The Amylin Circuit-Breaker
Restoring Glucagon Counterregulation in T1D
EXECUTIVE SUMMARY
We propose that a new dosing regimen for an amylin analog, pramlintide, is probably the key to restoring most of the glucagon counterregulatory response to hypoglycemia in Type 1 Diabetes. We think the clinical need and the possibility of success warrant clinical research aimed at testing our hypothesis.
Automated insulin delivery systems promise to reduce the therapy burden on T1D patients and improve time in range. But studies have not shown convincing evidence that AID can dramatically shrink the gap between healthy blood glucose levels and the chronic hyperglycemia characteristic of T1D. So long as that gap exists, the comorbidities and early mortality associated with T1D can be expected to continue.
The barrier to closing the gap with more intensive insulin therapy is the risk of hypoglycemia caused by a defect in glucagon counterregulation in T1D: islet alpha-cells fail to respond to the onset of hypoglycemia by increasing glucagon secretion to amplify hepatic glucose production. After decades of clinical research, a pharmaceutical strategy for correcting this defect remains elusive.
To restore normal alpha-cell secretory patterns in T1D, a new drug concept is needed that would suppress glucagon secretion in response to rising blood glucose, and that would stimulate glucagon secretion at the onset of hypoglycemia. Defining that new drug target will require a new model of alpha-cell homeostasis, a paradigm that is novel, yet plausible, and theoretically restores both appropriate glucagon suppression during hyperglycemia and stimulation during hypoglycemia. The paradigm should propose a new perspective on alpha-cell control mechanisms directly caused by the beta-cell deficit, and it should suggest a hypothetical drug target which can form the basis for clinical research. Ideally the paradigm should be testable immediately without requiring new drug discovery or delivery technology.
To this end we propose a new “circuit-breaker” model of counterregulation: During euglycemia alpha-cells are in a state of tonic inhibition by the neuroendocrine hormone amylin, which delivers its suppressing effect via the CNS. When beta-cells detect the onset of hyperglycemia, they increase this inhibition by secreting more amylin. When the brain detects the onset of hypoglycemia, it interrupts the amylin suppression signal, resulting in a rebound of glucagon secretion. Ergo, the circuit-breaker effect.
FDA-approved dosing of the amylin analog pramlintide results in overdosing and nausea at mealtimes and does not provide the tonic inhibition needed between meals and overnight. We propose that a dual hormone AID system with an algorithm that provides different insulin/amylin ratios for basal and bolus infusion rates could be the solution to restoring glucagon counterregulation in T1D, as well as to smoothing postprandial blood glucose.