Franz Matschinsky, MD (1931–2022): Paragon of Scientific Rigor and Curiosity Who Discovered Glucokinase as the Pancreatic Glucose Sensor

The international diabetes research community has lost a giant with the passing of Franz Matschinsky. Franz was a scientist’s scientist, whose important discovery of glucokinase as the glucose sensor controlling insulin secretion from pancreatic β-cells went against the dogma of his time but was highly reproducible and upheld by biochemistry and mouse and human genetics. His work is truly foundational for the field, and it has stood the test of time.

Franz was born in Breslau in Silesian Germany in 1931, a region that is now part of Poland, and moved with his family to Nord-Rhein-Westphalia in the northwest of Germany after World War II. He received a bachelor’s degree in basic medical science from Albert Ludwig University of Freiburg, where he was introduced to preclinical medicine. He then moved to the Ludwig Maximilian University of Munich, where he received his medical degree in 1958. He performed research in the laboratory of Professor Otto Wieland, where his first article, published in German, demonstrated a role for glucocorticoids in glycogen synthesis (1). During this period he met his future wife, Elke Fritz, to whom he was happily married for 57 years until her passing in 2019.

In 1963, Franz moved to Washington University in St. Louis, where he was appointed assistant professor in 1965 and rose to the rank of full professor only 6 years later. At Washington University, Franz was greatly influenced by Oliver H. Lowry, who developed microassays to measure enzyme activities, and Paul E. Lacy, who pioneered methods for isolating pancreatic islets. Franz drew on knowledge gained from his interactions with both investigators to adapt techniques of quantitative histochemistry to the study of glucose and energy metabolism in pancreatic islets. In a classic article published in the Journal of Biological Chemistry in 1968, Matschinsky and Ellerman (2) were the first to report the presence of the enzyme glucokinase—previously thought to be exclusive to the liver—in the pancreatic islets of Langerhans, and they noted that it had a high K_m for glucose relative to hexokinase. Years later, during a visit to Franz’s laboratory at the University of Pennsylvania, one of us (M.A.M.) saw two human eyelash balances, similar to quartz fiber balances described by Lowry, that Franz had made and used for this study. By quantifying the deflection caused by islets placed at the end of the eyelash, he was able to determine their mass, which was necessary to quantitatively assess the kinetics of pancreatic islet glucose usage. The balances even contained a small source of ionizing radiation to eliminate static charge that would have interfered with his very precise biochemical measurements, something that came to define Franz’s career.

Dr. Matschinsky was recruited to the University of Pennsylvania Medical School in 1978 to serve as the director of the Penn Diabetes Center and principal investigator on the Diabetes Research Center (DRC) grant, one of the very first funded by the National Institute of Diabetes and Digestive and Kidney Diseases and still in existence to this day. He led the DRC for the next 20 years and also served as chair of the Department of Biochemistry and Biophysics from 1984 to 1993. He trained numerous diabetes investigators who have gone on to become leaders in the field, including Barbara Corkey and Marc Prentki. Heather Collins, who was Franz’s doctoral student, remained his trusted colleague and laboratory manager for many years. Indeed, Franz remained an active faculty member in both the Department of Biochemistry and Biophysics and the Penn Institute for Diabetes, Obesity, and Metabolism (IDOM), which replaced the Penn Diabetes Center in 2005, for over 40 years, officially retiring only a year before his passing.

Franz often introduced the seminar speakers of the Penn DRC. These introductions were legendary for their joyful attitude and great sense of humor, often gently teasing the speakers and always taking up more of the hour than the speakers expected. Marc Prentki recounts that when he was about to leave Penn after 4 years in Franz’s laboratory, Franz introduced him at a DRC seminar by saying, “I acknowledge that you have been quite productive during the last years at Penn, with two children born following your hard work.” Franz remained an active faculty member in both the Department of Biochemistry and Biophysics as well as the IDOM until nearly the day of his passing in early April 2022.

At the time that Franz came to Penn, the glucose-sensing mechanism of the pancreas was hotly debated. He and his colleagues quite fairly noted that “the pancreatic islets might be responsive: (a) to glucose directly, (b) to changes in intermediates, cofactors, or both, resulting from metabolism of glucose, or (c) to glucose directly subject to modulation by intermediates, cofactors, or both, of glucose metabolism” (3). However, Franz noted that the K_m of glucokinase was very close to the concentration of glucose that stimulated insulin secretion, and he hypothesized that glucokinase itself was the long-sought-after glucose sensor in the islets of Langerhans. In 1981, he published his classic article in Diabetes in which he studied the biochemical properties of glucokinase in great detail and laid out a strong case for its importance in glucose sensing (4). Following this, his prescient review article in the American Journal of Physiology declared, “A deficiency of glucokinase would disturb glucose homeostasis. Decreased islet glucokinase would diminish islet glycolysis and would result in a higher set point of beta-cells for glucose-induced insulin release…. It is thus conceivable that certain forms of type 2 diabetes are due to a glucokinase deficiency” (5).

