There Are No Strategies for
Normalizing Alpha-Cell Response
Various ideas for correcting alpha-cell dysfunction in T1D have been tried and/or proposed:
Exogenous glucagon infusions quickly correct hypoglycemia in T1D. Lilly introduced Glucagon for Injection as an antidote to hypoglycemia in the 1950s. More recently, glucagon has been tested in dual insulin/glucagon infusion pumps to be used in AID systems. However, recent clinical studies showed no compelling benefit, [1] [2] [3] although there may be some advantage during exercise. [4] (Skeptics have described this idea as one foot pressing the gas while the other foot is pressing the brake.) Mini-dose glucagon packaged in convenient pens may be helpful for mild exercise-induced hypoglycemia. [5] But exogenous glucagon delivery is a treatment for a T1D symptom rather than a correction of the underlying pathophysiology.
A leptin agonist appears to suppress glucagon. Leptin is believed to control glucose homeostasis via a CNS mechanism. [6] Preclinical results were encouraging. [7] However, a human pilot study with metreleptin was disappointing, [8] perhaps because of immunogenicity. [9]
GLP-1 agonists may suppress glucagon secretion, but the interaction of GLP-1 with alpha-cells is controversial. [10] And, in the clinic liraglutide failed to suppress a meal-stimulated glucagon response. [11] As reported above, exenatide failed to improve therapy of T1D.
Somatostatin inhibitors increase the release of glucagon during hypoglycemia. Somatostatin is generally thought to play a minor role in inhibiting alpha-cells in non-diabetic animals and humans. [12] In T1D, elevated somatostatin is thought to suppress alpha-cell response to hypoglycemia, and exercise caused hypoglycemia in rats can be ameliorated by a somatostatin antagonist [13] (a patent has been issued to cover this idea [14]). Before human trials, the safety of non-specific effects would need to be established, because somatostatin targets many tissues, so nonspecific effects are a concern. Moreover, inhibiting suppression of postprandial and fasting plasma glucagon might aggravate hyperglycemia. [15]
Glucagon antagonists have been shown to block the effects of hyperglucagonemia. [16] Glucagon blockade has been studied for almost 40 years. [17] The focus of this research has been on type 2 diabetes, presumably because of the risk of hypoglycemia in T1D. Studies show a potential for improved glycemic control and decreased insulin doses. [18] However, observed side effects include weight gain, increased cholesterol, and alpha-cell hyperplasia. Lilly and Merck have pursued development of glucagon antagonists, but neither reported candidates in their pipelines as of March 2019. The long history of research without a late stage drug candidate is not encouraging.
Amylin agonists have been shown to suppress glucagon secretion. 57 Pramlintide has been on the market since 2006 but has failed to achieve widespread use in T1D because of an unfavorable trade off for patients between its clinical benefits and the burdens of extra injections and nausea. Importantly, there is currently no published model that implicates amylin deficiency in the failure of counterregulation.
Several other compounds have been suggested to augment the counterregulatory response to hypoglycemia in T1D; for example: (1) glucose-dependent insulinotropic polypeptide (GIP) increases glucagon responses in humans [19], and (2) partial blockade of nicotinic acetylcholine receptors can improve the counterregulatory response in rats. [20] However, these are early stage ideas that do not target the underlying etiology of T1D.
In summary: “Non-insulin adjunct therapies in type 1 diabetes have been proposed as a means of improving glycaemic control and reducing risk of hypoglycaemia. Evidence to support this approach is, however, scant and few pharmacological agents have proved effective enough to become part of routine clinical care.” (2018) [21]
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 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.
We propose in subsequent sections exactly that new paradigm: the proper dosing of the amylin agonist pramlintide to suppress glucagon during hyperglycemia and restore glucagon counterregulation during hypoglycemia.
Endnotes:
[1] Comparison of dual-hormone artificial pancreas single-hormone artificial pancreas and conventional insulin pump therapy for glycaemic control in patients with type 1 diabetes: an open-label randomized controlled crossover trial; Lancet Diabetes and Endocrinology 3:17-26 2015.
[2] Outpatient 60-hour day-and-night glucose control with dual-hormone artificial pancreas, single-hormone artificial pancreas, or sensor-augmented pump therapy is adults with type 1 diabetes: an open label, randomized, crossover, controlled trial; Diabetes, Obesity and Metabolism 19:713-20 2017.
[3] Single- and dual-hormone artificial pancreas for overnight glucose control in type 1 diabetes; J Clin Endocrinol Metab 101(1):214-23 2016.
[4] Efficacy of single-hormone and dual-hormone artificial pancreas during continuous and interval exercise in adult patients with type 1 diabetes: randomized controlled crossover trial; Diabetologia 59:2561-71 2016.
[5] Is mini-dose glucagon the answer to preventing exercise-related dysglycemia?; Diabetes Care 41:1842-3 2018.
[6] Leptin activates a novel CNS mechanism for insulin-independent normalization of severe diabetic hyperglycemia; Endocrinology 152(2):394-404 2011.
[7] Glucagon is the key factor in the development of diabetes; Diabetologia 59:1372-5 2016.
[8] Efficacy and safety of metreleptin therapy in patients with type 1 diabetes – A pilot study; Diabetes Care 40:694-7 2017.
[9] Immunogenicity associated with metreleptin treatment in patients with obesity or lipodystrophy; Clin Endocrinol 85:137-49 2016.
[10] Modulation of the pancreatic hormone, glucagon by the gut peptide, GLP-1 – Controversies, challenges and future directions; Emerging Trends in Chemical Sciences 1-9 2018.
[11] Pramlintide by not liraglutide suppresses meal-stimulated glucagon responses in type 1 diabetes; J Clin Endocrinol Metab 103(3):1088-94 2018.
[12] Glucagon secretion and signaling in the development of diabetes; Frontiers in Physiology 3:1-12 2012.
[13] Amelioration of hypoglycemia via somatostatin receptor type 2 antagonism in recurrently hypoglycemic diabetic rats; Diabetes 62:2215-22 2013..
[14] Method of controlling tight blood glucose by somatostatin receptor antagonists; US Patent No. 7,862,825 B2 2011.
[15] Can somatostatin antagonism prevent hypoglycaemia during exercise in type 1 diabetes?; Diabetologia 59:1632-35 2016.
[16] Clinical trials, triumphs, and tribulations of glucagon receptor antagonists; Diabetes Care 39:1075-7 2016.
[17] Hyperglycemia of diabetic rats decreased by a glucagon receptor antagonist; Science 215(4536):1115-6 1982.
[18] Adjunctive therapy for glucose control in patients with type 1 diabetes; Diabetes, Metabolic Syndrome and Obesity – Targets and Therapy 11:159-73 2018.
[19] Glucose-dependent insulinotropic polypeptide augments glucagon responses to hypoglycemia in type 1 diabetes; Diabetes 64:72-8 2015.
[20] Partial blockade of nicotinic acetylcholine receptors improves the counterregulatory response to hypoglycemia in recurrently hypoglycemic rats; Am J Physiol Endocrinol Metab 307(7):E580-8 2014.
[21] SGLT inhibitor adjunct therapy in type 1 diabetes; Diabetologia 61:2126-33 2018.