Increased Hexosamine Availability Similarly Impairs the Action of Insulin and IGF-1 on Glucose Disposal

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 Rd (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.