Daily Endocrinology Research Analysis
Three impactful studies span therapy and mechanism in metabolic endocrinology: a phase II RCT shows the pan-PPAR agonist chiglitazar substantially reduces liver fat in MASLD; a mechanistic study uncovers a glucose–α-ketoglutarate–JMJD1A–ChREBP epigenetic axis driving visceral adipogenesis; and imeglimin is shown to suppress glucagon secretion via α-cell EPAC2 signaling while altering α-cell identity. Together, they advance MASLD therapeutics and deepen understanding of adipose and islet biology.
Summary
Three impactful studies span therapy and mechanism in metabolic endocrinology: a phase II RCT shows the pan-PPAR agonist chiglitazar substantially reduces liver fat in MASLD; a mechanistic study uncovers a glucose–α-ketoglutarate–JMJD1A–ChREBP epigenetic axis driving visceral adipogenesis; and imeglimin is shown to suppress glucagon secretion via α-cell EPAC2 signaling while altering α-cell identity. Together, they advance MASLD therapeutics and deepen understanding of adipose and islet biology.
Research Themes
- Therapeutic modulation of metabolic liver disease (MASLD)
- Epigenetic nutrient sensing in adipose tissue
- Islet alpha-cell signaling and glucagon regulation by antidiabetic agents
Selected Articles
1. Chiglitazar in MASLD with hypertriglyceridemia and insulin resistance: A phase II, randomized, double-blind, placebo-controlled study.
In a multicenter phase II RCT (n=104), chiglitazar reduced MRI-PDFF by 28–40% versus 3% with placebo over 18 weeks, with dose-dependent effects. Liver injury markers (ALT, AST, γ-GT) improved and safety was favorable, with trends toward better lipids, insulin resistance, and fibrosis indicators.
Impact: This high-quality RCT demonstrates robust reductions in liver fat on a quantitative imaging surrogate in MASLD with an agent targeting PPARs, advancing a promising therapeutic modality in an area of unmet need.
Clinical Implications: Supports further phase III development of chiglitazar in MASLD/MASH, suggests patient subgroups (hypertriglyceridemia with insulin resistance) may benefit, and motivates incorporation of MRI-PDFF endpoints alongside histology in trials.
Key Findings
- Chiglitazar reduced MRI-PDFF by −28.1% (48 mg) and −39.5% (64 mg) vs −3.2% with placebo at 18 weeks.
- Between-group differences vs placebo were −24.9% (p<0.05) and −36.3% (p<0.001) for 48 mg and 64 mg, respectively.
- ALT, AST, and γ-GT improved significantly; lipid parameters, insulin resistance, metabolic syndrome, and fibrosis indicators trended better.
- Both doses were well tolerated; adverse events were mostly mild to moderate.
Methodological Strengths
- Multicenter randomized double-blind placebo-controlled design with prespecified MRI-PDFF primary endpoint
- Dose-ranging evaluation with consistent biomarker improvements
Limitations
- Short duration (18 weeks) with surrogate imaging endpoints without histologic confirmation
- Selective MASLD population (hypertriglyceridemia and insulin resistance); modest sample size (n=104)
Future Directions: Conduct phase III trials with longer follow-up, histologic endpoints (NASH resolution, fibrosis), cardiovascular/metabolic outcomes, and comparative effectiveness vs other PPAR or thyroid hormone receptor agonists.
2. Glucose-activated JMJD1A drives visceral adipogenesis via α-ketoglutarate-dependent chromatin remodeling.
The study delineates a glucose–α-ketoglutarate–JMJD1A–ChREBP epigenetic circuit that removes H3K9me2 at adipogenic loci and enables hyperplastic expansion of visceral fat during nutrient excess. JMJD1A deficiency shifts remodeling toward hypertrophy with inflammation, highlighting depot-specific control of adipogenesis.
Impact: Reveals a nutrient-sensitive chromatin mechanism linking glucose flux to adipose tissue expansion mode, offering tractable epigenetic targets to modulate unhealthy hypertrophy versus healthier hyperplasia.
Clinical Implications: Targeting the JMJD1A/NFIC/ChREBP axis may shift adipose remodeling away from inflammatory hypertrophy, potentially improving insulin sensitivity and cardiometabolic risk in obesity.
Key Findings
- Glucose raises nuclear α-ketoglutarate, activating JMJD1A to demethylate H3K9me2 at adipogenic loci (e.g., Pparg).
- NFIC recruits JMJD1A, enabling ChREBP binding and transcriptional activation—a feedforward nutrient–chromatin circuit.
- In vivo, JMJD1A is essential for de novo adipogenesis and hyperplastic expansion of visceral fat; deficiency causes hypertrophy and local inflammation.
Methodological Strengths
- Integrated mechanistic approach combining chromatin profiling with in vivo genetic models
- Identification of transcription factor cooperation (NFIC–ChREBP) at pre-marked promoters
Limitations
- Findings derived primarily from murine models; human depot-specific applicability remains to be confirmed
- Long-term metabolic outcomes and pharmacologic tractability of JMJD1A targeting were not assessed
Future Directions: Validate the axis in human adipose depots, define systemic consequences of modulating JMJD1A activity, and explore small-molecule or nutrient-based interventions to bias adipose remodeling.
3. Imeglimin suppresses glucagon secretion and induces a loss of α cell identity.
Imeglimin directly suppresses α-cell glucagon secretion by downregulating Gsα and limiting EPAC2-mediated secretion in response to low glucose, GIP, or adrenaline, and it induces loss of α-cell identity. The findings suggest dual implications: benefit in hyperglucagonemia but caution regarding α-cell phenotype.
Impact: Provides a clear mechanistic basis for imeglimin’s effects on α cells beyond glycemia, informing therapeutic use and safety monitoring, especially where counterregulation may be critical.
Clinical Implications: Imeglimin may mitigate hyperglucagonemia in type 2 diabetes, but clinicians should consider potential effects on α-cell identity and counterregulatory responses, especially in hypoglycemia-prone patients.
Key Findings
- Imeglimin directly suppresses glucagon secretion from α cells independent of insulin.
- Mechanism: reduced Gsα expression limits EPAC2-mediated glucagon release induced by low glucose, GIP, or adrenaline.
- Imeglimin attenuates α-cell Ca2+ signaling and induces loss of α-cell identity.
Methodological Strengths
- Mechanistic dissection across multiple α-cell stimuli (low glucose, GIP, adrenaline)
- Direct assessment of α-cell signaling (EPAC2, Ca2+) and identity markers
Limitations
- Preclinical mechanistic study; human in vivo counterregulatory effects not established
- Long-term consequences of α-cell identity changes were not assessed
Future Directions: Evaluate imeglimin’s impact on glucagon counterregulation and hypoglycemia risk in humans; clarify reversibility and functional significance of α-cell identity changes; explore patient stratification.