In vivo glucosamine infusion induces insulin resistance in normoglycemic but not in hyperglycemic conscious rats

L. Rossetti, Meredith A. Hawkins, W. Chen, J. Gindi, Nir Barzilai

Research output: Contribution to journalArticle

232 Citations (Scopus)

Abstract

To test the hypothesis that increased flux through the hexosamine biosynthetic pathway can induce insulin resistance in skeletal muscle in vivo, we monitored glucose uptake, glycolysis, and glycogen synthesis during insulin clamp studies in 6-h fasted conscious rats in the presence of a sustained (7-h) increase in glucosamine (GlcN) availability. Euglycemic (~ 7 mM) insulin (~ 2,500 pM) clamps with saline or GlcN infusions were performed in control (CON; plasma glucose [PG] = 7.4±0.2 mM), diabetic (D; PG = 19.7±1.1), and phlorizin-treated (3-wk) diabetic rats (D + PHL; PG = 7.6±0.9). 7-h euglycemic hyperinsulinemia with saline did not significantly decrease R(d) (360-420 min = 39.2±3.6 vs. 60-120 min = 42.2±3.7 mg/kg · min; P = NS). GlcN infusion raised plasma GlcN concentrations to ~ 1.2 mM and increased muscle and liver UDP-GlcNAc levels by 4-5-fold in all groups. GlcN markedly decreased R(d) in CON (360-420 min = 30.4±1.3 vs. 60-120 min = 44.1±3.5 mg/kg · min; P < 0.01) and D + PHL (360-420 min = 29.4±2.5 vs. 60-120 min = 43.8±2.9 mg/kg · min; P < 0.01), but not in D (5-7 h = 21.5±0.8 vs. 0-2 h = 24.3±1.1 mg/kg · min; P = NS). Thus, increased GlcN availability induces severe skeletal muscle insulin resistance in normoglycemic but not in chronically hyperglycemic rats. The lack of additive effects of GlcN and chronic hyperglycemia (experimental diabetes) provides support for the hypothesis that increased flux through the GlcN pathway in skeletal muscle may play an important role in glucose-induced insulin resistance in vivo.

Original languageEnglish (US)
Pages (from-to)132-140
Number of pages9
JournalJournal of Clinical Investigation
Volume96
Issue number1
StatePublished - 1995

Fingerprint

Glucosamine
Insulin Resistance
Glucose
Skeletal Muscle
Insulin
Phlorhizin
Hexosamines
Uridine Diphosphate
Biosynthetic Pathways
Hyperinsulinism
Glycolysis
Glycogen
Hyperglycemia
Muscles
Liver

Keywords

  • glucosamine
  • glucose uptake
  • glycogen synthesis
  • hyperglycemia
  • insulin resistance

ASJC Scopus subject areas

  • Medicine(all)

Cite this

In vivo glucosamine infusion induces insulin resistance in normoglycemic but not in hyperglycemic conscious rats. / Rossetti, L.; Hawkins, Meredith A.; Chen, W.; Gindi, J.; Barzilai, Nir.

In: Journal of Clinical Investigation, Vol. 96, No. 1, 1995, p. 132-140.

Research output: Contribution to journalArticle

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N2 - To test the hypothesis that increased flux through the hexosamine biosynthetic pathway can induce insulin resistance in skeletal muscle in vivo, we monitored glucose uptake, glycolysis, and glycogen synthesis during insulin clamp studies in 6-h fasted conscious rats in the presence of a sustained (7-h) increase in glucosamine (GlcN) availability. Euglycemic (~ 7 mM) insulin (~ 2,500 pM) clamps with saline or GlcN infusions were performed in control (CON; plasma glucose [PG] = 7.4±0.2 mM), diabetic (D; PG = 19.7±1.1), and phlorizin-treated (3-wk) diabetic rats (D + PHL; PG = 7.6±0.9). 7-h euglycemic hyperinsulinemia with saline did not significantly decrease R(d) (360-420 min = 39.2±3.6 vs. 60-120 min = 42.2±3.7 mg/kg · min; P = NS). GlcN infusion raised plasma GlcN concentrations to ~ 1.2 mM and increased muscle and liver UDP-GlcNAc levels by 4-5-fold in all groups. GlcN markedly decreased R(d) in CON (360-420 min = 30.4±1.3 vs. 60-120 min = 44.1±3.5 mg/kg · min; P < 0.01) and D + PHL (360-420 min = 29.4±2.5 vs. 60-120 min = 43.8±2.9 mg/kg · min; P < 0.01), but not in D (5-7 h = 21.5±0.8 vs. 0-2 h = 24.3±1.1 mg/kg · min; P = NS). Thus, increased GlcN availability induces severe skeletal muscle insulin resistance in normoglycemic but not in chronically hyperglycemic rats. The lack of additive effects of GlcN and chronic hyperglycemia (experimental diabetes) provides support for the hypothesis that increased flux through the GlcN pathway in skeletal muscle may play an important role in glucose-induced insulin resistance in vivo.

AB - To test the hypothesis that increased flux through the hexosamine biosynthetic pathway can induce insulin resistance in skeletal muscle in vivo, we monitored glucose uptake, glycolysis, and glycogen synthesis during insulin clamp studies in 6-h fasted conscious rats in the presence of a sustained (7-h) increase in glucosamine (GlcN) availability. Euglycemic (~ 7 mM) insulin (~ 2,500 pM) clamps with saline or GlcN infusions were performed in control (CON; plasma glucose [PG] = 7.4±0.2 mM), diabetic (D; PG = 19.7±1.1), and phlorizin-treated (3-wk) diabetic rats (D + PHL; PG = 7.6±0.9). 7-h euglycemic hyperinsulinemia with saline did not significantly decrease R(d) (360-420 min = 39.2±3.6 vs. 60-120 min = 42.2±3.7 mg/kg · min; P = NS). GlcN infusion raised plasma GlcN concentrations to ~ 1.2 mM and increased muscle and liver UDP-GlcNAc levels by 4-5-fold in all groups. GlcN markedly decreased R(d) in CON (360-420 min = 30.4±1.3 vs. 60-120 min = 44.1±3.5 mg/kg · min; P < 0.01) and D + PHL (360-420 min = 29.4±2.5 vs. 60-120 min = 43.8±2.9 mg/kg · min; P < 0.01), but not in D (5-7 h = 21.5±0.8 vs. 0-2 h = 24.3±1.1 mg/kg · min; P = NS). Thus, increased GlcN availability induces severe skeletal muscle insulin resistance in normoglycemic but not in chronically hyperglycemic rats. The lack of additive effects of GlcN and chronic hyperglycemia (experimental diabetes) provides support for the hypothesis that increased flux through the GlcN pathway in skeletal muscle may play an important role in glucose-induced insulin resistance in vivo.

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