Increased hexosamine availability similarly impairs the action of insulin and IGF-1 on glucose disposal

Meredith A. Hawkins, Nir Barzilai, Wei Chen, Ivo Angelov, Meizhu Hu, Pinchas Cohen, Luciano Rossetti

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Prolonged glucosamine (GlcN) infusion increases the skeletal muscle hexosamine concentration and induces peripheral insulin resistance in conscious rats. IGF-1 and insulin share common steps in signal transduction, and the action of IGF-1 on carbohydrate metabolism is preserved in certain insulin-resistant states. In our study, we attempted to delineate whether increased GlcN availability also impairs the effects of IGF-1 on glucose uptake (R(d)), glycolysis, and glycogen synthesis. We performed euglycemic IGF-1 (5 and 15 μg · kg-1 · min-1) and insulin (3 and 18 mU mg · kg- 1 · min-1) clamp studies at 0-2 h and 5-7 h in conscious rats (n = 44) during saline or GlcN infusions. GlcN infusion raised plasma GlcN levels to ~2.0 mmol/l and skeletal muscle uridinediphospho-n-acetylglucosamine to 80- 150 nmol/g (approximately three- to fivefold over basal). During physiological hyperinsulinemia (3 mU · kg-1 · min-1, plasma insulin ≃ 50 μU/ml), GlcN infusion caused comparable decreases in R(d) (15.7 ± 1.0 [5-7 h] vs. 21.7 ± 2.3 [0-2 h] mg · kg-1 · min-1; P < 0.01) and glycogen synthesis (5.4 ± 0.5 [5-7 h] vs. 10.4 ± 1.9 [0-2 h] mg · kg-1 · min-1; P < 0.005). Furthermore, GlcN markedly decreased R(d) by 7.8 ± 1.2 mg · kg-1 · min-1 (18.7 ± 0.7 [5-7 h] vs. 26.5 ± 1.3 [0-2 h] mg · kg-1 · min-1; P < 0.001 vs. control) during IGF-1 (5 μg · kg-1 · min-1) clamp studies. This decline was associated with a 26% decrease in the steady-state concentration of skeletal muscle Glc-6-P (286 ± 45 vs. 386 ± 36 nmol/g; P < 0.01) and was primarily caused by impaired glycogen synthesis (6.7 ± 0.5 [5-7 h] vs. 13.9 ± 0.9 [0-2 h] mg · kg-1 · min- 1; P < 0.005). The effects of GlcN infusion on glucose disposal (percentage decrease in R(d)) were correlated (r2 = 0.803; P < 0.01) with the skeletal muscle concentration of UDP-GlcNAc. To investigate whether IGF-1 can overcome GlcN-induced insulin resistance, GlcN and insulin (18 mU · kg-1 · min- 1) were infused for 7 h during euglycemic clamps, and IGF-1 (15 μg · kg- 1 · min-1) was superimposed during the final 2 h. GlcN infusion induced severe impairment of insulin action on R(d) (39.4 ± 3.2 [4-5 h] vs. 49.8 ± 3.6 [1-2 h] mg · kg-1 · min-1; P < 0.05), which the addition of IGF-1 failed to improve (35.9 ± 2.3 [6-7 h] vs. 39.4 ± 3.2 [4-5 h] mg · kg-1 · min-1; P > 0.1). In summary, GlcN induced severe resistance to the actions of both insulin and IGF-1 on glucose uptake and glycogen synthesis, and IGF-1 was unable to overcome GlcN-induced insulin resistance. Thus, it is likely that GlcN causes peripheral insulin resistance acting at a site common to both IGF-1 and insulin signaling pathways.

