Daily Endocrinology Research Analysis
Three impactful endocrinology papers span mechanistic, translational, and population-level advances. A Diabetologia study identifies spexin as a beta-cell–stimulating peptide that binds ATP1A1 to enhance insulin secretion and proliferation. Human stomach organoids transplanted in vivo can be reprogrammed to form insulin-producing cells, while a multinational cohort links GLP-1 receptor agonists with lower incident neurodegeneration in type 2 diabetes.
Summary
Three impactful endocrinology papers span mechanistic, translational, and population-level advances. A Diabetologia study identifies spexin as a beta-cell–stimulating peptide that binds ATP1A1 to enhance insulin secretion and proliferation. Human stomach organoids transplanted in vivo can be reprogrammed to form insulin-producing cells, while a multinational cohort links GLP-1 receptor agonists with lower incident neurodegeneration in type 2 diabetes.
Research Themes
- Peptide and ion-pump signaling to restore beta-cell function
- Organoid-based endocrine cell replacement strategies
- Incretin therapies and neurodegeneration risk in type 2 diabetes
Selected Articles
1. Peptide hormone spexin restores beta cell function and improves glycaemic control in mice via regulation of the sodium-potassium pump.
Spexin increased glucose-stimulated insulin secretion and beta-cell proliferation, improved glucose tolerance in diet-induced and STZ-diabetic mice, and bound ATP1A1 to inhibit Na+/K+-ATPase activity leading to membrane depolarization. These data position spexin as a mechanistically defined beta-cell–targeting peptide with therapeutic potential.
Impact: This work uncovers a concrete molecular target (ATP1A1) for spexin on beta cells and demonstrates in vivo metabolic efficacy, advancing beta-cell–centric diabetes therapeutics.
Clinical Implications: While preclinical, spexin or ATP1A1-modulating analogues could be developed to enhance insulin secretion and beta-cell mass. Translation will require human islet validation and safety profiling given ATP1A1’s ubiquitous expression.
Key Findings
- Spexin increased GSIS and beta-cell proliferation in mouse islets and in vivo.
- Spexin improved glucose tolerance in HFD-fed mice and reduced hyperglycaemia in HFD/STZ-diabetic mice with higher serum insulin.
- Pull-down/MS and binding assays showed spexin binds ATP1A1, inhibiting Na+/K+-ATPase activity and causing membrane depolarization.
Methodological Strengths
- Multiple in vivo models (diet-induced and STZ-induced diabetes) with concordant effects.
- Biochemical target identification (ATP1A1) with complementary pull-down and binding assays.
Limitations
- Preclinical mouse studies; human islet and clinical data are lacking.
- Potential off-target and safety concerns due to ubiquitous ATP1A1 expression; long-term effects not assessed.
Future Directions: Validate spexin–ATP1A1 signaling in human islets, define receptor pharmacology, assess chronic efficacy/safety, and explore beta cell–selective delivery.
AIMS/HYPOTHESIS: Clinical studies revealed that serum spexin level is positively associated with beta cell function. However, the role of spexin in beta cells remains unclear. We hypothesise that spexin treatment could influence beta cell function and modulate glucose homeostasis in vivo. METHODS: We analysed glucose-stimulated insulin secretion (GSIS) and beta cell proliferation in mice and isolated mouse islets. Using mice fed a high-fat diet (HFD) and an HFD/streptozocin (STZ)-induced diabetes mouse model, we investigated the effects of spexin on glucose homeostasis and beta cell function. We performed a pull-down/MS assay and a cell-based binding assay to identify the binding partner of spexin on the beta cell surface. An ion pump activity assay and Atp1a1 RESULTS: We observed that spexin treatment increased GSIS in chow-diet-fed mice and isolated mouse islets. Spexin treatment also promoted beta cell proliferation in mouse islets and pancreatectomised mice. Furthermore, spexin treatment improved glucose tolerance in HFD-fed mice and attenuated hyperglycaemia in an HFD/STZ-induced diabetes mouse model, along with an elevated serum insulin level and increased beta cell proliferation. Spexin showed specific binding to the beta cell surface. The pull-down/MS assay demonstrated that spexin bound to the α1 subunit of sodium-potassium ATPase (ATP1A1), resulting in pump activity inhibition and subsequent membrane depolarisation. In Atp1a1 CONCLUSIONS/INTERPRETATION: Our study highlights that spexin is a stimulatory factor for beta cell function and proliferation, and suggests that spexin is a diabetes therapeutic target for beta cell intervention.
2. Modeling in vivo induction of gastric insulin-secreting cells using transplanted human stomach organoids.
Human gastric organoids engineered with inducible reprogramming factors were transplanted and maintained in vivo for 6 months, acquiring stomach-like differentiation. Upon induction, reprogramming produced insulin-positive cells, modeling the feasibility of generating gastric insulin-secreting cells in vivo from human tissues.
Impact: This translational model demonstrates in vivo generation of insulin-positive cells from human gastric organoids, advancing a potential autologous cell-replacement strategy beyond pancreatic sources.
Clinical Implications: While not yet a therapy, this platform suggests a future path to autologous insulin-secreting cell generation from accessible tissues, potentially reducing donor dependence and immunosuppression.
Key Findings
- Human gastric organoids with inducible reprogramming factors were stably engrafted for 6 months and matured with stomach-like structure and composition.
- Induction of reprogramming factors in vivo led to formation of insulin-positive cells within transplanted organoids.
- The study models feasibility of generating gastric insulin-secreting cells from human tissues in vivo.
Methodological Strengths
- Human stem cell–derived organoids with inducible reprogramming provide a controlled translational platform.
- Long-term in vivo engraftment (6 months) demonstrating stability and differentiation before induction.
