Inhibition of Calcitonin Gene-related Peptide (CGRP) has the Potential to Extend First-phase Insulin Secretion

Abstract

The neuropeptide calcitonin gene-related peptide (CGRP), known to have a strong vasodilation effect, has also been reported to inhibit insulin secretion. However, the physiological effect of CGRP related to insulin secretion is still unknown. Here, we evaluated the effect of whole-body CGRP inhibition by anti-CGRP antibodies in mice using an oral glucose tolerance test. CGRP has 2 isotypes, alpha-CGRP and beta-CGRP, and we confirmed the antibody used in this study inhibits function of both. Then, we evaluated the effect of CGRP inhibition on insulin secretion and discovered that CGRP inhibition lead to extend first-phase insulin secretion in an antibody dose-dependent manner and nearly plateaued at 10 mg/kg, although the effect was not so large and didn’t affect plasma glucose level. We then measured the plasma antibody concentration and it was increased depending on administration dose. So, the effect of first-phase insulin secretion extension was determined to be the result of complete inhibition of CGRP by the antibody. These results indicate that CGRP has the potential to inhibit insulin secretion and shorten first-phase insulin secretion. However the effect of CGRP inhibition was not so large at least on healthy condition, and it indicates the effect of CGRP related to insulin secretion on healthy physiological condition may be limited.

Key words

calcitonin gene-related peptide (CGRP) - oral glucose tolerance test (OGTT) - insulin secretion - diabetes

^* Equal contribution.

