Daily Endocrinology Research Analysis
Analyzed 104 papers and selected 3 impactful papers.
Summary
Analyzed 104 papers and selected 3 impactful articles.
Selected Articles
1. Deleting Bmp4 in brown fat unlocks an arachidonic acid-AMPK axis to boost energy expenditure.
BAT-specific Bmp4 deletion or pharmacologic blockade of fatty acid esterification shifts AA availability to activate AMPK, boosting mitochondrial biogenesis and whole-body energy expenditure. Fasting thus engages an AA-centric sensing pathway that couples lipid storage suppression to enhanced oxidation.
Impact: This study uncovers a previously unrecognized AA–AMPK thermogenic switch governed by BMP4 in brown fat, offering a mechanistic basis for targeting lipid partitioning to enhance energy expenditure.
Clinical Implications: While preclinical, modulating BMP4 or downstream AA–AMPK signaling or FA esterification (e.g., DGAT inhibition) could inform anti-obesity strategies aimed at increasing thermogenesis.
Key Findings
- Fasting reprograms BAT to favor FA esterification/storage enriched in arachidonic acid (AA).
- BAT-specific Bmp4 deletion or DGAT inhibition enhances mitochondrial function and systemic energy expenditure.
- AA activates AMPK, increasing mitochondrial biogenesis and coupling reduced esterification to increased oxidation.
Methodological Strengths
- Time-course metabolic profiling with both genetic (BAT-specific Bmp4 KO) and pharmacologic (DGAT inhibition) perturbations
- Mechanistic linkage of lipid species (AA) to AMPK activation and mitochondrial biogenesis
Limitations
- Preclinical models without human validation limit immediate translational applicability
- Quantitative sample sizes and sex-specific effects were not detailed
Future Directions: Define human BAT AA–AMPK signaling relevance, assess safety/efficacy of DGAT or BMP4 modulation, and explore biomarkers of lipid partitioning for thermogenic response.
Fasting enhances lipolysis in white adipose tissue (WAT), releasing fatty acids (FAs) which are subsequently metabolized through β-oxidation in the liver and brown adipose tissue (BAT). Although BAT is a key site for FA utilization, the specific FAs taken up and oxidized during fasting-as well as their systemic metabolic effects-remain poorly defined. Time-course analysis revealed that fasting reprograms BAT to promote the esterification and storage of circulating FAs rather than their immediate oxidation. This lipid pool was selectively enriched in long-chain polyunsaturated fatty acids (LCPUFAs), particularly arachidonic acid (AA). Genetic (BAT-specific knockout of bone morphogenetic protein 4, Bmp4) or pharmacological (Inhibition of diacylglycerol acyltransferase, DGAT) disruption of this FA esterification process potently enhanced mitochondrial function and systemic energy expenditure. Mechanistically, AA activated AMP-activated protein kinase (AMPK), thereby enhancing energy expenditure through increased mitochondrial biogenesis. Our work reveals a fasting-inducible, AA-centric signaling pathway that senses lipid storage status. Through activation of AMPK, it couples suppressed FA esterification to enhanced oxidation, positioning BMP4 as a critical regulator of this metabolic switch.
2. What Makes the Difference? Predicting Glycemic Trajectories Following Initiation of Automated Insulin Delivery Systems in Youth With Type 1 Diabetes.
Among 713 youth starting AID, four TIR and three HbA1c trajectories were identified: all improved rapidly by 3 months, then plateaued or waned after 6 months. Fewer user-initiated boluses, higher insulin dose/kg, and fewer appointments predicted membership in the lowest TIR group; conversely, higher bolus frequency and lower dose/kg aligned with optimal HbA1c trajectories.
Impact: Provides actionable behavioral and dosing predictors of long-term AID success, informing personalized follow-up intensity and education to sustain early gains.
Clinical Implications: Use baseline bolus frequency and insulin dose/kg to risk-stratify youth at AID initiation, intensify coaching and appointment frequency for low-bolus/high-dose users, and plan reinforcement beyond 6 months when gains tend to wane.
Key Findings
- Identified four distinct TIR and three HbA1c trajectories over 18 months after AID initiation.
- Rapid improvements occurred by 3 months; improvements plateaued or declined after 6 months.
- Fewer boluses, higher insulin dose/kg, and fewer appointments predicted lowest TIR trajectory; more boluses and lower dose/kg predicted optimal HbA1c trajectory.
Methodological Strengths
- Large multicenter cohort (n=713) with 18-month follow-up and repeated measures
- Group-based trajectory modeling with multinomial regression adjusting for key covariates
Limitations
- Observational design limits causal inference on predictors
- Device heterogeneity and unmeasured psychosocial factors may confound trajectories
Future Directions: Test targeted behavioral interventions for low-bolus/high-dose users, evaluate device-specific effects, and assess strategies to sustain gains beyond 6 months.
