The Amylin Circuit-Breaker – Part 3
Where Do We Go From Here?


As laid out in Parts 1 and 2, we believe that there is compelling evidence amylin plays a key role in the glucagon counterregulatory response, and that a dosing regimen which mimics the diurnal profile of circulating amylin may be the key to achieving euglycemia in T1D.  And we think the payoff to patients and healthcare systems if this hypothesis is correct warrants clinical research aimed at testing its validity.

In this Part 3 we begin the process of translating the circuit-breaker hypothesis into specific objectives for clinical research.  We do this by asking a series of questions that are raised by Parts 1 and 2.  This list is a work-in-process, because we plan to use feedback about Parts 1 and 2 to expand the list and begin turning it into specific research proposals.


Questions Raised by the Amylin Circuit-Breaker Hypothesis

Diurnal hormone profiles

  • Are the Basu et al diurnal profiles representative of the general populations?

    • What do individual patient dose/responses look like?

    • Would studies specifically designed to capture complete diurnal profiles substantiate the Basu et al findings?

    • What would the diurnal profiles of amylin look like in these studies?

  • What are the population basal/bolus relationships for insulin and amylin studies with large numbers of subjects?

    • How do meal types and exercise affect the hormone ratios?

  • How do diurnal hormone ratios differ among individual subjects?

    • Do the differences correlate with differences in age or health?

    • Do the differences imply that dual hormone dosing ratios should be personalized?

Glucagon response to hyperglycemia

  • Why doesn’t a complex carbohydrate meal affect glucagon secretion?

  • Is there a meaningful time lag between rising glucose and glucagon suppression?

Glucagon response to hypoglycemia

  • Can imposing a basal level of circulating amylin restore the counterregulatory rebound in T1D?

  • Over what time frame of therapy will basal amylin therapy restore the counterregulatory response?

  • Can basal amylin therapy increase liver glycogen stores?

Non-glycemic forcings of alpha-cell secretion

  • Are there differences in glucagon diurnal profiles among individual T1D subjects?

  • Do meals or exercise change the non-glycemic diurnal response of glucagon?

Optimizing amylin dosing

  • What basal and bolus ratios for pramlintide/insulin best mimic endogenous amylin profiles in individual patients?

  • Can a long acting analog serve to cover the basal component of amylin replacement therapy?

  • Should meals and/or exercise influence the choice of dual hormone dosing ratios?

Amylin and insulin secretion rates 

  • Do different meal types result in different A/I ratios?

  • Do individuals differ with respect to A/I ratios?

  • Do morbidities influence A/I ratios, e.g. T2D or obesity?

Assay validation

  • Why do clinical researchers report problems with amylin assay results?

    • Might the problem be sample stickiness? 

List of questions current as of 5/8/2020.