Daily Endocrinology Research Analysis
Analyzed 99 papers and selected 3 impactful papers.
Summary
Three impactful endocrinology-related studies stood out today: a 10-year randomized comparison of distal versus standard Roux-en-Y gastric bypass in severe obesity, a mechanistic study showing SGLT2 inhibitors induce alpha-to-beta cell regeneration via PPARGC1A, and a population-based cohort linking adolescent-to-adult weight gain trajectories with higher risks of obesity-related and early-onset cancers. Together, they span mechanistic discovery to long-term clinical outcomes and prevention.
Research Themes
- Metabolic and bariatric surgery long-term outcomes
- Beta-cell regeneration mechanisms under SGLT2 inhibition
- Adolescent-to-adult weight trajectories and cancer risk
Selected Articles
1. Sodium-glucose cotransporter 2 inhibitors facilitate cell phenotype conversion of alpha cells through progenitors to beta cells by activating Ppargc1α in diabetic mice.
In diabetic mouse models and human islet systems, SGLT2 inhibitors increased islet and beta-cell areas by driving alpha-cell dedifferentiation to Ngn3+ progenitors and subsequent redifferentiation toward beta cells. Dapagliflozin elevated insulin and active GLP-1 secretion, shifted alpha-cell gene programs toward progenitor/beta-cell markers, and identified PPARGC1A as a required regulator of phenotype conversion.
Impact: This is a rigorous mechanistic study proposing an unexpected regenerative pathway for beta-cell neogenesis under SGLT2 inhibition, with clear translational potential for diabetes therapy.
Clinical Implications: Although preclinical, the findings suggest SGLT2 inhibitors may contribute to beta-cell mass restoration by reprogramming alpha cells via PPARGC1A, supporting trials that test combinatorial strategies (e.g., SGLT2i plus agents targeting PPARGC1A/PGC-1α) for disease modification.
Key Findings
- SGLT2 inhibitors increased islet and beta-cell areas in T2D mice and showed similar trends in T1D mice.
- Alpha cells dedifferentiated to Ngn3+ progenitors and then differentiated toward beta cells under SGLT2 inhibition.
- Dapagliflozin increased insulin and active GLP-1 release, downregulated alpha-cell markers, and upregulated progenitor/beta-cell markers; PPARGC1A was required for alpha-to-beta phenotype conversion.
Methodological Strengths
- Use of lineage-tracing mouse models (Ngn3+ progenitors and alpha-cell lineages) to establish cellular origins
- Cross-validation in mouse and human islets with RNA sequencing and functional secretion assays
Limitations
- Preclinical nature limits direct clinical generalizability; dosing and exposure may not mirror human pharmacokinetics
- Direct effects on beta cells were not observed; long-term safety and durability of reprogramming remain unknown
Future Directions: Initiate translational studies to test whether SGLT2 inhibitors, alone or combined with PPARGC1A modulators, promote beta-cell regeneration in humans; evaluate durability, safety, and glycemic durability in early-phase trials.
BACKGROUND: Sodium-glucose cotransporter 2 inhibitor (SGLT2i) improves beta-cell function in animals and humans with diabetes. Herein, we aimed to investigate the effects of SGLT2i on beta-cell regeneration, trace the origin of regenerated beta cells, and reveal the potential mechanism. METHODS: Type 2 and type 1 diabetic mice were treated with canagliflozin (10 mg/kg), dapagliflozin (1 mg/kg), or vehicle. Islet morphology was evaluated to investigate beta-cell regeneration. Inducible pancreatic neurogenin 3 (Ngn3)+ progenitor lineage-tracing mice and alpha-cell lineage-tracing mice were used to trace the origin of regenerated cells. Mouse and human islets, alpha cells, and beta cells were incubated with dapagliflozin (12.5 μmol/L) or vehicle. Insulin and glucagon-like peptide-1 (GLP-1) release, gene expression, and RNA sequencing analysis were performed to clarify the direct actions of SGLT2i and to screen potential targets. Alpha cells were transfected with peroxisome proliferator-activated receptor-γ coactivator 1α (Ppargc1α) plasmid or with Ppargc1α siRNA, followed by incubati
2. Effect of standard versus long alimentary limb distal Roux-en-Y gastric bypass on weight loss and nutritional outcomes at 10 years in patients with BMI 50-60 kg/m2-a secondary analysis of a randomized clinical trial.
