Isoflurane and Sevoflurane Induce Severe Hepatic Insulin Resistance in a Canine Model

<div><p>Introduction</p><p>Anesthesia induces insulin resistance, which may contribute to elevated blood glucose and adverse post-operative outcomes in critically ill patients, and impair glycemic control in surgical patients with diabetes. However, little is known about the mechanisms by which anesthesia impairs insulin sensitivity. Here we investigate the effects of anesthesia on insulin sensitivity in metabolic tissues.</p><p>Methods</p><p>Hyperinsulinemic-euglycemic clamps were performed in 32 lean (control diet; n = 16 conscious versus n = 16 anesthetized) and 24 fat-fed (6 weeks fat-feeding; n = 16 conscious versus n = 8 anesthetized) adult male mongrel dogs in conjunction with tracer methodology to differentiate hepatic versus peripheral insulin sensitivity. Propofol was administered as an intravenous bolus (3mg/kg) to initiate anesthesia, which was then maintained with inhaled sevoflurane or isoflurane (2–3%) for the duration of the procedure.</p><p>Results</p><p>Anesthesia reduced peripheral insulin sensitivity by approximately 50% in both lean and fat-fed animals as compared to conscious animals, and insulin action at the liver was almost completely suppressed during anesthesia such that hepatic insulin sensitivity was decreased by 75.5% and; 116.2% in lean and fat-fed groups, respectively.</p><p>Conclusion</p><p>Inhaled anesthesia induces severe hepatic insulin resistance in a canine model. Countermeasures that preserve hepatic insulin sensitivity may represent a therapeutic target that could improve surgical outcomes in both diabetic and healthy patients.</p></div

Insulin sensitivity with and without anesthesia.

<p>(A) Peripheral and (B) hepatic insulin sensitivity, as calculated from Rd and EGP, respectively was assessed under conscious (black bars) and anesthetized (white bars) conditions in lean and fat-fed animals (mean ± SEM).</p

Effects of anesthesia and diet on measures of glucose metabolism.

<p>Rd (A and B) and EGP (C and D) were assessed under conscious (black bars) and anesthetized (white bars) conditions in lean and fat fed animals (mean±SEM). Assessments were taken under low insulin (BASAL) conditions (A and C), and under the hyperinsulinemia induced by the CLAMP (B and D).</p

Weekly changes in body weight and body composition.

<p>(A) Body weight increased by week 2 and remained elevated throughout the six-week hypercaloric high-fat feeding period. (B) Visceral (white bar) and subcutaneous (black bar) adipose tissue calculated as area percent of total tissue. *P<.05 vs. week0; **P<.01 vs. week 0; ***P<.001 vs. week 0.</p

Glucose and FFA plasma levels at three time periods during 24-hr before and after fat feeding.

<p>(A) Plasma glucose and (B) plasma FFAs during 2–4 AM (hash bars), 8–8:30 AM (black bars), and 6–8 PM (white bars). *P<.05 vs. week0; **P<.01 vs. week 0; ***P<.001 vs. week 0.</p

Consistency of the hyperbolic relationship (DI) between insulin sensitivity and insulin secretion.

<p>Solid black hyperbolic curve =  average DI value for week 0; black solid square  =  average DI for week 0; open square  =  average DI for week 2; black solid triangle  =  average DI for week 4; open triangle  =  average DI for week 6. The hyperbola represents the curve on which the animals would have to remain to maintain a constant DI (DI = AIRg.SI = constant) and it is calculated as extrapolation of the average DI for week 0 over a range of insulin sensitivities.</p

Spearman’s rank correlation between fasting insulin and fasting FFA.

<p>Spearman’s rank correlation between fasting insulin and fasting FFA.</p

Observed fasting plasma insulin, glucose and FFAs.

<p>Fasting levels of (A) insulin, (B) glucose, and (C) FFA before and after fat feeding. *P<.05 vs. week0; **P<.01 vs. week 0; ***P<.001 vs. week 0.</p

Weekly estimates of insulin sensitivity, insulin secretion and whole-body insulin clearance.

<p>(A) SI, (B) AIRg, and (C) MCR of insulin. *P<.05 vs. week 0; **P<.01 vs. week 0; ***P<.001 vs week 0.</p

Anandamide significantly enhances insulin and glucagon secretion.

<p>Insulin, glucagon, and somatostatin concentrations were measured in batches of 100 islets from control-diet animals (n = 7) during static incubation with anandamide 10 μmol/L for 1 h. 3G, 3 mmol/L; 15G, 15 mmol/L glucose. Data are mean±S.E.M.</p