Citation: Sugumar,V.; Ang, K.P.; Alshanon, A.F.; Sethi, G.; Yong, P.V.C.; Looi, C.Y.; Wong, W.F. A Comprehensive Review of the Evolution of Insulin Development and Its Delivery Method. Pharmaceutics 2022, 14, 1406. https://doi.org/10.3390/ pharmaceutics14071406 Academic Editor: Alyssa Panitch Received: 30 April 2022 Accepted: 29 June 2022 Published: 4 July 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2022 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/). pharmaceutics Review A Comprehensive Review of the Evolution of Insulin Development and Its Delivery Method Vaisnevee Sugumar 1 , Kuan Ping Ang 2 , Ahmed F. Alshanon 3 , Gautam Sethi 4, *, Phelim Voon Chen Yong 5 , Chung Yeng Looi 5,6, * and Won Fen Wong 7, * 1 School of Medicine, Faculty of Health & Medical Sciences, Taylor’s University, 1, Jalan Taylors, Subang Jaya 47500, Malaysia; vaisneveesugumar@sd.taylors.edu.my 2 Department of Medical Microbiology, University Malaya Medical Center, Kuala Lumpur 59100, Malaysia; angkp@ummc.edu.my 3 Center of Biotechnology Researches, University of Al-Nahrain, Baghdad 10072, Iraq; ahmed.neama@brc.nahrainuniv.edu.iq 4 Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore 5 School of Biosciences, Faculty of Health & Medical Sciences, Taylor’s University, 1, Jalan Taylors, Subang Jaya 47500, Malaysia; phelim.yong@taylors.edu.my 6 Centre for Drug Discovery and Molecular Pharmacology (CDDMP), Faculty of Health & Medical Sciences, Taylor’s University, 1, Jalan Taylors, Subang Jaya 47500, Malaysia 7 Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia * Correspondence: phcgs@nus.edu.sg (G.S.); chungyeng.looi@taylors.edu.my (C.Y.L.); wonfen@um.edu.my (W.F.W.) Abstract: The year 2021 marks the 100th anniversary of the momentous discovery of insulin. Through years of research and discovery, insulin has evolved from poorly defined crude extracts of animal pan- creas to recombinant human insulin and analogues that can be prescribed and administered with high accuracy and efficacy. However, there are still many challenges ahead in clinical settings, particularly with respect to maintaining optimal glycemic control whilst minimizing the treatment-related side effects of hypoglycemia and weight gain. In this review, the chronology of the development of rapid- acting, short-acting, intermediate-acting, and long-acting insulin analogues, as well as mixtures and concentrated formulations that offer the potential to meet this challenge, are summarized. In addition, we also summarize the latest advancements in insulin delivery methods, along with advancement to clinical trials. This review provides insights on the development of insulin treatment for diabetes mellitus that may be useful for clinicians in meeting the needs of their individual patients. However, it is important to note that as of now, none of the new technologies mentioned have superseded the existing method of subcutaneous administration of insulin. Keywords: diabetes mellitus; transdermal; chemical enhancers; physical enhancers; non-invasive insulin delivery 1. Introduction Etymologically, the term “diabetes mellitus” is taken from both Greek and Latin words. “Diabetes” in ancient Greek means siphon or to pass through, whereas the Latin word “mellitus” means sweet taste. The ancient Greeks used to diagnose the disease by directly tasting a patient’s urine. It was not until the 19th century that a clinical test was developed to test for diabetes. This test was invented by Karl Trommer and tested for sugar in the urine using acid hydrolysis. Around 1894, Sir Edward Albert Sharpey-Schäfer suggested that the pancreatic islets might drive the effects of the pancreas on blood sugar control. Although he did not isolate the insulin protein, he coined the term “insulin” to describe this yet undiscovered substance. The discovery of insulin occurred in 1921 following the Pharmaceutics 2022, 14, 1406. https://doi.org/10.3390/pharmaceutics14071406 https://www.mdpi.com/journal/pharmaceutics