Extended Data Fig. 6: The SRRM3 locus responds to glucose and harbors genetic variants associated with fasting glucose and type 2 diabetes risk.

(A) Regional plot of Fasting Glucose GWAS variants from the CMDKP database (hugeamp.org). (B) Allele frequency and predicted impact on a Foxa2 binding motif for the SNP rs67070387 associated with elevated Fasting glucose. (C) Luciferase assay in INS-1E cells following transfection of a control reporter vector or carrying the genomic sequence surrounding rs67070387 with one or the other allele (n = 7 independent experiments). (D) Quantile-quantile (QQ) plots showing distribution of p-values associated with type 2 diabetes from²⁵ or fasting glucose from²⁶ for variants located in 1Kb genomic regions containing microexons. (E) SRRM3 expression and IsletMIC inclusion in human islets from non-diabetic (ND) and type 2 diabetes (T2D) individuals from³⁰ (n = 44 biologically independent samples). (F) Srrm3 expression and IsletMIC inclusion in islets from B6-ob/ob (OBOB) and New Zealand Obese (NZO) mice from³¹ (n = 5 animals). (G) SRRM3 expression and IsletMIC inclusion in human islets from non-diabetic (ND) and impaired glucose tolerant (IGT) individuals from²⁸ (n = 48 biologically independent samples). (H) SRRM3 expression and IsletMIC inclusion in human islets from non-diabetic (ND) impaired glucose tolerant (IGT) individuals from³⁰ (n = 50 biologically independent samples). (I) SRRM3 expression and IsletMIC inclusion in single beta cells from non-diabetic (ND) and type 2 diabetes (T2D) individuals from multiple studies (n = 8 biologically independent samples) (see methods). Data in (C, F–I) are shown as box-and-whisker plot, in which the lower and upper bounds of the box represent the upper and lower quartiles, the centre line represents the median and whiskers the 1.5x interquartile range. P values were obtained from Student’s two-tailed unpaired t-test (C) or two-sided Wilcoxon test (F).

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