EGP and glucose disposal did not differ in IFG and NFG subjects implying hepatic and extra-hepatic insulin resistance. This was confirmed during "pre-prandial" insulin infusion when glucose disposal was lower (p<0.05) and EGP higher (p<0.05) in IFG than NFG subjects. Higher EGP was increased (p<0.05) rates of gluconeogenesis in IFG. EGP was comparably suppressed in IFG and NFG groups during "prandial" insulin infusion indicating hepatic insulin resistance was mild. Glucose disposal remained lower (p<0.01) in IFG than NFG subjects.

Conclusions:: Hepatic and extra-hepatic insulin resistance contribute to fasting hyperglycemia in IFG with former being due at least in part to impaired insulin induced suppression of gluconeogenesis. However, since hepatic insulin resistance is mild and near maximal suppression of EGP occurs at portal insulin concentrations typically present in IFG subjects within thirty minutes of eating, extra-hepatic (but not hepatic) insulin resistance coupled with accompanying defects in insulin secretion is the primary cause of postprandial hyperglycemia.


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Copyright © 2007 by the American Diabetes Association.