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Muscle Uridine Diphosphate-Hexosamines Do Not Decrease Despite Correction of Hyperglycemia-Induced Insulin Resistance in Type 2 Diabetes

Divisions of Endocrinology (M.-J.J.P., A.R.H.) and General Internal Medicine (M.-J.J.P., C.J.T., J.A.L.), Department of Medicine, and Departments of Chemical Endocrinology (P.N.S., A.J.O., C.G.J.S.) and Neurology (B.G.v.E.), Laboratory for Pediatrics and Neurology (J.G.d.J.), University Medical Center, 6500 HB Nijmegen, The Netherlands

Address all correspondence and requests for reprints to: Marie-Jose Pouwels, M.D., Division of General Internal Medicine, Medisch Spectrum Twente, P.O. Box 50000, 7500 KA Enschede, The Netherlands. E-mail: m.j.pouwels{at}club.tip.nl.

Abstract

Animal studies suggest that overactivity of the hexosamine pathway, resulting in increased UDP-hexosamines [UDP-N-acetylglucosamine (UDP-GlcNAc) and UDP-N-acetylgalactosamine (UDP-GalNAc)] is an important mechanism by which hyperglycemia causes insulin resistance. This study was performed to test this hypothesis in patients with type 2 diabetes mellitus (DM).

Eight obese patients with uncontrolled DM type 2 and severe insulin resistance were treated with iv insulin for 28 ± 6 d aimed at euglycemia. Before and after iv insulin treatment, insulin sensitivity was measured using a hyperinsulinemic euglycemic clamp, and a muscle biopsy was taken for measurement of UDP-GlcNAc, UDP-GalNAc, UDP-glucose, and UDP-galactose levels. Also, isoelectric focusing patterns of serum transferrin and the urinary excretion of glycosaminoglycans as measures of final products of the hexosamine pathway were examined.

After euglycemia, insulin resistance improved, as demonstrated by an increase in the glucose infusion rate during the clamp from 12.7 ± 5.6 to 22.4 ± 8.8 µmol/kg·min (P < 0.0005) and a decrease in insulin requirement from 1.7 ± 0.9 to 1.1 ± 0.6 U/kg·d (P < 0.005), whereas metabolic control improved. Surprisingly, both UDP-GlcNAc, from 8.81 ± 1.21 to 12.31 ± 2.52 nmol/g tissue (P < 0.005), and UDP-GalNAc concentrations, from 4.49 ± 0.85 to 5.89 ± 1.55 nmol/g tissue (P < 0.05) increased. Isoelectric focusing patterns of serum transferrin and excretion of glycosaminoglycans were similar before and after euglycemia.

In conclusion, after amelioration of hyperglycemia- induced insulin resistance, UDP-hexosamines increased in skeletal muscle of patients with type 2 DM. These results do not support the hypothesis that accumulation of products of the hexosamine pathway plays a major role in hyperglycemia-induced insulin resistance.

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