Daily Endocrinology Research Analysis
Analyzed 97 papers and selected 3 impactful papers.
Summary
Three high-impact endocrinology studies span mechanistic discovery and population-level risk. A Nature Communications study maps a genome-wide CRISPR screen and in vivo QTLs to uncover Golgi-centered control of proinsulin with PDIA6 as a convergent regulator. Complementing this, Science Signaling links diabetic hyperglycemia to cognitive decline via Creb3 O-GlcNAcylation and lactate, while a large Diabetes Care cohort shows seasonal BMI amplitude independently predicts kidney function decline in type 2 diabetes.
Research Themes
- Beta-cell proteostasis and proinsulin trafficking mechanisms
- Metabolic drivers of diabetes-associated cognitive decline
- Anthropometric variability as a prognostic biomarker for diabetic kidney disease
Selected Articles
1. Proinsulin regulators identified with CRISPR screen and in vivo mouse QTL mapping.
A genome-wide CRISPR screen and mouse QTL mapping converge on Golgi-centered control of proinsulin and identify PDIA6 as a key regulator of proinsulin production. Trafficking toward Golgi increases, and away from Golgi decreases, intracellular proinsulin, independent of proinsulin folding.
Impact: This study provides a mechanistic atlas of proinsulin regulation with cross-validation in vivo, nominating PDIA6 and Golgi trafficking as actionable targets for diabetes.
Clinical Implications: PDIA6 and Golgi-trafficking pathways could be targeted to normalize proinsulin/insulin balance, informing biomarker development and therapeutic strategies for β-cell dysfunction in diabetes.
Key Findings
- A genome-wide CRISPR screen identified 84 regulators of the intracellular proinsulin/insulin ratio in β-cells.
- Functional annotation pinpointed Golgi trafficking as the primary axis controlling proinsulin storage and levels.
- Mouse QTL mapping converged on PDIA6; PDIA6 knockdown reduced Golgi/secretory granule proinsulin without affecting folding, impairing production via a UPR-independent mechanism.
Methodological Strengths
- Orthogonal validation combining genome-wide CRISPR screening with in vivo QTL mapping.
- Mechanistic perturbations confirmed across mouse and human β-cells.
Limitations
- Preclinical models (cell lines and mice) limit direct clinical generalizability.
- Potential context-dependence of trafficking effects across β-cell states and stressors.
Future Directions: Validate PDIA6 and Golgi trafficking targets in human islets ex vivo and in diabetic models in vivo; develop selective modulators and assess impacts on proinsulin/insulin ratio and glycemic control.
Altered proinsulin levels in β-cells and bloodstream are hallmarks of diabetes and other diseases, but our knowledge about the proinsulin regulators remains limited. Here we perform a genome-wide CRISPR screen to identify 84 proinsulin regulators that alter intracellular proinsulin/insulin ratio in a mouse β-cell line. The proinsulin regulators are distinct from the insulin regulators from a previous orthogonal CRISPR screen. Functional annotation of the proinsulin regulators highlights Golgi as the primary organelle for proinsulin storage and regulation. Trafficking towards the Golgi increases the intra-cellular proinsulin/insulin ratio, while trafficking away from the Golgi, including exocytosis and Golgi-to-ER retrograde transport, decreases the intracellular proinsulin levels. We also map mouse quantitative trait loci (QTLs) associated with plasma proinsulin levels and use the CRISPR screen results to pinpoint the causal genes within the QTL loci. Interestingly, protein disulfide isomerase Pdia6 is the strongest hit from both CRISPR screen and the in vivo QTL mapping. Knocking down Pdia6 significantly reduce proinsulin accumulation in Golgi and secretory granules. Intriguingly, Pdia6-depletion in both human and mouse β-cells does not affect the folding status of proinsulin but causes significantly impaired proinsulin production through a UPR-independent mechanism. Taken together, our genetic profiles provide mechanistic insights into the regulation of proinsulin/insulin homeostasis.
2. High glucose impairs cognitive function through Creb3 O-GlcNAcylation and increased lactate production.
Elevated plasma lactate independently predicts mild cognitive impairment in diabetes, and high glucose drives Creb3 O-GlcNAcylation in hippocampal neurons, stabilizing Creb3 and altering downstream gene expression. These findings mechanistically link glycolytic flux and O-GlcNAc signaling to diabetes-associated cognitive decline.
Impact: Bridges human prognostic biomarker evidence with cellular mechanisms that connect hyperglycemia to neurocognitive impairment in diabetes.
Clinical Implications: Plasma lactate may serve as a pragmatic biomarker for cognitive risk stratification in diabetes; pathways involving O-GlcNAcylation/Creb3 suggest novel therapeutic targets to prevent diabetes-associated cognitive decline.
Key Findings
- Prospective observational data show elevated plasma lactate is an independent predictor of mild cognitive impairment in diabetes.
