The Amylin Circuit-Breaker:
Restoring Glucagon Counterregulation in T1D

Introduction

The purpose of this presentation is to propose a novel hypothesis for a therapeutic strategy that may restore the glucagon counterregulatory response to hypoglycemia in Type 1 Diabetes (T1D).  In short, we believe that a neuroendocrine hormone, amylin, acts during euglycemia as a tonic inhibitor of alpha-cell secretion, and that hypoglycemia activates a neural circuit-breaker to interrupt this suppression signal, thereby releasing a glucagon counterregulatory rebound.  This model proposes that beta-cells are the primary sensors of hyperglycemia, that the brain is the primary sensor of hypoglycemia, and that amylin is central to the regulation of alpha-cells in glucose homeostasis.

The roadmap for this hypothesis aims to correct a shortcoming of previous alpha-cell model building efforts:  amylin is a missing link that has not been considered in models of glucagon counterregulation.  As recently as December 2018, a review of the role of the alpha-cell in diabetes contained no mention of amylin’s role in regulating glucagon secretion.[1]  We have been unable to find a single literature reference to the idea that amylin is a key player in the alpha-cell response to hypoglycemia.

Our discussion is organized into three parts and two appendices:

• Part 1: A New Model for Glucagon Counterregulation.  Technology advances focused on insulin therapy of T1D have stalled with respect to normalizing HbA1c, and the biggest barrier to achieving euglycemia is the risk of iatrogenic hypoglycemia.  None of the available adjunctive pharmaceutical therapies appear to offer promise for solving this problem, and so there is a pressing need for a new model of alpha-cell regulation.  We propose a new simple systems model of the alpha- and beta-cell regulatory network whereby (1) the beta-cells are the primary sensory mechanism for preventing hyperglycemia while (2) the brain is the primary sensory mechanism for preventing hypoglycemia.  We demonstrate how amylin can be expected to play the pivotal role in this model, and we cite clinical data that is indirectly supportive of our hypothesis.

• Part 2:  Getting the Amylin Dosing Right.  We propose a teleological rationale for beta-cell secretion of two glucoregulatory hormones, and we show how that rationale is supported by the physiology of these peptides and the resulting diurnal peripheral concentrations.  We then demonstrate that FDA-approved dosing of pramlintide does NOT mimic the natural profile, but rather causes overdosing at mealtimes and underdosing between meals and overnight.  We believe this incorrect dosing is the cause of the poor efficacy and tolerability that has limited the use of amylin replacement therapy and is the reason pramlintide has failed to demonstrate restoration of glucagon counterregulation.  We propose the use of an automated Dual Ratio Amylin/Insulin system to correct this problem, and we discuss the merits of other amylin agonist formulation and delivery strategies.

• Part 3:  Where Do We Go From Here.  We begin the process of defining the clinical research needed to confirm our circuit-breaker hypothesis by raising a series of questions that need answering.  We consider this a work-in-process that will evolve over time as we receive feedback on the hypotheses presented in Parts 1 and 2.

• Appendix A:  Alpha-Cell Response to Hyperglycemia.  We take a deep dive into recent data from diurnal studies of glucagon, and we show that (1) mealtime influx of blood glucose explains only about half of the normal daily variations in circulating glucagon concentrations, and that (2) alpha-cell response to hyperglycemia is eliminated by T1D.  This data is consistent with the idea that beta-cell secretion of amylin is the glucoregulatory signal which suppresses alpha-cell secretion in response to rising blood glucose.

• Appendix B:  Dual Ratio Amylin/Insulin Dosing.  We present details of the calculations that resulted in recommending 6µg/U basal and 2µg/U bolus as baseline infusion rates for personalizing dual hormone replacement therapy.

The goal of this presentation is to stimulate interest in starting clinical research aimed at testing our hypothesis that appropriate amylin replacement dosing can restore the glucagon counterregulatory response in T1D.  During the past half-century, much data about alpha-cell function has been accumulated and interpreted based on several physiological models.  Many contradictions have been observed, and these models remain controversial.  There is good reason to expect that some data aimed at validating these prior models will appear to contradict our hypothesis: glucose homeostasis is a complex system of multiple organs, signals, and redundancies which is difficult to decipher – especially if the physiologic models and confirmatory experiments have not considered a key component of the alpha-cell sensing system, the neuroendocrine hormone amylin.

For readers wishing more detail about amylin, the most comprehensive analysis of the hormone and its role in glucose homeostasis can be found in the book Amylin: Physiology and Pharmacology by Andrew Young, who is the world’s leading expert on amylin. [2] 

A note on the use of the royal “we” in this work:  The author wishes to acknowledge the collaborative help from a wide range of sources far more knowledgeable about glucose homeostasis and pathology, including both the authors of referenced works and colleagues who encouraged and supported the development of the amylin circuit-breaker hypothesis.

Howard E (Ted) Greene, Jr.
Founding CEO of Amylin Pharmaceuticals
April 2020

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Endnotes

[1]   The alpha cell in diabetes mellitus; Nature Reviews Endocrinology; 14:694-704 2018.

[2]  Amylin: Physiology and Pharmacology; Advances in Pharmacology Volume 52, Elsevier Academic Press 2005.

4/30/2020