Publications

Abstract

Precision medicine starts with a precision diagnosis. Yet up to 80% of cases of monogenic diabetes, a form of diabetes characterized by mutations in a single gene, are either overlooked or misdiagnosed. A genetic test for monogenic diabetes does not always lead to a precise diagnosis, as novel variants are often classified as variants of unknown significance. Variant interpretation requires collation of a framework of evidence, including population, computational, and segregation data, and can be assisted by functional analysis. The inclusion of functional data can be challenging, depending on the number of benign and pathogenic variants available for benchmarking assays. Glucokinase is the rate-limiting step for glucose metabolism in the pancreatic beta-cell and governs the threshold for glucose-stimulated insulin release. Loss-of-function alleles in the glucokinase (GCK) gene are a cause of stable fasting hyperglycemia from birth and/or diabetes. In this study, we functionally characterized 25 variants identified during diagnostic testing or in exome sequencing studies. We assessed their kinetic characteristics, stability, and interaction with pharmacological and physiological regulators. We integrated our functional data with existing data from the ClinGen Monogenic Diabetes Variant Curation Expert Review panel using a gene-specific framework to assist variant classification. We show how functional evidence can aid variant classification, thus enabling diagnostic certainty.

View details for DOI 10.3390/ijms27010156

View details for Web of Science ID 001657402100001

View details for PubMedID 41516031

View details for PubMedCentralID PMC12785307

Abstract

Gene discovery studies in individuals with diabetes diagnosed within 6 months of life (neonatal diabetes, NDM) can provide unique insights into the development and function of human pancreatic beta-cells. We describe the identification of homozygous PAX4 loss-of-function variants in 2 unrelated individuals with NDM: a p.(Arg126*) stop-gain variant and a c.-352_104del deletion affecting the first 4 PAX4 exons. We confirmed the p.(Arg126*) variant causes nonsense mediated decay in CRISPR-edited human induced pluripotent stem cell (iPSC)-derived pancreatic endoderm cells. Integrated analysis of CUT&RUN and RNA-sequencing in PAX4-depleted islet cell models identified genes directly regulated by PAX4 involved in both pancreatic islet development and glucose-stimulated insulin secretion. Both probands had transient NDM which remitted in early infancy but relapsed at the ages of 2.4 and 6.7 years, demonstrating that in contrast to mouse models, PAX4 is not essential for the development of human pancreatic beta-cells.

View details for DOI 10.1016/j.molmet.2025.102201

View details for PubMedID 40614820

Abstract

In the last two decades, significant progress has been made toward understanding the genetic basis of type 2 diabetes. An important supporter of this research has been the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), most recently through the Accelerating Medicines Partnership Program for Type 2 Diabetes (AMP T2D) and Accelerating Medicines Partnership Program for Common Metabolic Diseases (AMP CMD). These public-private partnerships of the National Institutes of Health, multiple biopharmaceutical and life sciences companies, and nonprofit organizations, facilitated and managed by the Foundation for the National Institutes of Health, were designed to improve understanding of therapeutically relevant biological pathways for type 2 diabetes. On the occasion of NIDDK's 75th anniversary, we review the history of NIDDK support for these partnerships, which saw the convergence of research directions prioritized by academic consortia, the pharmaceutical industry, and government funders. Although the NIDDK was not the sole originator or funder of these efforts, its support and leadership have been pivotal to the partnerships' success and have enabled their research to be broadly accessible through the AMP Common Metabolic Diseases Knowledge Portal (CMDKP) and the AMP Common Metabolic Diseases Genome Atlas (CMDGA). Findings from AMP CMD align with NIDDK's mission to conduct research and share results with the goal of improving health and quality of life.The Accelerating Medicines Partnership Program for Type 2 Diabetes (AMP T2D) and Accelerating Medicines Partnership Program for Common Metabolic Diseases (AMP CMD) were created to accelerate the translation of genetic and genomic data into knowledge about the biology of disease. Their goal was to gain a better understanding of the mechanisms underlying types 1 and 2 diabetes and prediabetes, obesity, cardiovascular disease, kidney disease, and nonalcoholic steatohepatitis. This work identified multiple genes and pathways underlying these diseases. The findings of AMP T2D and AMP CMD have implications for drug development and improved risk prediction, diagnosis, and treatment for common metabolic diseases.

View details for DOI 10.2337/db25-0042

View details for PubMedID 40272257