The Amylin Circuit-Breaker – Part 1
A New Model for Glucagon Counterregulation

Overview of Part 1

In Part 1 we lay out the logic and data supporting a novel hypothesis about the physiology regulating the counterregulatory response to hypoglycemia.  This chapter is organized around the following issues:

  • Why did we undertake this project?  Progress toward normalizing HbA1c in T1D has reached a point of diminishing returns well above healthy levels in spite of the advent of automated insulin delivery systems.  Inherent limitations in subcutaneous insulin delivery point to the need for adjunctive drug therapy to resume progress toward euglycemia.

  • Are there any promising candidates to fill this adjunctive role?  To date the obvious adjunctive drug candidates have proved disappointing. What’s needed is a new target for drug development.

  • Where should the search for a solution begin?  We believe the most promising target is the lack of response by alpha-cells to both rising and falling glucose in T1D.  Normalizing glucagon secretion would relax the most important constraint on insulin therapy: the risk of iatrogenic hypoglycemia.

  • What about existing strategies for restoring the glucagon counterregulatory response?  None of the approaches taken to date have successfully restored normal alpha-cell functions in T1D, and we can find no new ideas for doing so in the literature.

  • How should a new hypothesis be developed?  We believe the solution starts with constructing a new model of alpha-cell sensing of hypoglycemia that builds on data in the literature beyond the classical endocrinology.

  • What is the central concept of our new model?  Systems analysis supports the idea that alpha-cells require tonic inhibition during euglycemia, and that the counterregulatory response is a rebound triggered by the onset of hypoglycemia.

  • What is the likely suppression signal to alpha-cells?  We believe the neurohormone amylin is the alpha-cell inhibitor because (1) it is the most potent known suppressor of glucagon secretion, (2) hypoglycemia activates a “circuit-breaker” for this CNS mediated suppression, and (3) healthy amylin secretion is eliminated by T1D.

  • What data supports the amylin circuit-breaker hypothesis?  There is clinical evidence consistent with the idea, but no studies of counterregulation have considered the role of amylin.

  • Is the efficacy of islet transplants consistent with the hypothesis? We demonstrate how restoration of counterregulation by denervated, transplanted alpha-cells is consistent with the CNS circuit-breaker concept.

In Part 2 we address the issue of why a decade and a half of amylin replacement therapy has not already validated our hypothesis.