Daily Endocrinology Research Analysis
Analyzed 88 papers and selected 3 impactful papers.
Summary
Three high-impact endocrinology studies advance mechanistic, diagnostic, and prognostic understanding of diabetes and its complications. A JCI study identifies VE-cadherin Y685 phosphorylation as a tractable endothelial target to prevent early diabetic retinopathy; a JBC paper reveals α-cell glucagon as essential to adult β-cell mass and function; and a multimodality imaging study links a small, fat-laden pancreas to reduced β-cell mass and future type 2 diabetes risk.
Research Themes
- Endothelial junction signaling as a therapeutic target in diabetic retinopathy
- Paracrine α–β islet crosstalk and glucagon’s role in β-cell maintenance
- Structural imaging phenotypes of the pancreas predicting type 2 diabetes
Selected Articles
1. Disrupting VE-cadherin Y685 phosphorylation inhibits development of experimental diabetic and prediabetic retinopathy.
This mechanistic study shows that VE-cadherin Y685 phosphorylation drives endothelial junction internalization, Ang2 upregulation, and retinal hyperpermeability under diabetic/prediabetic stress. A Y685F knock-in protected mice from vascular leakage and neurovascular dysfunction, nominating VE-cadherin Y685 and O-GlcNAc–Ang2 signaling as actionable therapeutic nodes.
Impact: It identifies an upstream, targetable endothelial signaling event that precedes pericyte loss and vascular leakage in diabetic retinopathy, providing a concrete mechanistic basis for prevention strategies.
Clinical Implications: Pharmacologic inhibitors that prevent VE-cadherin Y685 phosphorylation or modulate O-GlcNAc/Ang2 signaling could preserve retinal barrier integrity in early diabetes/prediabetes; translational studies in humans are warranted.
Key Findings
- High glucose and NDPKB deficiency increased VE-cadherin Y685 phosphorylation, triggering junctional internalization and Ang2 upregulation.
- VE-cadherin Y685F mutation prevented endothelial barrier dysfunction, pericyte detachment, and vascular hyperpermeability in vivo.
- O-GlcNAc modification mediated Y685-dependent Ang2 induction; Y685F knock-in reduced O-GlcNAcylation and preserved neuronal function.
Methodological Strengths
- Genetic knock-in (Y685F) model enabling causal inference on a specific phosphorylation site in vivo
- Integrated in vitro/in vivo validation with proteomics and functional barrier assays
Limitations
- Preclinical mouse and cell models; human validation pending
- Therapeutic feasibility and safety of chronic VE-cadherin phosphorylation modulation not established
Future Directions: Test small molecules or biologics that inhibit Y685 phosphorylation/O-GlcNAc–Ang2 signaling in diabetic models and assess biomarkers of endothelial junction integrity in early human diabetic retinopathy.
Diabetic retinopathy involves early retinal vascular barrier breakdown and pericyte loss, yet the initiating molecular events remain poorly defined. Vascular endothelial cadherin (VE-cadherin), a key regulator of endothelial integrity, is notably reduced in diabetic and prediabetic nucleoside diphosphate kinase B-deficient (NDPKB-deficient) mouse retinas, particularly in the retinal deep capillary layer, and this decline precedes pericyte loss. In vitro, high glucose (HG) and NDPKB deficiency induced VE-cadherin Y685 phosphorylation, promoting its junctional internalization, activating the hexosamine biosynthesis pathway, and increasing angiopoietin 2 (Ang2), resulting in impaired endothelial barrier function and disrupting pericyte attachment. Preventing Y685 phosphorylation through VE-cadherin Y685F mutation blocked these HG- and NDPKB-driven pathological effects. Pharmacological intervention experiments identified protein O-linked β-N-acetyl glucosamine (O-GlcNAc) modification as a mediator of Y685-dependent Ang2 upregulation. In vivo, VE-cadherin Y685F-knockin mice were protected from diabetes- and prediabetes-induced vascular hyperpermeability, exhibited reduced protein O-GlcNAcylation and Ang2 induction, and maintained neuronal function. O-GlcNAc-enriched retinal proteomics further showed that the Y685F mutation restored balanced neurovascular and mitochondrial pathways. These findings highlight the potential of targeting VE-cadherin Y685 phosphorylation as a promising therapeutic approach to maintain retinal vascular integrity and attenuate the pathological progression of diabetic and prediabetic retinopathy.
2. Alpha-cell glucagon is essential for maintaining β-cell function and identity in adult mice.
Selective α-cell glucagon gene deletion in adult mice impairs β-cell mass and function, induces ER stress and islet inflammation, and worsens glucose tolerance. These deleterious effects are rescued by exogenous glucagon but not by GLP-1 agonism; β-cell glucagon receptor deletion did not reproduce the phenotype, implying alternative signaling routes.
Impact: It provides causal evidence that endogenous α-cell glucagon maintains adult β-cell identity/function, reshaping understanding of intra-islet crosstalk and informing therapeutic strategies that target glucagon pathways.
Clinical Implications: Therapies that suppress glucagon signaling may risk compromising β-cell health; approaches that fine-tune rather than abolish glucagon action could better preserve islet function in diabetes.
Key Findings
- α-cell–specific glucagon gene deletion reduced β-cell mass and function and worsened glucose tolerance, with ER stress and islet inflammation.
