Daily Endocrinology Research Analysis
A double-blind RCT found once-weekly semaglutide markedly improved HbA1c, weight, and physical quality of life in antipsychotic-treated patients with schizophrenia, prediabetes, and obesity without worsening psychiatric symptoms. Two mechanistic studies advanced endocrine biology: one identified a PDPN–TGF-β1 autocrine loop driving islet stellate cell activation and islet fibrosis in diabetes, and another showed FGF21 and GDF15 act synergistically to maintain metabolic homeostasis in mice lackin
Summary
A double-blind RCT found once-weekly semaglutide markedly improved HbA1c, weight, and physical quality of life in antipsychotic-treated patients with schizophrenia, prediabetes, and obesity without worsening psychiatric symptoms. Two mechanistic studies advanced endocrine biology: one identified a PDPN–TGF-β1 autocrine loop driving islet stellate cell activation and islet fibrosis in diabetes, and another showed FGF21 and GDF15 act synergistically to maintain metabolic homeostasis in mice lacking OPA1 in thermogenic adipocytes.
Research Themes
- GLP-1 receptor agonists for metabolic dysfunction in serious mental illness
- Mechanisms of islet fibrosis in diabetes
- Endocrine crosstalk from thermogenic adipose tissue (FGF21/GDF15 synergy)
Selected Articles
1. Semaglutide Treatment of Antipsychotic-Treated Patients With Schizophrenia, Prediabetes, and Obesity: The HISTORI Randomized Clinical Trial.
In a multicenter, double-blind RCT of 154 SGA-treated adults with schizophrenia, prediabetes, and overweight/obesity, semaglutide (up to 1.0 mg weekly for 30 weeks) reduced HbA1c by 0.46% and body weight by 9.21 kg versus placebo, with 81% achieving HbA1c <5.7% vs 19% on placebo. Physical quality of life improved without worsening psychiatric symptoms; gastrointestinal adverse events were more frequent.
Impact: This high-quality RCT addresses an urgent cardiometabolic need in serious mental illness, demonstrating clinically meaningful glycemic and weight benefits without psychiatric deterioration.
Clinical Implications: Semaglutide can be considered to manage antipsychotic-associated weight gain and prediabetes in schizophrenia, with monitoring for gastrointestinal adverse events. Findings support integrating GLP-1RA therapy into metabolic care pathways in psychiatric populations.
Key Findings
- HbA1c decreased by 0.46% and body weight by 9.21 kg with semaglutide versus placebo over 30 weeks.
- 81% of semaglutide-treated participants achieved HbA1c <5.7% vs 19% with placebo (P<.001).
- Physical quality of life improved; no significant change in PANSS-6 or mental QoL.
- Gastrointestinal adverse events were more frequent with semaglutide; serious adverse events were similar.
Methodological Strengths
- Multicenter, double-blind, placebo-controlled randomized design with trial registration (NCT05193578).
- High completion rate (91.5%) and prespecified clinically relevant endpoints (HbA1c, weight, QoL).
Limitations
- 30-week duration limits long-term safety and durability assessment.
- Dose limited to 1.0 mg/week; generalizability to other doses or agents is uncertain.
Future Directions: Longer, pragmatic trials assessing cardiovascular outcomes, psychiatric stability, and comparative effectiveness versus lifestyle or metformin in diverse psychiatric populations are warranted.
