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). *Nature Communications, 16*(1), 5758.
The insulin-producing cells in the pancreas, known as islet 尾 cells, are not all the same鈥攖hey come in different subtypes with varying levels of gene activity and functions. In this study, researchers explored when and how these differences among 尾 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 尾 cells perform鈥攆or 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鈥攁 known risk factor for diabetes鈥攖he offspring have fewer 尾 cells of the subtype that responds well to glucose.The researchers also showed that the same gene patterns used to define 尾-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 尾-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+听and M–N+听progenitor-derived 尾 cells have different proliferation rate, viability, and secretory function.
a听The scheme for M+N+听sub-lineage marking.听b鈥�e听尾-cell proliferation assays in听MNT听mice.听b听An image (single and merged channels) showing P24 尾-cell subtype proliferation [tdT+听(red) and tdT–], using Ki67 (white) and insulin (green) co-staining. White arrows, tdT–Ki67+听cells; yellow arrows, tdT+Ki67+听cells. 15 mice were examined, yielding similar results.听c听The % of Ki67-expressing tdT+听or tdT–听尾 cells in each of the 15 mice (m: males, f: females).听d听A tdT+听尾 cell with dividing nuclei (yellow arrow), detectable in all 15 mice.听e听The proportions (mean鈥�+鈥塖EM) of tdT+尾 cells at P2 and P60, obtained using scRNA-seq (Supplementary_data_file_).听P-values听in c and e are from unpaired t-tests with two-sided type-two error. 鈥渘鈥� in (e), numbers of mice (4 P2 and 6 P60).听f鈥�j听尾-cell apoptosis in听MNmG听mice.听f听A 尾 cell (insulin+, white) expressing Casp (green) but not mG (red)(white arrows). Merged and single channels are included.听g听An mG+Casp3+听尾 cell (white arrow). (h,听i) highlight the mG+Ins+听cell (broken white circle) in the Ins and MG channels of (g).听j听% of Casp3+听尾-cell subtypes.听P-value听is from a paired student t-test with two-sided type-two error. In (j), 3 P4 and 3 P7 mice were counted (>1500 尾 cells counted in each). (k-o) Insulin secretion in PSIs from 尾-cell subtypes of听MNT听islets.听k,听l听FACS sorting and PSI production of tdT+and tdT–听PSIs (DAPi was used for excluding dead cells). (m-o) Insulin secretion under G2.8, G20, or G20K. The % (mean鈥�+鈥塖EM) of total insulin secreted was presented.听m,听n听Results of 2-month old听MNT听female or male mice, respectively.听o听PSI secretion from 8-month-old听MNT听mice (males and females).听P-values are from unpaired t-test with a two-sided type-two error. Only those听p鈥�<鈥�0.05 were shown. 鈥渘鈥�, the number of individual GSIS assays using different PSIs, done on 2 or 3 days using preps from different mice. Scale bars, 20 渭m.