Original languageEnglish (US)
Pages (from-to)1734-1743
Number of pages10
JournalDiabetes
Volume45
Issue number12
StatePublished - 1996

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Hexosamines
Glucosamine
Insulin-Like Growth Factor I
Insulin
Glucose
Insulin Resistance
Glycogen
Vascular Resistance
Skeletal Muscle
Acetylglucosamine
Carbohydrate Metabolism
Hyperinsulinism
Glycolysis
Signal Transduction

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Increased hexosamine availability similarly impairs the action of insulin and IGF-1 on glucose disposal. / Hawkins, Meredith A.; Barzilai, Nir; Chen, Wei; Angelov, Ivo; Hu, Meizhu; Cohen, Pinchas; Rossetti, Luciano.

In: Diabetes, Vol. 45, No. 12, 1996, p. 1734-1743.

Research output: Contribution to journalArticle

Hawkins, MA, Barzilai, N, Chen, W, Angelov, I, Hu, M, Cohen, P & Rossetti, L 1996, 'Increased hexosamine availability similarly impairs the action of insulin and IGF-1 on glucose disposal', Diabetes, vol. 45, no. 12, pp. 1734-1743.
Hawkins, Meredith A. ; Barzilai, Nir ; Chen, Wei ; Angelov, Ivo ; Hu, Meizhu ; Cohen, Pinchas ; Rossetti, Luciano. / Increased hexosamine availability similarly impairs the action of insulin and IGF-1 on glucose disposal. In: Diabetes. 1996 ; Vol. 45, No. 12. pp. 1734-1743.
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abstract = "Prolonged glucosamine (GlcN) infusion increases the skeletal muscle hexosamine concentration and induces peripheral insulin resistance in conscious rats. IGF-1 and insulin share common steps in signal transduction, and the action of IGF-1 on carbohydrate metabolism is preserved in certain insulin-resistant states. In our study, we attempted to delineate whether increased GlcN availability also impairs the effects of IGF-1 on glucose uptake (R(d)), glycolysis, and glycogen synthesis. We performed euglycemic IGF-1 (5 and 15 μg · kg-1 · min-1) and insulin (3 and 18 mU mg · kg- 1 · min-1) clamp studies at 0-2 h and 5-7 h in conscious rats (n = 44) during saline or GlcN infusions. GlcN infusion raised plasma GlcN levels to ~2.0 mmol/l and skeletal muscle uridinediphospho-n-acetylglucosamine to 80- 150 nmol/g (approximately three- to fivefold over basal). During physiological hyperinsulinemia (3 mU · kg-1 · min-1, plasma insulin ≃ 50 μU/ml), GlcN infusion caused comparable decreases in R(d) (15.7 ± 1.0 [5-7 h] vs. 21.7 ± 2.3 [0-2 h] mg · kg-1 · min-1; P < 0.01) and glycogen synthesis (5.4 ± 0.5 [5-7 h] vs. 10.4 ± 1.9 [0-2 h] mg · kg-1 · min-1; P < 0.005). Furthermore, GlcN markedly decreased R(d) by 7.8 ± 1.2 mg · kg-1 · min-1 (18.7 ± 0.7 [5-7 h] vs. 26.5 ± 1.3 [0-2 h] mg · kg-1 · min-1; P < 0.001 vs. control) during IGF-1 (5 μg · kg-1 · min-1) clamp studies. This decline was associated with a 26{\%} decrease in the steady-state concentration of skeletal muscle Glc-6-P (286 ± 45 vs. 386 ± 36 nmol/g; P < 0.01) and was primarily caused by impaired glycogen synthesis (6.7 ± 0.5 [5-7 h] vs. 13.9 ± 0.9 [0-2 h] mg · kg-1 · min- 1; P < 0.005). The effects of GlcN infusion on glucose disposal (percentage decrease in R(d)) were correlated (r2 = 0.803; P < 0.01) with the skeletal muscle concentration of UDP-GlcNAc. To investigate whether IGF-1 can overcome GlcN-induced insulin resistance, GlcN and insulin (18 mU · kg-1 · min- 1) were infused for 7 h during euglycemic clamps, and IGF-1 (15 μg · kg- 1 · min-1) was superimposed during the final 2 h. GlcN infusion induced severe impairment of insulin action on R(d) (39.4 ± 3.2 [4-5 h] vs. 49.8 ± 3.6 [1-2 h] mg · kg-1 · min-1; P < 0.05), which the addition of IGF-1 failed to improve (35.9 ± 2.3 [6-7 h] vs. 39.4 ± 3.2 [4-5 h] mg · kg-1 · min-1; P > 0.1). In summary, GlcN induced severe resistance to the actions of both insulin and IGF-1 on glucose uptake and glycogen synthesis, and IGF-1 was unable to overcome GlcN-induced insulin resistance. Thus, it is likely that GlcN causes peripheral insulin resistance acting at a site common to both IGF-1 and insulin signaling pathways.",
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T1 - Increased hexosamine availability similarly impairs the action of insulin and IGF-1 on glucose disposal

