Website Table of Contents

Executive Summary

Introduction

Part 1: A New Model for Glucagon Counterregulation

• A breakthrough is needed for treating T1D

• No adjunctive drug candidates promise to overcome insulin infusion defects

• Alpha-cell dysfunction should be the focus of the new T1D model

• There are no strategies for normalizing alpha-cell response

• The new model focuses on alpha-cell sensing of hypoglycemia

• Systems analysis supports the idea of an alpha-cell inhibitor

• Amylin is the ideal alpha-cell inhibitor

• There is anecdotal support for the amylin circuit-breaker hypothesis

• Intrahepatic islet transplants demonstrate correct amylin replacement

Part 2: Getting the Amylin Dosing Right

• Beta-cells secrete two hormones for a good reason

• Physiology points to differences in hormone diurnal profiles

• Amylin is the more “basal” of the two beta-cell hormones

• Mealtime dosing of pramlintide is dysfunctional

• The solution is dual hormone automated insulin delivery

Part 3: Where Do We Go From Here?

Appendix A: Alpha-Cell Response to Hyperglycemia in Health and Type 1 Diabetes

• Introduction

• Data sources

• Constructing diurnal profiles

• Diurnal profiles compared: healthy vs. T1D

• The glycemic alpha-cell regulation model

• The nonglycemic alpha-cell regulation model

• The integrated alpha-cell regulation model

Appendix B: Derivation of Appropriate Dual Ratio Amylin/Insulin Dosing

Appendix C: US Patent 9,656,017 Infusion Delivery Devices and Methods

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