472 Decreased Mortality in Acute Pancreatitis Related to Early Aggressive Hydration

Abstract

Background: Gastroparesis is a well recognized complication of diabetes and can contribute to poor glycemic control. Diabetic gastroparesis is associated with loss of interstitial cells of Cajal. We have previously studied gastroparesis by serially measuring gastric emptying in diabetic NOD mice and demonstrated that delayed gastric emptying is associated with loss of up-regulation of heme oxygenase-1 (HO1), an increase in oxidative stress and loss of Kit. Induction of HO1 reversed delayed gastric emptying, lowered markers of oxidative stress and restored Kit expression. HO1 catalyzes the breakdown of heme into iron, biliverdin and carbon monoxide (CO). The metabolite of HO1 that restores normal gastric function is not known. Aims: Determine whether inhalation of CO can reduce oxidative stress, increase Kit expression and reverse delayed gastric emptying in diabetic NODmice.Methods: Gastric emptying of solids was measured using a [13C]octanoic acid based breath test. Mice were considered diabetic when blood glucose levels were >250 mg/dL. Mice that developed delayed gastric emptying (T1/2 >118min) received either CO by inhalation (250 ppm for 6 hours daily) or not. Serum malondialdehyde was measured as a marker of oxidative stress. Kit and HO1 expression levels were determined in immunoblots of protein extracted from the external muscle layers of the body and antrum of the stomach. Statistical analyses were done using paired t test and Mann Whitney rank-sum test for non parametric data. Results: 8 NOD mice with delayed gastric emptying were studied (mean T1/2±SEM: 160±10 min, normal 67-118 min). CO treatment reversed the gastric emptying delay in all 4 mice within 2 weeks of treatment (mean T1/2±SEM: 81±5 min, n=4), whereas gastric emptying remained delayed in all the control animals (mean T1/2±SEM: 181±8 min, n = 4). In CO treated mice, malondialdehyde levels were reduced from 394±21 nmol/ml to 41±14 nmol/ml, mean±SEM, n = 3, p 0.05, Mann Whitney). Conclusions: CO decreased oxidative stress and increased Kit expression and reversed diabetic gastroparesis in NODmice without an increase in HO1 expression. These data suggest that the production of CO by HO1 is a major contributor to the protective effect of HO1 on diabetic gastroparesis in mice. Supported by NIH DK68055 and DK57061.