Age-Dependent Pancreatic Gene Regulation Reveals Mechanisms Governing Human β Cell Function

Abstract

SUMMARY Intensive efforts are focused on identifying regulators of human pancreatic islet cell growth and maturation to accelerate development of therapies for diabetes. After birth, islet cell growth and function are dynamically regulated; however establishing these age-dependent changes in humans has been challenging. Here we describe a multimodal strategy for isolating pancreatic endocrine and exocrine cells from children and adults to identify age-dependent gene expression and chromatin changes on a genomic scale. These profiles revealed distinct proliferative and functional states of islet α-cells or β-cells, and histone modifications underlying age-dependent gene expression changes. Expression of SIX2 and SIX3, transcription factors without prior known functions in the pancreas and linked to fasting hyperglycemia risk, increased with age specifically in human islet β-cells. SIX2 and SIX3 were sufficient to enhance insulin content or secretion in immature β-cells. Our work provides a unique resource to study human-specific regulators of islet cell maturation and function.

Age-dependent human β cell proliferation induced by glucagon-like peptide 1 and calcineurin signaling

“…46). These findings are also supported by studies here (Figure 2A) and elsewhere (10,33) revealing that GLP1R expression did not detectably change with age in human islet β cells. An additional finding from our work is that human α cell and δ cell proliferation also appears to decline with age, corroborating a recent mass cytometry-based study (47).…”

“…GLP1R mRNA levels were similar in juvenile and adult human islets (Figure 2A), suggesting that human β cell GLP-1R expression is not age-dependent. Moreover, in FACSisolated islet cell subsets, GLP1R mRNA was principally expressed in β cells and was very low, or not detectable, in α cells (Supplemental Figure 2, A-C), consistent with prior findings (10,(31)(32)(33)(34)(35).…”

“…To test the hypothesis that human β cell proliferative response to the GLP-1 analog Ex-4 is age-dependent, we used an in vivo transplantation strategy with human islets from juveniles and adults (3,4,10,26). Here we report that Ex-4 stimulates β cell proliferation in transplanted juvenile, but not adult, human islets, and that this response requires intact calcineurin/NFAT signaling.…”

“…During postnatal β cell growth, studies in rodents suggest that hallmark β cell functions such as glucose sensing and insulin secretion mature (6)(7)(8)(9)(10). The mechanisms controlling age-dependent β cell proliferation and maturation are being intensely investigated, since deciphering these could accelerate development of β cell expansion strategies (3,4,8,(10)(11)(12)(13).…”

Distinct roles for the mTOR pathway in postnatal morphogenesis, maturation and function of pancreatic islets

“…mTORC1-Raptor is essential for β-cell maturation and acquisition of function, while mTORC2-Rictor contributes to islet morphogenesis. Recently, studies of human juvenile islets determined that they are transcriptionally distinct from adult islets, implying that human islets might also undergo significant postnatal maturation (Arda et al, 2016). Therefore, understanding the molecular basis of islet maturation and morphogenesis in response to enteral nutrients is of clinical importance.…”