Impairment of insulin-stimulated glucose utilization is associated with burn-induced insulin resistance in mouse muscle by hyperinsulinemic-isoglycemic clamp

Abstract

Burn-induced insulin resistance is associated with increased morbidity and mortality; however, the impact of burn injury on tissue-specific insulin sensitivity and its molecular mechanisms with consideration of insulin state remains unknown in rodent models. This study was designed to characterize a burn mouse model with tissue-specific insulin resistance under insulin clamp conditions. C57BL6/J mice were subjected to 30% full-thickness burn injury and underwent the combination of hyperinsulinemic isoglycemicclamp (HIC) and positron emission tomography (PET). Hepatic glucose production (HGP) and peripheral glucose disappearance rate (Rd) were measured at different time points up to 7 days post injury. Burned mice showed a significant fasting hypoglycemia and hypoinsulinemia (P < 0.01) on post-burn day (PBD) 3 and 7 along with significantly higher energy expenditure (P < 0.01). HICon PBD 3 demonstrated that burn injury induced systemic insulin resistance, resulting from a significant decrease in insulin-stimulated Rd (33.0 +/- 10.2 vs 68.3 +/- 5.9 mg/kg/min; P < 0.05). In contrast, HGP of burned and sham mice was comparable both in the basal and clamp period. PET on PBD 3 showed a lower insulin-stimulated 18F-labeled 2-fluoro-2-deoxy-D-glucose uptake in the quadriceps of burned mice compared with sham-burned mice. Gastrocnemius muscle harvested from burned mice on PBD 3 showed decreased insulin-stimulated tyrosine phosphorylation of insulin receptor substrate-1 to 34.7% of that in sham-burn mice by immunoblotting analysis (P < 0.05). These findings suggest that impaired insulin-stimulated Rd in skeletal muscle, not elevated HGP, plays a role in the development of burn-induced insulin resistance in a mouse model.