Daily Endocrinology Research Analysis
Analyzed 32 papers and selected 3 impactful papers.
Summary
Mechanistic work identifies intestinal aPKC/GLUT1 activation as a driver of glucose excretion, nominating a druggable pathway for diabetes and weight loss. A small randomized trial shows algorithmic CGM-based basal insulin titration markedly improves time-in-range versus SMBG-guided titration. Preclinical data reveal the brown fat–derived lipid 12,13-diHOME ameliorates MASLD via Sestrin2-dependent AMPK/ULK1-mediated lipophagy.
Research Themes
- Mechanism-guided metabolic therapeutics
- Algorithmic and remote glycemic management
- Adipose–liver crosstalk and lipophagy in MASLD
Selected Articles
1. Atypical protein kinase C activation drives intestinal glucose excretion in diabetes mellitus.
This mechanistic study shows that activating atypical PKC in the intestine drives GLUT1-mediated uptake of circulating glucose and its secretion into the lumen, recapitulating intestinal glucose excretion. Pharmacologic activation with prostratin replicated the effect without oncogenic proliferation, nominating the aPKC/GLUT1 axis as a therapeutic target for diabetes and weight loss.
Impact: It uncovers a previously unrecognized, druggable intestinal pathway controlling systemic glucose disposal with direct translational potential.
Clinical Implications: Targeted activation of intestinal aPKC/GLUT1 could be explored to lower glycemia and body weight; however, human safety, dose, and long-term metabolic effects require rigorous clinical evaluation.
Key Findings
- PKC activation reproduced transcriptomic signatures of intestinal glucose excretion.
- Atypical PKC (aPKC) facilitated GLUT1-mediated intestinal glucose excretion without inducing proliferative signals.
- Genetic activation of intestinal aPKC increased serum glucose uptake into tissue and excretion into the lumen.
- Prostratin activated aPKC and induced intestinal glucose excretion, highlighting a druggable pathway.
Methodological Strengths
- Convergent validation across transcriptomics, genetic activation, and pharmacologic modulation.
- In vivo intestinal targeting with non-tumorigenic activation of aPKC minimizing proliferative risk.
Limitations
- Entirely preclinical with no human intervention data.
- Long-term metabolic, microbiome, and safety consequences of sustained intestinal glucose excretion are unknown.
Future Directions: First-in-human studies of intestinal aPKC modulators (e.g., prostratin analogs), dose–response and safety profiling, and biomarker development to monitor intestinal glucose flux.
Intestinal glucose excretion, defined as increased intestinal serum glucose uptake and secretion into the lumen, influences bariatric surgery-associated glycaemic control. Here, we investigate molecular mechanisms that activate intestinal glucose excretion. We evaluate altered transcriptomes in variable intestinal glucose excretion models and big data-based drug discovery systems. We show that protein kinase C (PKC) activation mimics transcriptome alterations observed during intestinal glucose excretion. Among PKC subfamilies, atypical PKC (aPKC) facilitates glucose transporter 1 (GLUT1)-mediated intestinal glucose excretion without inducing oncogenic proliferation. Intestinal aPKC activation via transposon expression vector induces serum glucose uptake into intestinal tissues and excretion into the lumen. Prostratin, a non-tumorigenic phorbol ester, activates aPKC and induces a similar effect on intestinal glucose excretion. We identify the prostratin and aPKC/GLUT1 signalling pathways as putative targets for treating diabetes, providing insights into the future development of antidiabetic and weight-loss drugs.
2. Safety and Feasibility of Algorithmic Continuous Glucose Monitoring-Based Titration in People with Type 2 Diabetes Using Insulin Degludec, With or Without Noninsulin Glucose-Lowering Drugs: A 16-Week Randomized Controlled Trial.
In a 16-week, two-site randomized trial (n=30), weekly algorithmic CGM-based titration of insulin degludec increased time-in-range from 54.1% to 75.3% versus 50.2% to 55.3% with SMBG-based titration, with an estimated treatment difference of +14.6 percentage points. The intervention was feasible, safe, and improved overall glycemic metrics.
Impact: Provides randomized evidence that standardized, algorithmic CGM-guided basal insulin titration can substantially improve glycemic control versus SMBG-guided approaches.
Clinical Implications: Health systems could implement remote, CGM-guided algorithmic titration workflows to accelerate basal insulin optimization while maintaining safety; larger pragmatic trials should validate scalability and long-term outcomes.
Key Findings
- Algorithmic CGM-based titration increased TIR by +20.3%-points versus +8.3%-points with SMBG-based titration.
- The estimated treatment difference in TIR was +14.6%-points, meeting noninferiority criteria and suggesting superiority.
- Intervention was feasible and safe with favorable overall glycemic metrics over 16 weeks.
Methodological Strengths
- Randomized, registered trial with CGM-derived objective endpoints.
- Standardized algorithm and centralized weekly dose notifications across two sites.
Limitations
- Small sample size (n=30) and open-label design limit generalizability.
