Fig. 6: HNF1A haploinsufficiency gradually impairs scβ-cell function in vivo.

a–c Human C-peptide (pM) and human insulin levels in plasma of ad libitum-fed mice transplanted with HNF1A-MODY iPSC-derived endocrine cells (HNF1A +/R200Q and R200Q-corrected WT). a Plasma human C-peptide (pM) and b human insulin secretion (mU/L) in mice transplanted with HNF1A-MODY iPSC-derived endocrine cells (R200Q Het n = 10 and R200Q corr. WT n = 5) in ad libitum-fed state and during an iPGTT (t0, t30, and t60). p-values were b: p < 0.001, b, c: p < 0.01 and c: p < 0.05. c Blood glucose concentrations (mg/dl) in ad libitum-fed mice transplanted with HNF1A-MODY iPSC-derived endocrine cells (R200Q Het n = 21 and R200Q corr. WT n = 32). Mice (R200Q Het n = 8, R200Q corr. WT n = 8 and Ctl n = 5) were injected (red arrow) with STZ. d Human C-peptide (pM), e human insulin (mU/L) (R200Q Het n = 9 and R200Q corr. WT n = 6), and f hINS (pM)/hCPEP (pM) secretion ratios monitored in plasma of ad libitum-fed mice weeks before (−1) and after (5 and 6) STZ treatment. p-values were b, d: p < 0.01; c: p < 0.05. g Quantification of hINS(pM)/hCPEP(pM) content ratios from isolated grafts. h, i IPGTT in mice transplanted with HNF1A-MODY iPSC-derived endocrine cells (R200Q Het n = 5 and R200Q corr. WT n = 4) 6 weeks post STZ treatment in ad libitum-fed state and during an iPGTT (t0, t30 and t60). h Blood glucose concentrations (mg/dl) and i human insulin secretion (mU/L) in plasma. p-values were b p < 0.01, d/c and c: p < 0.05. (R200Q Het n = 5 and R200Q corr. WT n = 4). j HbA1C (%) in mice transplanted with HNF1A-MODY -iPSC-derived endocrine cells or non-transplanted (Ctl) 9 weeks after STZ treatment. All mice were transplanted with iPSC-derived endocrine cells at day 27 of differentiation, and grafts were isolated 30–35 weeks post-transplantation for ex vivo analysis. All protein concentrations were measured by ELISA. For scatter plots, each point in the plot represents an independent biological experiment (n). Data are represented as mean ± SEM. Different letters designate significant differences within groups. p-values were *p < 0.05, **p < 0.01, ***p < 0.001; two-tailed t-test. n.s. non-significant. See also Figs. S11–S13.