Amylin Is the Ideal
Alpha-Cell Inhibitor
In 1987 scientists discovered that beta-cells produce a companion hormone to insulin: amylin (sometimes known as islet amyloid polypeptide [IAPP]). (For a 2015 review of amylin’s physiology and pathology, see reference [1].) It seems reasonable to hypothesize that this second secretion is also a key player in glucose homeostasis: teleologically a beta-cell secreted, amidated peptide is an energy hill that Mother Nature wouldn’t climb without good reason. [2]
In fact, three decades of research have shown that amylin plays a complementary role to insulin in regulating glucose homeostasis: [3]
Insulin controls glucose efflux (disappearance) from plasma by increasing glucose transport into liver, muscle, and fat storage.
Amylin controls glucose influx (appearance) into plasma by:
Slowing gastric emptying, which is the primary regulator of the rate of caloric influx from the stomach to systemic circulation. [4] Gastric emptying rate has been estimated to account for about 34% of the variance in peak plasma glucose after a 75-g oral glucose load, [5] and amylin is the most potent among the hormones known to regulate gastric emptying. [6]
Inducing satiety, which controls the amount of food intake and thereby exogenous glucose absorption. 92
Suppressing glucagon secretion, which controls the rate of endogenous glucose production from the liver. Amylin has a potent (EC50 = 18 pM) and profound (~70% inhibition) effect to inhibit amino-acid stimulated glucagon secretion.[7] This suppression is a direct signal to alpha-cells that is not secondary to the slowing of gastric emptying. 107
As shown in Exhibit 9, amylin is a potent suppressor of postprandial alpha-cell secretion. [8]
Importantly, amylin exerts its glucoregulatory effects through the central nervous system:
Amylin’s primary receptor binding sites are in the brain, and the receptors with access to plasma peptides are in the area postrema. 100 The area postrema provides direct access to neurons of brain areas with vital roles in autonomic control of systems critical to regulating feeding and metabolism, and, the area postrema has been the source of several anti-diabetic and anti-obesity targets. [9]
Amylin’s glucagon suppression effects have been shown to be extrinsic to the pancreas. [10]
Amylin’s modulation of gastric emptying requires an intact vagus nerve. [11]
Amylin is a neuroendocrine hormone which participates in glucose homeostasis via the central nervous system.
Today it is widely recognized that insulin and amylin balance glucose fluxes at mealtime to prevent hyperglycemia, and an amylin agonist – pramlintide or SYMLIN – is FDA approved as an adjunct to insulin therapy. Pramlintide is indicated for modest HbA1c reductions in T1D: FDA approved labeling says 0.33% HbA1c, which is helpful but not exciting. 20 Moreover, studies have shown pramlintide provides ancillary benefits, including postprandial glucose smoothing [12] and weight loss. [13]
In March 2020, a dual hormone, insulin-amylin AID system was reported that used separate pumps programmed to deliver a fixed dose ratio of pramlintide to insulin for 24-hours. [14] TIR improved from 74% to 84% in the rapid insulin with pramlintide arm compared to the insulin-only arm, and the eAG pointed to an improvement in HbA1c from 6.6% to 6.3%, about the same as with pramlintide delivered with injection pens. These results stimulated an editorial in the same issue titled Rediscovery of the Second Beta-Cell Hormone which concluded, “The good news for now is that we are rediscovering that diabetes is a two hormone deficiency disorder and beginning to test the potential of co-replacement by continuous infusion systems to overcome the limitations of replacing insulin alone.” [15]
Encouraging news because the hassle of mealtime injections is the biggest barrier to amylin replacement therapy. However, we are unaware that any of the studies completed, underway, or planned are designed to examine amylin’s role in the glucagon counterregulatory defect of T1D.
What points to amylin as the
key to restoring counterregulation?
