cells Review Inducible Pluripotent Stem Cells as a Potential Cure for Diabetes Kevin Verhoeff 1, * , Sarah J. Henschke 2 , Braulio A. Marfil-Garza 1 , Nidheesh Dadheech 3 and Andrew Mark James Shapiro 4   Citation: Verhoeff, K.; Henschke, S.J.; Marfil-Garza, B.A.; Dadheech, N.; Shapiro, A.M.J. Inducible Pluripotent Stem Cells as a Potential Cure for Diabetes. Cells 2021, 10, 278. https:// doi.org/10.3390/cells10020278 Academic Editor: Adrian Kee Keong Teo Received: 1 January 2021 Accepted: 24 January 2021 Published: 30 January 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Department of Surgery, University of Alberta, Edmonton, AB T6G 2B7, Canada; marfilga@ualberta.ca 2 Department of Emergency Medicine, University of Saskatchewan, Saskatoon, SK S7N 0W8, Canada; shenschk@ualberta.ca 3 Alberta Diabetes Institute, University of Alberta, Edmonton, AB T6G 2B7, Canada; dadheech@ualberta.ca 4 FRCS (Eng) FRCSC MSM FCAHS, Clinical Islet Transplant Program, Alberta Diabetes Institute, Department of Surgery, Canadian National Transplant Research Program, Edmonton, AB T6G 2B7, Canada; jshapiro@ualberta.ca * Correspondence: verhoeff@ualberta.ca; Tel.: +1-780-984-1836 Abstract: Over the last century, diabetes has been treated with subcutaneous insulin, a discovery that enabled patients to forego death from hyperglycemia. Despite novel insulin formulations, patients with diabetes continue to suffer morbidity and mortality with unsustainable costs to the health care system. Continuous glucose monitoring, wearable insulin pumps, and closed-loop artificial pancreas systems represent an advance, but still fail to recreate physiologic euglycemia and are not universally available. Islet cell transplantation has evolved into a successful modality for treating a subset of patients with ‘brittle’ diabetes but is limited by organ donor supply and immunosuppression requirements. A novel approach involves generating autologous or immune-protected islet cells for transplant from inducible pluripotent stem cells to eliminate detrimental immune responses and organ supply limitations. In this review, we briefly discuss novel mechanisms for subcutaneous insulin delivery and define their shortfalls. We describe embryological development and physiology of islets to better understand their role in glycemic control and, finally, discuss cell-based therapies for diabetes and barriers to widespread use. In response to these barriers, we present the promise of stem cell therapy, and review the current gaps requiring solutions to enable widespread use of stem cells as a potential cure for diabetes. Keywords: islet cell transplant; diabetes; inducible pluripotent stem cells; immunosuppression; immune reset; insulin 1. Insulin as a Treatment, Not a Cure In 1889, Oskar Minkowski and Joseph von Mering completed a canine pancreatectomy and induced fatal diabetes mellitus (DM). This experiment demonstrated the central role of the pancreas in glycemic control [1]. In 1893, Williams and Harsant working in Bristol, UK, attempted to transplant pancreatic fragments taken from a freshly slaughtered sheep and placed them subcutaneously in a boy dying of diabetic ketoacidosis, with unsuccessful results [2]. Even throughout the journey to discover insulin, Banting’s initial trials focused on subcutaneous injection of an unpurified pancreatic slurry, and the first patient treated developed a sterile buttock abscess [3]. Although Banting, Best, Collip and Macleod subsequently prepared more purified insulin extracts using acid-alcohol to dissolve the insulin and prevent degradation by exocrine enzymes, Banting’s acceptance speech for the 1923 Nobel Prize in Physiology and Medicine concluded with these words: “Insulin is not a cure for diabetes; it is a treatment. It enables the diabetic to burn sufficient carbohydrates, so that proteins and fats may be added to the diet in sufficient quantities to provide energy for the economic burdens of life [3].” Cells 2021, 10, 278. https://doi.org/10.3390/cells10020278 https://www.mdpi.com/journal/cells