Sleep Disordered Breathing and Glucose Regulation

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DESCRIPTION( provided by applicant): Sleep Disordered Breathing (SDB) and type 2 diabetes mellitus are serious health problems associated with obesity. Recent epidemiological studies have shown that SDB may be linked to insulin resistance and glucose regulation, independent of obesity. However, the mechanisms by which SDB may affect glucose and insulin regulation are unknown. Putatively, the intermittent hypoxia (IH) and sleep fragmentation of SDB may impact on glucose regulation. Hypoxia could affect the insulin-glucose axis through upregulation of hypoxia-inducible factor- I alpha (HIF- 1alpha) which activates expression of glucose transporters, resulting in decreased blood glucose levels. On the other hand, sleep fragmentation could lead to stress and activation of insulin counter-regulatory hormones, such as cortisol and epinephrine, resulting in increased blood glucose levels. In our Preliminary Data we show that IH causes a biphasic response consisting of a decrease in blood glucose levels after one week followed by a rise in blood glucose after three weeks of exposure. Furthermore, the absence of the metabolic hormone leptin resulted in a more pronounced hyperglycemic phase in response to IH compared to wildtype mice. Our major hypothesis is that SDB causes biphasic changes in glucose homeostasis. The early decrease in blood glucose is due to hypoxic activation of HIF- 1alpha and upregulation of glucose transporters. The late increase in blood glucose is due to sleep fragmentation activating insulin counter-regulatory hormones, and this effect is exacerbated by leptin deficiency. In order to test our hypotheses we will utilize a mouse model of IH as well as a mouse model of SDB. We will use wildtype mice, with and without dietary obesity, as well as leptin deficient ob/ob mice and transgenic HIF- 1alpha mice. In Specific Aim I we will determine-nine the time course of changes in blood glucose, serum insulin, insulin counterregulatory hormones, and tissue glucose transporters during IH in lean and obese mice. In Specific Aim 2 we will separate the effects of IH and sleep fragmentation on glucose regulation. In Specific Aim I we will specifically examine the role of HIF- 1alpha and leptin in glucose responses to IH using transgenic mice. Thus, this study will examine mechanistically how SDB affects glucose regulation, which could have a significant impact on both fields of SDB and diabetes.