Limitations
- Abstract truncation limits reported functional characterization (e.g., glucose responsiveness, secretion dynamics).
- Safety, scalability, and immunogenicity assessments are not addressed at this stage.
Future Directions: Define functional maturity (glucose-stimulated secretion), durability, and safety; optimize reprogramming efficiency and delivery; evaluate autologous sourcing and immune compatibility.
Insulin-dependent diabetes could be treated by supplying patients with primary pancreatic islets or other types of insulin-secreting cells. Functional insulin-secreting cells can be induced in situ from the murine stomach using defined genetic factors, offering a promising method to directly produce autologous insulin-secreting cells. Here, we modeled whether such gastric insulin-secreting (GINS) cells could be generated in vivo from human stomach tissues. We produced human gastric organoids (hGOs) from human embryonic stem cells engineered with inducible expression of reprogramming factors. The hGOs were stably transplanted for 6 months and showed robust cytodifferentiation resembling the human stomach in structure and cellular composition. Upon hGO maturation in vivo, we activated the reprogramming factors and observed the formation of insulin
3. Neurodegeneration onset with glucagon-like peptide-1 receptor agonists in people with type 2 diabetes: a real-world multinational cohort study.
In over 214,000 matched adults with T2D, initiating GLP-1 receptor agonists was associated with a lower risk of incident neurodegenerative disorders versus DPP4 inhibitors (HR 0.81) and versus basal insulin in a separate cohort. Benefits were consistent across sex, age strata, and across semaglutide, liraglutide, and dulaglutide; Parkinson’s disease risk was not reduced.
Impact: This large, multinational, target-comparable cohort provides real-world evidence that GLP-1 RAs may confer neuroprotective benefits in T2D, informing drug selection and prioritizing prospective trials.
Clinical Implications: When choosing glucose-lowering therapy for T2D—especially in patients at high cognitive risk—GLP-1 RAs may offer added neurodegeneration risk reduction. However, causal inference requires randomized trials and mechanistic studies.
Key Findings
- GLP-1 RA initiation was associated with lower composite neurodegeneration onset versus DPP4i (HR 0.81; absolute risk difference −0.6%).
- Lower risks observed for dementia, Alzheimer’s disease, and vascular dementia; no significant reduction for Parkinson’s disease.
- Associations were consistent across sex, age groups, and across semaglutide, liraglutide, and dulaglutide; similar direction versus basal insulin.
Methodological Strengths
- Very large, multinational EHR cohort with 1:1 propensity score matching and Cox modeling.
- Robust subgroup analyses across sex, age, and specific GLP-1 RA agents; comparator analyses versus DPP4i and basal insulin.
Limitations
- Observational design susceptible to residual confounding and misclassification in EHR data.
- Unmeasured factors (e.g., education, baseline cognition, lifestyle) may influence outcomes.
Future Directions: Conduct randomized trials testing GLP-1 RAs for neuroprotection in T2D and elucidate mechanisms (central vs vascular pathways). Evaluate cognitive outcomes and biomarkers longitudinally.
BACKGROUND: Type 2 diabetes (T2D), affecting approximately 12% of the global population and over 30% of older adults, is among the most prevalent and fast-growing risk factors for neurodegenerative disorders. Evidence is lacking on whether specific glucose-lowering agents may reduce the risk of neurodegeneration onset in people living with T2D. METHODS: In this retrospective cohort study, we utilized the TriNetX platform, which contains electronic health records of over 170 million people worldwide. We propensity-score matched (1:1) people with T2D lacking evidence of neurodegeneration who initiated glucagon-like peptide-1 receptor agonists (GLP-1 RAs) or dipeptidyl peptidase-4 inhibitors (DPP4i) (2010-2021). In a separate analytical cohort, we compared individuals initiating GLP-1 RA with those initiating basal insulin. Follow-up continued for ≤ 5 years. We used Cox proportional-hazard regression models to assess the risk of the composite outcome of developing new neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease, dementia subtypes, and other synucleinopathies. We also assessed each component individually. Analyses were repeated among subgroups defined by sex, age, and the specific GLP-1 RA initiated. RESULTS: Overall, 214,442 matched individuals initiated GLP-1 RAs or DPP4i (109,731 women, mean age 58.6 years [SD 12], and mean HbA1c 7.7% [1.4]). During a 4.0-year mean follow-up, neurodegenerative disorder onset occurred in 2,393 (2.2%) and 3,062 (2.9%) people initiating GLP-1 RAs and DPP4i, respectively (hazard ratio of 0.81 [95% CI 0.77 to 0.86]; absolute risk difference - 0.6% [- 0.8 to - 0.5]). The associations were separately observed among women (0.78 [0.72 to 0.84]) and men (0.90 [0.83 to 0.98]), individuals aged ≥ 65 years old (0.82 [0.78 to 0.87]) or < 65 years old (0.84 [0.70 to 1.00]), and in those initiating semaglutide (0.75 [0.67 to 0.84]), liraglutide (0.77 [0.70 to 0.84]), or dulaglutide (0.82 [0.77 to 0.88]). The hazard ratios for dementia, Alzheimer's disease, vascular dementia, and Parkinson's disease onset were 0.76 [0.72 to 0.81], 0.77 [0.68 to 0.87], 0.75 [0.67 to 0.85], and 1.04 [0.93 to 1.17] with GLP-1 RAs versus DPP4i, respectively. The results were in the same direction when comparing individuals initiating GLP-1 RAs with those initiating basal insulin. CONCLUSIONS: In a real-world cohort of people living with T2D with a multinational representation, the initiation of GLP-1 RAs, compared to DPP4i or basal insulin, was associated with a lower risk of new-onset neurodegeneration. These data support the rationale for dedicated clinical trials to assess the potential neuroprotective properties of GLP-1 RAs in this population.