At 10 years, distal long-alimentary-limb RYGB produced greater BMI and total weight loss than standard RYGB in patients with BMI 50–60 kg/m2, but it was associated with more malnutrition, diarrhea, and vitamin D deficiency, and all observed deaths occurred in the distal group. Cardiometabolic disease prevalence and HRQOL were similar between groups.
Impact: This long-term randomized comparison directly informs limb-length choices in bariatric surgery for severe obesity by balancing superior weight loss against higher nutritional risks.
Clinical Implications: For BMI 50–60 kg/m2, distal long-alimentary-limb RYGB can be considered for enhanced long-term weight loss, but requires intensified nutritional monitoring, vitamin D supplementation, and readiness for revisional surgery in malnutrition cases.
Key Findings
- Distal RYGB achieved greater 10-year BMI reduction (14.7 vs 12.0 kg/m2) and total weight loss (28.2% vs 23.0%) than standard RYGB.
- Higher rates of malnutrition, diarrhea, and vitamin D deficiency occurred after distal RYGB; four revisional surgeries for malnutrition were needed.
- All observed deaths (3.5% overall) occurred in the distal RYGB group; cardiometabolic disease prevalence and HRQOL did not differ at 10 years.
Methodological Strengths
- Randomized comparison with 10-year follow-up in a severe obesity cohort
- Comprehensive assessment of weight, nutritional outcomes, comorbidities, and HRQOL
Limitations
- Secondary analysis with 69.9% follow-up at 10 years; potential attrition bias
- Single-country, two-center trial may limit generalizability; not blinded
Future Directions: Define patient selection criteria optimizing benefit-risk for distal limb lengthening, and standardize postoperative nutritional surveillance and supplementation protocols to mitigate malnutrition.
OBJECTIVE: Identifying the optimal metabolic bariatric surgery approach for patients with severe obesity with a BMI ≥50 kg/m2 remains challenging. The aim of this long-term follow-up of a randomized clinical trial (RCT) was to compare distal long alimentary limb Roux-en-Y gastric bypass (RYGB) with standard RYGB for 10-year weight loss and nutritional outcomes. METHOD: Secondary analysis of a 10-year follow-up of an RCT with initially 113 patients (BMI 50-60 kg/m2) randomized to either standard (n = 57, 50 cm biliopancreatic/150 cm alimentary limb) or distal long alimentary limb RYGB (n = 56, 50 cm biliopancreatic/150 cm common limb) from March 2011 to April 2013 at two Norwegian hospitals. The final data collection date was 15 August 2023. The primary focus was weight loss (BMI reduction, %total weight loss) and other secondary outcomes included cardiometabolic risk factors, nutritional status, and health-related quality of life (HRQOL). RESULTS: Of 113 patients, 79 (69.9%, mean age 50 (s.d. 8.7) years, 50 (63%) females) patients were available for 10-year follow-up (41 standard RYGB, 38 distal RYGB). The 10-year mortality rate was 3.5% (4/113) and all deaths occurred after distal RYGB. One death may have been associated with the surgery in a patient with previously undiagnosed liver cirrhosis at the time of operation. Mean BMI reduction from baseline was 12.0 kg/m2 (95% c.i., 10.8 to 13.2) after standard RYGB and 14.7 kg/m2 (95% c.i., 13.5 to 15.9) after distal RYGB with a between-group difference of 2.7 kg/m2 (95% c.i., 1.0 to 4.5, P = 0.002). The mean percentage total weight loss from baseline was 23.0% (95% c.i., 20.8 to 25.2) after standard RYGB and 28.2% (95% c.i., 26.0 to 30.5) after distal RYGB, with a between-group difference of 5.3% (95% c.i., 2.1 to 8.4, P = 0.001). The distal RYGB group had higher rates of malnutrition (1/57 standard versus 5/56 distal; P = 0.12), diarrhoea (7/57 standard versus 15/56 distal; P = 0.05), and vitamin D deficiency (24/41 standard versus 32/38 distal; P = 0.01). There were no differences between the groups in the prevalence of type 2 diabetes, hypertension, dyslipidaemia, or metabolic syndrome at 10-year follow-up. Four patients underwent revisional surgery due to malnutrition after distal RYGB. There were no statistically significant differences in HRQOL scores between the groups at 10 years (SF-36 physical 44.2 versus 44.1, mental 50.3 versus 47.3; OWLQOL 63 versus 61; all P > 0.2). CONCLUSIONS: Distal long alimentary limb RYGB resulted in greater weight loss after 10 years with a higher risk of malnutrition, diarrhoea, and vitamin D deficiency. TRIAL REGISTRATION: Clinicaltrials.gov NCT00821197.
