Massimo Pietropaolo, MD (1957–2022): A Gentle Physician and Inquisitive Experimentalist in Type 1 Diabetes Research

This article celebrates the scientific contributions to diabetes research and the life of Massimo Pietropaolo, MD (Fig. 1). He passed in the summer of 2022, at 65 years of age, following a valiant battle with cancer. Max, as he was known to family, friends, and colleagues, was born on 24 February 1957, in Palmi, Italy, a small town on the southern tip of the Italian peninsula. He was the first of two sons born to Michele and Concetta. Max grew up with his brother Renato, and they remained very close in their relationship despite living on different continents for over 30 years (Fig. 2). His parents were hard-working and caring people who raised their children with strong moral values and the belief that one’s work is a fundamental contribution to the community. Michele and Concetta provided both children with a serene and nurturing environment, supported their education, and encouraged them to pursue their passions above all. As a boy and adolescent, Max played basketball for his hometown team and studied music (piano), interests that he enjoyed throughout his life. Max would share his love for basketball and Italian soccer with his children, teaching them how to play. He also enjoyed watching American football (Steelers and Lions), basketball (Lakers), and baseball (Red Sox and Astros) with family and friends. His love of New Orleans jazz and blues ultimately inspired Max to take trombone lessons and learn improvisation in his later years. In high school, Max developed a passion for classical literature, memorizing passages from Dante Alighieri’s Divine Comedy, from which he would still recite in later years, surprising everyone with his memory! Max formed an interest in science and medicine, starting quite early in life, with sometimes explosive results using his self-made home chemistry laboratory. As a teenager, Max observed a surgery, which further cemented his desire to study medicine. Growing up, Max embraced values of social responsibility, community, service, and friendship. He connected with people throughout his life, developing relationships based upon openness, integrity, compassion, and respect. His inquisitive mindset combined with these characteristics defined his nature and are what made him a successful physician-scientist.

In 1975, upon graduating from Palmi High School with a degree in “Maturità Classica” (classical studies), he enrolled in the Medical School at the University of Perugia, a most prestigious university in Italy established in 1308. As Perugia is in central Italy, about 500 miles/800 km from Palmi, Max had to leave his family and hometown to pursue his medical studies. He would remain in Perugia for 13 years, obtaining his MD degree in 1983 and completing his residency in internal medicine, with honors, in 1988. In medical school, he developed a strong interest in type 1 diabetes, which would remain the focus of his life’s scientific work and clinical efforts. At this time, he was mentored by Drs. Paolo Brunetti and Riccardo Calafiore, who were pioneering islet purification and encapsulation techniques. Dr. Calafiore considered Max his “younger brother” (himself being in the early stages of his career) and shared the following memory from when he reviewed Max’s graduation thesis on the insulin receptor:

In 1988, Max obtained a clinical position in his hometown, yet he declined and instead chose to pursue diabetes research. For most people in Italy, there is always the desire to be close to family, and deciding to leave his family and town behind was not easy. In 1989, Max started a postdoctoral fellowship with George Eisenbarth, MD, PhD, a global leader in type 1 diabetes research, then at the Joslin Diabetes Center, Harvard Medical School, Boston, MA. He was joined by two other research fellows from Italy, Drs. Roberto Gianani and Alberto Pugliese, with whom he would cement life-long friendships (Fig. 3). In 1992, they all followed Dr. Eisenbarth to the Barbara Davis Center for Childhood Diabetes, University of Colorado, in Denver. During this time, Max maintained a dual appointment as an investigator at the University of Perugia (1991–1996).

Both in Boston and in Denver, Max was a key driver on studies of autoantigens and autoantibodies in type 1 diabetes. He painstakingly discovered and enumerated several autoantigens, which at that the time was a very laborious process that required screening λ gt11 libraries generated from islets. That meticulous effort led to one of his seminal lifetime contributions, the discovery of the ICA69 autoantigen, its cloning, and its initial characterization (2), showing that ICA69 is preferentially expressed in pancreatic islet cells (3). Max was involved in the discovery that genes coding for diabetes autoantigens (including ICA69) are expressed in the human thymus, with implications for self-tolerance or lack thereof in settings of type 1 diabetes (4,5). He contributed to the modeling of autoantibodies for improved prediction of type 1 diabetes (6), showing that the presence of multiple autoantibodies is, indeed, a major risk factor for disease development (7), with his work also leading to the development of autoantibody assays, such as those for ICA512 (IA-2), in collaboration with Roberto Gianani, MD (8). Peter Gottlieb, MD, from the Barbara Davis Center, remembered:

In 1995, Max began his career as an independent physician-scientist, to which he remained dedicated until the end. His career path took on a journey through many institutions in the U.S., starting with the University of Pittsburgh. There, he obtained his first National Institutes of Health grant, among others, which was continuously funded for more than 20 years. Max remained in Pittsburgh until 2006, rising to the rank of associate professor of pediatrics, medicine, and immunology, with tenure. Massimo Trucco, MD, and Nick Giannoukakis, PhD, his colleagues in Pittsburgh, shared:

Clayton Mathews, PhD, then also in Pittsburgh, recalls:

Max’s arrival in Pittsburgh marked the next steps in his life and career. The first event was his memorable wedding to Susan, followed some years later by the birth of their two sons, Michele and Giacomo (Fig. 4). In Pittsburgh, Max reestablished his clinical activity, where he saw patients in both pediatric and adult diabetes clinics. Dr. Dorothy Becker, from the Children’s Hospital of Pittsburgh, noted:

In addition, Mark Sperling, MD, editor in chief of the journal Pediatric Diabetes, recruited Max as an associate editor. As a sign of his dedication, Max continued in this role even after his next two academic relocations. Max and Susan continued long-lasting collaborations and friendships with Drs. Dorothy Becker and Ingrid Libman as well. Max vigorously applied his interests in discovering and measuring islet autoantibodies to their investigation of risk prediction by using the long-established serum collection of the Pittsburgh epidemiology studies. With Dr. Libman, Max expanded the study of islet cell autoantibodies to include African American children, and he noted that heterogeneity in the disease pathogenesis depended on race—this, at a time when most studies were (and largely still remain) primarily limited to Caucasian populations (9–11). Max also demonstrated the role of islet cell antibodies (ICA) as an additional risk biomarker beyond biochemical islet autoantibodies at a time the ICA assay was going out of fashion. Typical of his sense of humor and Italian heritage, Max titled this paper “Viva ICA,” but the journal editor requested the name be changed (12). However, he was able to present a “Viva ICA” poster at the 2004 American Diabetes Association’s Scientific Sessions (13) and a “Cytoplasmic Islet Cell Antibodies 30th Birthday” poster at the 2004 Immunology of Diabetes Society meeting. He contributed to the realization that type 1 diabetes is not just a disease of children by demonstrating the presence of islet autoantibodies in elderly patients with type 2 diabetes (14). He further advanced prediction studies by incorporating the use of genetics and reporting that certain genetic variants increase risk of progression to diabetes even among individuals lacking islet cell autoantibodies (15).

Max collaborated with Michele Solimena, MD, PhD, professor of molecular diabetology, Technical University of Dresden Medical School, Dresden, Germany, to further advance the molecular characterization of the ICA69 antigen. Max reported on its gene transcriptional regulation (16) and demonstrated that ICA69 is an arfaptin-related protein, a Rab2 effector regulating endoplasmic reticulum–Golgi trafficking in insulinoma cells (Fig. 5). Max also showed that manipulating ICA69 expression leads to impaired anterograde transport of autoantigenic secretory granule protein precursors (e.g., pro-ICA512 and chromogranin A) and reduced stimulated insulin secretion. This work demonstrated that ICA69 is a novel Rab2 effector that regulates the early transport of insulin secretory granule proteins (17). This revelation of ICA69 as a potential regulator of insulin secretory granules sparked interest for continued studies and collaborations on the role of ICA69-PICK1 (protein interacting with C kinase 1) heterodimer formation and its role in immature insulin granule biogenesis and insulin secretion (18). Michele Solimena remembers:

In 2006, Max was recruited to the University of Michigan and promoted to the rank of tenured professor of internal medicine, pediatrics, microbiology, and immunology. His colleague, Peter Arvan, MD, PhD, shared some remembrances:

Martin Myers, MD, PhD, reminisced about their work together on the Diabetes editorial board:

Max’s membership in the Brehm Coalition also enhanced a decades-long friendship with Mark Atkinson, PhD, from the University of Florida. In 2007, Mark was developing the concept for a program that would obtain pancreatic tissues from organ donors with or at increased risk for type 1 diabetes. This effort, now known as nPOD (Network for Pancreatic Organ Donors with Diabetes), would eventually become the world’s largest resource for tissues and would aid in understanding the pathogenic mechanisms underlying type 1 diabetes. Mark shared the following thoughts:

The years at Michigan saw Max contribute to diabetes research in many ways. He was among the early promoters of the concept that diabetes is a heterogeneous disorder, developed a mathematical model for improved prediction that considered dynamic changes in β-cell function together with the roles of regulatory and effector T cells, and reported that autoantibodies against the extracellular domain of the IA-2 autoantigen were independently associated with an increased risk of progression to type 1 diabetes (19–23). In addition, Max discovered sequence variation in the promoter of region of the Ica69 gene in nonobese diabetic mice that impacted binding to the autoimmune regulator (AIRE) transcription factors, leading to reduced thymic expression of Ica69 and impaired tolerance. Specifically, in a mouse model he created, impaired thymic expression of the ICA69 autoantigen was followed by autoimmune manifestations, including the development of diabetes, thyroiditis, and gastritis (24,25).