- Short duration (16 weeks) without hard clinical outcomes or cost-effectiveness data.
Future Directions: Conduct larger, pragmatic multicenter RCTs testing scalability, hypoglycemia risk, patient-reported outcomes, and cost-effectiveness of CGM-guided algorithmic titration.
BACKGROUND: Continuous glucose monitoring (CGM) is increasing in insulin-treated type 2 diabetes (T2D). Yet, standardized CGM-based insulin titration is lacking. This study evaluated the feasibility of algorithmic CGM-based titration compared with self-monitoring blood glucose (SMBG) titration. METHODS: We conducted a 16-week, two-site, randomized controlled trial in adults with T2D (glycated hemoglobin 7%-9%) using degludec and adjunctive noninsulin agents, without rapid-acting insulin. Participants were assigned (2:1) to weekly algorithmic CGM-based dose changes with open CGM (EXP) or weekly SMBG-based titration with blinded CGM (CTR). Both groups received dose notifications via phone. The primary endpoint was the change in CGM-measured time in range (TIR, 70-180 mg/dL) from baseline to week 16, tested for noninferiority (-5%-percentage points [%-pt]). The trial is registered at ClinicalTrials.gov: NCT06111508. RESULTS: A total of 30 participants were randomized. Mean (standard deviation) TIR increased from 54.1% (22.5%) to 75.3% (19.3%) in EXP and from 50.2% (22.1%) to 55.3% (22.7%) in CTR. Mean change was +20.3%-pt versus +8.3%-pt, yielding an estimated treatment difference (EXP - CTR) of +14.6%-pt; one-sided 95% confidence interval (CI) lower bound was +4.0%-pt, exceeding the noninferiority margin ( CONCLUSIONS: Using CGM and receiving algorithmic CGM-based titrations were feasible, safe, and had favorable overall glycemic metrics. Long-term impact should be confirmed in broader populations.
3. 12,13-diHOME ameliorates MASLD by regulating Sestrin2-mediated AMPK/ULK1/Lipophagy in obese mice.
In obese mice, the brown fat–derived lipid 12,13-diHOME improved insulin sensitivity, reduced circulating lipids, and alleviated steatosis and fibrosis by enhancing lipophagy via Sestrin2-dependent AMPK/ULK1 activation and mTOR inhibition. Loss of benefit in Sesn2-deficient mice and cells confirms pathway dependence.
Impact: Elucidates an adipose–liver signaling axis and validates a tractable lipophagy pathway with clear therapeutic potential for MASLD.
Clinical Implications: Pharmacologic augmentation of Sestrin2–AMPK/ULK1-mediated lipophagy or 12,13-diHOME analogs may offer a novel therapy for MASLD; translation will require dose, safety, and efficacy studies in humans.
Key Findings
- 12,13-diHOME improved insulin sensitivity and reduced plasma triglycerides and free fatty acids in HFD-fed mice.
- Hepatic steatosis and fibrosis were alleviated via enhanced lipophagy with increased Sestrin2 and AMPK/ULK1 activation and suppressed mTOR phosphorylation.
- Protective effects were abolished in Sestrin2-deficient mice and cells, demonstrating pathway dependence.
Methodological Strengths
- Use of Sesn2 knockout and wild-type controls enables causal inference for pathway dependence.
- Comprehensive phenotyping (metabolic parameters, histology, and pathway proteins) strengthens mechanistic validity.
Limitations
- Findings are limited to mouse models and cell systems with uncertain human translatability.
- Dosing, pharmacokinetics, and off-target effects of 12,13-diHOME were not fully characterized.
Future Directions: Evaluate 12,13-diHOME analogs or Sestrin2 agonists in large animal models and early-phase clinical trials, including biomarkers of lipophagy and liver histologic endpoints.
Obesity-driven metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by hepatic lipid accumulation and impaired lipid metabolism. Enhancing lipophagy, the autophagic degradation of lipid droplets, represents a promising therapeutic strategy. Sestrin2, a stress-responsive protein, promotes lipophagy via the AMPK/ULK1 pathway. Here, we investigated the role of 12,13-diHOME, a brown adipose tissue-derived lipid, in modulating MASLD via Sestrin2. Male Sesn2 knockout and wild-type mice were fed a high-fat diet (HFD) and treated with 12,13-diHOME. Metabolic parameters, liver histology, and lipophagy-related protein expression were analyzed. 12,13-diHOME improved insulin sensitivity, reduced plasma triglycerides and free fatty acids, and alleviated hepatic steatosis and fibrosis by enhancing lipophagy in wild-type mice. Mechanistically, 12,13-diHOME increased Sestrin2 expression, activated AMPK/ULK1 signaling, inhibited mTOR phosphorylation, and enhanced lipophagic degradation of lipid droplets. These effects were abolished in Sesn2-deficient mice and cells, demonstrating that Sestrin2 is essential for 12,13-diHOME's protective actions. Our findings identify 12,13-diHOME as a potential therapeutic agent for MASLD via Sestrin2-mediated lipophagy.