The sites and mechanisms of postoperative insulin resistance

Abstract: The Sites and Mechanisms of Postoperative InsulinResistance by Jonas Nygren, M.D. Departments of Surgery and Endocrinology and Diabetes, Karolinska Hospital and Institute, SE-171 76, Stockholm, Sweden In Sweden with nine million inhabitants, 450,000 operations(outpatients excluded) are performed every year resulting in2,250,000 treatment days in hospital. Surgical operations are part ofthe treatment for 44% of all patients admitted to hospital careoccupying 24% of all hospital beds. The majority of these patientsundergo an elective surgical procedure. Therefore, it is important toreduce the side effects of surgery, such as the catabolic response. Insulin is a key anabolic hormone which regulates not only themetabolism of glucose, but also the metabolism of fat and protein.Insulin resistance is a main feature of the catabolic response tosurgery and other trauma. However, the sites and mechanisms of thepostoperative insulin resistance remain to be clearly defined.Furthermore, it is not known whether changes in postoperative insulinsensitivity have any impact on patient outcome. Therefore, insulinsensitivity and glucose kinetics ([6,6,2H2]-D-glucose) weredetermined using hyperinsulinemic, normoglycemic clamps and indirectcalorimetry, before and after elective surgery in patients undergoingabdominal surgery (n = 18) or total hip replacement (n = 13). Thepatients were undergoing surgery after the traditional overnight fast(n = 17) or in a carbohydrate fed state. The carbohydrate fed statewas achieved by infusions of glucose and insulin 3-4 hours before andduring surgery (n = 7) or by intake of a carbohydrate drink (400 ml,50 g carbohydrates) 2-3 hours before surgery (n = 7). Glucose infusion rates required to maintain normoglycemia duringclamps (M-value) were reduced after surgery in the overnight fastedpatients, indicating the development of postoperative insulinresistance. Endogenous glucose production was moderately increasedafter surgery. The suppressibility of endogenous glucose productionby insulin was preserved postoperatively. Thus, most of the reductionin insulin sensitivity after surgery was due to a defect in glucosedisposal. Since postoperatively, a similar reduction in both glucoseoxidation and nonoxidative glucose disposal was observed, a defect inglucose transport probably underlies a decrease in insulinsensitivity. Energy expenditure increased after surgery and fatoxidation rates were less suppressed by insulin infusions. Onlymoderate changes were found in glucagon and cortisol levels ahersurgery. To single out the effects of surgery from the effects of thecommon perioperative treatment with bed rest and hypocaloricnutntion, insulin sensitivity was measured in healthy subjects (n =6), before and after a 24 hour period of hypocaloric nutrition and/orbed rest. Insulin sensitivity was reduced after 24 hours hypocaloncnutrition alone while the same period of immobilization had noeffect. One group of patients was treated with infusions of insulin andglucose before and during total hip replacement and compared tocontrols. In the insulin and glucose treated patients, insulinsensitivity remained unaffected immediately after surgery whileinsulin sensitivity was reduced in the control patients, undergoingthe same operation after an ovemight fast. A more convenient way to administer carbohydrates would be as abeverage instead of an intravenous infusion. To test the possibilityof administrating carbohydrates orally before the operation, gastricemptying of an isoosmolar carbohydrate rich drink (400 ml, 12%carbohydrates) was detenmined using gamma camera technique (99Tcm).Despite increased anxiety preoperatively, gastric emptying of thedrink was completed 90 minutes after intake in patients in themorning of surgery. When the carbohydrate drink was given to patients2-3 hours before elective colorectal surgery, postoperative insulinsensitivity was markedly improved as compared to patients undergoingsimilar surgical procedures after an overnight fast. Multiple regression analysis showed that 72% of the variability inthe relative reduction in insulin sensitivity after electiveabdominal surgery could be predicted by the duration of surgery (p =0.0002) and the carbohyd rate access preoperatively (p = 0.0005).Furthermore, the length of hospital stay was related to the degree ofpostoperative insulin resistance (relative change in M-valuespostoperatively vs hospital stay in postoperative days, r = -0.60, p= 0.018). In addition, 64% of the vanability in hospital stay was predicted bythe type of surgery (hip or abdominal) (p = 0.0001), duration ofsurgery (p = 0.010) and whether the patients were fasted orcarbohydrate fed before surgery (p = 0.004). Thus, carbohydratefeeding seems to be a better preparation than overnight fastingbefore surgery by improving postoperative insulin sensitivity andpatient recovery following elective surgery. Key words: Surgery, Insulin resistance, Glucosemetabolism, Glucose clamping technique, Gastric emptying,Immobilization, Preoperative fasting, ICF-I, Hospital stay, Stableisotopes ISBN 91-628-2695-6 Stockholm 1997