Daily Endocrinology Research Analysis
Analyzed 75 papers and selected 3 impactful papers.
Summary
Analyzed 75 papers and selected 3 impactful articles.
Selected Articles
1. Antecedent hypoglycaemia impairs glucagon secretion by enhancing somatostatin-mediated negative feedback control.
This mechanistic study shows that prior hypoglycaemia sensitizes δ-cells to α-cell signals, driving somatostatin hypersecretion that suppresses counter-regulatory glucagon release. The effect is mimicked by α-cell activation or high glucagon and prevented by GCGR or CREB inhibition, revealing a plastic, paracrine circuit underlying islet metabolic memory.
Impact: It identifies a concrete paracrine mechanism for impaired counter-regulation after hypoglycaemia, a major barrier in insulin-treated diabetes. Targetable nodes (GCGR, CREB) offer translational avenues to prevent recurrent hypoglycaemia.
Clinical Implications: Suggests therapeutic strategies to prevent recurrent hypoglycaemia by modulating δ–α paracrine signaling (e.g., GCGR antagonism or CREB pathway modulation). It also supports adjusting hypoglycaemia avoidance protocols to interrupt islet ‘metabolic memory’.
Key Findings
- α-cell-derived glutamate and glucagon co-activate δ-cells via AMPA and glucagon receptors to establish feedback control of glucagon secretion.
- Antecedent hypoglycaemia sensitizes δ-cells and induces long-lasting structural/functional changes, leading to somatostatin hypersecretion and impaired counter-regulatory glucagon release.
- Chemogenetic α-cell activation or high exogenous glucagon mimicked the phenotype; GCGR or CREB inhibition prevented it, indicating targetable nodes in the circuit.
Methodological Strengths
- Mechanistic dissection with receptor pharmacology and chemogenetic manipulation to establish causality.
- Demonstration of durable structural/functional plasticity consistent with islet ‘metabolic memory’.
Limitations
- Preclinical mechanistic work; human validation of the δ–α paracrine plasticity remains to be shown.
- Potential species/model dependencies and context-specificity of islet interactions.
Future Directions: Translate findings to humans using islet microphysiology, test GCGR/CREB-targeting strategies to reduce hypoglycaemia in insulin-treated diabetes, and map reversibility of δ-cell sensitization.
Somatostatin, produced by pancreatic islet δ cells, is a key intra-islet paracrine factor that regulates the secretion of the glucoregulatory hormones insulin and glucagon from β cells and α cells, respectively. Here, we show that glutamate and glucagon released by α cells cooperatively activate neighbouring δ cells through AMPA and glucagon receptors, thereby enabling spatiotemporal feedback control of glucagon secretion. Crucially, prior hypoglycaemia enhances this mechanism by sensitizing δ cells to α cell-derived factors and inducing long-lasting structural and functional changes that facilitate δ cell and α cell paracrine interaction. This culminates in somatostatin hypersecretion that impairs counter-regulatory glucagon release. These hypoglycaemia-driven effects were emulated by chemogenetic activation of α cells or high concentrations of exogenous glucagon but prevented by inhibitors of glucagon receptors or the transcription factor CREB. This plasticity represents a key component of the islet's 'metabolic memory', which, through impaired counter-regulatory glucagon secretion, increases the occurrence of recurrent hypoglycaemia that complicates the management of insulin-dependent diabetes.
2. Human MASLD is a diurnal disease driven by multisystem insulin resistance and reduced insulin availability at night.
In patients with MASLD, multiple pathogenic pathways are preferentially activated at night, including hepatic/peripheral insulin resistance, increased DNL, and elevated NEFAs, while nocturnal insulin availability is reduced due to lower secretion and higher clearance. These diurnal defects persist after weight loss, implying a primary chronometabolic driver and guiding the timing of diet, exercise, and therapies.
Impact: This is among the first human stable isotope studies mapping day–night metabolic fluxes in MASLD, reframing the disease as diurnally driven and actionable via chronotherapy.
Clinical Implications: Supports time-of-day personalization for nutrition, exercise, and drug delivery in MASLD, potentially prioritizing evening targets to blunt nocturnal DNL and insulin resistance.
Key Findings
- Nighttime increases in hepatic/peripheral insulin resistance, DNL, and systemic NEFAs characterize MASLD.
- Nocturnal plasma insulin is reduced due to both decreased secretion and increased clearance.
- Diurnal metabolic abnormalities persist after weight loss and liver fat reduction, indicating a primary chronometabolic driver.
Methodological Strengths
- Day–night metabolic phenotyping with state-of-the-art stable isotope tracers.
- Integrated multi-tissue proteomics across plasma, adipose, and skeletal muscle.
Limitations
- Sample size and setting not detailed in the abstract; generalizability requires larger, multi-center validation.
- Observational physiological design limits causal inference regarding timing interventions.
Future Directions: Test time-specific interventions (feeding windows, exercise timing, chronotherapy) in RCTs; validate nocturnal targets and molecular pathways for therapeutic development.
