Daily Endocrinology Research Analysis
Today’s top endocrinology papers span basic-to-clinical translation: a Nature Metabolism study uncovers a redox-dependent hepatic switch that prioritizes lactate or glycerol for gluconeogenesis and differentially supports high- vs. low-intensity exercise; a randomized trial shows a stepped-care, incentives-enhanced diabetes prevention program reduces incident diabetes over 3 years; and a large multi-ancestry GWAS identifies four loci associated with hypoglycemia risk in medication-treated diabet
Summary
Today’s top endocrinology papers span basic-to-clinical translation: a Nature Metabolism study uncovers a redox-dependent hepatic switch that prioritizes lactate or glycerol for gluconeogenesis and differentially supports high- vs. low-intensity exercise; a randomized trial shows a stepped-care, incentives-enhanced diabetes prevention program reduces incident diabetes over 3 years; and a large multi-ancestry GWAS identifies four loci associated with hypoglycemia risk in medication-treated diabetes, with context-specific effects by therapy and diabetes type.
Research Themes
- Redox regulation of hepatic gluconeogenesis and exercise metabolism
- Behavioral economics and stepped-care in diabetes prevention
- Pharmacogenomics of hypoglycemia risk in diabetes
Selected Articles
1. Redox-dependent liver gluconeogenesis impacts different intensity exercise in mice.
Using liver-specific knockout mice, the authors demonstrate a redox-dependent hepatic “switch” that prioritizes lactate- versus glycerol-driven gluconeogenesis and differentially supports high- versus low-intensity exercise. Loss of Pck1 impairs high-intensity performance but enhances low-intensity capacity via glycerol gluconeogenesis, whereas loss of Gyk yields the opposite phenotype. The compensatory substrate shift depends on NAD redox balance.
Impact: This study uncovers a previously unrecognized hepatic redox-dependent mechanism that links substrate selection in gluconeogenesis to specific exercise capacities, advancing fundamental metabolic physiology with translational implications for exercise and metabolic disease management.
Clinical Implications: Insights into hepatic redox control of substrate use may inform personalized exercise prescriptions (e.g., targeting lactate vs. glycerol pathways) and therapeutic strategies that modulate hepatic redox state to optimize performance or glycemic control in metabolic diseases.
Key Findings
- Liver-specific Pck1 knockout decreased high-intensity exercise capacity but increased low-intensity capacity via enhanced glycerol-derived gluconeogenesis.
- Liver-specific Gyk knockout produced the opposite effect, enhancing lactate-driven gluconeogenesis and high-intensity performance while impairing low-intensity capacity.
- The compensatory switch between lactate and glycerol gluconeogenesis is dependent on NAD redox balance.
Methodological Strengths
- In vivo mechanistic dissection using complementary liver-specific knockout models (Pck1 and Gyk).
- Phenotype-function linkage through direct exercise capacity testing aligned with metabolic pathway manipulation.
Limitations
- Mouse model findings require validation in humans to confirm translational relevance.
- Detailed quantification of redox intermediates and tissue-specific contributions beyond liver were not fully elaborated in the abstract.
Future Directions: Test whether modulating hepatic NAD redox state or substrate availability can enhance targeted exercise performance and improve glycemic control in humans with metabolic disease.
Hepatic gluconeogenesis produces glucose from various substrates to meet energy demands. However, how these substrates are preferentially used under different conditions remains unclear. Here, we show that preferential supplies of lactate and glycerol modulate hepatic gluconeogenesis, thereby impacting high-intensity and low-intensity exercise capacities, respectively. We find that liver-specific knockout of phosphoenolpyruvate carboxykinase 1 (L-Pck1KO), which blocks gluconeogenesis from lactate, decreases high-intensity exercise capacity but increases low-intensity exercise capacity by enhancing gluconeogenesis from glycerol. Conversely, liver-specific knockout of glycerol kinase (L-GykKO), which inhibits glycerol-derived gluconeogenesis, induces the opposite effects by enhancing gluconeogenesis from lactate. Given that these compensatory steps depend on NAD
2. Effectiveness of an Incentives-Enhanced Stepped Care Intervention Program in Diabetes Prevention in a Multiethnic Asian Prediabetes Cohort: Results From the Pre-DICTED Randomized Controlled Trial.
