Heterogeneous endocrine cell composition defines human islet functional phenotypes

Key results

1. ShownEndocrine cell composition, rather than donor traits or islet morphology, tracked insulin secretion. A higher β cell percentage went with more stimulated insulin release; higher α and δ cell percentages went with less. Islet diameter, area and perimeter showed no association with any secretion trait.

   Scaled coefficients in eight-covariate regressions (n = 299): β cell % vs glucose-stimulated b = 0.23 (p = 2.31 x 10^−4), cAMP-potentiated b = 0.35 (p = 1.18 x 10^−8) and KCl-mediated insulin secretion b = 0.30 (p = 1.16 x 10^−6); δ cell % vs glucose stimulation index b = –0.13 (p = 0.02) and low glucose plus adrenaline inhibition index b = –0.19 (p = 1.76×10^−3). · Islet composition strongly influences hormone…; DISCUSSION; Figure legends

2. SuggestedA type 2 diabetes (T2D) genetic risk score (GRS) built from 338 variants was positively associated with islet δ cell percentage, whether or not HbA1c was included as a covariate.

   268 genotyped donors; covariates were age, sex, BMI, isolation center, culture and transit times and five genetic principal components. b = 0.17, p = 0.019 with HbA1c; b = 0.17, p = 0.016 without. Without HbA1c, the T2D GRS was also positively associated with glucagon content. With HbA1c included, no other T1D or T2D GRS association with secretion or content was significant. · Genetic risk for diabetes is associated with…; EXTENDED DATA FIGURE AND TABLE LEGENDS; Figure legends

3. SuggestedIn Human Pancreas Analysis Program (HPAP) islet scRNA-seq, genes nearest the T2D GRS variants were enriched among genes upregulated in δ cells. HHEX, DGKB and GLP1R were among the GRS genes expressed in δ cells.

   87,505 islet cells (1877 δ cells) from 44 donors without diabetes. The 338 variants mapped to 303 nearest genes; 181 of 303 (60%) were expressed in δ cells at mean normalized counts > 0.01. Tests were Wilcoxon rank-sum in scanpy with Benjamini-Hochberg correction, plus a Fisher test for enrichment; the text prints no enrichment statistic. · Genetic risk for diabetes is associated with…; DISCUSSION; Differentiational expression of predicted T2D…; Figure legends

4. ShownEndocrine composition varied widely between donors and differed by sex and ancestry. Female donors had more α and fewer β cells, and Asian or East Asian donors had more β cells. Age, BMI, HbA1c, isolation center and processing times had no detectable effect on composition.

   Mean 58% β (range 25 – 92%), 34% α (3 – 68%) and 8% δ (1 – 19%), roughly 4-, 22- and 19-fold variation. Global effects on β and α percentages: reported race or ethnicity (p = 0.003), genetic ancestry (p = 0.0004). Asian vs White and East Asian vs European donors had more β and fewer α cells (p = 0.0007 and p = 0.0001), based on 12 Asian and 11 East Asian donors. · Islet composition is influenced by sex, reported…; DISCUSSION; Figure legends

5. ShownAfter adjusting for covariates and multiple testing, donor age, sex and reported race or ethnicity showed no association with secretion. BMI was linked to glucagon traits, predicted ancestry to basal insulin, and pre-shipment culture and transit times to several insulin and glucagon traits.

   BMI coefficients: basal glucagon b = –0.20 (p = 0.005), KCl-mediated glucagon b = –0.17 (p = 0.03), glucose inhibition of glucagon b = 0.15 (p = 0.03). Unadjusted Spearman links, e.g. age vs cAMP-potentiated insulin (r = –0.15), were not retained after adjustment. Secretion did not differ between donors with HbA1c < 5.7% (n = 223) and ≥ 5.7% (n = 76). · Islet secretory function is highly heterogeneous…; DISCUSSION; EXTENDED DATA FIGURE AND TABLE LEGENDS