Can the Combination of Incretin Agents and Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors Reconcile the Yin and Yang of Glucagon?  Ronald M. Goldenberg, MD, FRCPC, Subodh Verma, MD, PhD, FRCSC, Bruce A. Perkins, MD, MPH, FRCPC, Jeremy D. Gilbert, MD, FRCPC, Bernard Zinman, CM MD, FRCPC  Canadian Journal of Diabetes  Volume 41, Issue 1, Pages 6-9 (February 2017) DOI: 10.1016/j.jcjd.2016.08.001 Copyright © 2016 Canadian Diabetes Association Terms and Conditions

Figure 1 Incretin agents and SGLT2 inhibitors have contrasting effects on glucagon secretion and hepatic glucose production. Incretin agents, via a GLP-1 effect, are generally associated with a suppression of glucagon production and, in turn, hepatic glucose production. SGLT2 inhibitors act directly on pancreatic alpha cells to promote glucagon secretion and subsequent hepatic gluconeogenesis. Canadian Journal of Diabetes 2017 41, 6-9DOI: (10.1016/j.jcjd.2016.08.001) Copyright © 2016 Canadian Diabetes Association Terms and Conditions

Figure 2 Glucose uptake by pancreatic alpha cells (adapted from Hattersley and Thorens [38]). Glucose metabolism within the alpha cell is catalyzed by glucokinase (GK). Until recently, glucose transporter 1 (GLUT1) was thought to be solely responsible for the entry of glucose into pancreatic alpha cells. Recent findings, however, suggest that the SGLT2 transporter, which is believed to be regulated locally by hepatocyte nuclear factor 4alpha (HNF4ɑ), may assist in pancreatic glucose influx. Accordingly, the rise in circulating glucagon may be attributed, in part, to the reduced glucose transport into alpha cells brought about by SGLT2 inhibitors. Canadian Journal of Diabetes 2017 41, 6-9DOI: (10.1016/j.jcjd.2016.08.001) Copyright © 2016 Canadian Diabetes Association Terms and Conditions