In a 751-participant RCT of a multiethnic prediabetes cohort, an incentives-enhanced stepped-care program (lifestyle first, add metformin for persistent high risk) reduced 3-year diabetes incidence from 47.3% to 34.8% (adjusted RR 0.74). About one-quarter received metformin and nearly half received cash incentives; adverse events were mainly metformin-related GI symptoms.
Impact: Provides high-quality, pragmatic evidence that combining behavioral economics with stepped pharmacotherapy meaningfully reduces diabetes conversion in real-world multiethnic settings.
Clinical Implications: Health systems could implement incentives-enhanced stepped-care pathways for prediabetes, starting with structured lifestyle programs and adding metformin for persistent high risk, to improve prevention outcomes.
Key Findings
- Three-year diabetes incidence was reduced from 47.3% (control) to 34.8% (intervention); adjusted RR 0.74 (95% CI 0.62–0.88).
- 26.4% of intervention participants escalated to metformin; 45.1% received cash incentives tied to session attendance and ≥5% weight loss.
- Adverse events were more frequent in the intervention arm, predominantly metformin-related gastrointestinal symptoms.
Methodological Strengths
- Randomized controlled design with modified intention-to-treat analysis over 3 years.
- Pragmatic stepped-care framework reflecting real-world escalation from lifestyle to pharmacotherapy with predefined criteria.
Limitations
- Adverse events and adherence dynamics may partly reflect metformin tolerability rather than the incentives per se.
- Generalizability beyond Singapore’s healthcare context and incentive structures requires evaluation.
Future Directions: Assess cost-effectiveness, scalability, and optimal incentive structures across diverse health systems, and evaluate long-term cardiometabolic outcomes beyond diabetes incidence.
OBJECTIVE: Diabetes prevention in real-world settings is affected by the challenge of intervention adherence and difficulty in sustaining behavior change. This study evaluated the effectiveness of a stepped care prevention program, enhanced with financial incentives, in reducing the risk of diabetes conversion in a multiethnic prediabetes cohort in Singapore. RESEARCH DESIGN AND METHODS: The Pre-Diabetes Interventions and Continued Tracking to Ease Out Diabetes (Pre-DICTED) trial was a randomized controlled trial involving 751 overweight or obese individuals with impaired glucose tolerance, impaired fasting glucose, or both. Participants were assigned to standard care (control arm) or a stepped care intervention program, starting with lifestyle interventions for 6 months before adding metformin for participants who remained at high risk of diabetes conversion based on study visit assessments. Intervention arm participants also received financial incentives for attending lifestyle sessions and for achieving ≥5% weight loss. The primary end point was the proportion of participants developing diabetes at 3 years in the modified intention-to-treat population. RESULTS: After 3 years, 34.8% of participants in the intervention arm developed diabetes compared with 47.3% in the control arm (adjusted risk difference -10.93%; 95% CI -18.04 to -3.81; P = 0.003). The adjusted relative risk was 0.74 (95% CI 0.62-0.88; P < 0.001). In the intervention arm, 26.4% of participants received metformin, and 45.1% received cash incentives. Adverse events were more common in the intervention arm, mainly because of metformin-related gastrointestinal symptoms. CONCLUSIONS: A stepped care diabetes prevention program, enhanced with financial incentives, effectively reduced diabetes conversion in a multiethnic Asian prediabetes cohort.
