β Cell tone is defined by proglucagon peptides through cAMP signaling

Abstract

Paracrine interactions between pancreatic islet cells have been proposed as a mechanism to regulate hormone secretion and glucose homeostasis. Here, we demonstrate the importance of proglucagon-derived peptides (PGDPs) for α to β cell communication and control of insulin secretion. Signaling through this system occurs through both the glucagon-like peptide receptor (Glp1r) and glucagon receptor (Gcgr). Loss of PGDPs, or blockade of their receptors, decreases insulin secretion in response to both metabolic and nonmetabolic stimulation of mouse and human islets. This effect is due to reduced β cell cAMP and affects the quantity but not dynamics of insulin release, indicating that PGDPs dictate the magnitude of insulin output in an isolated islet. In healthy mice, additional factors that stimulate cAMP can compensate for loss of PGDP signaling; however, input from α cells is essential to maintain glucose tolerance during the metabolic stress induced by high-fat feeding. These findings demonstrate an essential role for α cell regulation of β cells, raising the possibility that abnormal paracrine signaling contributes to impaired insulin secretion in diabetes. Moreover, these findings support reconsideration of the role for α cells in postprandial glucose control.

Alanine, arginine, and proline but not glutamine are the feed-back regulators in the liver-alpha cell axis in mice

“…When evaluating the fold changes from baseline, the amino acids that increased glucagon secretion included the following: cysteine (Table 1). To our surprise, glutamine (1.0±0.05, P=0.2) did not stimulate glucagon secretion as previously described (9). The baseline values did not differ between the 19 amino acids (all comparisons P>0.9).…”

“…In several species alanine, arginine, proline, glycine, and lysine seem to be potent stimulators of glucagon secretion, whereas the BCAAs have not been reported to influence secretion (17,33,52), except for one study that found 20 min of valine and leucine infusion to stimulate glucagon secretion in the perfused rat pancreas (3) (table 3). We administered 1 mM of each amino acid, which is substantially higher than the circulating concentration of any amino acid (which ranges from 6 µmol/L to 600 µmol/L in C57BL/6JRj mice (20)) (table 1), but lower than the 10-25 mM applied in other studies done in isolated islets, in which the majority of amino acids have been found to stimulate glucagon secretion (3,9,10,17).…”

“…In isolated mouse islets prolonged administration of amino acids lead to alpha cell proliferation (57), and alanine, glutamate, glutamine, and leucine have in particular been associated with alpha cell proliferation (15,30). In perifused mouse islet, alanine (10 mM) has been shown to be a more potent stimulant of glucagon secretion than glutamine (10 mM) (10), however in another perifused islet study by the same group, glutamine (10 mM) and arginine (1 mM) were both found to be potent stimulators of glucagon secretion (9). In several species alanine, arginine, proline, glycine, and lysine seem to be potent stimulators of glucagon secretion, whereas the BCAAs have not been reported to influence secretion (17,33,52), except for one study that found 20 min of valine and leucine infusion to stimulate glucagon secretion in the perfused rat pancreas (3) (table 3).…”

“…GRA increased plasma amino acid concentrations, and we believe that the GRA augmented glucagon secretion may be due to feedback mechanisms involving amino acids and/or beta-and delta-cell secretory products. The augmented insulin secretion in GRA treated mice in response to mixture 4 is surprising since glucagon has been shown to induce insulin secretion (9,59,70). We therefore expected GRA treatment to, if anything, decrease insulin secretion.…”

Nutrient regulation of the islet epigenome controls adaptive insulin secretion

“…Insulin produced by pancreatic β-cells is the key stimulus for carbohydrate metabolism, and therefore it is critical that insulin secretion is adjusted commensurate with changes in energy state 1 . The insulin secretory response to feeding is primarily controlled by glucose and potentiated by intra-islet glucagon 7,8 and incretin hormones such as Glp-1 through stimulation of cAMP production [9][10][11] . The postprandial increase of serum glucose accelerates glucose metabolism within the β-cell to initiate a signalling cascade involving ATP-stimulated plasma membrane depolarization, Ca 2+ influx, and insulin vesicle exocytosis 12 .…”