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.
UNLABELLED: In mice, glucagon regulates lipid metabolism by activating receptors in the liver; however, its role in human lipid metabolism is incompletely understood. Here we describe three normal-weight individuals from a consanguineous family with early-onset hepatic steatosis and/or cirrhosis. Using exome sequencing, we found they were homozygous for two missense variants in the glucagon receptor gene (GCGR). In cells, the double GCGR mutation reduced cell membrane expression and signaling, resulting in an almost complete loss of function. Carriers of pathogenic GCGR mutations had substantially elevated circulating glucagon and amino acid levels and increased adiposity. Introducing the double GCGR mutation into human induced pluripotent stem cell-derived hepatocytes using CRISPR/Cas9 caused increased lipid accumulation. Our results provide an explanation for increased liver fat seen in clinical trials of GCGR antagonists and reduced liver fat in people with obesity and steatotic liver disease treated with GCGR agonists. ARTICLE HIGHLIGHTS: In this study, we investigated a consanguineous family in whom normal-weight individuals had hepatic steatosis and cirrhosis. Using whole-exome sequencing we found two rare homozygous variants in the glucagon receptor (GCGR) gene that cosegregated with the phenotype. In cells, the GCGR mutations result in a loss of function and increased lipid accumulation. These results highlight the potential risks associated with GCGR antagonists and the benefits of GCGR agonists, currently in clinical trials.
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.
BACKGROUND: Limited research has been done to evaluate the combined effect of energy reduction, Mediterranean diet (MedDiet), and physical activity on type 2 diabetes incidence. OBJECTIVE: To evaluate whether an energy-reduced MedDiet (erMedDiet) plus physical activity reduces diabetes incidence compared with a standard MedDiet. DESIGN: Prespecified secondary outcome analysis in the PREDIMED (Prevención con Dieta Mediterránea)-Plus randomized, single-blinded, controlled trial. (ISRCTN Registry: ISRCTN89898870). SETTING: 23 centers across Spain. PARTICIPANTS: 4746 adults aged 55 to 75 years with metabolic syndrome and overweight or obesity, without prior cardiovascular disease or diabetes. INTERVENTION: Participants were randomly assigned 1:1 to an intervention group receiving an erMedDiet (planned reduction of 600 kcal per day), increased physical activity, and behavioral strategies for reducing weight, or a control group receiving ad libitum MedDiet advice. MEASUREMENTS: Diabetes incidence was based on the American Diabetes Association criteria. Anthropometric measurements were obtained annually. Cox regression models were used to assess the intervention effect. RESULTS: The 6-year absolute risk was 12.0% (95% CI, 11.9% to 12.1%) in the control group (349 cases) and 9.5% (CI, 9.4% to 9.5%) in the intervention group (280 cases). Over a median 6-year follow-up, diabetes incidence was 31% (CI, 18% to 41%) relatively lower in the intervention group compared with the control group, with an absolute risk reduction of -2.6 cases (CI, -2.7 to -2.4) per 1000 person-years. The intervention group attained better adherence to the erMedDiet, higher physical activity levels, and greater reductions in body weight and waist circumference. LIMITATION: Secondary outcome, single-blinded design, and self-reported dietary adherence. CONCLUSION: An intensive intervention with the MedDiet adding caloric reduction, physical activity, and modest weight loss was more effective than only an ad libitum MedDiet in reducing diabetes incidence in overweight/obese persons with metabolic syndrome. PRIMARY FUNDING SOURCE: Instituto de Salud Carlos III.
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).
BACKGROUND: Recombinant human granulocyte macrophage-colony stimulating factor (rhGM-CSF) is predominantly applied in hematologic disorder therapy. Emerging research suggests its efficacy in wound healing. This study aims to validate the effect and molecular mechanisms of rhGM-CSF on diabetic/non-diabetic wound healing. METHODS: Two full-thickness wounds were created on the backs of C57BL/6J mice. The caudal wounds were treated daily with topical rhGM-CSF (1.0 μg/cm2), while the cranial wounds received saline. Patients with diabetic lower extremity ulcers were randomized into rhGM-CSF intervention (2.0 μg/cm2 infiltration) and control group. The primary endpoint was the overall percentage area reduction by one month. The wound tissues were stained with HE and immunofluorescence. Western blot was performed to analyze macrophage subtypes. RESULTS: Topical administration of rhGM-CSF significantly accelerated wound healing in C57BL/6J mice with an average healing rate of 2.53±0.25 mm2/day. Increase in the capillary marker CD31 and the expression of vascular endothelial growth factor (VEGF)A was observed after rhGM-CSF intervention. The clinical trial included 48 subjects with comparable baseline characteristics between the rhGM-CSF (n=27) and control (n=21) groups. The rhGM-CSF group showed significantly greater overall percentage area reduction (97.7±8.9%) vs. controls (P<0.05). Mechanistically, the rhGM-CSF intervention resulted in a significant reduction in M1-type macrophages and an increase in M2-type macrophages, with M2a predominating at day 5 and M2d dominating at day 10 post-injury. CONCLUSIONS: Our study suggested that topical administration of rhGM-CSF can promote the healing of both diabetic and non-diabetic wounds, which is partly attributed to promoting the transformation of macrophages to M2 subtype.