Hypoglycemia contributes substantially to the morbidity and mortality of patients with type 1 diabetes and advanced type 2 diabetes, and new strategies are needed to restore physiologic defense mechanisms against the development of severe hypoglycemic episodes. The overall aim of this application is to enhance understanding of the mechanisms contributing to the recovery of glucose counterregulation and hypoglycemia symptom recognition in patients with long standing type 1 diabetes and hypoglycemia unawareness through the investigation of novel cellular and technologic approaches to the amelioration of problematic hypoglycemia. This application builds on our recent studies demonstrating that intrahepatic islet cell transplantation can restore both islet cell and sympathoadrenal responses to hypoglycemia and normalize defective glucose counterregulation. Whether this effect is dependent on sympathetic neural or hormonal (epinephrine) input to the transplant islets is unknown, and will be investigated in the present proposal to understand its importance to protection from hypoglycemia, and inform efforts to derive islets from stem cells for transplantation outside of the liver. In addition, we have shown that implementation of real-time continuous glucose monitoring can significantly improve the endogenous glucose production response to insulin-induced hypoglycemia, although this improvement in glucose counterregulation was not observed until 18 months post-intervention. Whether residual nocturnal hypoglycemia may delay recovery in glucose counterregulation will be examined in the present proposal implementing overnight hypoglycemia avoidance with use of continuous glucose monitoring and automated suspension of insulin delivery. Specifically, we will examine 1) whether the recovery of glucose counterregulation afforded by intrahepatic islet transplantation is dependent on adrenergic input to the islets, and in the absence of an islet transplant 2) whether more stringent avoidance of hypoglycemia afforded by automated suspension of insulin delivery can restore glucose counterregulation in patients with long standing disease, and finally 3) whether clinical metrics of hypoglycemia severity and glycemic lability accurately identify patients with absent physiologic responses required to defend against the development of low blood glucose.

Public Health Relevance

Hypoglycemia remains a major barrier to the attainment of target levels of glycemic control for the majority of patients with type 1 and insulin-dependent type 2 diabetes. Moreover, a substantial portion of adult patients with type 1 diabetes experience life-threatening episodes of severe hypoglycemia, and those with long standing disease complicated by hypoglycemia unawareness and glycemic lability share the greatest burden of recurrent, problematic hypoglycemia and its related morbidity and mortality. This group of patients is most in need of new treatment strategies to restore physiologic defense mechanisms against the development of low blood glucose such as islet cell transplantation and sensor augmented pump therapy with automated suspension of insulin delivery being evaluated in the present proposal.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Arreaza-Rubin, Guillermo
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University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
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Rickels, M R; Markmann, E; Naji, A (2018) Successful pregnancies after islet transplantation for type 1 diabetes. Am J Transplant :
Rickels, Michael R; Stock, Peter G; de Koning, Eelco J P et al. (2018) Defining outcomes for ?-cell replacement therapy in the treatment of diabetes: a consensus report on the Igls criteria from the IPITA/EPITA opinion leaders workshop. Transpl Int 31:343-352
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Rickels, Michael R; Fuller, Carissa; Dalton-Bakes, Cornelia et al. (2015) Restoration of Glucose Counterregulation by Islet Transplantation in Long-standing Type 1 Diabetes. Diabetes 64:1713-8
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Rickels, Michael R; Kong, Stephanie M; Fuller, Carissa et al. (2014) Insulin sensitivity index in type 1 diabetes and following human islet transplantation: comparison of the minimal model to euglycemic clamp measures. Am J Physiol Endocrinol Metab 306:E1217-24

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