Thaman, S. | bioRxiv Science

bioRxiv2024

Heterogeneous endocrine cell composition defines human islet functional phenotypes

Phenotyping and genotyping initiatives within the Integrated Islet Distribution Program (IIDP), the largest source of human islets for research in the U.S., provide standardized assessment of islet preparations distributed to researchers, enabling the integration of multiple data types. Data from islets of the first 299 organ donors without diabetes, analyzed using this pipeline, highlights substantial heterogeneity in islet cell composition associated with hormone secretory traits, sex, reported race and ethnicity, genetically predicted ancestry, and genetic risk for type 2 diabetes (T2D). While and {beta} cell composition influenced insulin and glucagon secretory traits, the abundance of {delta} cells showed the strongest association with insulin secretion and was also associated with the genetic risk score (GRS) for T2D. These findings have important implications for understanding mechanisms underlying diabetes heterogeneity and islet dysfunction and may provide insight into strategies for personalized medicine and {beta} cell replacement therapy.

physiology↗

bioRxiv2024

Loss of RREB1 reduces adipogenesis and improves insulin sensitivity in mouse and human adipocytes

There are multiple independent genetic signals at the Ras-responsive element binding protein 1 (RREB1) locus associated with type 2 diabetes risk, fasting glucose, ectopic fat, height, and bone mineral density. We have previously shown that loss of RREB1 in pancreatic beta cells reduces insulin content and impairs islet cell development and function. However, RREB1 is a widely expressed transcription factor and the metabolic impact of RREB1 loss in vivo remains unknown. Here, we show that male and female global heterozygous knockout (Rreb1+/-) mice have reduced body length, weight, and fat mass on high-fat diet. Rreb1+/- mice have sex- and diet-specific decreases in adipose tissue and adipocyte size; male mice on high-fat diet had larger gonadal adipocytes, while males on standard chow and females on high-fat diet had smaller, more insulin sensitive subcutaneous adipocytes. Mouse and human precursor cells lacking RREB1 have decreased adipogenic gene expression and activated transcription of genes associated with osteoblast differentiation, which was associated with Rreb1+/- mice having increased bone mineral density in vivo. Finally, human carriers of RREB1 T2D protective alleles have smaller adipocytes, consistent with RREB1 loss-of-function reducing diabetes risk.

physiology↗