Deciphering islets and circulating microRNAs signatures to explore new putative key regulators of glucose tolerance and beta cell dysfunction in Type 2 Diabetes

The complex pathogenesis of Type 2 Diabetes (T2D) involves a progressive decline in beta cell function, coupled with insulin resistance. A deeper understanding of how beta cells adapt or fail in response to insulin resistance represents a critical gap to elucidate the natural progression of the disease. However, research into human islet morphology remains limited due to difficulty of accessing pancreatic tissue samples. Moreover, the lack of specific circulating biomarkers mirroring islet plasticity and impairment further complicates the prediction of rapid disease progression. Circulating non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), offer promise as stable, detectable biomarkers in plasma, reflecting metabolic states of pancreatic islets and potentially aiding in the understanding of beta cell failure mechanisms in T2D. To dissect ncRNAs profile in pancreatic islets and in plasma samples during glucose tolerance stages progression, we took advantage from a cohort of Normal Glucose Tolerant (NGT), Impaired Glucose Tolerant (IGT) and Type 2 Diabetic (T2D) living donors undergoing partial pancreatectomy together with their accurate metabolic characterization. The analysis of small RNAs, conducted on pancreatic islets and plasma samples from individuals with different stages of glucose tolerance (NGT, IGT, T2D), revealed that miRNAs constitute the predominant class and exhibit significant associations with metabolic parameters and beta cell function. Within pancreatic islets, four miRNAs were differentially expressed among the NGT, IGT, and T2D groups, with two of them (miR-129-5p and miR-148a-3p) showing differential expression even according to a new stratification based on parameters such as glucose and rate sensitivity, which are useful for identifying specific markers of beta cell dysfunction. Among these, miR-148a-3p emerged as the most promising islet marker due to its association with the target gene ATP6AP2, suggesting a key role in regulating incretin-mediated insulin secretion. As for circulating miRNAs, plasma analysis identified eleven miRNAs differentially expressed among NGT, IGT, and T2D groups, with three (miR-34a-5p, miR-1306-5p, and miR-335-5p) specifically correlated with beta cell dysfunction. This set of three circulating miRNAs, combined with a minimal set of clinical baseline data, demonstrated the ability to predict rate sensitivity, i.e. early alterations in insulin secretion, making them as promising biomarkers for assessing T2D development risk. Overall, these findings suggest that specific miRNAs, both islet-derived and circulating, may serve as novel tools for the early detection of beta cell dysfunction and damage, offering new opportunities for the diagnosis and treatment of T2D.