Review Loss of Reg proteins’ protection of islet b cells in chronic pancreatitis: A potential mechanism for the pathogenesis of type 3c diabetes Chongmin Huan 1 , Albert Stanek 2 , Cathy Mueller 3 , Peiqi Ou 4 , Sue Dong 5 , Joshua Zhang 3 , Ramy Abdel-Naby 3 and Rainer Gruessner 3 Abstract Type 3c diabetes mellitus (T3cDM) is a type of pancreatogenic diabetes. This form of diabetes has been significantly under- appreciated, but is now receiving increased attention because of the recent recognition of its high incidence in chronic pancreatitis (CP) and other pancreatic diseases with irrepa- rable loss of acinar cells. CP-associated T3cDM is character- ized by insulin insufficiency resulting from pancreatic exocrine damage. However, how loss of acinar cells leads to insulin insufficiency in CP is practically unknown. Based on our review of the relevant literature and studies in our laboratory, we propose that lost protection from acinar cell – secreted regen- erating proteins results in injury of the islet b cells in CP. Validation of this model may help in better understanding of the pathophysiology of T3cDM. Addresses 1 Department of Surgery and Cell Biology, State University of New York, Downstate Medical Center, Brooklyn, NY 11203, United States 2 Department of Surgery and Pathology, State University of New York, Downstate Medical Center, Brooklyn, NY 11203, United States 3 Department of Surgery, State University of New York, Downstate Medical Center, Brooklyn, NY 11203, United States 4 School of Graduate Studies, State University of New York, Downstate Medical Center, Brooklyn, NY 11203, United States 5 College of Medicine, State University of New York, Downstate Medi- cal Center, Brooklyn, NY 11203, United States Corresponding author: Huan, Chongmin (chongmin.huan@down- state.edu) Current Opinion in Endocrine and Metabolic Research 2019, 5:21 – 28 This review comes from a themed issue on Endocrinology of Aging Edited by Bu B. Yeap and Rong Yuan For a complete overview see the Issue and the Editorial Available online 27 February 2019 https://doi.org/10.1016/j.coemr.2019.02.005 2451-9650/© 2019 Elsevier Ltd. All rights reserved. Introduction Diabetes represents a significant challenge for health care of the elderly. According to CDC’s United States Diabetes Statistics Report, approximately 12 million American seniors are affected by diabetes, and the prevalence in those aged 65 years and older reaches 25.2% [1]. It has been estimated that more than 9% of all diabetes is attributable to type 3c diabetes mellitus (T3cDM) [2], which has been recently defined by the American Diabetes Association as ‘other specific types of diabetes due to diseases of the exocrine pancreas’ [3]. This form of diabetes typically shows up later in life at a median age of 59 years and is caused by insufficient insulin production secondary to the diseases of the exocrine pancreas such as pancreatic cancers, cystic fibrosis, and trauma, but most frequently occurs among patients with chronic pancreatitis (CP) [3,4]. Unfortu- nately, the prevalence and consequences of T3cDM have been falsely and significantly underestimated. As a result, many patients with T3cDM were misdiagnosed and treated for type 2 diabetes mellitus (T2DM), which led to severe adverse effects [4e8]. Only recently have consensus guidelines for the diagnosis and treatment of the disorder been developed [9]. With the numbers of pancreatic surgery procedures and the prevalence of CP growing globally, T3cDM is increasingly gaining impor- tance [10]. With improved imaging techniques for detecting path- ogenic alterations in the pancreas and better quantifi- cation of exocrine pancreatic functions, patients with CP were found to account for approximately 75% of T3cDM. Consistently, altered glucose metabolism was found in 70% of CP patients, and among these, almost 30% demonstrated diabetes [11,12]. Cohort studies showed that more than half of the patients with diabetes secondary to CP received insulin treatment [13,14], in line with consensus recommendations for insulin ther- apy in the guidelines for T3cDM [9]. Despite these advances, relatively little is known about the cellular and molecular dysregulations that lead to insulin insuffi- ciency in T3cDM [15], and this hampers the develop- ment of mechanistic approaches for more effective management of T3cDM. Insulin insufficiency in CP was presumptively attrib- uted to the physical restraint of islets and their blood supply because of tissue fibrosis, despite the lack of any Available online at www.sciencedirect.com ScienceDirect Current Opinion in Endocrine and Metabolic Research www.sciencedirect.com Current Opinion in Endocrine and Metabolic Research 2019, 5:21 – 28