Daily Endocrinology Research Analysis

Hereditary pheochromocytoma and paraganglioma (hPPGL) is caused by pathogenic mutations in succinate dehydrogenase (SDH) genes, commonly SDHB. However, over 80% of SDHB missense variants are classified as variants of uncertain significance (VUS), limiting clinical interpretation and diagnostic utility of germline testing. To provide functional evidence of SDHB allele pathogenicity or benignity, we developed a cellular complementation assay that quantifies intracellular succinate/fumarate ratios as a readout of SDH enzymatic activity. This assay reliably distinguished pathogenic from benign alleles with high fidelity, outperforming and complementing computational predictions. Functional assessment of patient-derived VUS alleles supported reclassification of 87% of tested variants and revealed that mutations in the iron-sulfur cluster domain were amorphic, while those at or beyond the C-terminal residue Tyr273 retained function. Variants associated with Leigh syndrome retained activity, consistent with their biallelic inheritance and distinct pathogenic mechanisms from SDHB-related tumorigenesis. Notably, hypomorphic pathogenic SDHB variants correlated with increased head and neck paraganglioma occurrence, revealing a genotype-phenotype relationship. Functional characterization of SDHB missense variants supports clinical classification, informs hPPGL risk stratification, and has immediate diagnostic impact.

Mixed hematopoietic chimerism after allogeneic hematopoietic cell transplantation (HCT) promotes tolerance of transplanted donor-matched solid organs, corrects autoimmunity, and could transform therapeutic strategies for autoimmune type 1 diabetes (T1D). However, development of non-toxic bone marrow conditioning protocols is needed to expand clinical use. We developed a chemotherapy-free, non-myeloablative (NMA) conditioning regimen that achieves mixed chimerism and allograft tolerance across MHC barriers in NOD mice. We obtained durable mixed hematopoietic chimerism in prediabetic NOD mice using anti-c-Kit monoclonal antibody, T-cell depleting antibodies, JAK1/2 inhibition, and low-dose total body irradiation prior to transplantation of MHC-mismatched B6 hematopoietic cells, preventing diabetes in 100% of chimeric NOD:B6 mice. In overtly diabetic NOD mice, NMA conditioning followed by combined B6 HCT and islet transplantation durably corrected diabetes in 100% of chimeric mice without chronic immunosuppression or graft-versus-host disease (GVHD). Chimeric mice remained immunocompetent, as assessed by blood count recovery and rejection of 3rd party allogeneic islets. Adoptive transfer studies and analysis of autoreactive T cells confirmed correction of autoimmunity. Analysis of chimeric NOD mice revealed central thymic deletion and peripheral tolerance mechanisms. Thus, with NMA conditioning and cell transplantation, we achieved durable hematopoietic chimerism without GVHD, promoted islet allograft tolerance, and reversed established T1D.

BACKGROUND: Subgroups of adult-onset diabetes, namely severe autoimmune diabetes (SAID), severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), and mild obesity-related diabetes (MOD) or mild age-related (MARD) diabetes, have been defined with clinical variables and a machine-learning approach. Our aim was to describe their long-term outcomes and mortality. METHODS: In this prospective cohort study in Sweden, we used data from two subsets of the All New Diabetics in Scania (ANDIS) project cohort of individuals diagnosed with diabetes at regional care centres and enrolled within 1 year of diagnosis. Included participants were 18 years or older, did not have pancreatitis, and had complete data for cluster variables. We used GAD antibodies, Homeostasis Model Assessment 2 β cell and insulin resistance indices, BMI, HbA FINDINGS: Between Jan 1, 2008, and Nov 3, 2016, for ANDIS1 and Nov 4, 2016, and April 6, 2022, for ANDIS2, a total of 25 590 were screened for eligibility, resulting in 19 076 participants being included in the analysis (9057 from ANDIS1 and 10 019 from ANDIS2; 11 171 men and 7905 women). The median follow-up time was 9·63 years (IQR 4·05) in ANDIS1 and 2·83 years (2·76) in ANDIS2. The SAID and SIDD subgroups had the highest HbA INTERPRETATION: Diabetes subgroups could inform on outcomes, as well as guide treatment and follow-up needed for newly diagnosed individuals with diabetes. SIRD stands out as a high-risk subgroup that is not identified by conventional glycaemia-based risk factors, but bears risk of early onset end-organ damage and would benefit from identification and treatment before the diagnosis of diabetes. FUNDING: Swedish Research Council, Avtal om Läkarutbildning och Forskning Swedish government grants, Diabetes Wellness Sweden, the Swedish Heart and Lung Foundation, the Crafoord Foundation, the Swedish Diabetes Foundation, the Novo Nordisk Foundation, the Bo and Kerstin Hjelt Foundation, the Albert Påhlsson Research Foundation, Vinnova, and AstraZeneca.