Glycobiology World Congress

Biography

Biography: William L Holland

Abstract

Insulin promotes the uptake and storage of carbohydrates, as well as other nutrients in skeletal muscle and adipose. It simultaneously represses secretion of glucagon (insulin’s counter-regulatory hormone) and subsequent glucose efflux from the liver. The hepatic glucose production stimulated by glucagon has been thought to play a significant role in the development of hyperglycemia. Just as insulin insufficiency can lead to elevated glucagon secretion, impaired insulin and leptin actions upon the alpha cell can also promote hyperglucagonemia and hyperglycemia. Sphingolipids, such as ceramides and glucosylceramides, are important bioactive lipid metabolites which can impair Akt-mediated signal transduction. We have demonstrated that ceramide is sufficient to impair insulin-induced suppression of glucagon from cultured glucagon-producing alpha-cells. Here, we elucidate the role of sphingolipid accumulation in aberrant glucagon production in vivo, we have used novel mouse models to drive expression of acid ceramidase under the control of a pre-proglucagon promoter. The local overexpression of acid ceramidase within the alpha cell is sufficient to improve insulin- or leptin-mediated Akt signaling within the alpha cell and prevent aberrant glucagon production. Induction of the acid ceramidase transgene is sufficient to reverse hyperglycemia within 48 hours in type 2 diabetic mice. Moreover, it is sufficient to prevent the onset of diabetes in ob/ob mice. Similarly, inducing the cre-lox mediated excision of glucosylceramide synthase within the alpha cell reverses glucagon overproduction and restores glycemia. Collectively, these data suggest that aberrant accumulation of ceramides or glucosylceramides within the alpha cell may be a causal link between insulin resistance and frank diabetes.