Mechanisms of Insulin Resistance Following Injury

Abstract

To assess the mechanisms of insulin resistance following injury, we examined the relationship between insulin levels and glucose disposal in nine nonseptic, multiple trauma patients (average age 32 years, Injury Severity Score 22) five to 13 days postinjury. Fourteen age-matched normals served as controls. Using a modification of the euglycemic insulin clamp technique, insulin was infused in 35 two-hour studies using at least one of four infusions rates (0.5, 1.0, 2.0 or 5.0 mU/kg min). Basal glucose levels were maintained by a variable infusion of 20% dextrose using bedside glucose monitoring and a servo-control algorithm. The amount of glucose infused reflected glucose disposal (M, mg/kg.min). Tracer doses of (6,6,2D2) glucose were administered in selected subjects to determine endogenous glucose production. At plasma insulin concentrations less than 100 microU/ml, responses in both groups were similar. However, maximal glucose disposal rates were significantly less in the patients than in the controls (9.17 +/- 0.87 mg/kg . min vs. 14.3 +/- 0.78, mean +/- SEM, p less than 0.01). Insulin clearance rates in the patients were almost twice that seen in controls. To further characterize this decrease in insulin responsiveness, we studied six additional patients and 12 controls following the acute elevation of glucose 125 mg/dl above basal (hyperglycemic glucose clamp). In spite of exaggerated endogenous insulin production in the patients (80-200 microU/ml vs. 30--70 in controls), M was significantly lower (6.23 +/- 0.59 vs. 9.46 +/- 0.79, p less than 0.02). In conclusion, this study demonstrated that (1) the maximal rate of glucose disposal is reduced in trauma patients; (2) the metabolic clearance rate of insulin in the injured patients is almost twice normal and; (3) insulin resistance following injury appears to occur in peripheral tissues, probably skeletal muscle, and is consistent with a postreceptor defect.

Tight glycemic control in critical care – The leading role of insulin sensitivity and patient variability: A review and model-based analysis

“…It determines the resulting glucose level for any given inputs, and thus how much insulin is required to achieve tight control, at least to the dose where insulin effect saturates [82][83][84][85]. More specifically, in the model used in this study, it accounts for the net effect of any suppression or increase in endogenous insulin and glucose production, and the rate of peripheral glucose uptake.…”

Impact of metoprolol on insulin sensitivity in the ICU

“…Critically ill patients already have significant peripheral insulin resistance (Black et al, 1982) and may therefore be less likely to show further large reductions caused by reduced blood flow or receptor downregulation compared to healthy subjects. This saturation of the physiological effect may explain the limited reduction of insulin sensitivity in critically ill patients compared with 'healthy' individuals seen in this study.…”

“…Increased secretion of counterregulatory hormones stimulate endogenous glucose production and reduces peripheral insulin sensitivity, resulting in hyperglycaemia (Black et al, 1982, McCowen et al, 2001, Mizock, 2001. Tight control of blood glucose to normal levels has been shown to reduce mortality and organ failure , Krinsley, 2003, Van den Berghe et al, 2006, Van den Berghe et al, 2001 Tight glycaemic control (TGC) is already difficult to achieve in critically ill patients due to their insulin resistant state, and may be made even more difficult by treatment with metoprolol.…”

First pilot trial of the STAR-Liege protocol for tight glycemic control in critically ill patients

“…A maximum insulin rate of 6 U/h is prescribed for safety and to avoid insulin saturation effects [26,27]. Similarly, the insulin rate rise per intervention is limited to +1U/h if the previous insulin rate is < 1U/h and to +2U/h otherwise to avoid over responding to sudden changes or larger sensor errors.…”