The Amylin Circuit-Breaker – Part 2
Getting the Amylin Dosing Right

The amylin circuit-breaker model is an hypothesis built on published knowledge about alpha-cell regulation and amylin physiology.  It proposes that appropriately dosed amylin replacement therapy might not only correct prandial hyperglucagonemia, but also restore the glucagon counterregulatory response in T1D.

However, an amylin agonist – pramlintide – has been used to treat T1D since 2005 without any documented evidence of lowering the risk of iatrogenic hypoglycemia.  Moreover, the poor benefit-to-burden tradeoff has discouraged widespread use of pramlintide.  How, then, can the disappointing history of pramlintide be explained if the amylin circuit-breaker model is correct?

In this Part 2 we address the following topics:

  • Why do beta-cells make two hormones?  We believe this teleological question points to a novel hypothesis about amylin secretion: diurnal profiles of insulin and amylin need to be different to achieve glycemic homeostasis.

  • How could beta-cells generate two different diurnal profiles?  Differences in peptide clearance and secretion rates of amylin and insulin would result in different pulsatile diurnal profiles to optimize timing of signals that regulate glucose influx and efflux.

  • How do the plasma profiles of insulin and amylin compare?  Available data support the conclusions that circulating levels of these two hormones generate variable ratios over diurnal cycles, and that amylin exposure is primarily basal as opposed to the bolus exposure of insulin.

  • How well does pramlintide dosing mimic endogenous amylin?  Comparison of FDA-approved pramlintide dosing results in vivo to endogenous amylin diurnal profiles provides an explanation for the poor efficacy and tolerability of mealtime injections.

  • How could pramlintide dosing be changed to better mimic endogenous amylin profiles?  We propose that dual hormone AID systems using different basal and bolus ratios of pramlintide to insulin would optimize amylin replacement therapy.  Other approaches using formulations and devices now under development might also restore some of the counterregulatory response in T1D.

In Part 3 we make a start at designing clinical research aimed at testing our hypothesis.