Document Type
Article
Publication Date
11-1-2025
Original Citation
Kursawe R,
Bandesh K,
Krishnan S,
Liu K,
Bhuiyan R,
Stitzel ML.
From Human to Mouse and Back Again: Genetic and Genomic Ta(i)les of Islet Dysfunction in Type 2 Diabetes. Annu Rev Genet. 2025;59(1):289–314.
Keywords
JGM, Diabetes Mellitus, Type 2, Animals, Humans, Mice, Islets of Langerhans, Genetic Predisposition to Disease, Genomics, Disease Models, Animal, Insulin
JAX Source
Annu Rev Genet. 2025;59(1):289–314.
ISSN
1545-2948
PMID
40803767
DOI
https://doi.org/10.1146/annurev-genet-020525-114513
Grant
The Stitzel lab is supported by National Institute of Diabetes and Di- gestive and Kidney Diseases (NIDDK) grants R01DK118011, R01DK136671, R01DK117137, and U24DK138515. R.M.B. is supported by Ruth L. Kirschstein Individual Predoctoral National Research Service Award F30DK130582
Abstract
Type 2 diabetes (T2D) is a complex genetic disease with substantial environmental inputs leading to glucose homeostasis defects. Insulin production is central to proper glucose control, and islet cell dysfunction and death lie at the nexus of T2D genetics and pathophysiology. Comprehensive identification of genes and pathways contributing to these processes is essential for mechanistic understanding and therapeutic targeting. Here, we summarize the latest human and mouse T2D genetic and genomic studies and assess how these parallel variant-to-function efforts and associated data contribute convergent or complementary insights and new opportunities to dissect T2D islet (dys)function. We distill mechanistic and phenotypic studies of candidate T2D effector genes into prevailing themes by which these T2D risk genes likely contribute to islet dysfunction. We assess how recent molecular and metabolic studies in genetically diverse mice (i.e., Collabo-rative Cross, Diversity Outbred) help to nominate new putative T2D effector genes and processes for future exploration and provide examples where these studies illuminate potential limitations of studies using inbred mice. Finally, we discuss opportunities to address knowledge gaps and modeling challenges to translate T2D genetic associations into molecular and pathophysiologic understanding.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.