3. Adolescent to adulthood weight trajectories and the risk of obesity-related cancers, overall and early-onset: a population-based cohort study.
Across 800,024 individuals with 7.6 million person-years, persistent or rising weight from adolescence to adulthood increased risks of obesity-related cancers overall and before age 55. Each 5% weight gain raised hazards by ~3%, with site-specific increases notably for uterine, kidney, thyroid, colorectal, and postmenopausal breast cancers.
Impact: This large, well-powered cohort clarifies trajectory-dependent cancer risk, reinforcing early-life weight management as a cancer prevention strategy and informing risk stratification.
Clinical Implications: Clinicians should emphasize sustained weight management beginning in adolescence to mitigate risks of obesity-related and early-onset cancers; trajectory-informed counseling may refine screening priorities for high-risk individuals.
Key Findings
- Compared with lean-to-lean trajectories, lean-to-high and high-to-high trajectories had higher risks of obesity-related cancers (HR 1.31 and 1.47, respectively).
- Each 5% weight gain was associated with a 3% increase in overall and early-onset obesity-related cancer risk.
- Cancer-specific risk increases were observed for uterine (8% per 5% weight gain), kidney (5%), thyroid (4%), colorectal (3%), and postmenopausal breast cancer (3%).
Methodological Strengths
- Very large population-based cohort with measured BMI in adolescence and adulthood and long follow-up
- Trajectory classification and site-specific cancer analyses with adjusted hazard models
Limitations
- Observational design susceptible to residual confounding (diet, physical activity, socioeconomic factors)
- Potential misclassification due to varying intervals between BMI measurements and changes in healthcare access over decades
Future Directions: Integrate lifestyle and genetic data to refine trajectory-based risk models; test whether early, sustained weight interventions reduce early-onset cancer incidence in pragmatic trials.
BACKGROUND: High body mass index (BMI) is a modifiable cancer risk factor, projected to surpass smoking as the leading preventable risk factor. The impact of weight change from late adolescence to adulthood on cancer risk remains unclear. We aimed to assess the association between adolescence-to-adulthood BMI trajectories and obesity-related cancer risk. METHODS: A population-based cohort study of 800,024 people (45.1% women) insured by a large state-mandated health provider. BMI was measured during military pre-recruitment evaluations during 1967-2018 in adolescence and in subsequent clinic visits in adulthood during 1998-2020. Follow-up began one year after an adult BMI measurement until cancer diagnosis, death, transfer to another health provider, or December 16, 2021. BMI trajectories from adolescence to adulthood were classified as lean-to-lean, lean-to-high, high-to-lean, and high-to-high (cutoff: sex-specific and age-specific 85th percentile in adolescence, defined according to the United States Centers for Disease Control and Prevention growth charts, and 25 kg/m FINDINGS: During 7,610,263 person-years, 6,376 people were diagnosed with obesity-related cancers, at a mean age of 53.3 ± 9.8 years. Adjusted hazard ratios (HRs) were 1.31 (95% confidence interval [CI], 1.24-1.39) for lean-to-high, 1.01 (95% CI, 0.78-1.31) for high-to-lean, and 1.47 (95% CI, 1.34-1.61) for high-to-high groups, compared to the lean-to-lean group. Respective HRs for early-onset obesity-related cancers were 1.33 (95% CI, 1.20-1.47), 0.88 (95% CI, 0.60-1.31), and 1.39 (95% CI, 1.20-1.61). Each 5% weight gain conferred a 3% increased hazard (95% CI, 1.02-1.03), with a similar 3% increase for early-onset cancers (95% CI, 1.02-1.04). Cancer-specific risks included 3% (95% CI, 1.02-1.04) for postmenopausal breast cancer, 3% (95% CI, 1.01-1.04) for colorectal cancer, 4% (95% CI, 1.02-1.05) for thyroid cancer, 5% (95% CI, 1.04-1.07) for kidney cancer, and 8% (95% CI, 1.06-1.09) for uterine cancer. Some cancers, including leukemia and non-Hodgkin's lymphoma, were not associated with weight gain but were positively associated with high adolescent BMI. INTERPRETATION: Maintaining a healthy BMI from adolescence to adulthood may reduce obesity-related cancer risk, including early-onset, highlighting the importance of early weight management strategies. FUNDING: Novo Nordisk, Israel.