β2-adrenergic regulation of stress hyperglycemia following hemorrhage in the obese Zucker rat.

John S Clemmer,Silu Lu,Lusha Xiang,Robert L Hester,Peter N Mittwede

doi:10.14814/phy2.12215

Abstract

Stress hyperglycemia following trauma has been shown to potentiate morbidity and mortality. Glucose control in obese patients can be challenging due to insulin resistance. Thus, understanding the mechanisms for glucose generation following hemorrhage may provide important insights into alternative options for glycemic control in obesity. Obesity is characterized by elevated glycogen and increased hepatic β2‐adrenergic activity, which play major roles in glucose production after hemorrhage. We hypothesized that, in obesity, hepatic glycogenolysis is enhanced during stress hyperglycemia due to increased hepatic β2‐adrenoceptor activation. Hemorrhage was performed in conscious lean Zucker (LZ) and obese Zucker rats (OZ) by withdrawing 35% total blood volume over 10 min. Liver glycogen content and plasma levels of glucose, insulin, and glucagon were measured before and 1 h after hemorrhage. The hyperglycemic response was greater in OZ as compared to LZ, but glycogen content was similarly reduced in both groups. Subsequently, OZ had a greater fall in insulin compared to LZ. Glucagon levels were significantly increased 1 h after hemorrhage in LZ but not in OZ. To test the direct adrenergic effects on the liver after hemorrhage, we treated animals before hemorrhage with a selective β2‐adrenoceptor antagonist, ICI‐118,551 (ICI; 2 mg/kg/h, i.v.). After hemorrhage, ICI significantly reduced hyperglycemia in both LZ and OZ, independent of hormonal changes, but there was a significantly decreased hepatic glycogenolysis in OZ. These results suggest that the hemorrhage‐induced hepatic glycogenolysis is likely glucagon‐dependent in LZ, whereas the β2‐adrenoceptor plays a greater role in OZ.

Highlights

Hemorrhage is the leading cause of death after traumatic injury (Sauaia et al 1995; Boulanger et al 2007) with hemorrhage being the primary hyperglycemic stimulus in trauma models (Ma et al 2003; Xu et al 2008)
obese Zucker rats (OZ) Mean arterial blood pressure (MAP) was higher at 15 min and lower at 30 min compared to lean Zucker (LZ)
The major findings of this study are: (1) OZ, as compared to LZ, exhibited a significantly greater hyperglycemia in response to hemorrhage; (2) treatment with a b2-adrenoceptor antagonist decreased glucose levels in LZ and OZ, indicating a direct effect of sympathetic stimulation on glycogenolysis after hemorrhage; (3) ICI treatment blocked the decrease in hepatic glycogen in OZ after hemorrhage with a no significant effect in LZ, suggesting a greater b2-adrenoceptor-mediated glycogenolysis in OZ after hemorrhage; and (4) as compared to LZ, insulin, and glucagon levels were suppressed to a greater extent after hemorrhage in OZ and likely contributed to the altered hyperglycemic responses

Summary

Introduction

Hemorrhage is the leading cause of death after traumatic injury (Sauaia et al 1995; Boulanger et al 2007) with hemorrhage being the primary hyperglycemic stimulus in trauma models (Ma et al 2003; Xu et al 2008). There is a rapid increase in plasma glucose by an increased glycogenolysis through sympathetic activation of the hepatic b2 adrenoceptor (Arinze and Kawai 1983; Kawai and Arinze 1983) and indirectly through insulin and glucagon regulation. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

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