Despite improvements in the management of type 1 diabetes (T1D), including insulin analogs, insulin pump therapy, and most recently, continuous glucose monitoring, the risk of hypoglycemia continues to serve as a major barrier to the achievement of near-normal glucose control. Two common obstacles to near-normal glucose control remain night-time hypoglycemia and post-prandial glycemic instability. Decreased hormonal counter-regulatory responsiveness to hypoglycemia at night and after repeated episodes of hypoglycemia places patients with T1D attempting to achieve tight control at high risk of severe hypoglycemia due to hypoglycemia unawareness. Non-physiological insulin delivery frequently results in early post-prandial hyperglycemia and late post-prandial hyperinsulinemia, affecting not only glycemic control but also contributing as well to unpredictable daytime hypoglycemia. It is likely that no manual, """"""""open-loop"""""""" therapeutic insulin regimen will be able to optimally control glycemia in patients with T1D, and biological islet- cell replacement is presently unfeasible. """"""""Closed-loop"""""""" automated artificial pancreas systems, consisting of an insulin pump to precisely deliver variable amounts of insulin, a continuous glucose sensor to accurately determine the glucose levels, and effective algorithms to determine insulin delivery rates based on real-time glucose readings, remains the most promising intervention to control glycemia and reduce hypoglycemia exposure. The objectives of this study are (1) to determine whether night-time closed-loop therapy can reduce or eliminate nocturnal hypoglycemia and restore counter-regulatory hormone responsiveness to hypoglycemia in subjects with recurrent nocturnal hypoglycemia;and (2) to investigate whether the use of incretins such as pramlintide and exenatide, when used in conjunction with closed-loop therapy, can optimize prandial glycemic control, eliminating or reducing both early post-prandial hyperglycemia and late post-prandial hypoglycemia. These studies will be performed with the Medtronic ePID system, which in several studies, has shown promise as a first-generation closed-loop device. Our center has a demonstrated track record in clinical T1D research and a well-recognized leader in studies involving hypoglycemia and closed-loop therapy. The proposed studies are novel, important, and likely to advance our understanding not only of T1D and hypoglycemia, but also closed-loop glucose control in general.
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