13C-nuclear magnetic resonance spectroscopy studies of hepatic glucose metabolism in normal subjects and subjects with insulin-dependent diabetes mellitus

Abstract

To determine the effect of insulin-dependent diabetes mellitus (IDDM) on rates and pathways of hepatic glycogen synthesis, as well as flux through hepatic pyruvate dehydrogenase, we used 13C-nuclear magnetic resonance spectroscopy to monitor the peak intensity of the C1 resonance of the glucosyl units of hepatic glycogen, in combination with acetaminophen to sample the hepatic UDP-glucose pool and phenylacetate to sample the hepatic glutamine pool, during a hyperglycemic-hyperinsulinemic clamp using [1-13C]-glucose. Five subjects with poorly controlled IDDM and six age-weight-matched control subjects were clamped at a mean plasma glucose concentration of ∼9 mM and mean plasma insulin concentrations ∼400 pM for 5 h. Rates of hepatic glycogen synthesis were similar in both groups (∼0.43±0.09 μmol/ml liver min). However, flux through the indirect pathway of glycogen synthesis (3 carbon units ↠ glycogen) was increased by ∼50% (P < 0.05), whereas the relative contribution of pyruvate oxidation to TCA cycle flux was decreased by ∼30% (P < 0.05) in the IDDM subjects compared to the control subjects. These studies demonstrate that patients with poorly controlled insulin-dependent diabetes mellitus have augmented hepatic gluconeogenesis and relative decreased rates of hepatic pyruvate oxidation. These abnormalities are not immediately reversed by normalizing intraportal concentrations of glucose, insulin, and glucagon and may contribute to postprandial hyperglycemia.