Amylin replacement is now well documented as helpful in controlling postprandial blood glucose. But, how well does amylin’s known physiology match up to the alpha-cell switch-off signal parameters discussed above? To summarize:
Central to T1D etiology. Amylin is secreted by beta-cells, which is the basic defect in T1D. If it were an important player in glucose homeostasis, its absence in T1D could be expected to play a central role in the pathogenesis of this disease. Thus, it makes sense to consider how amylin deficiency could result in alpha-cell disruption.
Potent alpha-cell inhibitor. Amylin’s known actions on alpha-cells are consistent with tonic inhibition of glucagon as proposed by the in silico switch-off model. Amylin is a potent alpha-cell inhibitor, which should make it a key player in any glucagon-centric model of T1D. [16] [17] Its alpha-cell regulatory role is implied by its plasma increases at mealtime with insulin, which is the time when glucagon suppression is most needed to minimize hepatic glucose output.
Hypoglycemia interrupts inhibition. Because amylin’s glucoregulatory effect is routed through the CNS, amylin’s alpha-cell inhibitor effect is interrupted when the brain detects hypoglycemia. Amylin suppresses glucagon secretion during euglycemia and hyperglycemia, but during hypoglycemia this suppression is cancelled.
Basal levels for tonic inhibition. Whereas insulin’s diurnal profile concentrates most of its daily exposure in mealtime spikes, amylin’s diurnal profile has a greater basal component.
The next two sections elaborate on these latter two observations.
The amylin “circuit-breaker”
With respect to gastric emptying, several studies have demonstrated that hypoglycemia accelerates gastric emptying in healthy and T1D subjects. For example, in one study of healthy subjects, during hypoglycemia the half-times for emptying half their stomachs were about 60% less than during euglycemia: [18]
What causes hypoglycemia to accelerate gastric emptying? Answer: in response to hypoglycemia, a CNS-mediated circuit-breaker trips, which cancels amylin’s neural signal to slow gastric emptying. This cancellation occurs independent of circulating amylin concentrations, as shown in Exhibit 10. In this experiment, euglycemic rats were injected with human insulin and either rat amylin or saline immediately before being gavaged with an acaloric gel containing dye, which produced a wide range of plasma glucose levels. At 20 minutes post-gavage, stomach contents were analyzed for dye retention. [19]
Note that below about 50 mg/dl amylin has no effect on the rate of gastric emptying.
This circuit-breaker effect has also been confirmed for glucagon suppression in humans. Exhibit 11 shows results from a study during which T1D subjects were infused with pramlintide while maintained in either euglycemic or hypoglycemic clamps. During euglycemia alpha-cell secretion was depressed in the pramlintide arm, but this suppression ended with the onset of the hypoglycemic clamp. [20]
These data demonstrate that amylin’s glucose regulatory effects are subject to a CNS-mediated circuit-breaker which kicks open when blood glucose levels in the brain drop into the hypoglycemia range. Even when circulating amylin levels are elevated, the onset of hypoglycemia triggers the circuit-breaker, which immediately shuts down amylin’s restraining effects on glucagon and gastric emptying, thereby amplifying influxes of both hepatic and nutrient glucose.
Based on a Google Scholar search, this amylin circuit-breaker does not appear to be widely understood beyond a core group of amylin researchers. In fact, just the opposite impression was created when pramlintide was first approved for clinical use: the drug developed a reputation for causing hypoglycemia in T1D patients. During clinical trials the FDA mandated that insulin dosing be held constant, because the studies were designed to demonstrate the independent effects of amylin replacement on HbA1c; as a result patients experienced iatrogenic hypoglycemia from having too much insulin onboard at the same time their glucagon counterregulatory response was defective. To mitigate this risk, the approved labeling for pramlintide recommends reducing premeal short-acting insulin doses by 50%.
Amylin provides tonic inhibition
Circulating amylin exhibits a greater basal component than circulating insulin. In one study about 65% of daily insulin exposure in healthy nondiabetics is associated with prandial surges; in another study, the prandial surges accounted for about 74% of daily exposure. [21] Exhibit 12 demonstrates the results from the first study graphically. In contrast, over 60% of daily amylin exposure is from the basal component as shown in Exhibit 13.