In 2014, Max was recruited to Baylor College of Medicine, with appointments as a tenured professor of medicine, pathology, and immunology and as the McNair Scholar, a program of the McNair Medical Institute at the Robert and Janice McNair Foundation (Fig. 6). Max served as the director of the Baylor Type 1 Diabetes Program and as the associate director of the Diabetes Research Center. Marco Marcelli, MD, was his colleague at the University of Perugia, and they later reunited at Baylor. He shared the following:

At Baylor, Max continued his innovative research on type 1 diabetes. He conducted studies in nonobese diabetic mice to evaluate the therapeutic potential of CD19+IgM+ cells (26) and of chimeric antigen receptor T cells (27). Collaborating with mathematicians, he modeled the impact of thymic expression of self-molecules on self-tolerance (28). In 2020, along with other medical experts, Max developed a comprehensive consensus statement and therapeutic guidelines for patients with latent autoimmune diabetes of adults, which today remain valuable tools for physicians seeking appropriate diagnosis and treatment of disease (29). Max expanded on the importance of autoantibody responses to the extracellular portion of the autoantigen IA-2, now including patients with type 2 diabetes (30), suggesting that these antibodies help identify a subset of patients with ketosis-prone diabetes (31). He then discovered a new class of IA-2 autoantibodies directed against a novel variant discovered to have three amino acid substitutions. His study of first-degree relatives of type 1 diabetes probands from the National Institute of Diabetes and Digestive and Kidney Diseases TrialNet Pathway to Prevention study revealed that positivity for autoantibodies to this novel IA-2 variant was associated with increased risk of progression to stage 3 disease in those negative for the standard IA-2 autoantibodies and positive for autoantibodies to GAD65 and/or insulin. This represented an important advance for disease prediction (32). In his final work, published posthumously, Max demonstrated that the use of continuous glucose monitoring metrics can aid in identifying individuals who are likely to progress from stage 2 disease (preclinical) to stage 3 disease (33), again in the well-characterized TrialNet cohort. With the recent U.S. Food and Drug Administration approval (November 2022) of teplizumab as an intervention that delays progression from stage 2 to stage 3 disease, the implications of his study are highly impactful to both clinical trials and clinical practice.

Max was also an astute clinician and would often make himself available to patients outside his normal clinic schedule. Dr. Mandeep Bajaj shared:

Dr. Madhuri Vasudevan shared her experience with Max as a mentor on the management of continuous glucose monitoring:

Since 2020, Max’s insatiable curiosity and unwavering dedication have broadened our understanding of type 1 diabetes to the autoimmune diabetes triggered by the immune checkpoint inhibitors used in cancer treatment (34). This research delved into whether immune checkpoint inhibitor–induced diabetes is a fresh manifestation of primary autoimmune disorders or if it emerges as a discrete disease entity. Max led a collaboration with Hyun-Sung Lee, MD, PhD (35), an emerging surgeon-immunologist who expressed his admiration for Max, sharing:

During his career, Max held many leadership positions, including serving as chair of National Institutes of Health–National Institute of Diabetes and Digestive and Kidney Diseases study sections, cochair of the JDRF Biomarker Working Group, and steering committee member of the Type 1 Diabetes TrialNet. Among his academic achievements are career development awards from the American Diabetes Association and JDRF; the Columbus Day Award from the Italian American Society, New York, NY; the Outstanding Alumni Achievement Award, University of Perugia Medical School, Italy, where he was invited to give a lecture commemorating the 700th anniversary of his alma mater in the presence of other alumni from around the world; the League of Research Excellence Award, from the University of Michigan; and many more.

This memorial would fall short if it failed to note that Massimo was also a loving husband and father. His beloved wife Susan was his partner in life and professionally as well, from the mid-1990s when they first met at the University of Colorado. Side-by-side they shared a beautiful life together with a deep love of family. Among other things, they enjoyed traveling, oftentimes blending their vacations with visits to each other’s relatives in Colorado, Texas, or Italy. Together, they raised their children in their Catholic faith with a love for family, friends, community, and the fearlessness to pursue their dreams and create their own unique futures.

In closing, Massimo Pietropaolo was a dedicated physician-scientist who deserves our recognition and gratitude, as he was a major contributor to, and instigator of, the progress made in type 1 diabetes research over the last 30 years. Max strongly believed in the collegiality of research, in sharing ideas, and in working toward preventing type 1 diabetes. His contributions have fundamentally advanced type 1 diabetes prediction and will facilitate ongoing efforts that seek disease prevention. For those of us privileged to know Max, there remains the indelible memory of an outstanding physician-scientist and wonderful human being, a lasting smile and encouraging enthusiasm for family, friends, and patients. Max was a humble, kind, and giving friend for life.