Daily Endocrinology Research Analysis
A multicenter randomized, double-blind trial shows the traditional Chinese medicine Shenzhuo Formula matches irbesartan in reducing proteinuria but better preserves renal function in diabetic kidney disease, with mechanistic links to chemokine suppression. A randomized, energy-matched trial demonstrates that ketogenic dieting rapidly remodels the gut microbiome in severe obesity with prediabetes. A large retrospective study of 68Ga-DOTANOC PET/CT reveals a higher prevalence but a lower malignanc
Summary
A multicenter randomized, double-blind trial shows the traditional Chinese medicine Shenzhuo Formula matches irbesartan in reducing proteinuria but better preserves renal function in diabetic kidney disease, with mechanistic links to chemokine suppression. A randomized, energy-matched trial demonstrates that ketogenic dieting rapidly remodels the gut microbiome in severe obesity with prediabetes. A large retrospective study of 68Ga-DOTANOC PET/CT reveals a higher prevalence but a lower malignancy rate of incidentalomas than previously reported, informing diagnostic workups.
Research Themes
- Randomized integrative therapy for diabetic kidney disease with mechanistic multi-omics
- Diet-induced microbiome remodeling in severe obesity/prediabetes
- Risk stratification of incidental findings on somatostatin receptor PET
Selected Articles
1. Randomized controlled clinical trial of Shenzhuo Formula in the treatment of macroalbuminuria in diabetic kidney disease and its inflammation-modulating mechanisms.
In a multicenter, double-blind RCT (n=120), Shenzhuo Formula achieved proteinuria reduction comparable to irbesartan but better preserved renal function and improved symptom scores, with favorable safety. Multi-omics suggested benefits may be mediated by suppressing CX3CL1/MCP-1-driven inflammation.
Impact: This is a rigorous randomized, active-controlled trial integrating mechanistic omics, providing both efficacy and biological plausibility for a TCM-based intervention in DKD.
Clinical Implications: SZF may be considered as an adjunct or alternative to ARB therapy for DKD with macroalbuminuria, particularly where renal function preservation is prioritized. Mechanistic data support targeting chemokine pathways.
Key Findings
- In a double-blind multicenter RCT (n=120), SZF matched irbesartan in reducing proteinuria.
- SZF was superior in preserving renal function and improving TCM symptom scores.
- Mechanistic analyses (inflammation proteomics, kidney scRNA-seq) implicated suppression of CX3CL1/MCP-1–mediated inflammation.
- Safety profile was favorable with no major safety signals.
Methodological Strengths
- Randomized, double-blind, double-dummy, active-controlled, multicenter design
- Integration of Bayesian efficacy modeling and multi-omics mechanistic analyses
Limitations
- Trial duration and specific renal endpoints timing not detailed in the abstract
- Generalizability outside the studied population and settings requires confirmation
Future Directions: Confirm findings in larger, longer RCTs with hard renal outcomes and explore chemokine-targeted combination strategies.
BACKGROUND: Shenzhuo Formula (SZF), a modified Didang Tang, is used for diabetic kidney disease (DKD), though high-quality evidence is limited. METHODS: In a randomized, double-blind, double-dummy, active-controlled, multicenter trial, irbesartan (IRB) was the control. A Bayesian model assessed efficacy. Mechanistic studies included Olink inflammation proteomics, single-cell RNA sequencing (scRNA-seq) of KK-Ay mouse kidneys, and RESULTS: A total of 120 DKD patients with macroalbuminuria were randomized (SZF CONCLUSIONS: SZF matched IRB in proteinuria reduction but was superior in preserving renal function and improving traditional Chinese medicine symptoms in DKD, with good safety. Benefits may involve suppression of CX3CL1/MCP-1-mediated inflammation.
2. Spatially diffuse cAMP signalling with oppositely biased GLP-1 receptor agonists in β-cells despite differences in receptor localisation.
Despite marked differences in GLP-1R internalization between exendin-asp3 and exendin-phe1, β-cell cAMP/PKA/ERK signaling was spatially diffuse with minimal localization-specific differences. Rapidly internalizing exendin-asp3 accumulated in endosomes but was less efficient at driving cAMP production and insulin secretion than the slower-internalizing ligand.
Impact: The study challenges the assumption that endosomal signaling is a dominant driver for GLP-1R agonist efficacy, informing the rational design of biased agonists for diabetes and obesity.
Clinical Implications: Drug developers should not equate enhanced internalization/endosomal binding with superior β-cell cAMP signaling or insulinotropic effects; ligand optimization should consider whole-cell signaling efficiency.
Key Findings
- Live-cell biosensing showed β-cell cAMP/PKA/ERK signaling is widely distributed with minimal dependence on GLP-1R localization (surface vs endosome).
- Exendin-asp3 caused greater endosomal GLP-1R accumulation than exendin-phe1 but drove less cAMP production and insulin secretion.
- Bioorthogonal labeling confirmed divergent trafficking, yet signaling outputs did not map to receptor internalization.
- Findings refine understanding of biased GLP-1R agonism relevant to T2D/obesity therapeutics.