Over the next decade, Dr. Matschinsky continued to strengthen the case that glucokinase serves as the central β-cell glucose sensor, but some in the field thought it might be just one of many enzymes involved in glucose sensing. A PubMed search of “glucokinase glucose sensor” reveals 12 articles prior to 1992; 11 of these were from Franz’s laboratory and the other was from his Penn colleague Peter Ronner (6). Then, in April of 1992, genetic analysis of a family with maturity-onset diabetes of the young (MODY) by a collaborative effort of the laboratories of Phillip Froguel, Graeme Bell, and David Cohen implicated glucokinase as the causal gene for MODY2, the first diabetes gene to be discovered (7). This article, which had a profound impact due to it being the first diabetes gene to be identified, was rapidly followed by more genetic evidence from the laboratories of Permutt and Kadowaki (8,9). The genetics proved that Franz was right, and since that time the role of glucokinase has become widely accepted, with hundreds of articles and every diabetes textbook confirming the critical role of glucokinase predicted and discovered by Franz Matschinsky. It should be noted that, consistent with his generous and collaborative nature, Franz gave great credit to others who influenced the early stages of his work on glucokinase (10).

Franz’s career was marked by his undying devotion to all things glucokinase. He understood the kinetics of the enzyme at the deepest imaginable level, often referring to the Hill coefficient, glucose S_0.5, turnover rate, and other parameters when discussing the effects of MODY mutations or the glucokinase regulatory protein on the kinetics of the enzyme. When asked why this was, he said that it was his job as a biochemist to study a topic in penetrating depth. Franz also analyzed the role of glucokinase in tissues besides the pancreas, especially the liver, where another of his predictions, namely, that “decreased liver glucokinase would cause less efficient hepatic glucose disposal” (5), has also been widely confirmed and is a major rationale for the development of glucokinase activators to treat diabetes.

Indeed, Franz was extremely excited and motivated by the discovery of glucokinase activators by scientists at Hoffman LaRoche in 2003 but was perplexed when difficulties arose during clinical trials. He told us that “they just did not dose the patients right” and insisted to the end that “critically important molecular and cell biological details about this enzyme serving many diverse and cell-specific functions remain to be elucidated” (11). Even in his late 80s, Franz and his longtime associate Nicolai Doliba collaborated with Li Chen of Hua Medicine to better understand the role of glucokinase in liver as a target for type 2 diabetes. His scientific curiosity and love of discovery continues to serve as an inspiration to all three authors of this memorial and to many others.

For his lifetime of achievements, Franz Matschinsky received many awards, including the Solomon A. Berson Plenary Lecture International Diabetes Federation Medal (1988), the Elliott Proctor Joslin Medal (1992), the Paul-Langerhans-Plakette (1996), the Paul Lacy Medal (2011), and the Rolf Luft Award (2020). He was especially proud to have received the Banting Medal for Scientific Achievement from the American Diabetes Association in 1995. Franz loved the American Diabetes Association and was a superb editor in chief of Diabetes from 2001 to 2006, where his associate editors, including two of us (K.H.K. and M.A.L.) as well as his invaluable assistant Vesselina Panteva, marveled at his fairness and judgement in leading the journal to new heights.

In addition to possessing scientific acumen, Franz was a superb person and sincere friend of many. He was a wonderful collaborator. One of us (M.A.M.) had the great honor and pleasure of a 33-year friendship, including a longstanding collaboration on the gene regulation of glucokinase not only in pancreatic islets but also in the gut (12,13). While teaching another of us (K.H.K.) all he knows about islet biology and hormone secretion, Franz suggested a study of the impact of glucokinase in pancreatic α-cells that confirmed his hunch that this enzyme also controls the set point for glucagon secretion in a cell-autonomous fashion (14). Franz’s excitement about biochemistry and metabolic homeostasis was palpable, and toward the end of his career he shared his more philosophical work with longtime collaborator David Wilson (15). Franz particularly delighted in helping other scientists make discoveries related to insulin secretion; most notably, his longstanding collaboration with Charlie Stanley at the Children’s Hospital of Philadelphia elucidated biochemical and genetic mechanisms of monogenic forms of diabetes and hypoglycemia related to disorders of insulin secretion. The translation of his work to humans was always a priority, and, with Penn colleagues Clyde Barker and Ali Naji, Franz pioneered physiologic studies of isolated pancreatic islets from healthy individuals and patients with diabetes. He was also a key advisor to the Human Pancreas Analysis Program for Type 2 Diabetes as well as to the IDOM/DRF Islet Biology Core, now directed by his close colleague Doris Stoffers.

The current chair of the Department of Biochemistry and Biophysics at Penn, Kristen Lynch, and the director of IDOM (M.A.L.) are deeply appreciative of Franz’s mentorship. It is not an understatement to say that we stand on the shoulders of a giant, often drawing on Franz’s deep knowledge of metabolism as well as his sage-like wisdom. We deeply appreciate that Franz always encouraged us to do things as we saw fit, enthusiastically supporting the pursuit of new scientific directions and the hiring of new faculty. This was clear from his incredibly helpful advice (to M.A.L.) over multiple successful renewals of the Penn DRC grant. His influence extended to the current generation of young faculty and trainees, who were thankful for their exposure to his gentle but insightful questions and comments at IDOM lectures and symposia. In 2019, the Penn IDOM Symposium was a special event that served as a tribute to Franz’s remarkable life and contributions.

The legacy of Franz Matschinsky will live on in his three children (Stephan, Benno, and Tanja) and their children, in his many trainees and colleagues, and in the textbooks that teach the mechanism of glucose sensing in the pancreas and the wonders of glucokinase.