Hepatic lipid and glucose metabolism have been shown to be under tight circadian control in pre-clinical models. However, it remains unknown whether diurnal patterns exist in functional processes governing intrahepatic lipid accumulation in humans. We performed metabolic phenotyping, including state-of-the-art stable isotope techniques, during day and night in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and overweight controls (NCT05962099). The primary outcome was diurnal change in hepatic de novo lipogenesis (DNL), alongside a number of secondary outcomes, including changes in hepatic glucose production, glucose disposal, plasma non-esterified fatty acids (NEFAs), and whole-body glucose and lipid oxidation. We show that nighttime metabolic dysfunction is a hallmark of MASLD with multiple pathogenic pathways upregulated at night, including hepatic and peripheral insulin resistance, DNL, and systemic NEFA exposure. Insulin resistance is compounded by lower plasma insulin levels at night, secondary to reduced insulin secretion and elevated insulin clearance. Diurnal differences persist when performing identical investigations after weight loss with liver fat reductions, suggesting that nighttime metabolic dysfunction may be a primary driver of steatosis. These findings will help establish the optimal window for energy intake, exercise, and medication delivery in patients with MASLD. Integrated proteomics of plasma, adipose, and skeletal muscle tissue across day and night also identified a number of specific molecular targets that may offer therapeutic potential in the treatment of metabolic disease.
3. Soluble Urokinase Plasminogen Activator Receptor (suPAR) Mediates the Impact of Diabetes on Adverse Outcomes in Coronary Artery Disease.
In a 4,324-participant cohort (median follow-up 6.9 years), higher suPAR levels in T2D patients mediated more than half of the diabetes-associated risk for cardiovascular death and other adverse outcomes, whereas hs-CRP did not. Adjustment for suPAR substantially attenuated the T2D risk signal, positioning suPAR as a key mechanistic and prognostic marker.
Impact: By quantifying mediation, this study elevates suPAR from a risk correlate to a potential causal pathway linking T2D to adverse CHD outcomes, guiding biomarker-driven risk stratification and therapeutic targeting.
Clinical Implications: Supports incorporating suPAR into risk stratification for T2D with CHD and motivates trials testing suPAR-lowering strategies to reduce cardiovascular events.
Key Findings
- T2D participants had higher suPAR levels (median 3,260 vs 2,792 pg/mL).
- Adjusted HR for cardiovascular death with T2D (1.38) attenuated to 1.18 (P=0.1) after adjusting for suPAR, but not after hs-CRP adjustment.
- Causal mediation analysis showed suPAR mediated >50% of T2D’s effect on adverse outcomes.
Methodological Strengths
- Prospective biobank cohort with long follow-up and adjudicated outcomes.
- Robust adjustment and regression-based causal mediation analyses comparing suPAR with hs-CRP.
Limitations
- Observational design limits causal inference; residual confounding cannot be excluded.
- Generalizability beyond a single biobank cohort requires external validation.
Future Directions: Randomized trials to test suPAR-lowering interventions and their impact on cardiovascular outcomes in T2D; evaluate integration of suPAR into clinical risk models.
OBJECTIVE: Type 2 diabetes (T2D) is a significant risk factor for adverse outcomes in coronary heart disease (CHD). We investigated whether inflammation and immune dysregulation, measured using soluble urokinase plasminogen activator receptor (suPAR) and high-sensitivity C-reactive protein (hs-CRP) levels, mediate this risk. RESEARCH DESIGN AND METHODS: Patients with and without CHD enrolled in the Emory Cardiovascular Biobank had suPAR (ViroGates, Denmark) and hs-CRP levels measured and were followed for 1) cardiovascular death, 2) a composite of incident myocardial infarction and cardiovascular death, and 3) all-cause death. Fine and Gray or Cox proportional hazards models adjusted for demographic, clinical, and treatment variables were used. Regression-based causal mediation analyses were performed. RESULTS: A total of 4,324 participants (mean [SD] age 64 [11.9] years, 36% women, 31.8% with T2D) were followed for a median of 6.9 years. SuPAR levels were higher in those with T2D (median [interquartile range] 3,260 [2,503-4,463] vs. 2,792 [2,217-3,600] pg/mL). T2D was associated with a higher adjusted risk (hazard ratio [HR] 1.38; 95% CI 1.16, 1.63; P < 0.001) of cardiovascular death that was greatly attenuated (HR 1.18; 95% CI 0.99, 1.40; P = 0.1) after adjustment for suPAR, but not hs-CRP, levels. Similar findings were observed for the other outcomes. SuPAR, but not hs-CRP, levels mediated >50% of the effect of T2D on adverse outcomes. CONCLUSIONS: The impact of T2D on adverse outcomes is significantly mediated through chronic inflammation and immune dysregulation, estimated using suPAR levels. Whether novel therapies for reducing suPAR levels will impact CHD risk in T2D warrants further investigation.