Weekly Endocrinology Research Analysis
This week highlighted mechanistic discovery in monogenic neonatal diabetes (TMEM167A implicating ER-to-Golgi trafficking), large-scale genetic subtyping that reframes obesity by separating adiposity from cardiometabolic risk, and a high-impact phase 3 trial showing substantial weight loss with once-daily oral semaglutide 25 mg. Across the week, multiomics, single-cell transcriptomics, and optimized diagnostic assays (LC‑MS/MS) advanced risk prediction and screening, while real-world and trial da
Summary
This week highlighted mechanistic discovery in monogenic neonatal diabetes (TMEM167A implicating ER-to-Golgi trafficking), large-scale genetic subtyping that reframes obesity by separating adiposity from cardiometabolic risk, and a high-impact phase 3 trial showing substantial weight loss with once-daily oral semaglutide 25 mg. Across the week, multiomics, single-cell transcriptomics, and optimized diagnostic assays (LC‑MS/MS) advanced risk prediction and screening, while real-world and trial data clarified safety signals for widely used therapies (GLP‑1RAs). These findings push toward more precise genetic and molecular stratification, broaden therapeutic options (including oral peptide formulations), and suggest immediate diagnostic and therapeutic implementation opportunities.
Selected Articles
1. Recessive TMEM167A variants cause neonatal diabetes, microcephaly, and epilepsy syndrome.
Genome sequencing in six patients identified biallelic TMEM167A variants as a novel cause of a syndrome with neonatal diabetes, severe microcephaly, and frequent epilepsy. Functional studies in EndoC‑βH1 and iPSC‑derived β cells showed TMEM167A loss or patient variant impairs ER‑to‑Golgi trafficking, increases ER stress sensitivity, disrupts proinsulin trafficking, and causes β‑cell dysfunction.
Impact: Identifies a new monogenic disease gene and a mechanistic link between ER‑to‑Golgi trafficking and β‑cell failure, advancing understanding of neonatal diabetes biology and enabling targeted genetic testing.
Clinical Implications: Add TMEM167A to genetic testing panels for neonatal diabetes/MEDS to enable earlier diagnosis, genetic counseling, and consideration of experimental ER‑stress–modulating therapies; anticipate syndromic comorbidities (microcephaly, epilepsy).
Key Findings
- Biallelic TMEM167A variants identified in six patients presenting with neonatal diabetes, severe microcephaly; five had epilepsy.
- TMEM167A is highly expressed in human pancreas and brain, consistent with the syndrome phenotype.
- Knockdown or patient p.Val59Glu variant impaired ER‑to‑Golgi trafficking, increased ER stress sensitivity in β cells, and disrupted proinsulin trafficking.
- iPSC‑derived β cells bearing the variant exhibited functional defects consistent with diabetes.
2. Genetic subtyping of obesity reveals biological insights into the uncoupling of adiposity from its cardiometabolic comorbidities.
A multi‑trait GWAS in 452,768 UK Biobank participants defined continuous 'uncoupling' phenotypes that quantify how adiposity can be genetically dissociated from cardiometabolic risk. The study identified 266 variants across 205 loci where adiposity‑increasing alleles associated with lower cardiometabolic risk and developed a genetic risk score to capture this uncoupling, enabling precision risk stratification.
Impact: Reframes obesity as genetically heterogeneous and often uncoupled from cardiometabolic disease, challenging BMI-centric risk models and offering a path toward precision prevention and treatment allocation based on genetic subtypes.
Clinical Implications: Pending prospective validation, genetic subtyping and GRS could refine cardiometabolic risk prediction at a given BMI and help prioritize interventions for individuals whose adiposity carries disproportional cardiometabolic risk.
Key Findings
- Multi‑trait GWAS of 452,768 individuals defined continuous adiposity–cardiometabolic uncoupling phenotypes.
- 266 genetic variants across 205 loci were identified where adiposity‑increasing alleles associated with lower cardiometabolic risk.
- A genetic risk score was developed to quantify the uncoupling phenotype for potential use in risk stratification.
3. Oral Semaglutide at a Dose of 25 mg in Adults with Overweight or Obesity.
In a 71‑week double‑blind RCT of adults without diabetes and with overweight/obesity (n=307), once‑daily oral semaglutide 25 mg produced a mean −13.6% weight change versus −2.2% for placebo at week 64 (difference −11.4 percentage points; P<0.001) and higher rates of ≥5–20% weight loss, with more gastrointestinal adverse events reported.
Impact: Provides high‑quality phase 3 evidence that an oral GLP‑1 formulation can approach injectable-level efficacy for weight loss, expanding accessible treatment options and informing prescribing choices.
Clinical Implications: Oral semaglutide 25 mg is a viable option for chronic weight management in adults without diabetes, but clinicians should weigh gastrointestinal tolerability and discuss adherence, and await head‑to‑head comparisons with injectable formulations for positioning.
Key Findings
- Mean percent weight change at week 64: −13.6% (oral semaglutide) vs −2.2% (placebo); difference −11.4 percentage points (95% CI −13.9 to −9.0; P<0.001).
- Higher proportions achieved ≥5%, ≥10%, ≥15%, and ≥20% weight loss with semaglutide (all P<0.001).
- Gastrointestinal adverse events were more common with semaglutide (74.0% vs 42.2%).