Paracrine Interactions within the Pancreatic Islet Determine the Glycemic Set Point

• Published in: Cell metabolism 2018-03, Vol.27 (3), p.549-558.e4
• Main Authors: Rodriguez-Diaz, Rayner, Molano, R. Damaris, Weitz, Jonathan R., Abdulreda, Midhat H., Berman, Dora M., Leibiger, Barbara, Leibiger, Ingo B., Kenyon, Norma S., Ricordi, Camillo, Pileggi, Antonello, Caicedo, Alejandro, Berggren, Per-Olof
• Format: Article
• Language: English
• Subjects: alpha cell; Animals; beta cell; Diabetes Mellitus, Experimental; glucagon; Glucagon - metabolism; Glucagon-Secreting Cells - metabolism; Glucose - metabolism; glucose homeostasis; glycemia; glycemic set point; human pancreatic islet; humanized mouse; Humans; Hypoglycemic Agents - pharmacology; insulin secretion; Insulin-Secreting Cells - metabolism; Islets of Langerhans Transplantation; Macaca fascicularis; Medicin och hälsovetenskap; Mice; Mice, Inbred C57BL; Mice, Nude; Paracrine Communication; paracrine signaling; Receptors, Glucagon - antagonists & inhibitors
• ISSN: 1550-4131; 1932-7420; 1932-7420
• DOI: 10.1016/j.cmet.2018.01.015

Every animal species has a signature blood glucose level or glycemic set point. These set points are different, and the normal glycemic levels (normoglycemia) of one species would be life threatening for other species. Mouse normoglycemia can be considered diabetic for humans. The biological determinants of the glycemic set point remain unclear. Here we show that the pancreatic islet imposes its glycemic set point on the organism, making it the bona fide glucostat in the body. Moreover, and in contrast to rodent islets, glucagon input from the alpha cell to the insulin-secreting beta cell is necessary to fine-tune the distinctive human set point. These findings affect transplantation and regenerative approaches to treat diabetes because restoring normoglycemia may require more than replacing only the beta cells. Furthermore, therapeutic strategies using glucagon receptor antagonists as hypoglycemic agents need to be reassessed, as they may reset the overall glucostat in the organism. [Display omitted] •Species-specific glycemic set points are transferred with islet transplantation•The pancreatic islet thus carries the information to impose the glycemic set point•The glycemic set point does not depend on islet graft mass•Control of glycemia by insulin secretion relies on paracrine input from alpha cells It is not known if there is a leading organ that maintains blood glucose levels within the narrow physiological range. Rodriguez-Diaz and colleagues show that the pancreatic islet serves as the systemic glucostat and that paracrine glucagon input from alpha cells is essential for setting the glycemic set point. Therapeutic strategies using glucagon receptor antagonists to lower glycemia should thus be reassessed.