The research groups of Prof. Yu Xiao and Prof. Gong Yaoqin from the School of Basic Medical Sciences and the Key Laboratory of Experimental Teratology (Ministry of Education) of Shandong University made a breakthrough in the field of glucose metabolism and islet paracrine circuit recently.
The research paper "A cullin 4B-RING E3 ligase complex fine-tunes pancreatic δ cell paracrine interactions" was published online in the Journal of Clinical Investigation on Jul. 12. The group members, Ph.D candidates Li Qing, Yang Fan and associate Professor Cui Min, are the co-first authors of the paper, with Professor Yu Xiao and Professor Gong Yaoqin as corresponding authors.
Diabetes mellitus is caused by deficiency of insulin secretion from pancreatic islet β cells and/or insulin resistance in liver, muscle and adipocytes, resulting in glucose intolerance and hyperglycemia. The pancreatic islets of Langerhans are composed of at least 5 different cell types, including insulin-secreting β cells, glucagon-secreting α cells, somatostatin-secreting δ cells, ghrelin-secreting ε cells and pancreatic polypeptide-secreting pp cells. The functions of different cell types within Langerhans islets are precisely regulated by paracrine interactions, and they coordinate the rate and level of reciprocal insulin and glucagon secretion, thereby maintaining glucose homeostasis in response to changes in nutrient levels in different physiological contexts. The disruption of this fune-tuned islet circuit by aberrant regulation of paracrine islet interactions plays an important role in the development of diabetes. For example, the loss of the important paracrine factor urocortin3 (Ucn3) in pancreatic β cells caused dysregulation of a somatostatin-mediated negative feedback loop between islet δ and β cells, thus resulting in aberrant glucose-induced insulin secretion and contributing to the pathophysiology of diabetes. In spite of these progresses, whether an epigenetic regulatory mechanism underlies the crosstalk between pancreatic δ and β cells has not been investigated.
Recently, Yu's laboratory in Shandong University with her collaborators have found that a super-complex comprising the cullin 4B-RING E3 ligase (CRL4B) and polycomb repressive complex 2 (PRC2) epigenetically regulates somatostatin secretion in islets. Constitutive ablation of CUL4B, the core component of the CRL4B-PRC2 complex, in δ cells impaired glucose tolerance and decreased insulin secretion through enhanced somatostatin release. Moreover, mechanistic studies revealed that the CRL4B-PRC2 complex controls intracellular calcium and cAMP levels by epigenetically regulating the expression of the Cav1.2 calcium channel and adenylyl cyclase 6 (AC6) and modulating somatostatin secretion. In response to high glucose levels or urocortin-3 stimulation, increased expression of CUL4B and the PRC2 subunit EZH2 and reciprocal decreases in Cav1.2 and AC6 expression were found to regulate somatostatin secretion. Our results reveal an epigenetic regulatory mechanism of δ cell paracrine interactions in which CRL4B-PRC2 complexes, Cav1.2, and AC6 expression fine-tune somatostatin secretion and facilitate glucose homeostasis in pancreatic islets.
The research in Yu's laboratory is focused on the glucose metabolism and islet circuit. Professor Yu has published a series of works in Cell Research, Cell Reports, Diabetologia etc. The research in Gong's laboratory is focused on the key component of E3 ligase complex – CUL4B. Professor Gong has published a series of works in Cancer Cell, Am J Hum Genet., J Cell Biol., Cancer Research, Diabetes etc. This work was supported by NSFC and Shandong Provincial Natural Science Foundation.
Written by Yu Xiao
Edited by Xie Tingting