The amylin basal component of daily exposure is consistent with the need for the tonic inhibition of alpha-cell secretion.
The amylin circuit-breaker model
We now propose the following revision of the Farhy et al simple system model:
In our model, rising blood glucose is sensed by the beta-cells, which increase secretion of amylin, which activates receptors in the brain, which transmits the amylin signal to the alpha-cells, which respond by decreasing secretion of glucagon. The onset of hypoglycemia is sensed by the brain, which throws the circuit-breaker, which shuts off the amylin signal, causing the alpha-cells to rebound with a surge in glucagon secretion.
If this model is correct, then amylin replacement is an ideal fit with our pharmaceutical criteria for restoring counterregulation in T1D:
Next, we address the obvious question: is this amylin circuit-breaker model consistent with research results in the field of glucagon counterregulation?
Endnotes:
[1] Amylin: pharmacology, physiology, and clinical potential; Pharmacological Reviews 67:564-600 2015.
[2] Peptide amidation: Production of peptide hormones in vivo and in vitro; Biotechnology and Bioprocess Engineering 6:244-251 2001.
[3] Glucose metabolism and regulation: beyond insulin and glucagon; Diabetes Spectrum 17(3):183-90 2004.
[4] Calories and gastric emptying: a regulatory capacity with implications for feeding; Am J Physiol 236(5):R254-60 1979.
[5] Relationship between oral glucose tolerance and gastric emptying in normal healthy subjects; Diabetologia 36:857-62 1993.
[6] Dose-responses for the slowing of gastric emptying in a rodent model by glucagon-like peptide (7-36)NH2, amylin, cholecystokinin, and other possible regulators of nutrient uptake; Metabolism 45:1-3 1996.
[7] Inhibition of Glucagon Secretion; in Amylin: Physiology and Pharmacology, page 151-71 2005.
[8] The human amylin analog, pramlintide, corrects postprandial hyperglucagonemia inpatients with type 1 diabetes; Metabolism 51:636-41 2002.
[9] Brainstem sensing of meal-related signals in energy homeostasis; Neuropharmacology 63:31-45 2012.
[10] Selective amylin inhibition of the glucagon response to arginine is extrinsic to the pancreas; Am J Physiol Endocrinol Metab 280:E443-9 2001.
[11] Amylin modulation of gastric emptying in rats depends upon an intact vagus nerve; Diabetes 45(suppl.2):235A 1996.
[12] Considering pramlintide therapy for postprandial blood glucose control; Diabetes Spectrum 20:108-14 2007.
[13] The role of pramlintide for weight loss; the Annals of Pharmacotherapy 44:538-45 2010.
[14] A Novel Dual-Hormone Insulin-and-Pramlintide Artificial Pancreas for Type 1 Diabetes: A Randomized Controlled Crossover Trial; Diabetes Care 43:597-606 2020.
[15] Rediscovery of the Second Beta-Cell Hormone: Co-replacement With Pramlintide and Insulin in Type 1 Diabetes; Diabetes Care 43:518-21 2020.
[16] Dose-response for glucagonostatic effect of amylin in rats; Metabolism 46:67-70 1997.
[17] The human amylin analog, pramlintide, corrects postprandial hyperglucagonemia in patients with type 1 diabetes; Metabolism 51:636-41 2002.
[18] Hypoglycemia increases the gastric emptying rate in healthy subjects; Diabetes Care 18:674-6 1995.
[19] Hypoglycemia Overrides Amylin-Mediated Regulation of Gastric Emptying in Rats; Diabetes 47:93-7 1998.
[20] Acute effects of the human amylin analog AC137 on basal and insulin-stimulated euglycemic and hypoglycemic fuel metabolism in patients with insulin-dependent diabetes mellitus; Journal of Clinical Endocrinology and Metabolism 81:1083-9 1996.
[21] Diurnal patter to insulin secretion and insulin action in healthy individuals; Diabetes 61:2691-700 2012.