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.
BACKGROUND: Studies of type 1 diabetes in sub-Saharan Africa have suggested that the clinical phenotype might differ from phenotypes reported elsewhere. We aimed to establish whether type 1 diabetes diagnosed in children and young adults in three countries across sub-Saharan Africa is of autoimmune origin. METHODS: In this observational, cross-sectional study, we identified participants without obesity from outpatient clinics in government and private hospitals in Cameroon, Uganda, and South Africa who were of self-reported Black African ethnicity with young-onset (age <30 years), insulin-treated, clinically diagnosed type 1 diabetes.
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.
OBJECTIVE: To assess the impact of recombinant human parathyroid hormone (1-84) [rhPTH(1-84)] compared with placebo, in combination with conventional therapy with vitamin D and/or calcium supplements, on health-related quality of life (HRQoL) in patients with symptomatic chronic hypoparathyroidism (cHypoPT). DESIGN: Randomized, double-blind, placebo-controlled, phase 3b-4 study (ClinicalTrials.gov ID: NCT03324880). METHODS: Eligible patients with symptomatic cHypoPT were randomized to receive subcutaneous rhPTH(1-84) 25-100 µg/day or placebo. The primary endpoint was the change from baseline to week 26 in Hypoparathyroidism Symptom Diary (HypoPT-SD) symptom subscale score. Key secondary endpoints were changes from baseline to week 26 in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue and in 36-item Short Form Health Survey physical component summary (SF-36v2 PCS).
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.
Gonadal sex determination relies on tipping a delicate balance involving the activation and repression of several transcription factors and signaling pathways. This is likely mediated by numerous noncoding regulatory elements that shape sex-specific transcriptomic programs. To explore the dynamics of these in detail, we performed paired time series of transcriptomic and chromatin accessibility assays on pre-granulosa and Sertoli cells throughout their development in the embryo, making use of new and existing mouse reporter lines. Regulatory elements were associated with their putative target genes by linkage analysis, and this was complemented and verified experimentally using promoter capture Hi-C. We identified the transcription factor motifs enriched in these regulatory elements along with their occupancy, pinpointing LHX9/EMX2 as potentially critical regulators of ovarian development. Variations in the DNA sequence of these regulatory elements are likely to be responsible for many of the unexplained cases of individuals with differences of sex development.