Human Islet <scp>miR</scp> ‐199a‐5p and <scp>miR</scp> ‐214‐3p Associate With Donor Age, <scp>BMI</scp> , and Sex and Mediate Cellular Aging in Islet‐Derived Cells

OBJECTIVES: Human islets are widely researched to understand pathophysiological mechanisms leading to diabetes. Sex, age, and body mass index (BMI) are key donor traits influencing islet function, which is also regulated by an intricate network of microRNAs. METHODS: Here, we profiled 754 microRNAs and 58 191 gene transcripts (19 919 protein-coding) in up to 131 different human islet donor preparations (without diabetes) and assessed their association with donor traits. Additionally, the effect of the age-associated key microRNAs on relative telomere length in human islet-derived cells was evaluated. RESULTS: MicroRNA discovery analyses identified miR-199a-5p and miR-214-3p to be associated (adjusted p-value ≤ 0.05) with all three traits (i.e., sex, age, and BMI); miR-147b-3p with sex and age; miR-378a-5p with sex and BMI; miR-542-3p, miR-34a-3p, miR-34a-5p, miR-497-5p and miR-99a-5p with age and BMI. After adjusting for covariates, 612 protein-coding gene transcripts associated with sex (excluding those from sex-chromosomes), 902 with age, and 250 with BMI. MicroRNA-199a-5p and miR-214-3p levels negatively correlated with mRNAs critical in islet function, metabolic regulation, and senescence. In vitro validation studies verified that inhibition of two common microRNAs (miR-199a-5p/-214-3p) slowed down telomere length shortening in human islet-derived cells. CONCLUSIONS: Our analyses identify human islet microRNAs associated with donor traits and provide evidence that these microRNAs can potentially modulate cellular aging phenotype (reflected by relative telomere length) in human islet-derived cells.