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 micro mol/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.