Susumu Seino, MD, DMSci (1948–2021): A Pioneer in the Biology of Insulin Secretion

Susumu Seino, Professor and Endowed Chair, Division of Molecular and Metabolic Medicine, Kobe University Graduate School of Medicine, died in Osaka, Japan, on 14 April 2021 from complications of coronavirus disease 2019 (COVID-19). He will be remembered as an insightful, rigorous, and creative investigator who expanded our knowledge of β-cell function and the regulation of insulin secretion and, by those of us who were fortunate enough to call him a friend, as a most generous, cultivated, selfless, kind, and caring individual.

Susumu Seino was born on 5 July 1948 in Matsue City, Shimane Prefecture, on the West Coast of Japan. He was the youngest of three boys (Yoshiki, Yutaka, and Susumu) born to Kazuo and Chieko Seino. His father was professor of pediatrics at Tottori University and hailed from a long line of medical professionals. His forebears had been doctors for nearly 400 years. They came to Matsue from Sendai, where Susumu’s ancestor was a physician to the fearsome Date Masamune (1567–1636), the one-eyed feudal lord (Daimyo) of the Date clan who turned Sendai into the main city of the Tohoku region of Northeast Japan during the Tokugawa shogunate (1603–1868). The medical tradition in the Seino family continues to this day, and his brothers Yoshiki and Yutaka are highly respected academic investigators (Okayama University and Kyoto University, respectively). Yutaka Seino is especially well-known in the diabetes world for his pioneering studies of diabetes in the Japanese population as well as for studies of incretins and advancing their use as a diabetes treatment.

Susumu left home early to attend Osaka Prefectural Kitano High School in Osaka. He was an exchange student in Paris before enrolling at the Kobe University School of Medicine in 1968, where he earned his MD in 1974. He lived in the heyday of the 1968 students’ protest movement against the renewal of the U.S.–Japan security guarantees, which he recalled as a time when “everyone enjoyed great personal freedom,” although the protests shut down many Japanese universities, including Kobe University, for a whole year. While in medical school, he was awestruck by the lectures of Yasutomi Nishizuka, who was studying intracellular signal transduction and was the discoverer of the protein kinase C pathway, and Hiroo Imura, who studied endocrinology and diabetes, and he found his calling in research. After graduating from Kobe University, he trained in medicine and endocrinology at Amagasaki Prefectural and Kitano Hospitals, where he credited Dr. Mikio Yawata and Dr. Masaki Ikeda for inspiring him to pursue a career in diabetes. He then joined the laboratory of Professor Hiroo Imura, who had moved from Kobe University to Kyoto University and in whose laboratory his older brother Yutaka also worked, where he “cut his research teeth” studying somatostatin secretion. He earned his Doctor of Medical Science (DMSci) (equivalent to a PhD) from Kyoto University School of Medicine in 1982.

In 1981, Susumu traveled to Athens to attend his first international science meeting and present a poster. While there he met the endocrinologist Arthur (Aaron) Vinik, who offered him a postdoctoral position at the University of Michigan on the spot. Thus began the American phase of his career. At the University of Michigan, he befriended Professor Stefan (Steve) Fajans, a distinguished endocrinologist who first described maturity-onset diabetes of the young. Fajans arranged for Susumu to visit Professor John Karam in the Metabolic Research Unit at the University of California San Francisco (where Hiroo Imura had trained many years before) to learn molecular biology. In 1984, Dr. Karam introduced him to Graeme Bell, who then was a senior scientist at Chiron Corporation. This meeting led to their scientific partnership, which spanned from 1984 to 1991 and continued as a brotherly bond until Susumu’s untimely death. He introduced Bell to Japan’s people, history, and culture and became the conduit for many talented Japanese researchers to work in the Bell laboratory.

