Brown, Monica E., Miranda, Verda E., Nevills, Simone, Hu, Ruiying, Dadi, Prasanna K., Simmons, Alan J., Xu, Yanwen, Yang, Yilin, Yagan, Mahircan, Najam, Sadia, Sampson, Leesa L., Magnuson, Mark A., Jacobson, David A., Lau, Ken S., Hodges, Emily, & Gu, Guoqiang. (2025). Pancreatic islet β-cell subtypes are derived from biochemically-distinct and nutritionally-regulated islet progenitors. *Nature Communications, 16*(1), 5758. https://doi.org/10.1038/s41467-025-60831-0
The insulin-producing cells in the pancreas, known as islet β cells, are not all the same—they come in different subtypes with varying levels of gene activity and functions. In this study, researchers explored when and how these differences among β cells arise, and how long each subtype keeps its unique characteristics.They found that even before these cells fully develop, their early-stage versions (called progenitor cells) already show differences in gene expression and DNA patterns. These early differences influence how the mature β cells perform—for example, how well they release insulin, how quickly they multiply, and how long they survive. These variations were seen in both male and female mice.The subtypes differ in the genes involved in making insulin or in how the cells respond to sugar in the blood. These differences are linked to variations in DNA regions called enhancers, which help control gene activity. One important finding was that when a mother is obese during pregnancy—a known risk factor for diabetes—the offspring have fewer β cells of the subtype that responds well to glucose.The researchers also showed that the same gene patterns used to define β-cell subtypes in mice could be used to identify similar subtypes in humans. In people with diabetes, there were fewer cells of the subtype that is better at responding to glucose.In short, this study shows that the diversity of β-cell types can be traced back to early development and is influenced by the mother’s nutrition. These findings could help us better understand and eventually improve treatments for diabetes.
Fig. 1: M+N+ and M–N+ progenitor-derived β cells have different proliferation rate, viability, and secretory function.
a The scheme for M+N+ sub-lineage marking. b–e β-cell proliferation assays in MNT mice. b An image (single and merged channels) showing P24 β-cell subtype proliferation [tdT+ (red) and tdT–], using Ki67 (white) and insulin (green) co-staining. White arrows, tdT–Ki67+ cells; yellow arrows, tdT+Ki67+ cells. 15 mice were examined, yielding similar results. c The % of Ki67-expressing tdT+ or tdT– β cells in each of the 15 mice (m: males, f: females). d A tdT+ β cell with dividing nuclei (yellow arrow), detectable in all 15 mice. e The proportions (mean + SEM) of tdT+β cells at P2 and P60, obtained using scRNA-seq (Supplementary_data_file_1). P-values in c and e are from unpaired t-tests with two-sided type-two error. “n” in (e), numbers of mice (4 P2 and 6 P60). f–j β-cell apoptosis in MNmG mice. f A β cell (insulin+, white) expressing Casp (green) but not mG (red)(white arrows). Merged and single channels are included. g An mG+Casp3+ β cell (white arrow). (h, i) highlight the mG+Ins+ cell (broken white circle) in the Ins and MG channels of (g). j % of Casp3+ β-cell subtypes. P-value is from a paired student t-test with two-sided type-two error. In (j), 3 P4 and 3 P7 mice were counted (>1500 β cells counted in each). (k-o) Insulin secretion in PSIs from β-cell subtypes of MNT islets. k, l FACS sorting and PSI production of tdT+and tdT– PSIs (DAPi was used for excluding dead cells). (m-o) Insulin secretion under G2.8, G20, or G20K. The % (mean + SEM) of total insulin secreted was presented. m, n Results of 2-month old MNT female or male mice, respectively. o PSI secretion from 8-month-old MNT mice (males and females). P-values are from unpaired t-test with a two-sided type-two error. Only those p < 0.05 were shown. “n”, the number of individual GSIS assays using different PSIs, done on 2 or 3 days using preps from different mice. Scale bars, 20 μm.
