Calcitonin gene-related peptide: neuroendocrine communication between the pancreas, gut, and brain in regulation of blood glucose

Abstract

Background: Calcitonin gene-related peptide (CGRP), a ubiquitous neuropeptide, plays a diverse and intricate role in chronic low-grade inflammation, including conditions such as obesity, type 2 diabetes, and diabetes of the exocrine pancreas. Diabetes of exocrine pancreas is characterised by chronic hyperglycemia and is associated with persistent low-grade inflammation and altered secretion of certain pancreatic and gut hormones. While CGRP may regulate glucose homeostasis and the secretion of pancreatic and gut hormones, its role in chronic hyperglycemia after acute pancreatitis (CHAP) is not known. The aim of this study was to investigate the association between CGRP and CHAP.Methods: Fasting blood samples were collected to measure insulin, HbA1c, CGRP, amylin, C-peptide, glucagon, pancreatic polypeptide (PP), somatostatin, gastric inhibitory peptide, glicentin, glucagon-like peptide-1 and 2, and oxyntomodulin. Modified Poisson regression analysis and linear regression analyses were conducted. Five statistical models were used to adjust for demographic, metabolic, and pancreatitisrelated risk factors.Results: A total of 83 patients were recruited. CGRP was significantly associated with CHAP in all five models (P-trend <0.005). Further, it was significantly associated with oxyntomodulin (P<0.005) and glucagon (P<0.030). Oxyntomodulin and glucagon independently contributed 9.7% and 7%, respectively, to circulating CGRP variance. Other pancreatic and gut hormones were not significantly associated with CGRP.Conclusions: CGRP is involved in regulation of blood glucose in individuals after acute pancreatitis. This may have translational implications in prevention and treatment of diabetes of the exocrine pancreas.

Antidiabetic Medications and Mortality Risk in Individuals With Pancreatic Cancer–Related Diabetes and Postpancreatitis Diabetes: A Nationwide Cohort Study

“…These population-based data are in line with the recent studies by the COMSOS group into early pathogenetic events in PPDM that showed that individuals with PPDM are characterized by hyperinsulinemia, decreased insulin sensitivity, lipolysis of adipose tissue, and gut dysfunction (among other features) (36)(37)(38)(39)(40)(41)(42)(43)(44), which can (at least in part) be reverted by metformin. In addition, a 2018 study showed that the antidiabetic effect of metformin in living cells is linked to iron metabolism (45), and two 2018 clinical studies by the COSMOS group independently established the connection between iron metabolism and PPDM (46,47).…”

Global epidemiology and holistic prevention of pancreatitis

“…Taken together, these data suggest that, contrary to common belief, mechanical destruction of the islets of Langerhans as a result of pancreatic necrosis (with or without surgery) is not the only cause of PPDM-A. The pathogenesis of PPDM-A is being actively investigated, with the key mechanisms identified thus far being persistent low-grade inflammation 32–34 , dysfunction of the pancreas-gut-brain axis 35–37 , lipolysis of adipose tissue 38–40 and insulin resistance 41–43 .…”

Gut Hormone Responses to Mixed Meal Test in New-Onset Prediabetes/Diabetes After Acute Pancreatitis

“…For example, a 2014 study showed that α-melanocyte stimulating hormone triggers secretion of GLP-1 and peptide YY from the L cells [30]. Another study demonstrated that gastrin-releasing peptide is significantly associated with peptide YY [31] whereas calcitonin gene-related peptide and vasoactive intestinal peptide are significantly associated with oxyntomodulin [32,33]. Investigation of circulating levels of oxyntomodulin in individuals with NODAP vs. type 2 diabetes is now warranted to determine if decreased oxyntomodulin levels are a characteristic feature of NODAP.…”