OBJECTIVE: To identify glycemic trajectories following automated insulin delivery (AID) initiation in youth with type 1 diabetes and associated factors. RESEARCH DESIGN AND METHODS: We used group-based trajectory modeling to characterize groups for time in range (TIR) and hemoglobin A1c (HbA1c), measured at baseline and at 3, 6, 12, and 18 months of AID use, in 713 youth (ages 6-18). Multinomial logistic regression estimated associations between clinical and sociodemographic predictors and glycemic trajectories. RESULTS: Four TIR and three HbA1c trajectories emerged. All trajectories showed rapid improvement from baseline to 3 months, continued but gradual improvement between 3 and 6 months, followed by waning or sustained improvements after 6 months. Only a small subset (group 4, 12.7%) achieved TIR ≥70%, although more (43.3%) reached an HbA1c <7%. In the TIR model after adjusting for age, sex, type 1 diabetes duration, and prior treatment, participants with fewer user-initiated boluses (odds ratio [OR] 2.46; 95% CI 1.78, 3.39), higher insulin doses/kg (OR 1.54; 95% CI 1.25, 1.91), and fewer appointments (OR 2.69; 95% CI 1.21, 6.00) had higher odds of membership in the lowest TIR group (group 1) than in the highest TIR group (group 4). In the HbA1c model, lower baseline insulin doses/kg and more boluses were associated with membership in the most optimal group. CONCLUSIONS: Distinct glycemic trajectories exist following AID initiation, with all groups experiencing rapid early improvements in TIR and HbA1c that plateau or decline over time. Baseline bolus frequency and insulin doses/kg remain key predictors, highlighting the persistent influence of preexisting behaviors and insulin needs on long-term outcomes.
3. GPR180 deficiency impairs mitochondrial function and insulin secretion in pancreatic β-cells.
GPR180 deficiency causes β-cell–autonomous impairment of first-phase insulin secretion by disrupting mitochondrial substrate use, anaplerosis, and ATP generation, with membrane depolarization and reduced respiration, independent of glucose uptake or mitochondrial biogenesis.
Impact: Reveals a previously unrecognized GPCR that couples β-cell mitochondrial competence to insulin secretion, nominating GPR180 as a potential therapeutic target for β-cell dysfunction in diabetes.
Clinical Implications: Targeting GPR180 or its signaling could enhance first-phase insulin secretion in diabetes by restoring β-cell mitochondrial efficiency; biomarker development may stratify patients with impaired β-cell energetics.
Key Findings
- GPR180 loss impairs first-phase insulin secretion and glucose tolerance without altering insulin sensitivity.
- Defects are β-cell–autonomous: confirmed in β-cell–specific knockout mice and MIN6 cells.
- GPR180 regulates mitochondrial substrate utilization, anaplerotic TCA support, and ATP generation; deficiency causes mitochondrial depolarization and reduced oxygen consumption.
Methodological Strengths
- Convergent in vivo (β-cell–specific knockout) and in vitro (MIN6) evidence
- Comprehensive bioenergetic phenotyping linking mitochondrial function to secretion
Limitations
- Ligands and upstream signaling of GPR180 in β-cells remain to be defined
- Human islet validation and translational pharmacology are pending
Future Directions: Identify endogenous/therapeutic ligands of GPR180, validate findings in human islets, and test pharmacologic modulation for restoring first-phase secretion.
OBJECTIVE: G protein-coupled receptor 180 (GPR180) has been implicated in systemic energy metabolism, primarily in adipose tissue and the liver. Given impaired whole-body glucose tolerance following GPR180 dysfunction, we aimed to determine whether GPR180 regulates pancreatic β-cell function. We investigated whether GPR180 contributes to β-cell insulin secretion by modulating metabolic processes that couple glucose sensing to mitochondrial energy production. METHODS: Phenotyping of whole-body (Gpr180 RESULTS: Loss of GPR180 impaired first-phase insulin secretion and glucose tolerance without affecting insulin sensitivity. These defects were β-cell-autonomous, as confirmed in the bGpr180-KO mice and in MIN6 cells. Functional studies revealed that GPR180 regulates mitochondrial substrate utilization, anaplerotic support of the TCA cycle, and ATP generation without affecting glucose uptake or mitochondrial biogenesis. In particular, Gpr180-deficient β cells showed mitochondrial membrane depolarization, reduced oxygen consumption, and endoplasmic reticulum remodeling, altering the local mitochondrial microenvironment. In vivo, Gpr180 deletion in β cells led to downregulation of mitochondrial gene programs in islets, along with altered endocrine cell identity. CONCLUSIONS: GPR180 is a previously unrecognized regulator of pancreatic β-cell metabolic competence and identity, linking defects in insulin secretion with alterations in mitochondrial function and endocrine cell identity.