There Is Anecdotal Support For
the Amylin Circuit-Breaker Hypothesis
We are proposing a revised model of counterregulation that substitutes amylin for insulin in the alpha-cell switch-off model. Our theory therefore predicts that glucagon secretion should be more closely correlated with amylin plasma levels than with insulin. In fact, this prediction is confirmed by data shown in Exhibit 14. [1]
To quote the source article: “When glucagon secretion was correlated with the insulin and amylin concentrations, both total and supra-basal area-under-the-curve, no significant relationship was detected. However, when glucagon secretion was correlated with the dynamic secretions of amylin and insulin (from C–peptide), i.e. their changes from basal, a significant correlation between the secretion of glucagon and that of amylin (R = −0·6, P = 0·008), but not with that of insulin (R = −0·2, P = 0·4) was found. When the subject with very high insulin secretion was excluded, the correlation was even weaker.”
If C-peptide secretion is used as a proxy for residual beta-cell function, C-peptide has been shown to correlate negatively with glucose instability in T1D as shown in Exhibit 15. [2]
To quote the authors: “Given that T1DM is the only condition in which such glucose volatility occurs and that T1DM is the only condition in which the islets are devoid of beta-cells, the possibility of a causal relationship between the volatility and the loss of paracrine control of glucagon secretion by insulin (substitute amylin!) seems quite plausible.” [3]
A study published in February 2020 found the following: “(W)e demonstrated significant associations between residual C-peptide secretion and lower glucose variability and low-glucose events in flash glucose monitoring users. These associations were independent of prevailing HbA1c and diabetes duration.” [4]
These findings point to the beta-cells as playing a central role in maintaining blood glucose stability, which is consistent with our theory that amylin is the regulatory link between beta- and alpha-cells.
It’s important to note that the effects of amylin have NOT been considered in any interpretation of results aimed at confirming the insulin switch-off model. Recall the 1983 experiment by Unger et al which implied that beta-cells do not regulate alpha-cell secretion; by manipulating only insulin, they clearly missed considering any effects of amylin and the CNS circuit-breaker. [10]
“(G)lucagon responses were absent during insulin-induced hypoglycemia in diabetic patients who were plasma C-peptide negative but present in patients who were plasma C-peptide positive and suggested that it was the absence of beta-cell function that might be causally related to defective alpha-cell dysfunction during hypoglycemia.”
“Cryer et al. have championed the hypothesis that defective glucagon secretion during hypoglycemia in diabetic patients might be due to the lack of a switch-off signal from the beta-cell. This hypothesis had earlier been rejected by Bolli et al., who examined glucagon responses during hypoglycemia under conditions of varying exogenous insulin and glucose levels in clamp studies in normal subjects. They found similar glucagon responses under all conditions and concluded that hypoglycemia is the primary signal for glucagon secretion independent of insulin levels.”
In these experiments Bolli et al administered exogenous insulin, but NOT exogenous amylin. So, the results support the conclusion that insulin is not the alpha-cell suppression signal. But, we believe they were infusing the wrong beta-cell hormone to confirm the switch-off model.
Bottom line, experimental designs and interpretations of glucagon counterregulation studies would have been very different had researchers considered the biology of amylin. Reflecting the lack of interest in amylin, at the 2018 American Diabetes Association Scientific Sessions, there were only three presentations that mentioned amylin out of 2,490 oral, poster, and late-breaking submissions. [11]
Endnotes:
[1] Inverse relation between amylin and glucagon secretion in healthy and diabetic human subjects; European Journal of Clinical Investigation 33:316-22 2003.
[2] Correlation between minimal secretory capacity of pancreatic beta-cells and stability of diabetic control; Diabetes 37:81-8 1988.
[3] Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover; The Journal of Clinical Investigation 122:4-12 2012.
[4] Preserved C-peptide secretion is associated with fewer low-glucose events and lower glucose variability on flash glucose monitoring in adults with type 1 diabetes; Diabetologia 63:906-14 2020.
[5] Restoration of glucose counterregulation by islet transplantation in long-standing type 1 diabetes; Diabetes 64:1713-8 2015.
[6] Glucagon, catecholamine and pancreatic polypeptide secretion in type 1 diabetic recipients of pancreas allografts; J Clin Invest 86:2008-13 1990.
[7] Pancreas transplantation restores epinephrine response and symptom recognition during hypoglycemia in patients with long-standing type 1 diabetes and autonomic neuropathy; Diabetes 46:249-57 1997.
[8] Glycemic thresholds for activation of counterregulatory hormone and symptom responses in islet transplant recipients; The Journal of Clinical Endocrinology & Metabolism; 92:873-9 2007.
[9] Autonomic mediation of glucagon secretion during hypoglycemia – implications for impaired alpha-cell responses in type 1 diabetes; Diabetes 47:995-1005 1998.
[10] Regulation of alpha-cell function by the beta-cell during hypoglycemia in Wistar rats: the “switch-off” hypothesis; Diabetes 53:1482-7 2004.
[11] http://diabetes.diabetesjournals.org/content/suppl/2018/07/05/67.Supplement_1.DC1
[12] Amylin and the integrated control of nutrient influx; Advances in Pharmacology 52:67-77 2005.