The autoimmunity associated with type 1 diabetes often begins in the first years of life, and the diagnosis of type 2 diabetes is rapidly rising among children and teens.
Data from the SEARCH for Diabetes in Youth study — a national initiative tracking the epidemiology of the disease in the United States — shows a significant increase in annual diagnoses for both type 1 and type 2 diabetes in individuals under age 20 between 2002 and 2018.
While diabetic ketoacidosis, a complication of diabetes that occurs when the body lacks enough insulin to use blood sugar for energy, remains a leading cause of mortality in children at the time of diagnosis, an innovative study published in Nature Communications is opening new doors to saving young lives.
Through the ultimate altruism of families who donated their children's organs for research, a cross-institutional team of scientists has made new discoveries about how the young pancreas forms and functions –– attempting to get at the root causes of the extreme susceptibility to dysfunction that is established during the infant to juvenile period of pancreas maturation.
In the study, researchers mapped pancreatic islet development in 123 pediatric organ donors without diabetes, tracking their growth from birth through the first decade of life.
"This study is dedicated to these donors — the children — and their loved ones, without whom this work would not be possible," said Marcela Brissova, PhD, Research Professor of Medicine at Vanderbilt Health and a co-lead of the study. "Their courage in consenting to donation has allowed these short lives to have a profound impact, and we will continue to build scientific discovery based on these gifts."
The pancreas is the body's master metabolic engine. While 98% of the organ works to digest food, tiny, cellular clusters called the islets of Langerhans work to keep blood sugar levels balanced. Each islet is a powerhouse — a multicellular mini-organ housing hormone-producing endocrine cells, blood vessels, immune cells and other cell types. The human pancreas contains about 2 million of these cellular communities, and their inner workings change dynamically through time and as diabetes develops .
Using quantitative analyses and advanced, high-definition tissue imaging approaches — including confocal microscopy and whole-slide multiplex imaging — to track more than 30 unique biological markers, the investigative team built the most detailed map ever created of the growing pancreas and connected these findings to islet function.
Notably, when examining isolated cells, glucagon-producing alpha cells were noted to take longer to fully mature, while insulin-producing beta cells are equipped to respond to metabolic signaling much earlier in life.
Other key findings include:
- Significant variation in pancreas weight at birth: Differences in human pancreas size, islet structure and cell composition appear remarkably early. Most notably, pancreas weight — a potential biomarker for increased risk of type 1 diabetes — was seen to vary by nearly four times from one infant to another.
- Slower beta cell growth: After birth, the rate of endocrine cell proliferation rapidly declines. Insulin-producing beta cells grow at a much lower rate than scientists previously believed, building evidence supporting the idea that an adult's beta cell mass is largely determined during prenatal development and the first decade of life.
- Postnatal islet cell neogenesis (new cell generation): The identification of presumed multipotent progenitor cells suggests endocrine cells can still be created well after birth. Additionally, immune cells (specifically macrophages) were present, hinting that they help guide postnatal islet endocrine cell development.
- Delayed wiring of the network (innervation): While blood vessels reach islet cells at birth, essential nerve connections were seen to develop later. Compared with rodent models, human islet cells may rely much more heavily on local chemical signals to communicate and function.
- Asynchronous maturation (uneven timing): When examining isolated cells, glucagon-producing alpha cells were noted to take longer to fully mature, while insulin-producing beta cells are equipped to respond to metabolic signaling much earlier in life.
Previously, detailed observation of the young pancreas was hindered by limited access to early human tissue and imaging constraints. To accelerate global research, the massive imaging dataset generated in this study has been made publicly available via the Neonatal Development & Early Life Pancreas (HANDEL-P) collection on Pancreatlas , an online image resource housed at Vanderbilt Health.
"The pancreas is an incredibly dynamic organ during the first decade of life, which is precisely when cellular dysfunction is often first noted," said study co-lead Mark Atkinson, PhD, Jeffrey Keene Family Professor at the University of Florida.
Study co-lead Christopher V. Wright, DPhil, Professor of Cell and Developmental Biology at Vanderbilt University, added: "It's been remarkable to analyze pancreas growth and islet formation in the largest pediatric cohort to date so we can better understand postnatal development, early cellular structures and hormone secretion."
Developing a comprehensive understanding of pediatric pancreatic islet development provides a crucial framework for future studies and for integrating emerging genetic data related to islet biology and diabetes risk.
"We are excited to continue to build on this work as we move toward the earlier diagnosis and prevention of diabetes, as well as improved, more personalized treatments," said Alvin C. Powers, MD, Joe C. Davis Professor of Biomedical Science, Co-Director of the Vanderbilt Diabetes Center, and a co-lead of the study.
These investigations underscore the importance of interdisciplinary collaboration across islet biology, physiology, computational biology, developmental biology, and pediatric endocrinology, as reflected in the co-first authors of this study, Diane Saunders, PhD; Fan Feng, PhD; Alexander Hopkirk, MBA; Kristie Aamodt, MD, PhD; Nathaniel Hart, PhD; and Fong Cheng Pan, PhD.
The pediatric pancreata were obtained through partnerships with the Network of Pancreatic Organ Donors with Diabetes, the International Institute for Advancement of Medicine, and the National Disease Research Interchange.
The study was supported by The Leona M. and Harry B. Helmsley Charitable Trust, through the Human Atlas of the Neonatal Developmental and Early Life-Pancreas, Pancreatlas, and additional grants. This work was also supported by the Human Islet Research Network and Human Pancreas Analysis Program, the National Institutes of Health (R24DK106755, U01DK123716, U01DK123743, U01DK120456, UC4DK104211, UC4DK108120, U01DK104218, UC4DK112232, UC4DK112217, R01DK117147, R01DK129469, U01DK123594, U01DK135017, OD0426640, U54EY032442, U24DK138515, OT2OD038003, U24DK097771, and P60DK020593) and the Department of Veterans Affairs.
This research was performed with additional support from the Network for Pancreatic Organ Donors with Diabetes, and a collaborative type 1 diabetes research project supported by the Barbara D. Cammett Breakthrough T1D (formerly JDRF) Center of Excellence in New England. Whole-slide imaging was performed in the Islet and Pancreas Analysis Core of the Vanderbilt Diabetes and Research Training Center (P60DK020593). Confocal microscopy was performed in part through use of the Vanderbilt Cell Imaging Shared Resource (P30CA068485, P60DK020593, P30DK058404 and U24DK059637).
