SUMO downregulates GLP-1-stimulated cAMP generation and insulin secretion

Abstract

Rajan S, Torres J, Thompson MS, Philipson LH. SUMO downregulates GLP-1-stimulated cAMP generation and insulin secretion. Am J Physiol Endocrinol Metab 302: E714 -E723, 2012. First published January 10, 2012; doi:10.1152/ajpendo.00486.2011.-Glucagon-like peptide-1 (GLP-1)-based incretin therapy is becoming central to the treatment of type 2 diabetes. Activation of incretin hormone receptors results in rapid elevation of cAMP followed by enhanced insulin secretion. However, the incretin effect may be significantly impaired in diabetes. The objective of this study is to investigate downregulation of GLP-1 signaling by small ubiquitin-related modifier protein (SUMO). Mouse islets exposed to high glucose showed increased expression of endogenous SUMO transcripts and its conjugating enzyme Ubc-9. Overexpression of SUMO-1 in mouse insulinoma 6 (MIN6) cells and primary mouse ␤-cells resulted in reduced static and real-time estimates of intracellular cAMP upon receptor stimulation with exendin-4, a GLP-1 receptor (GLP-1R) agonist. GLP1-R was covalently modified by SUMO. Overexpression of SUMO-1 attenuated cell surface trafficking of GLP-1R, which resulted in significantly reduced insulin secretion when stimulated by exendin-4. Partial knock down of SUMO-conjugating enzyme Ubc-9 resulted in enhanced exendin-4-stimulated insulin secretion in mouse islets exposed to high glucose. Thus, SUMO modification of the GLP-1R could be a contributing factor to reduced incretin responsiveness. Elucidating mechanisms of GLP-1R regulation by sumoylation will help improve our understanding of incretin biology and of GLP-1-based treatment of type 2 diabetes.

A post-translational balancing act: the good and the bad of SUMOylation in pancreatic islets

“…These observations are in line with what my laboratory [14,18,19] and others [12,20] have shown using complementary models, including in human islets. We know, for example, that increasing SUMOylation blunts glucose-stimulated insulin secretion by directly inhibiting insulin exocytosis [14,21], and that islet Senp1 knockout results in glucose intolerance without affecting islet mass or insulin content [18].…”

“…SUMOylation at the plasma membrane is now reasonably well-appreciated as a mechanism regulating ion channels and receptors, including the glucagon-like peptide-1 receptor in beta cells [20]. My group and others have also shown that SUMOylation regulates exocytotic membrane fusion [14,23], and this appears to be mediated by direct SUMOylation of exocytotic proteins and consequent regulation of protein-protein interactions amongst members of the secretory machinery [21].…”

“…Thus, while loss of SUMOylation sensitises ROS-mediated beta cell loss, the degree to which metabolic stress or immune attack influence SUMOylation per se is unclear. The ability of high glucose culture, presumably a state of oxidative stress, to upregulate SUMO transcripts and UBC9 protein hints that this could be a feed-forward mechanism [20]. Also, recent work has suggested that palmitate-induced oxidative stress transiently increases NRF2 protein levels [29], although it is not yet known whether this results from a SUMO-dependent stabilisation.…”

Isocitrate-to-SENP1 signaling amplifies insulin secretion and rescues dysfunctional β cells

“…Indeed, SENP1 alone can enhance insulin exocytosis, but this action is blocked under oxidizing conditions (32). SUMOylation may play diverse roles in pancreatic islet biology (33), having recently been implicated in metabolism (34), incretin receptor signaling (35), excitability (36), and survival (37). Importantly, the role for SENP1 in insulin secretion and in vivo glucose homeostasis remains to be resolved.…”

“…Islet SENP1 regulates glucose homeostasis in vivo by controlling the glucose-dependent amplification of insulin secretion. Reduced expression of SENP1 in islet cells protects against apoptosis (37), while increasing SUMOylation may impair insulin secretion (30,35). To determine the role of SENP1 in vivo, we generated SENP1 fl/fl mice and crossed them with the Pdx1-Cre line (49) to generate a tissue-selective knockout (herein referred to as pSENP1-KO; Figure 7A) mice and with the Pdx-CreER line (50) to generate an inducible β cell-specific knockout (herein referred to as iβSENP1-KO) ] i responses in pSENP1-KO islets ( Figure 8E).…”