Daily Endocrinology Research Analysis
A multicountry study in sub-Saharan Africa reveals a distinct non-autoimmune, insulin-deficient diabetes subtype among young people clinically labeled as type 1 diabetes, reshaping diagnostic paradigms. A randomized, placebo-controlled trial shows rhPTH(1-84) significantly improves symptom burden and quality of life in chronic hypoparathyroidism. Complementing these clinical insights, a multi-omics map of mouse gonadal supporting cells identifies regulatory programs and candidate factors (LHX9/E
Summary
A multicountry study in sub-Saharan Africa reveals a distinct non-autoimmune, insulin-deficient diabetes subtype among young people clinically labeled as type 1 diabetes, reshaping diagnostic paradigms. A randomized, placebo-controlled trial shows rhPTH(1-84) significantly improves symptom burden and quality of life in chronic hypoparathyroidism. Complementing these clinical insights, a multi-omics map of mouse gonadal supporting cells identifies regulatory programs and candidate factors (LHX9/EMX2) relevant to ovarian development and differences of sex development.
Research Themes
- Diabetes heterogeneity and precision phenotyping
- Hormone replacement improving quality of life in hypoparathyroidism
- Gene regulatory mechanisms in sex determination and DSD
Selected Articles
1. Non-autoimmune, insulin-deficient diabetes in children and young adults in Africa: evidence from the Young-Onset Diabetes in sub-Saharan Africa (YODA) cross-sectional study.
Across Cameroon, Uganda, and South Africa, many young insulin-treated patients clinically labeled as type 1 diabetes lacked islet autoantibodies and had genetic profiles inconsistent with autoimmune T1D, yet showed insulin deficiency, indicating a non-autoimmune, insulin-deficient subtype. This phenotype was also evident among Black but not White individuals in the US SEARCH cohort, underscoring etiologic heterogeneity and the need to refine diagnostic pathways.
Impact: This study challenges the assumption that all young-onset insulin-treated diabetes in Africa is autoimmune, proposing a distinct non-autoimmune insulin-deficient subtype with genetic and immunologic support.
Clinical Implications: Diagnostic algorithms for young-onset diabetes in Africa (and in Black populations elsewhere) should incorporate islet autoantibodies, type 1 diabetes genetic risk scores, and C-peptide to avoid misclassification and tailor therapy.
Key Findings
- A substantial subset of young insulin-treated patients lacked islet autoantibodies and had low type 1 diabetes genetic risk scores while being insulin-deficient.
- Evidence of this non-autoimmune, insulin-deficient phenotype was present in Black but not White individuals in the US SEARCH cohort.
- Findings support etiologic heterogeneity of clinically diagnosed type 1 diabetes in sub-Saharan Africa and call for refined diagnostic pathways.
Methodological Strengths
- Multicountry, standardized cross-sectional ascertainment with antibody, C-peptide, and genetic risk profiling
- External comparison with SEARCH US cohorts enhances generalizability
Limitations
- Cross-sectional design precludes longitudinal outcome inference
- Clinic-based recruitment may introduce selection bias
Future Directions: Prospective longitudinal studies to define incidence, natural history, and optimal treatment of non-autoimmune insulin-deficient diabetes in African and diaspora populations; genomic and environmental risk mapping.
2. rhPTH(1-84) for hypoparathyroidism: a randomized study of patient-reported outcomes.
In 93 randomized patients with symptomatic chronic hypoparathyroidism, rhPTH(1-84) plus conventional therapy significantly improved the HypoPT-SD symptom subscale (LS mean difference −0.53; 95% CI −0.90 to −0.15; P=0.003) versus placebo. FACIT-Fatigue and SF-36v2 PCS also improved more with rhPTH(1-84), with a safety profile consistent with prior studies and no new signals.
Impact: Provides high-quality randomized evidence that PTH replacement improves patient-reported symptom burden and HRQoL beyond biochemical control in chronic hypoparathyroidism.
Clinical Implications: Supports incorporating rhPTH(1-84) for symptomatic cHypoPT patients to improve HRQoL alongside conventional vitamin D/calcium, with patient-reported outcomes informing shared decision-making.
Key Findings
- Primary endpoint met: greater improvement in HypoPT-SD symptom subscale with rhPTH(1-84) vs placebo (LS mean difference −0.53; P=0.003).
- Key secondary endpoints (FACIT-Fatigue and SF-36v2 PCS) improved significantly more with rhPTH(1-84).
- Safety consistent with prior studies; no new safety signals identified over 26 weeks.
Methodological Strengths
- Randomized, double-blind, placebo-controlled, registered phase 3b–4 trial
- Use of validated patient-reported outcome instruments (HypoPT-SD, FACIT, SF-36v2)
Limitations
- Modest sample size (n=93) and 26-week duration limit long-term inference
- Primary outcomes centered on PROs; generalizability to broader cHypoPT populations and cost-effectiveness remain to be studied
Future Directions: Longer-term RCTs and pragmatic studies to assess durability, safety, dosing strategies, and cost-effectiveness of rhPTH(1-84), including comparisons with long-acting PTH analogs.
3. The gene regulatory landscape driving mouse gonadal supporting cell differentiation.
Paired time-series RNA-seq and ATAC-seq across embryonic pre-granulosa and Sertoli cells, coupled with promoter capture Hi-C, mapped regulatory elements to target genes and identified enriched TF motifs/occupancy. The study highlights LHX9/EMX2 as critical regulators of ovarian development and suggests regulatory element variation may underlie unexplained DSD cases.
Impact: Delivers a high-resolution regulatory atlas of gonadal supporting cell differentiation with mechanistic candidates (LHX9/EMX2), bridging developmental genomics to human DSD genetics.
Clinical Implications: Findings inform variant interpretation in DSD by prioritizing regulatory elements and TFs implicated in ovarian development, potentially guiding genetic diagnosis.
Key Findings
- Paired time-series transcriptomic and chromatin accessibility profiling in pre-granulosa and Sertoli cells mapped dynamic regulatory elements.
- Promoter capture Hi-C linked regulatory elements to target genes, enabling motif/occupancy analyses.
- LHX9/EMX2 identified as candidate critical regulators of ovarian development; regulatory element variation may explain unsolved DSD cases.
Methodological Strengths
- Integrated multi-omics time-series design (RNA-seq, ATAC-seq) in defined cell lineages
- Experimental validation of regulatory interactions via promoter capture Hi-C
Limitations
- Mouse-based developmental model may limit immediate translational applicability to humans
- Functional perturbation studies of specific TFs/elements are needed to confirm causality
Future Directions: Functional validation (e.g., CRISPR perturbations) of candidate TFs and regulatory elements; systematic human variant interpretation frameworks integrating this atlas for DSD diagnostics.