3. Genome-Wide Association Study of Hypoglycemia in Adults With Diabetes in the Million Veteran Program.
A multi-ancestry GWAS in >105,000 medication-treated adults with diabetes identified four loci (SIX2/SIX3, HLA-DQB1/DQA2, TCF7L2, SLC16A11) associated with hypoglycemia, replicated in UK Biobank and ACCORD. Effects varied by diabetes type and therapy exposure (e.g., sulfonylureas vs. insulin), highlighting pharmacogenomic context.
Impact: Identifies common genetic variants tied to hypoglycemia risk in treated diabetes across ancestries with replication, laying groundwork for precision risk stratification and safer therapy selection.
Clinical Implications: Genetic information could augment risk assessment for hypoglycemia, informing choice and dosing of insulin or sulfonylureas, and monitoring strategies in high-risk genotypes.
Key Findings
- Four loci (rs12712928 SIX2/SIX3; rs1064173 HLA-DQB1/DQA2; rs35198068 TCF7L2; rs113748381 SLC16A11) reached genome-wide significance for hypoglycemia.
- Replication in independent cohorts (UK Biobank and ACCORD) supported robustness.
- Context-specific associations: chromosome 2 locus with sulfonylurea exposure; chromosome 6 locus with insulin exposure; one chr6 signal specific to likely type 1 diabetes.
Methodological Strengths
- Large multi-ancestry sample with stratified GWAS and meta-analysis.
- Independent replication and medication-stratified secondary analyses.
Limitations
- Phenotype definition based on EHR glucose values and ED visits may introduce misclassification.
- Observational genetic associations cannot infer causality or clinical utility without prospective validation.
Future Directions: Prospective studies integrating genotype into clinical decision support to test whether therapy tailoring by risk alleles reduces hypoglycemia without compromising glycemic control.
UNLABELLED: Hypoglycemia is a preventable adverse treatment effect in diabetes patients, but genetic markers to identify those with increased susceptibility are lacking. We performed a case/control genome-wide association study (GWAS) of hypoglycemia in U.S. Million Veteran Program (MVP) participants with medication-treated diabetes. Case participants had an outpatient random serum/plasma glucose <70 mg/dL or an emergency department visit for hypoglycemia. GWAS was stratified by race/ethnicity, adjusted for age at MVP enrollment, sex, and top 10 population-specific principal components, followed by multipopulation meta-analysis. Secondary analyses examined genetic associations with hypoglycemia stratified by diabetes medication exposure as well as replication in UK Biobank and the Action to Control Cardiovascular Risk in Diabetes clinical trial. The study included 72,244 (22,045 case participants) non-Hispanic White participants, 24,162 (10,441 case participants) non-Hispanic Black participants, and 9,196 (2,800 case participants) Hispanic participants. Four loci had genome-wide significant associations with hypoglycemia in multipopulation meta-analysis: rs12712928 (chromosome 2, SIX2/SIX3 locus), rs1064173 (chromosome 6, HLA-DQB1/DQA2 locus), rs35198068 (chromosome 10, TCF7L2 locus), and rs113748381 (chromosome 17, SCL16A11 locus). All four loci replicated in at least one independent cohort, and the magnitude of associations with hypoglycemia varied by diabetes type. Genome-wide analyses may complement candidate pharmacogenetic studies to identify risk markers of adverse drug effects. ARTICLE HIGHLIGHTS: Genetic variants associated with hypoglycemia risk in individuals with medication-treated diabetes have not been evaluated genome-wide. The specific question we asked was whether common genetic variants are associated with hypoglycemia among individuals with diabetes treated with glucose-lowering medications. We found four genomic loci were associated with hypoglycemia in a genome-wide association study. One locus-on chromosome 6-was associated with hypoglycemia only in individuals with likely type 1 diabetes, and two loci-on chromosome 2 and chromosome 6-were associated with hypoglycemia only in the context of treatment with sulfonylureas (chromosome 2) or with insulin (chromosome 6). Genetic variants may help identify individuals with diabetes at increased hypoglycemia risk, but additional study is needed to address the clinical utility of genetic data to inform hypoglycemia risk.