Susumu applied for a fellowship with Donald F. Steiner (discover of proinsulin) at the University of Chicago and moved there in 1985. Graeme Bell was recruited to the University of Chicago by Steiner, Howard Tager (recipient of the Lilly Award for his pioneering studies of insulin gene mutations), Arthur Rubenstein (who developed the clinical applications of insulin processing through studies of proinsulin and C-peptide), and Kenneth Polonsky (who pioneered the biology of β-cell defects in type 2 diabetes) in 1986. Susumu and his wife Mitsuko (who was Bell’s first laboratory manager and technician) were instrumental in turning the Bell laboratory into a hotbed of discoveries and a leading center of diabetes research. Susumu initially worked with both Steiner and Bell and then with Bell. It was an exciting and very productive period, including cloning of glucose transporters and the human insulin receptor and identification of first mutations in insulin, members of the somatostatin receptor family, and many other β-cell proteins (1–5). During this period, Susumu once remarked that, being older and more experienced than other postdoctoral researchers, he had to work twice as hard to be competitive.

The Chicago years led to a spate of contributions to our understanding of the basic pathophysiology of diabetes, and he trained the next generation of American (John Buse, Charles Burant, and Nancy Cox) and Japanese (Jun Takeda, Yuichiro Yamada, Kazuki Yasuda, and many others) diabetes investigators. These included advances not only in the molecular biology of β-cell function at a time when insulin resistance reigned supreme as the leading cause of diabetes but also in the pioneer age of type 2 diabetes genetics (4,6–12). Seino and Bell’s work was instrumental to redirect attention to the β-cell as a key hub of diabetes pathogenesis and opened the path to investigate genetic susceptibility to diabetes. The β-cell “revival” of the early 2000s, which brought about most of the new additions to the diabetes pharmacopeia, can also be traced back to their efforts.

In 1991, Seino was invited by Professor Masaru Taniguchi (immunologist and discoverer of natural killer T cells) to take up a professorship at Chiba University School of Medicine. Susumu then began studies that led to the discovery of the structure of the ATP-sensitive potassium channel (K_ATP channel) that links glucose metabolism and insulin secretion. Coming as he did from the intensely competitive, technically sophisticated environment at the University of Chicago, he found himself starting from nothing: no equipment and few, if any, helpers. However, things slowly fell into place. Before long, he recruited a young physician scientist from Kyoto University, Nobuya Inagaki, and convinced him to work on the molecular biology of insulin secretion. As Susumu said later, meeting Nobuya was his “lucky break.” Together, they established a connection with a talented young electrophysiologist, Toru Gonoi, and began to work on the K_ATP channel. Having gathered evidence of a role for this channel in insulin secretion, they reached out to Joe and Lydia Bryan, who had just made the seminal advance of cloning the sulfonylurea receptor, SUR1, and together they showed that the K_ATP channel was composed of two subunits, an inward rectifier potassium channel member, Kir6.2, and SUR1. The discovery was of enormous and fundamental importance not only for the metabolic regulation of insulin secretion but also for the structure–function relationship of ion channels in general. The manuscript, submitted to Science, was accepted virtually unchanged (13). Important clinical lessons also arose from it, including the mechanism of permanent neonatal diabetes, due to activation of mutations of the channel, as well as persistent hyperinsulinemic hypoglycemia of infancy, due to loss-of-function mutations of the channel subunits (14). This also laid the groundwork for new treatment approaches. In addition, the discovery of the molecular and functional diversity of K_ATP channels in different tissues contributed to understanding the mechanisms of the extrapancreatic actions of sulfonylureas (15).

Around this time, Takashi Miki joined Susumu’s laboratory, and together they began generating animal models of K_ATP channel gain and loss of function, bequeathing to the international research community a wealth of transgenic and knockout animals, in addition to cell lines, that have become standard tools to analyze the functions of these proteins not only in diabetes but in heart (16), brain (17), and neurodegenerative disease (18).

