Formation of a Human β-Cell Population within Pancreatic Islets Is Set Early in Life

Context: Insulin resistance can be compensated by increased functional pancreatic beta-cell mass; otherwise, diabetes ensues. Such compensation depends not only on environmental and genetic factors but also on the baseline beta-cell mass from which the expansion originates. Objective: Little is known about assembly of a baseline beta-cell mass in humans. Here, we examined formation of beta-cell populations relative to other pancreatic islet cell types and associated neurons throughout the normal human lifespan. Design and Methods: Human pancreatic sections derived from normal cadavers aged 24 wk premature to 72 yr were examined by immunofluorescence. Insulin, glucagon, and somatostatin were used as markers for beta-, alpha-, and delta-cells, respectively. Cytokeratin-19 marked ductal cells, Ki67 cell proliferation, and Tuj1 (neuronal class III beta-tubulin) marked neurons. Results: Most beta-cell neogenesis was observed preterm with a burst of beta-cell proliferation peaking within the first 2 yr of life. Thereafter, little indication of beta-cell growth was observed. Postnatal proliferation of alpha- and delta-cells was rarely seen, but a wave of ductal cell proliferation was found mostly associated with exocrine cell expansion. The beta-cell to alpha-cell ratio doubled neonatally, reflecting increased growth of beta-cells, but during childhood, there was a 7-fold change in the beta-cell to delta-cell ratio, reflecting an additional loss of delta-cells. A close association of neurons to pancreatic islets was noted developmentally and retained throughout adulthood. Negligible neuronal association to exocrine pancreas was observed. Conclusion: Human baseline beta-cell population and appropriate association with other islet cell types is established before 5 yr of age. (J Clin Endocrinol Metab 97: 3197-3206, 2012)