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Abstract
Peptides derived from the glucagon gene Gcg, for example, glucagon and glucagon-like peptide 1 (GLP-1), act as physiological regulators of fuel metabolism and are thus of major interest in the pathogenesis of diseases, such as type-2 diabetes and obesity, and their therapeutic management. Glicentin-related pancreatic polypeptide (GRPP) is a further, 30 amino acid Gcg-derived peptide identified in human, mouse, rat, and pig. However, the potential glucoregulatory function of this peptide is largely unknown. Here, we synthesized rat GRPP (rGRPP) and a closely related peptide, rat GRPP-like peptide (rGRPP-LP), and investigated their actions in the liver and pancreas of adult male rats by employing isolated-perfused organ preparations. Rat GRPP and rGRPP-LP did not affect glucose output from the liver, but both elicited potent inhibition of glucose-stimulated insulin secretion (GSIS) from the rat pancreas. This action is unlikely to be mediated by glucagon or GLP-1 receptors, as rGRPP and rGRPP-LP did not stimulate cyclic adenosine monophosphate (cAMP) production from the glucagon or GLP-1 receptors, nor did they antagonize glucagon- or GLP-1-stimulated cAMP-production at either receptor. GRPP and GRPP-LP may be novel regulators of insulin secretion, acting through an as-yet undefined receptor.
Highlights
Preproglucagon, derived from the Gcg gene, is the peptide precursor for several important endocrine hormones and shows a tissue-specific processing pattern (Fig. 1)
There were no significant differences in the glucose responses of livers to glucagon between those perfused with any treatment compared with the control group
No significant difference in insulin secretion was observed during the perfusion of 5-mmol LÀ1 glucose between pancreases perfused with rat GRPP (rGRPP), rGRPP-LP, and glucagon compared with the control group (Fig. 3)
Summary
Preproglucagon, derived from the Gcg gene, is the peptide precursor for several important endocrine hormones and shows a tissue-specific processing pattern (Fig. 1). GLP-1 is an incretin that has given rise to two new classes of antidiabetic agents: the GLP-1 agonists and, indirectly, the dipeptidyl peptidase-4 (DPP4) inhibitors Glucagon is another potent Gcg-derived glucoregulatory hormone whose main physiological role is to increase glucose output from the liver. In that study, which employed a local circulation preparation of the canine pancreas, the administration of human GRPP and human glicentin 1–16 reportedly caused slight increases in plasma insulin and decreases in plasma glucagon (Ohneda and Ohneda 1988) This tantalizing finding suggests that GRPP might be an unrecognized regulator of GSIS. We questioned whether rGRPP and rGRPP-LP can act like GLP-1 to modulate GSIS in the rat pancreas and/or, like glucagon, to modulate glucose production in the liver
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