However, a question now arose: how is glucose metabolism coupled with the other signals regulating insulin secretion, namely, G-protein signaling, oxidative phosphorylation, and granule trafficking? An initial answer came from the discovery of a small G-protein involved in the localization of voltage-dependent calcium channels, kir/Gem (19). Susumu and his colleagues demonstrated a link between G-protein signaling and insulin secretion that was to shape much of his subsequent work in Kobe (20).

In 2003, Susumu returned to Kobe as a professor of Cellular and Molecular Medicine at Kobe University in newly built laboratories on Port Island. It was a new beginning, as the city was emerging from the destructive Hanshin earthquake. His laboratory grew in personnel and scope. Although other universities lured him with generous offers, he remained at heart a “Kōbekko,” a real Kobe native. Kobe allowed him to concentrate on his work without distractions and to run his laboratory as an extended family, where soon international researchers started to flock from the world over, attracted by his reputation and human touch. In 2008, when Professor Masato Kasuga became head of the Research Institute of the National Center for Global Health and Medicine in Shinjuku, Tokyo, Susumu was asked to take over leadership of the Section on Diabetes, Metabolism, and Endocrinology of Kobe University, the position vacated by Kasuga. Having started his career as a physician, Susumu went back to his roots and actively participated in clinical rounds as well as clinical research at Kobe University.

Dr. Miki, Dr. Tadao Shibasaki, and Dr. Norihide Yokoi had moved with him from Chiba in 2003 to help him start the next, very productive phase of scientific discovery. Having cloned a family of somatostatin receptors expressed in the β-cell, they demonstrated a Gi-protein-coupled receptor pathway affecting insulin secretion (21). This discovery has not only enhanced our understanding of inhibitory mechanisms regulating insulin secretion but also contributed to the development of subtype-specific agonists for treatment of endocrine tumors. Subsequently, Seino and Harumi Takahashi discovered that the cAMP-binding protein cAMP-GEFII (Epac2) interacts with SUR1 and mediates cAMP-induced insulin granule exocytosis in a protein kinase A (PKA)–independent manner (22). The discovery unveiled a novel pathway of cAMP signaling, which until then had been thought to be mediated exclusively by PKA-dependent mechanisms. Seino’s Epac2 studies established its critical role in incretin/cAMP-induced insulin secretion and defined the pathway integrating Gs-protein-coupled receptor signaling with insulin granule exocytosis (21). This is the pathway by which incretins potentiate insulin secretion through cAMP signaling, paving the way for incretin-based treatments that have revolutionized diabetes care.

Seino’s continuing studies of Epac2 led to another key contribution having to do with the diversity of the sulfonylurea mechanism of action. They developed an Epac2 fluorescence resonance energy transfer sensor that unexpectedly demonstrated that Epac2 is a direct target of sulfonylureas. Seino and his colleagues found that sulfonylurea-induced insulin secretion was significantly reduced in Epac2 knockout mice and that sulfonylureas and cAMP cooperatively activate Epac2 to augment insulin secretion (23). This study illustrated a novel mechanism of sulfonylurea action in addition to its effects on inhibition of the K_ATP channels, further enhancing our understanding of sulfonylurea actions and their use for better treatment of diabetes.

The next question was, how are the two phases of insulin release, the glucose-dependent and the cAMP-dependent phases, mechanistically integrated? Seino and his colleagues demonstrated that glutamate in pancreatic β-cells acts as a key signal linking glucose metabolism and incretin/cAMP action to potentiate insulin granule exocytosis. He clarified the two important steps in this mechanism: 1) production of cytosolic glutamate through the malate-aspartate shuttle by glucose metabolism and 2) transport of cytosolic glutamate into insulin granules by cAMP signaling (24). He also found that impaired glutamate production correlates well with impaired incretin-induced insulin secretion in animal models of diabetes and obesity. These findings provided a model to understand the impairment of incretin-induced insulin secretion in type 2 diabetes as well as new approaches for treating patients unresponsive to incretin therapies.