- Exogenous glucagon reversed β-cell dysfunction; GLP-1 analog did not, indicating glucagon-specific support of β-cells.
- β-cell–specific glucagon receptor deletion did not replicate the phenotype, suggesting noncanonical signaling mediates glucagon’s β-cell support.
Methodological Strengths
- Cell-type–specific gene deletions enabling causal dissection of α→β signaling
- Rescue experiments with exogenous glucagon to confirm specificity
Limitations
- Mouse models may not fully recapitulate human islet architecture and physiology
- Molecular identity of noncanonical β-cell pathways mediating glucagon’s effect remains undefined
Future Directions: Map β-cell signaling nodes downstream of glucagon support; evaluate effects of glucagon-modulating drugs on human islets and in diabetogenic models.
Several studies have analyzed the effect of glucagon on β-cells and glucose homeostasis, either by ablating α-cells or by globally deleting the glucagon/glucagon receptor gene. To investigate possible interactions between α- and β-cells, and the effect of α-cells on β-cells/glucose homeostasis, we generated mouse models to allow deletion of the glucagon gene in α-cells (acute-α-GCG-KO) and the glucagon receptor gene in β-cells of adult mice. Specific deletion of the glucagon gene in the α-cell in adult mice led to impaired glucose tolerance, reduced β-cell mass and function, islet inflammation, β-cell ER stress, and altered β-cell ultrastructure. Notably, these detrimental effects were reversed by exogenous glucagon administration, but not by the glucagon-like peptide-1 (GLP-1) analog exendin-4, indicating that glucagon deficiency specifically harms β-cells. Interestingly, acute ablation of α-cells in acute-α-GCG-KO mice reversed the alteration in glucose homeostasis and in β cells, suggesting that α-cells lacking glucagon gene expression can negatively impact β-cells, perhaps by some unknown factor/s. To investigate the role of the β-cell's glucagon receptor on the observed effect of glucagon gene deletion, we specifically deleted the glucagon receptor gene in β-cells, either congenitally or acutely in the adult mouse; here, there were no changes in β-cells and glucose homeostasis, suggesting that the effect of glucagon on β-cells can be mediated via other signaling pathways. Conclusion: Glucagon gene deletion in α-cells of adult mice is detrimental to β-cells, and this effect is reversed by glucagon administration, suggesting that glucagon deficiency is specifically injurious to β-cells.
3. Structural determinants of beta-cell failure in type 2 diabetes: a multimodality imaging study.
Across PET/CT, UK Biobank, and longitudinal validation, a small, high–intra-pancreatic-fat pancreas associates with reduced estimated β-cell mass, diminished insulin secretion, and substantially increased T2D risk. Findings support a structural pancreatic phenotype underpinning β-cell failure.
Impact: It triangulates imaging and epidemiology to define a structural risk phenotype for T2D, refining risk stratification and motivating pancreas-focused preventive strategies.
Clinical Implications: Pancreatic volume and fat metrics may improve T2D risk prediction; interventions that reduce intra-pancreatic fat or preserve pancreatic volume could help maintain β-cell capacity.
Key Findings
- Small pancreatic volume plus high intra-pancreatic fat correlated with reduced estimated β-cell mass and lower insulin secretion.
- In UK Biobank, the small/high-fat pancreas phenotype had the highest adjusted odds of T2D versus large/low-fat pancreas (aOR ~1.71).
- Longitudinal validation showed the small/high-fat pancreas conferred >3-fold increased T2D hazard.
Methodological Strengths
- Triangulation across PET/CT mechanistic estimates, large-scale biobank, and longitudinal validation
- Consistent associations linking structure (volume, fat) to function (β-cell mass proxy, secretion) and incident risk
Limitations
- β-cell mass estimated indirectly via PET tracer; potential measurement error
- Residual confounding and selection biases in observational components
Future Directions: Standardize pancreas imaging metrics and test whether lifestyle/pharmacologic strategies that reduce intra-pancreatic fat preserve β-cell function and reduce incident T2D.
BACKGROUND: Individuals with type 2 diabetes (T2D) tend to have a smaller pancreas and lower beta-cell mass; however, whether this is cause or consequence of T2D is unclear. We investigated the connection between pancreatic volume, beta-cell mass, beta-cell function, and T2D risk, and whether intra-pancreatic fat deposition (IPFD) modifies these associations. METHODS: We conducted three complementary studies. In a PET/CT study (N = 52), beta-cell mass was estimated using [ RESULTS: In the PET/CT study, smaller pancreatic volume (r = 0.66 [95% CI: 0.47-0.80]) combined with higher IPFD (r = 0.29 [95% CI: 0.011-0.53]) was associated with reduced estimated beta-cell mass, which in turn was linked to lower insulin secretion (r = 0.48 [95% CI: 0.22-0.68]). In the UK Biobank, individuals with small pancreas that contained much fat (small/high-fat pancreas) had the highest T2D likelihood (adjusted-odds ratio: 1.71 [95% CI: 1.42-2.07]) compared to those with large/low-fat pancreas. Validation in the longitudinal study showed adjusted-hazard ratios for T2D of 3.12 (1.40-6.96) for small/high-fat, 0.99 (0.58-1.67) for large/high-fat, and 0.74 (0.26-2.14) for small/low-fat pancreas. CONCLUSION: The combination of a small pancreas and high IPFD is associated with increased T2D risk, supporting a structural phenotype linked to beta-cell failure.