IMPORTANCE: Patients with schizophrenia have reduced life expectancy due to cardiovascular disease and obesity-related type 2 diabetes, exacerbated by second-generation antipsychotic (SGA) medication. Existing interventions have shown limited effect. OBJECTIVES: To assess the effect of the once-weekly glucagon-like peptide-1 receptor agonist semaglutide in SGA-treated adults (aged 18-60 years) with schizophrenia, prediabetes (glycosylated hemoglobin A1c [HbA1c], 5.7%-6.4% of total hemoglobin) (to convert HbA1c from percentage of total hemoglobin to mmol/mol, use the following formula: (HbA1c % - 2.152)/0.09148), and overweight or obesity (body mass index [BMI], calculated as weight in kilograms divided by height in meters squared, ≥27). DESIGN, SETTING, AND PARTICIPANTS: This placebo-controlled, double-blinded randomized clinical trial was conducted from January 2022 to May 2024, with 30 weeks of follow-up, among regional community-based mental health services in 2 regions of Denmark (Region of Southern Denmark and Region of Zealand). SGA-treated patients with schizophrenia, prediabetes, and overweight or obesity were randomized to semaglutide or placebo. Data analysis was completed from May 2024 to January 2025. INTERVENTION: Once-weekly subcutaneous semaglutide or placebo for 30 weeks; semaglutide was titrated up to 1.0 mg/week over 8 weeks. MAIN OUTCOMES AND MEASURES: The primary outcome was change in HbA1c. Secondary end points included changes in body weight, schizophrenia symptoms based on Positive and Negative Syndrome Scale 6 (PANSS-6) score, and physical and mental quality of life (QoL) (assessed via the 36-item Short Form Survey, version 2 [SF-36v2]).
2. Podoplanin-TGF-β1 Autocrine Loop: Pivotal Regulator of Islet Stellate Cell Activation via Cell Deformation, Orchestrating Islet Fibrosis in Diabetes.
Using diabetic mice and primary islet stellate cells, the study shows that PDPN knockdown reduces ISC activation and islet fibrosis, improving insulin expression and fasting glycemia. AGEs induce PDPN; PDPN overexpression activates ISCs via cell deformation and TGF-β1 secretion, which in turn upregulates PDPN through TGF-β1/SMAD2/3 signaling, establishing a PDPN–TGF-β1 autocrine loop.
Impact: This study elucidates a novel, targetable autocrine loop linking AGEs to islet stellate cell activation and fibrosis, providing mechanistic insight into islet failure in diabetes.
Clinical Implications: The PDPN–TGF-β1 axis may serve as a therapeutic target or biomarker to limit islet fibrosis and preserve beta-cell function in diabetes.
Key Findings
- PDPN knockdown in diabetic mice reduced islet stellate cell activation and islet fibrosis, improving insulin expression and fasting glucose.
- Advanced glycation end products (AGEs) induced PDPN expression in islet stellate cells.
- PDPN overexpression activated ISCs via cell deformation and TGF-β1 secretion; TGF-β1 activated SMAD2/3 signaling, further inducing PDPN and ISC activation (autocrine loop).
Methodological Strengths
- Integrated in vivo (diabetic mice) and in vitro (primary ISCs) approaches with genetic gain- and loss-of-function.
- Comprehensive phenotyping including ECM deposition, ISC markers, insulin secretion, and glucose tolerance tests.
Limitations
- Preclinical mouse and cell models; human validation is lacking.
- Therapeutic modulation of the PDPN–TGF-β1 axis was not tested pharmacologically.
Future Directions: Validate PDPN–TGF-β1 signaling in human islets and diabetic pancreas, and test pharmacologic or antibody-based inhibitors targeting the axis in relevant models.