- High glucose increases O-GlcNAcylation of Creb3 in hippocampal neurons, preventing ubiquitination and stabilizing Creb3.
- Stabilized Creb3 upregulates downstream target gene expression, mechanistically linking hyperglycemia to cognitive deficits.
Methodological Strengths
- Integration of human prospective biomarker evidence with mechanistic neuronal experiments.
- Molecular dissection of post-translational modification (O-GlcNAcylation) and protein stability in disease context.
Limitations
- Human component is observational, limiting causal inference.
- Downstream targets and pathway generalizability require further validation in human tissues.
Future Directions: Validate lactate-based risk stratification in multi-center cohorts; test pharmacologic or lifestyle interventions that modulate glycolysis/O-GlcNAcylation/Creb3 to preserve cognition in diabetes.
The high glucose levels characteristic of diabetes can lead to increases in glucose metabolism through the process of glycolysis, resulting in greater production of lactate and in a monosaccharide-based posttranslational modification called O-GlcNAcylation. Here, we identified O-GlcNAcylation and lactate production as the molecular mechanisms underlying high glucose-induced cognitive impairment, a prevalent complication of diabetes. A prospective observational study revealed that elevated plasma concentrations of lactate were an independent risk factor for predicting mild cognitive impairment in patients with diabetes. High-glucose treatment of mouse hippocampal neurons increased the O-GlcNAcylation of the transcription factor Creb3, which stabilized the protein by preventing its ubiquitination. The increase in Creb3 subsequently up-regulated the expression of the downstream target gene
3. Seasonal BMI Amplitude and Risk of Kidney Function Decline in Japanese Adults With Type 2 Diabetes (JDDM 82).
In a nationwide, multicenter cohort of 6,700 Japanese adults with T2D, greater intra-annual BMI fluctuation independently predicted ≥40% eGFR decline and other renal outcomes over 6.8 years. Seasonal BMI amplitude may serve as a modifiable prognostic marker for kidney risk.
Impact: Introduces a simple, routinely available metric—seasonal BMI amplitude—to identify T2D patients at higher risk for kidney function decline, supported by robust modeling and multiple renal endpoints.
Clinical Implications: Incorporating seasonal BMI variability into risk assessment could prompt targeted lifestyle timing strategies and closer eGFR monitoring; interventional trials should test whether dampening BMI seasonality slows CKD progression.
Key Findings
- Each 1-SD increase in seasonal BMI fluctuation was associated with higher risk of ≥40% eGFR decline (HR 1.23, 95% CI 1.16–1.31).
- Highest versus lowest tertile of BMI fluctuation conferred a 1.72-fold risk for ≥40% eGFR decline (95% CI 1.42–2.09).
- Associations were consistent for ≥30% eGFR decline, creatinine doubling, incident CKD stage ≥3; longitudinal models showed steeper eGFR decline with high fluctuation.
Methodological Strengths
- Large, nationwide multicenter cohort with median 6.8-year follow-up and multiple renal endpoints.
- Advanced seasonal-trend LOESS modeling with multivariable Cox regression and sensitivity analyses including time-varying medications.
Limitations
- Observational design cannot exclude residual confounding.
- Generalizability beyond Japanese clinical settings and modeling assumptions for monthly BMI may be limited.
Future Directions: Test interventions to reduce seasonal BMI amplitude and evaluate effects on eGFR slope; validate risk stratification in diverse populations and integrate with wearable/CGM-derived behavioral seasonality.
OBJECTIVE: Body weight variability is linked to cardiometabolic outcomes, but its renal impact in type 2 diabetes remains uncertain. We tested whether the magnitude of seasonal BMI fluctuation is independently associated with kidney function decline. RESEARCH DESIGN AND METHODS: We analyzed a nationwide, multicenter Japanese cohort (2014-2020). Monthly BMI was modeled using seasonal-trend locally estimated scatterplot smoothing to quantify each participant's within-year peak-to-trough difference. The primary outcome was ≥40% decline in estimated glomerular filtration rate (eGFR). Secondary outcomes were ≥30% eGFR decline, creatinine doubling, incident chronic kidney disease (CKD) stage ≥3, and kidney failure. Associations were estimated using multivariable Cox models with clinic as a random effect. RESULTS: Among 6,700 outpatients (median follow-up: 6.8 years), 779 reached the primary end point. Each 1-SD increase in BMI fluctuation was associated with higher risk of ≥40% eGFR decline (hazard ratio [HR] 1.23, 95% CI 1.16-1.31). The highest versus lowest tertile showed a 1.7-fold increased risk (HR 1.72, 95% CI 1.42-2.09). Patterns were consistent for ≥30% eGFR decline (HR 1.18, 95% CI 1.13-1.23), creatinine doubling (HR 1.30, 95% CI 1