Postoperativ insulinresistens - relasjoner til inflammasjon og immunmodulering

Hyperinsulinemic euglycemic step clamping with tracer glucose infusion and labeled glucose infusate for assessment of acute insulin resistance in pigs The study established hyperinsulinemic euglycemic step clamping with tracer glucose infusion and labeled glucose infusate for assessment of acute insulin resistance in anesthetized pigs and for combination with invasive investigative methods. Tracer enrichment was measured during D-[6,6-2H2]glucose infusion before and after surgical instrumentation. Three-step hot-GINF HEC was performed subsequent to major surgical trauma (n
8). Surgical trauma elicited pronounced peripheral and moderate hepatic insulin unresponsiveness and apparently diminished metabolic insulin clearance. Step hot-GINF HEC seems suitable for assessment of acute insulin resistance in anesthetized pigs, and combination with invasive investigative methods requiring surgical instrumentation can be accomplished without the premises for utilization of the technique being altered, but attention must be paid to alterations in metabolic insulin clearance. Single-dose carbohydrate treatment in the immediate preoperative phase diminishes development of postoperative peripheral insulin resistance Background & aims: Preoperative oral carbohydrate (CHO) treatment is known to reduce postoperative insulin resistance, but the necessity of a preoperative evening dose is uncertain. We investigated the effect of single-dose CHO treatment two hours before surgery on postoperative insulin sensitivity. Methods: Thirty two pigs were randomized to 4 groups followed by D-[6,6-2H2] glucose infusion and hyperinsulinemic-euglycemic step clamping. Two groups received a morning drink of carbohydrate (CHO/surgery and CHO/control). Counter-regulatory hormones, free fatty acids (FFA) and liver and muscle glycogen content were measured serially. Results: Glucose infusion rates needed to maintain euglycemia were higher after CHO/surgery than fasting/surgery during low and high insulin clamping. The control groups exhibited identical insulin sensitivity. Compared to their respective controls, insulin-stimulated whole-body glucose disposal was significantly reduced after fasting/surgery, but not after CHO/surgery. CHO reduced FFA perioperatively and during the clamp procedures, but did not affect hepatic insulin sensitivity, liver and muscle glycogen content or counter-regulatory hormone profiles. A strong negative correlation between peripheral insulin sensitivity and mean cortisol levels was seen in fasted, but not in CHO loaded pigs. Conclusions: Single-dose preoperative CHO treatment is sufficient to reduce postoperative insulin resistance, possibly due to the antilipolytic effects and antagonist properties of preoperative hyperinsulinemia on the suppressant actions of cortisol on carbohydrate oxidation. Preoperative carbohydrate supplementation attenuates post-surgery insulin resistance via reduced inflammatory inhibition of the insulin-mediated restraint on muscle pyruvate dehydrogenase kinase 4 expression Background & aims We hypothesized that the so far poorly understood improvement in postoperative insulin sensitivity, when surgery is preceded by a CHO drink, occurs via attenuation of skeletal muscle inflammatory responses to surgery, improved insulin signaling and attenuated expression of muscle pyruvate dehydrogenase kinase (PDK) 4. Methods Vastus lateralis muscle biopsies, collected before and after major abdominal surgery and during postoperative hyperinsulinaemic-euglycaemic clamping to either CHO-supplemented drink 2 h before surgery, or preoperative overnight fasting, were analyzed by fast qRT-PCR and IR-Western blotting. Conclusions Preoperative carbohydrate supplementation was found to ameliorate postoperative insulin sensitivity by reducing muscle inflammatory responses and improved insulin inhibition of FOXO1-mediated PDK4 mRNA and protein expression after surgery.
This thesis introduces an experimental model which can be extended with further interventions and modified with additional metabolic tracers, inter-organ blood sampling and flow measurements to investigate the metabolic and cellular effects of more complex formulated oral perioperative supplements eventually leading to new clinical alternatives on the quest to optimize perioperative nutritional care. MAIN CONCLUSIONS 1. Step hot-GINF HEC is a feasible technique and seems well suited for porcine research models on acute insulin resistance, but attention must be paid to alterations in circulating insulin. Combination with invasive research techniques requiring extensive surgical instrumentation can be accomplished without the premises for utilization of the technique being altered. 2. Single-dose preoperative oral carbohydrate supplementation two hours prior to surgery is sufficient to reduce development of peripheral insulin resistance and maintain oxidative glucose disposal immediately after major surgery in pigs. 3. The postoperative improvement in glucose disposal is prophylactic by nature and seems to be limited to surgically stressed animals by antilipolytic effects and antagonist properties of preoperative hyperinsulinaemia on the suppressant actions of cortisol on carbohydrate oxidation. 4. Oral carbohydrate administration in the immediate preoperative phase reduces the skeletal muscle inflammatory response to surgical trauma, the interference of inflammatory mediators with insulin downstream signal transduction, and improves the ability of insulin to suppress FOXO1-mediated PDK4 expression in skeletal muscle after surgery. This could, at least in part, explain the prophylactic effect of carbohydrate treatment on development of postoperative peripheral insulin resistance. 5. In line with the molecular data, isolated impairment in skeletal muscle mitochondrial pyruvate oxidation capacity develops along with peripheral insulin resistance in the postoperative phase after major abdominal surgery. 6. Mitochondrial ROS release is increased in both skeletal muscle and liver after surgery, whereas mitochondria from skeletal muscle exhibit increased fatty acidinduced uncoupling. The causal relationship between these changes and the decline in insulin sensitivity remains to be determined.