The activation of islet stellate cells (ISCs) plays an important role in islet fibrosis, which leads to impaired islet function. While our previous work showed that the expression of the Pdpn gene was significantly increased in activated ISCs, it remains unknown whether Pdpn is responsible for islet fibrosis. This study was aimed at elucidating its function on islet fibrosis, along with the exploration of the underlying mechanisms. Then, diabetic mice were used for in vivo studies, while primary ISCs were used for in vitro experiments. Podoplanin (PDPN) expression was manipulated using gene knockdown and overexpression techniques. Beta-cell function was assessed by insulin secretion and glucose tolerance tests. Islet fibrosis was evaluated by quantifying extracellular matrix deposition and ISCs activation markers using histological staining and immunohistochemistry, respectively. The effects of advanced glycation end products (AGEs) and TGF-β1 on PDPN expression and the corresponding mechanisms of ISCs activation were investigated. Finally, it was found that knocking down PDPN in diabetic mice led to reduced ISCs activation and islet fibrosis, accompanied by improved insulin expression and lower fasting blood glucose. AGEs were found to induce PDPN expression in ISCs. The overexpression of PDPN triggers the activation of ISCs via cell deformation and TGF-β1 secretion. Interestingly, TGF-β1 in turn activates the TGF-β1/SMAD2/3 pathway by binding to TGF-βRI, inducing the expression of PDPN and the activation of ISCs. In summary, PDPN regulates the activation of ISCs through a mechanism involving cell deformation and a PDPN-TGF-β1 autocrine feedback loop, thereby significantly contributing to islet fibrosis in diabetes.
3. FGF21 and GDF15 Act Synergistically to Regulate Systemic Metabolic Homeostasis in Mice Lacking OPA1 in Thermogenic Adipocytes.
By deleting Fgf21 and Gdf15 in OPA1-deficient thermogenic adipocytes, the study demonstrates that these BAT-derived hormones act synergistically: their combined loss impairs glucose tolerance and attenuates resistance to diet-induced obesity and insulin resistance seen in OPA1 BKO mice. Findings point to therapeutic potential of combined FGF21/GDF15 strategies.
Impact: This work reveals synergistic endocrine control from thermogenic adipose tissue, refining the mechanistic basis for anti-obesity and metabolic therapies targeting FGF21 and GDF15.
Clinical Implications: Combined FGF21 and GDF15 modulation may yield superior metabolic benefits versus monotherapy, informing design of next-generation multi-hormone therapeutics.
Key Findings
- Thermogenic adipocyte-specific triple knockout (Opa1, Fgf21, Gdf15) impaired glucose tolerance in young mice.
- Combined loss of Fgf21 and Gdf15 blunted the diet-induced obesity resistance and insulin resistance improvements characteristic of OPA1 BKO mice.
- FGF21 and GDF15 act synergistically to maintain glucose homeostasis and resistance to DIO in the OPA1-deficient BAT context.
Methodological Strengths
- Cell-type-specific genetic triple knockout to dissect hormone synergy in vivo.
- Diet challenges with comprehensive metabolic phenotyping (glucose tolerance, insulin sensitivity, obesity resistance).
Limitations
- Findings are in mouse models; translational relevance to humans remains to be established.
- Pharmacologic co-activation or replacement with recombinant hormones was not tested.
Future Directions: Assess combined pharmacologic FGF21 and GDF15 therapies in preclinical models and define biomarkers predicting response to dual-hormone strategies.
OBJECTIVE: Our previous studies showed that mice lacking the mitochondrial fusion protein optic atrophy 1 (OPA1 BKO) in brown adipose tissue (BAT) have high metabolic rates and are resistant to diet-induced obesity (DIO) via effects partially mediated by independent actions of fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) secretion from BAT. We examined whether FGF21 and GDF15 act synergistically, contributing to the systemic metabolic adaptations reported in OPA1 BKO mice. METHODS: We generated mice simultaneously lacking the Opa1, Fgf21, and Gdf15 genes in thermogenic adipocytes (TKO) and assessed energy homeostasis and glucose metabolism after regular chow or high-fat diet feeding. RESULTS: Young TKO mice fed regular chow had impaired glucose tolerance, while insulin sensitivity was unchanged. Notably, combined Fgf21 and Gdf15 deletion in OPA1 BKO significantly blunted the resistance to DIO and insulin resistance observed in OPA1 BKO mice. CONCLUSIONS: FGF21 and GDF15 act synergistically to maintain glucose homeostasis and promote resistance to DIO in mice lacking OPA1 in BAT, highlighting the potential of combined therapies using FGF21 and GDF15 for the treatment of metabolic disorders.