Methodological Strengths
- Use of bioorthogonal labeling and fluorescent agonist conjugates to verify trafficking
- Compartment-specific live biosensors in β-cell lines and primary islets, plus perfused pancreas assays
Limitations
- In vitro and ex vivo models; lack of clinical outcome data
- Pharmacological concentration ranges; translational dosing relationships remain to be defined
Future Directions: Test whether whole-cell signaling efficiency predicts glycemic outcomes in vivo and incorporate these metrics into lead optimization of GLP-1R agonists.
Internalisation of G protein-coupled receptors (GPCRs) can contribute to altered cellular responses by directing signalling from non-canonical locations, such as endosomes. If signalling processes are locally constrained, active receptors in different subcellular locations could produce different downstream effects. This phenomenon may be relevant to the optimal targeting of the glucagon-like peptide-1 receptor (GLP-1R), a type 2 diabetes and obesity target GPCR for which several ligands with varying internalisation tendency have been discovered. To investigate, we compared the signalling localisation effects of two prototypical GLP-1RAs with opposite signal bias and effects on GLP-1R trafficking: exendin-asp3 (ExD3), a full agonist that drives rapid internalisation, and exendin-phe1 (ExF1), which shows much slower internalisation. After using bioorthogonal labelling and fluorescent agonist conjugates to verify the divergent trafficking patterns of ExF1 and ExD3 in β-cell lines and primary pancreatic islets, we used live cell biosensors to monitor signalling at different subcellular locations. This revealed that cAMP/PKA/ERK signalling in β-cells is in fact distributed widely across the cell over short- (<5 minutes) and medium-term (up to 60 minutes) stimulation at pharmacological (>10 pM) concentrations, with no major differences in signal localisation that could be linked to internalised versus cell surface-bound GLP-1R. Moreover, washout experiments highlighted that, whilst fast-internalising ExD3 shows much greater accumulation and binding to GLP-1R in endosomes than slow-internalising ExF1, it is a rather inefficient driver of both cAMP production in β-cells and insulin secretion from perfused rat pancreata. These data provide a greater understanding of the cellular effects of biased GLP-1R agonism.
3. Taxonomic and functional shifts in the microbiome of severely obese, prediabetic patients: Ketogenic diet versus energy-matched standard diet.
In a randomized, energy-matched trial, short-term ketogenic dieting in severely obese, prediabetic adults decreased alpha diversity via loss of Lachnospiraceae, increased Bacteroidaceae, shifted microbial functional pathways, and raised serum acetate, unlike a standard diet. This supports microbiome-mediated mechanisms for KD beyond calorie restriction.
Impact: Provides randomized evidence that KD rapidly and specifically remodels gut microbial taxonomy and function independent of caloric intake, informing dietary strategies and mechanistic trials in metabolic disease.
Clinical Implications: When prescribing KD for severe obesity/prediabetes, anticipate microbiome restructuring; biomarker monitoring (e.g., SCFAs) and personalization may optimize metabolic benefits.
Key Findings
- Ketogenic diet reduced alpha diversity primarily via loss of Lachnospiraceae and increased Bacteroidaceae compared to an energy-matched standard diet.
- Functional profiling showed KD-specific alterations in genes for energy metabolism, amino acid synthesis, nucleic acid activity, RNA modification, and vitamin biosynthesis.
- Serum acetate significantly increased after KD, supporting microbiome-metabolite links.
- Baseline obese-prediabetic cohort had lower alpha diversity and higher interindividual variability than healthy controls.
Methodological Strengths
- Randomized, energy-matched dietary comparison controlling for caloric intake
- Combined taxonomic and functional microbiome profiling with serum metabolite measurement
Limitations
- Short-term intervention; durability and clinical outcomes (glycemia, weight) not reported in abstract
- Sample size and exact duration not specified in the abstract
Future Directions: Longer trials linking microbiome shifts to metabolic endpoints and testing adjunctive microbial-targeted therapies alongside KD.
AIMS: Obesity and type 2 diabetes mellitus (T2DM) are among the leading global health challenges of the 21st century. While caloric restriction remains the cornerstone of weight loss interventions, ketogenic diets (KD), characterised by low carbohydrate and high fat intake, have been shown to improve metabolic health partly by modulating the gut microbiome. This study investigated the effects of a short-term KD on gut microbiome composition and function in severely obese, prediabetic patients, compared to an energy-matched standard diet (SD). METHODS: In a randomised trial, patients with BMI >35 kg/m RESULTS: At baseline, prediabetic patients exhibited greater interindividual variability and lower alpha diversity than healthy controls. KD resulted in a significant reduction of alpha diversity, largely driven by a selective loss of Lachnospiraceae, with a concomitant increase in Bacteroidaceae. Functional profiling revealed that KD, but not SD, altered genes coding for enzymes involved in energy metabolism, amino acid synthesis, nucleic acid activity, RNA modification, and vitamin biosynthesis. Additionally, serum acetate levels increased significantly following KD. CONCLUSIONS: These findings underscore that KD, independent of caloric intake, acutely remodels the gut microbiome's taxonomic and functional landscape, highlighting the microbiome as a potential mediator of KD's metabolic effects.