Daily Endocrinology Research Analysis
Three studies advance endocrinology today: human loss-of-function mutations in the glucagon receptor link glucagon signaling to early hepatic steatosis with mechanistic validation; an energy-reduced Mediterranean diet plus physical activity lowered type 2 diabetes incidence versus ad libitum Mediterranean diet in a large RCT secondary analysis; and a small randomized clinical study with mechanistic data shows topical rhGM-CSF accelerates diabetic wound healing via macrophage polarization.
Summary
Three studies advance endocrinology today: human loss-of-function mutations in the glucagon receptor link glucagon signaling to early hepatic steatosis with mechanistic validation; an energy-reduced Mediterranean diet plus physical activity lowered type 2 diabetes incidence versus ad libitum Mediterranean diet in a large RCT secondary analysis; and a small randomized clinical study with mechanistic data shows topical rhGM-CSF accelerates diabetic wound healing via macrophage polarization.
Research Themes
- Glucagon signaling and hepatic lipid metabolism
- Lifestyle-based prevention of type 2 diabetes
- Immunomodulation to enhance wound repair in diabetes
Selected Articles
1. Glucagon Receptor Deficiency Causes Early-Onset Hepatic Steatosis.
A consanguineous family harbored homozygous GCGR missense variants causing near-complete receptor loss-of-function, elevated glucagon and amino acids, adiposity, and hepatic steatosis. CRISPR-engineered iPSC hepatocytes carrying the same variants showed increased lipid accumulation, mechanistically linking impaired glucagon signaling to human steatosis and informing risk–benefit considerations for GCGR antagonists and agonists.
Impact: This is among the first human genetic and mechanistic demonstrations that impaired GCGR signaling drives hepatic steatosis, directly informing development and safety of GCGR-targeted therapies.
Clinical Implications: Genetic or pharmacologic GCGR inhibition may promote hepatic steatosis; clinicians and developers should monitor liver fat with GCGR antagonists, while GCGR agonists may benefit patients with obesity and steatotic liver disease.
Key Findings
- Two rare homozygous missense GCGR variants cosegregated with early-onset hepatic steatosis/cirrhosis in a consanguineous family.
- Double GCGR mutations reduced membrane expression and signaling in cells, causing near-complete loss-of-function with elevated circulating glucagon and amino acids and increased adiposity.
- CRISPR/Cas9 introduction of the same variants into human iPSC-derived hepatocytes increased lipid accumulation, mechanistically linking GCGR loss to steatosis.
- Findings explain increased liver fat in GCGR antagonist trials and reduced liver fat with GCGR agonists.
Methodological Strengths
- Integrated human genetics with functional validation in cell models, including CRISPR-edited iPSC-derived hepatocytes.
- Consistent biochemical phenotype (high glucagon and amino acids) supporting receptor loss-of-function.
Limitations
- Single-family study limits generalizability and effect size estimation.
- Lack of longitudinal clinical outcomes beyond steatosis/cirrhosis and adiposity.
Future Directions: Expand to larger cohorts to assess variant spectrum and penetrance; evaluate liver outcomes in patients receiving GCGR antagonists/agonists; explore therapeutic modulation of amino acid metabolism.
2. Comparison of an Energy-Reduced Mediterranean Diet and Physical Activity Versus an Ad Libitum Mediterranean Diet in the Prevention of Type 2 Diabetes : A Secondary Analysis of a Randomized Controlled Trial.
In PREDIMED-Plus, a prespecified secondary analysis showed that an energy-reduced Mediterranean diet combined with physical activity reduced incident type 2 diabetes by 31% over a median 6 years versus advice for ad libitum Mediterranean diet, with greater weight and waist reductions and higher activity.
Impact: Large randomized trial evidence supporting an intensified lifestyle strategy within the Mediterranean diet framework to prevent type 2 diabetes in high-risk older adults.
Clinical Implications: For overweight/obese adults with metabolic syndrome, combining caloric reduction and structured physical activity with Mediterranean diet counseling should be prioritized to reduce diabetes incidence.
Key Findings
- Compared with ad libitum MedDiet counseling, erMedDiet plus physical activity reduced type 2 diabetes incidence by 31% over a median 6 years.
- Absolute risk was 12.0% in control versus 9.5% in intervention, with an absolute risk reduction of −2.6 cases per 1000 person-years.
- Intervention participants showed better diet adherence, higher physical activity, and greater reductions in weight and waist circumference.
Methodological Strengths
- Large, multicenter randomized controlled design with prespecified secondary endpoint.
- Long follow-up with standardized ADA diagnostic criteria and annual anthropometry.
Limitations
- Secondary outcome analysis and single-blinded design may introduce bias.
- Dietary adherence largely self-reported.
Future Directions: Assess cost-effectiveness and implementation strategies in primary care; evaluate scalability and subgroup effects (e.g., by age, sex, baseline HbA1c) and maintenance beyond 6 years.
3. Effect of rhGM-CSF in promoting wound healing via macrophage immunomodulation.
Topical rhGM-CSF accelerated wound healing in mice and, in a randomized clinical study of 48 patients with diabetic lower extremity ulcers, produced a significantly greater area reduction at one month versus control. Mechanistically, rhGM-CSF increased angiogenic markers and shifted macrophages from M1 to reparative M2 phenotypes (M2a at day 5, M2d at day 10).
Impact: Combines a randomized clinical signal with mechanistic insights into macrophage polarization, supporting repurposing of rhGM-CSF as an immunomodulatory therapy for diabetic wounds.
Clinical Implications: Topical rhGM-CSF may be considered for diabetic lower extremity ulcers to accelerate healing, pending larger blinded trials to confirm efficacy, durability, and safety.
Key Findings
- In mice, topical rhGM-CSF increased healing rate (2.53±0.25 mm2/day) and angiogenic markers (CD31, VEGFA).
- Randomized clinical trial (n=48) showed significantly greater one-month percentage area reduction in the rhGM-CSF group versus control.
- rhGM-CSF decreased M1 macrophages and increased M2 subsets (M2a at day 5, M2d at day 10), supporting an immunomodulatory mechanism.
Methodological Strengths
- Translational design integrating animal experiments with a randomized clinical comparison.
- Cellular and molecular profiling of macrophage phenotypes supporting mechanism of action.
Limitations
- Small, short-duration clinical trial with limited detail on blinding and secondary outcomes.
- No data on hard endpoints (e.g., infection, amputation) or long-term recurrence.
Future Directions: Conduct multicenter, blinded RCTs to evaluate healing rates, time to closure, safety, and limb salvage; optimize dosing and delivery; define biomarkers of response (M2 polarization).