274-LB: The Anti-inflammatory Effects of Insulin and Hydrocortisone Combination in Obese Subjects

Glucocorticoids have been used as the major class of anti-inflammatory agents for over 60 years. However, they have well known side effects including weight gain, adiposity, muscle loss, osteoporosis and diabetogenicity. We have recently described the induction of specific pro-inflammatory genes by a single large dose of hydrocortisone (HC) in normal weight subjects. Since our group discovered the anti-inflammatory actions of insulin, we have now hypothesized that a combination of insulin with a high dose of a HC may neutralize the proinflammatory effects of HC and offer a safe anti-inflammatory combination. Eight obese subjects (BMI:31-46 kg/m², age: 29-63 years, 3 females) were randomized into a cross over study to be injected in two separate visits (a week apart) with 300 mg of HC (?60 mg prednisolone) intravenously with or without an infusion of 2U/h of insulin with 5% dextrose for 8 hours. HC injection alone induced a significant anti-inflammatory effect including suppression of CCR-2 (by 54±8%), IL-4 (by 68±14%) and TNF-α (by 35±10%) expression in mononuclear cells (MNC). However, the HC injection also induced an increase in the expression of HMG-B1, TLR2, TLR4, TLR9, JNK-1 and RANK-L (by 43±12%, 57±9%, 62±17%, 69±15%, 89±19% and 61±11% over the baseline, respectively, P<0.05 for all). Plasma glucose and FFA concentrations also increased significantly following the HC injection alone. Insulin infusion along with the HC injection further suppressed the expression of CCR-2, TNF-α and IL-4 in MNC and completely inhibited the HC induced increases in FFA concentrations and in HMG-B1, TLR-2, TLR-9 and RANK-L expression (p<0.05 vs. HC alone). In addition, insulin infusion not only inhibited the HC induced increases in JNK-1 and TLR4 expression but also suppressed levels below baseline (by 27±14% and 22±10%, p<0.001 vs. HC alone). Thus, the infusion of insulin at a low dose with a high dose of HC or other corticosteroids may constitute an ideal anti-inflammatory cocktail in the in- patient setting.