AU - Hawkins, Meredith A.

AU - Barzilai, Nir

AU - Chen, Wei

AU - Angelov, Ivo

AU - Hu, Meizhu

AU - Cohen, Pinchas

AU - Rossetti, Luciano

PY - 1996

Y1 - 1996

N2 - Prolonged glucosamine (GlcN) infusion increases the skeletal muscle hexosamine concentration and induces peripheral insulin resistance in conscious rats. IGF-1 and insulin share common steps in signal transduction, and the action of IGF-1 on carbohydrate metabolism is preserved in certain insulin-resistant states. In our study, we attempted to delineate whether increased GlcN availability also impairs the effects of IGF-1 on glucose uptake (R(d)), glycolysis, and glycogen synthesis. We performed euglycemic IGF-1 (5 and 15 μg · kg-1 · min-1) and insulin (3 and 18 mU mg · kg- 1 · min-1) clamp studies at 0-2 h and 5-7 h in conscious rats (n = 44) during saline or GlcN infusions. GlcN infusion raised plasma GlcN levels to ~2.0 mmol/l and skeletal muscle uridinediphospho-n-acetylglucosamine to 80- 150 nmol/g (approximately three- to fivefold over basal). During physiological hyperinsulinemia (3 mU · kg-1 · min-1, plasma insulin ≃ 50 μU/ml), GlcN infusion caused comparable decreases in R(d) (15.7 ± 1.0 [5-7 h] vs. 21.7 ± 2.3 [0-2 h] mg · kg-1 · min-1; P < 0.01) and glycogen synthesis (5.4 ± 0.5 [5-7 h] vs. 10.4 ± 1.9 [0-2 h] mg · kg-1 · min-1; P < 0.005). Furthermore, GlcN markedly decreased R(d) by 7.8 ± 1.2 mg · kg-1 · min-1 (18.7 ± 0.7 [5-7 h] vs. 26.5 ± 1.3 [0-2 h] mg · kg-1 · min-1; P < 0.001 vs. control) during IGF-1 (5 μg · kg-1 · min-1) clamp studies. This decline was associated with a 26% decrease in the steady-state concentration of skeletal muscle Glc-6-P (286 ± 45 vs. 386 ± 36 nmol/g; P < 0.01) and was primarily caused by impaired glycogen synthesis (6.7 ± 0.5 [5-7 h] vs. 13.9 ± 0.9 [0-2 h] mg · kg-1 · min- 1; P < 0.005). The effects of GlcN infusion on glucose disposal (percentage decrease in R(d)) were correlated (r2 = 0.803; P < 0.01) with the skeletal muscle concentration of UDP-GlcNAc. To investigate whether IGF-1 can overcome GlcN-induced insulin resistance, GlcN and insulin (18 mU · kg-1 · min- 1) were infused for 7 h during euglycemic clamps, and IGF-1 (15 μg · kg- 1 · min-1) was superimposed during the final 2 h. GlcN infusion induced severe impairment of insulin action on R(d) (39.4 ± 3.2 [4-5 h] vs. 49.8 ± 3.6 [1-2 h] mg · kg-1 · min-1; P < 0.05), which the addition of IGF-1 failed to improve (35.9 ± 2.3 [6-7 h] vs. 39.4 ± 3.2 [4-5 h] mg · kg-1 · min-1; P > 0.1). In summary, GlcN induced severe resistance to the actions of both insulin and IGF-1 on glucose uptake and glycogen synthesis, and IGF-1 was unable to overcome GlcN-induced insulin resistance. Thus, it is likely that GlcN causes peripheral insulin resistance acting at a site common to both IGF-1 and insulin signaling pathways.