Susumu’s work had impacts on many different fields. His achievements and contributions were recognized by national and international awards and honors, including the 108th Japan Academy Prize, conferred by The Japan Academy in Tokyo. This prize recognizes annually the top 9 individuals in Japan in all areas of human endeavor, from medicine to biology and engineering as well as the arts. Seino received many other prizes for his research in diabetes, including the Manpei Suzuki International Prize for Diabetes Research by the Manpei Suzuki Diabetes Foundation, the Arthur Riggs Award by the City of Hope National Medical Center, The Medal of Honor with Purple Ribbon by the Emperor of Japan, the European Association for the Study of Diabetes Albert Renold Prize for Outstanding Achievements in Research, the Donald F. Steiner Award for Outstanding Achievement in Diabetes Research by the University of Chicago, the Stefan S. Fajans Lecture in Diabetes by the University of Michigan, and the Naito Foundation Research Prize, among others.

Susumu was a remarkable individual: cultured, cosmopolitan, and affable yet self-effacing. He was no prima donna, and he did not seek the spotlight. Rather, he engaged others with his charm, good nature, wits, and grace. He always had a kind word to say about everyone, and he cherished other people’s work more than his own. In 1990, he made freely available to some of us, no strings attached, the genomic maps of the insulin receptor gene. This was a time when mapping a 22-exon gene over 120 kb of DNA took smarts, stamina, and technical sophistication, yet he felt that he had done this work not for his own advancement but so that others could benefit from it. His reagents and transgenic animals were freely shared with anyone who asked and are a tangible legacy of his contribution. He was generous with colleagues and promoted his trainees, many of whom have risen to prominence in academia worldwide, including Charles Burant, John Buse, Louis Philipson, Nobuya Inagaki, Takashi Miki, Kotaro Minami, Kyu-Chang Won, Daisuke Yabe, Harumi Takahashi (who was working with Susumu on the mechanism of action of sulfonylureas and the glutamate hypothesis when the disease struck), and many others.

Susumu loved his country in ways that had none of the primal attraction to worn traditions and parochial quirks. He could wax poetic about Manyoshu and The Tale of Genji, two of the key texts of early Japanese literature, and he loved to explain in simple terms the meaning of the most complex Kanji notations that comprise one part of Japanese writing. He knew the work of Western Japanologists, such as Donald Keene and Hideo Levy, better than most Westerners. Nothing gave him greater satisfaction than hosting colleagues in Kobe, showing them around, taking them to the Arima Onsen or to Rokko-san, and opening new vistas even for those who had some level of familiarity with Japan. Behind his desk in his office stood a board where pictures taken with visitors from the world over would be carefully displayed, and he remembered each one of them with a fondness that denoted real care and interest for his colleagues. Susumu was an informed, socially aware member of society who did not shy away from criticizing institutions and people in power. He was also fun after business hours, with a taste for hard-to-find, original, and creative locales, like the Kyukyodo stationery store in the Shimogyo ward of Kyoto or the Kyoto branch of the restaurant Wakuden, where he loved to introduce his visiting friends to Fujiyama-san, his favorite chef. Among the many Japanese expressions he taught us, he was fond of explaining the word “mononoaware,” an appreciation for the fleeting nature of things. On his last meeting with one of us in Paris, he expressed a wish to visit Jean Paul Sartre’s tomb in the Montparnasse Cemetery. He recalled how he had plenty of time to read his work while his fellow students were agitating against the U.S.–Japan treaty in 1968. It was a beautiful, unseasonably warm Saturday afternoon. We crisscrossed the cemetery for hours as he expanded on the many exciting avenues that his latest article had opened and that he planned to pursue. (Just before his diagnosis with the COVID-19 virus, he had received the acceptance notice from the Journal of Clinical Investigation for this article, studies on which he had been working for nearly 10 years, demonstrating how signaling specificity among incretins was dictated by changes in G-protein coupling [25]). On that Paris afternoon, he sounded like a newly minted assistant professor eager to make an impact on the field. We were robbed of him too soon. He will be missed.

Duality of Interest. No potential conflicts of interest relevant to this article were reported.