• References

• 1 Pettersson M, Ahren B, Bottcher G et al. Calcitonin gene-related peptide: occurrence in pancreatic islets in the mouse and the rat and inhibition of insulin secretion in the mouse. Endocrinology 1986; 119: 865-869
• 2 Rasmussen TN, Bersani M, Schmidt P et al. Isolation and molecular characterization of porcine calcitonin gene-related peptide (CGRP) and its endocrine effects in the porcine pancreas. Pancreas 1998; 16: 195-204
• 3 Straub SG, Sharp GW. Glucose-stimulated signaling pathways in biphasic insulin secretion. Diabetes Metab Res Rev 2002; 18: 451-463
• 4 Curry DL, Bennett LL, Grodsky GM. Dynamics of insulin secretion by the perfused rat pancreas. Endocrinology 1968; 83: 572-584
• 5 Luzi L, DeFronzo RA. Effect of loss of first-phase insulin secretion on hepatic glucose production and tissue glucose disposal in humans. Am J Physiol 1989; 257: E241-E246
• 6 Seino S, Shibasaki T, Minami K. Dynamics of insulin secretion and the clinical implications for obesity and diabetes. J Clin Invest 2011; 121: 2118-2125
• 7 McLatchie LM, Fraser NJ, Main MJ et al. RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature 1998; 393: 333-339
• 8 Smillie SJ, Brain SD. Calcitonin gene-related peptide (CGRP) and its role in hypertension. Neuropeptides 2011; 45: 93-104
• 9 Wang X, Fiscus RR. Calcitonin gene-related peptide increases cAMP, tension, and rate in rat atria. Am J Physiol 1989; 256: R421-R428
• 10 Maton PN, Sutliff VE, Zhou ZC et al. Characterization of receptors for calcitonin gene-related peptide on gastric smooth muscle cells. Am J Physiol 1988; 254: G789-G794
• 11 Laufer R, Changeux JP. Calcitonin gene-related peptide elevates cyclic AMP levels in chick skeletal muscle: possible neurotrophic role for a coexisting neuronal messenger. EMBO J 1987; 6: 901-906
• 12 Kubota M, Moseley JM, Butera L et al. Calcitonin gene-related peptide stimulates cyclic AMP formation in rat aortic smooth muscle cells. Biochem Biophys Res Commun 1985; 132: 88-94
• 13 Gray DW, Marshall I. Human alpha-calcitonin gene-related peptide stimulates adenylate cyclase and guanylate cyclase and relaxes rat thoracic aorta by releasing nitric oxide. Br J Pharmacol 1992; 107: 691-696
• 14 Raddino R, Pela G, Manca C et al. Mechanism of action of human calcitonin gene-related peptide in rabbit heart and in human mammary arteries. J Cardiovasc Pharmacol 1997; 29: 463-470
• 15 Ando K, Pegram BL, Frohlich ED. Hemodynamic effects of calcitonin gene-related peptide in spontaneously hypertensive rats. Am J Physiol 1990; 258: R425-R429
• 16 Gardiner SM, Compton AM, Kemp PA et al. Antagonistic effect of human alpha-calcitonin gene-related peptide (8-37) on regional hemodynamic actions of rat islet amyloid polypeptide in conscious Long-Evans rats. Diabetes 1991; 40: 948-951
• 17 Benemei S, Nicoletti P, Capone JG et al. Migraine. Handb Exp Pharmacol 2009; 75-89
• 18 Hou Q, Barr T, Gee L et al. Keratinocyte expression of calcitonin gene-related peptide beta: implications for neuropathic and inflammatory pain mechanisms. Pain 2011; 152: 2036-2051
• 19 Yu Y, Lundeberg T, Yu LC. Role of calcitonin gene-related peptide and its antagonist on the evoked discharge frequency of wide dynamic range neurons in the dorsal horn of the spinal cord in rats. Regul Pept 2002; 103: 23-27
• 20 Sun RQ, Lawand NB, Willis WD. The role of calcitonin gene-related peptide (CGRP) in the generation and maintenance of mechanical allodynia and hyperalgesia in rats after intradermal injection of capsaicin. Pain 2003; 104: 201-208
• 21 Martinez A, Kapas S, Miller MJ et al. Coexpression of receptors for adrenomedullin, calcitonin gene-related peptide, and amylin in pancreatic beta-cells. Endocrinology 2000; 141: 406-411
• 22 Gram DX, Ahren B, Nagy I et al. Capsaicin-sensitive sensory fibers in the islets of Langerhans contribute to defective insulin secretion in Zucker diabetic rat, an animal model for some aspects of human type 2 diabetes. Eur J Neurosci 2007; 25: 213-223
• 23 Tanaka H, Shimaya A, Kiso T et al. Enhanced insulin secretion and sensitization in diabetic mice on chronic treatment with a transient receptor potential vanilloid 1 antagonist. Life Sci 2011; 88: 559-563
• 24 Gram DX, Hansen AJ, Wilken M et al. Plasma calcitonin gene-related peptide is increased prior to obesity, and sensory nerve desensitization by capsaicin improves oral glucose tolerance in obese Zucker rats. Eur J Endocrinol 2005; 153: 963-969
• 25 van Rossum D, Hanisch UK, Quirion R. Neuroanatomical localization, pharmacological characterization and functions of CGRP, related peptides and their receptors. Neurosci Biobehav Rev 1997; 21: 649-678
• 26 Bennett MM, Amara SG. Molecular mechanisms of cell-specific and regulated expression of the calcitonin/alpha-CGRP and beta-CGRP genes. Ann N Y Acad Sci 1992; 657: 36-49
• 27 Fukuoka T, Tokunaga A, Kondo E et al. Differential regulation of alpha- and beta-CGRP mRNAs within oculomotor, trochlear, abducens, and trigeminal motoneurons in response to axotomy. Brain Res Mol Brain Res 1999; 63: 304-315
• 28 Sarasa M, Terrado J, Mengod G et al. Differential expression of alpha-CGRP and beta-CGRP genes within hypoglossal motoneurons in response to axotomy. Brain Res Mol Brain Res 1996; 35: 269-277
• 29 Sams A, Yenidunya A, Engberg J et al. Equipotent in vitro actions of alpha- and beta-CGRP on guinea pig basilar artery are likely to be mediated via CRLR derived CGRP receptors. Regul Pept 1999; 85: 67-75
• 30 Ikawa K, Shimatani T, Azuma Y et al. Calcitonin gene-related peptide and somatostatin releases correlated with the area under the lafutidine concentration-time curve in human plasma. J Clin Pharm Ther 2006; 31: 351-356
• 31 Thompson BJ, Washington MK, Kurre U et al. Protective roles of alpha-calcitonin and beta-calcitonin gene-related peptide in spontaneous and experimentally induced colitis. Dig Dis Sci 2008; 53: 229-241
• 32 Al-Salam S, Hameed R, Parvez HS et al. Diabetes mellitus decreases the expression of calcitonin-gene related peptide, gamma-amino butyric acid and glutamic acid decarboxylase in human pancreatic islet cells. Neuro Endocrinol Lett 2009; 30: 506-510
• 33 Adeghate E, Ponery A. Diabetes mellitus influences the degree of colocalization of calcitonin gene-related peptide with insulin and somatostatin in the rat pancreas. Pancreas 2004; 29: 311-319
• 34 Wang W, Wang EQ, Balthasar JP. Monoclonal antibody pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther 2008; 84: 548-558