AB - Prolonged glucosamine (GlcN) infusion increases the skeletal muscle hexosamine concentration and induces peripheral insulin resistance in conscious rats. IGF-1 and insulin share common steps in signal transduction, and the action of IGF-1 on carbohydrate metabolism is preserved in certain insulin-resistant states. In our study, we attempted to delineate whether increased GlcN availability also impairs the effects of IGF-1 on glucose uptake (R(d)), glycolysis, and glycogen synthesis. We performed euglycemic IGF-1 (5 and 15 μg · kg-1 · min-1) and insulin (3 and 18 mU mg · kg- 1 · min-1) clamp studies at 0-2 h and 5-7 h in conscious rats (n = 44) during saline or GlcN infusions. GlcN infusion raised plasma GlcN levels to ~2.0 mmol/l and skeletal muscle uridinediphospho-n-acetylglucosamine to 80- 150 nmol/g (approximately three- to fivefold over basal). During physiological hyperinsulinemia (3 mU · kg-1 · min-1, plasma insulin ≃ 50 μU/ml), GlcN infusion caused comparable decreases in R(d) (15.7 ± 1.0 [5-7 h] vs. 21.7 ± 2.3 [0-2 h] mg · kg-1 · min-1; P < 0.01) and glycogen synthesis (5.4 ± 0.5 [5-7 h] vs. 10.4 ± 1.9 [0-2 h] mg · kg-1 · min-1; P < 0.005). Furthermore, GlcN markedly decreased R(d) by 7.8 ± 1.2 mg · kg-1 · min-1 (18.7 ± 0.7 [5-7 h] vs. 26.5 ± 1.3 [0-2 h] mg · kg-1 · min-1; P < 0.001 vs. control) during IGF-1 (5 μg · kg-1 · min-1) clamp studies. This decline was associated with a 26% decrease in the steady-state concentration of skeletal muscle Glc-6-P (286 ± 45 vs. 386 ± 36 nmol/g; P < 0.01) and was primarily caused by impaired glycogen synthesis (6.7 ± 0.5 [5-7 h] vs. 13.9 ± 0.9 [0-2 h] mg · kg-1 · min- 1; P < 0.005). The effects of GlcN infusion on glucose disposal (percentage decrease in R(d)) were correlated (r2 = 0.803; P < 0.01) with the skeletal muscle concentration of UDP-GlcNAc. To investigate whether IGF-1 can overcome GlcN-induced insulin resistance, GlcN and insulin (18 mU · kg-1 · min- 1) were infused for 7 h during euglycemic clamps, and IGF-1 (15 μg · kg- 1 · min-1) was superimposed during the final 2 h. GlcN infusion induced severe impairment of insulin action on R(d) (39.4 ± 3.2 [4-5 h] vs. 49.8 ± 3.6 [1-2 h] mg · kg-1 · min-1; P < 0.05), which the addition of IGF-1 failed to improve (35.9 ± 2.3 [6-7 h] vs. 39.4 ± 3.2 [4-5 h] mg · kg-1 · min-1; P > 0.1). In summary, GlcN induced severe resistance to the actions of both insulin and IGF-1 on glucose uptake and glycogen synthesis, and IGF-1 was unable to overcome GlcN-induced insulin resistance. Thus, it is likely that GlcN causes peripheral insulin resistance acting at a site common to both IGF-1 and insulin signaling pathways.

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