RARE DISEASE
Gluconeogenesis disorder
Gluconeogenesis disorder
Gluconeogenesis disorder
Drug discovery
0
drugs
With orphan designations
Overview
Gluconeogenesis disorders are rare inborn errors of metabolism caused by deficiencies in enzymes critical for glucose production, including pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-1,6-bisphosphatase, and glucose-6-phosphatase [1][11][16]. These defects impair fasting glucose homeostasis, leading to hypoglycemia, lactic acidosis, hepatomegaly, and secondary metabolic disturbances such as hypertriglyceridemia and hyperuricemia [1][4][17]. Long-term complications include growth retardation, hepatocellular adenomas, renal dysfunction, and neurologic sequelae from recurrent hypoglycemia [4][17][19].
Burden
High morbidity due to lifelong dietary restrictions, recurrent hospitalizations, and risks of hepatic/renal failure, hepatocellular carcinoma, and neurodevelopmental impairment [4][17][19]. Poor adherence to strict regimens exacerbates metabolic crises, while psychosocial challenges impact quality of life [19].
Therapies
Frequent carbohydrate meals and nocturnal uncooked cornstarch/Glycosade® to prevent hypoglycemia [3][4][17].
Allopurinol for hyperuricemia, lipid-lowering agents, and granulocyte colony-stimulating factor (G-CSF) for neutropenia in GSD Ib [11][12][19].
Emerging therapies include hepatic-targeted gene therapy (e.g., DTX401) and mRNA-based enzyme replacement [3][8].
Categories: rare genetic diseases, rare inborn errors of metabolism
Research Papers
503 drug discovery papers about Gluconeogenesis disorder, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
503 drug discovery papers about Gluconeogenesis disorder, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-11 | High-Protein Diet Ameliorates Cardiomyopathy in a Cardiac-Specific AGL Knockout Mouse Model: Association With Upregulated Hepatic Gluconeogenesis.
Glycogen storage disease type IIIa (GSDIIIa) causes progressive cardiomyopathy, and current high-fat dietary strategies lack consensus regarding long-term cardiovascular safety. We evaluated the efficacy and safety of high-protein versus high-fat diets in a novel cardiac-specific AGL knockout (CKO; AGLflox/flox/MHC-Cre) mouse model to specifically assess isolated cardiac responses. CKO mice were randomized at weaning to High-Protein (HPD), High-Protein High-Fat (HPHFD), or Low-Protein (LPD) diets, with approximate protein/fat/carbohydrate distributions of 40%/4%/50%, 40%/50%/10%, and 10%/4%/80%, respectively; CKO mice on normal diet (ND) and AGLflox/flox mice served as controls. Cardiac phenotypes and hepatic gluconeogenic enzymes were evaluated longitudinally up to 24 weeks. CKO-ND mice developed progressive cardiomyopathy with elevated myocardial glycogen at 24 weeks (32.01 ± 3.22 vs. 5.90 ± 2.21 mg/g in controls, p < 0.001), reduced left ventricular ejection fraction, and elevated serum creatine kinase. Both HPD and HPHFD significantly reduced myocardial glycogen burden (12.82 ± 3.58 and 15.07 ± 4.40 mg/g, p < 0.001), restored systolic function, and normalized hypertrophy. However, HPHFD induced distinct hyperlipidemia, whereas HPD maintained a stable lipid profile. Furthermore, therapeutic benefits in high-protein groups were associated with upregulated hepatic rate-limiting gluconeogenic enzymes (FBP2, PCK1). In this cardiac-specific AGL knockout model, a high-protein, non-high-fat diet attenuated cardiac glycogen accumulation and systolic dysfunction without the hyperlipidemia observed with the high-fat regimen. These preclinical findings support further evaluation of high-protein dietary strategies for GSDIIIa cardiomyopathy and suggest a possible liver-heart metabolic axis involving hepatic gluconeogenesis.
2026-08-04 | Hepatic Neu1 deficiency drives metabolic dysregulation via GCGR desialylation-dependent cAMP-PKA signaling and inflammatory response in old mice.
Neuraminidase 1 (Neu1) plays a crucial role in the removal of sialic acid from glycoproteins and glycolipids, significantly influencing hepatic glycolipid metabolism. However, its precise contributions to liver gluconeogenesis and bile acid metabolism are not well defined. Although the sialylation of the hepatic glucagon receptor (GCGR) has been linked to the regulation of hepatic glucose homeostasis, the impact of Neu1 on hepatic gluconeogenesis through the desialylation of GCGR remains to be elucidated. To explore the physiological function of Neu1 in liver glycolipid metabolism, we constructed liver-specific Neu1 knockout mice. Glucagon induced HepG2 cells were used to assess the role of Neu1 in gluconeogenesis. Phenotypic analysis indicated that these knockout mice exhibited a late-onset glycolipid metabolism disorder. Mechanistically, Neu1 deficiency caused the upregulation of key gluconeogenic genes, with cAMP-PKA signaling and the sialylation mediated activation of GCGR influencing the Akt-FoxO1 pathway, contributing to the disruption of hepatic glucose metabolism in 21-month-old Neu1 deficient mice. Transcriptomic analysis revealed an increase in lipogenesis and bile acid synthesis pathways in the livers of aged Neu1 knockout mice. Notably, there were significant alterations in steroid hormone biosynthesis, with elevated levels of lithocholic acid and allolithocholic acid detected in the Neu1 deficient mice. Additionally, the activation of inflammatory responses and reduced lipolysis seemed to correlate with the observed abnormalities in glycolipid metabolism. These results indicate that Neu1 is essential for GCGR-dependent gluconeogenesis, suggesting that Neu1 could be a potential therapeutic target for addressing hepatic glycolipid metabolism disorders associated with aging.
2026-08-03 | Metformin's disruption of gluconeogenesis in type 2 diabetes impairments of the cori and alanine cycles as hidden drivers of metabolic waste accumulation, NF-κBHIF-1α-mediated low-grade inflammation, and multisystem dysfunction.
Gluconeogenesis, a dual-purpose pathway in type 2 diabetes mellitus (T2DM), not only synthesizes glucose but also clears metabolic waste via the Cori cycle (lactate recycling through LDH, PC, PEPCK) and Alanine cycle (nitrogen disposal via ALT, GDH, urea cycle), preventing acidosis, ROS accumulation, and ammonia toxicity. Metformin, the cornerstone T2DM therapy, inhibits gluconeogenesis by targeting mitochondrial complex I, elevating AMP/ATP ratios, and activating AMPK-PKCι/λ signaling to repress CREB-CRTC2-driven PEPCK/G6Pase expression, disrupting these cycles. This leads to lactate, pyruvate, and ammonia buildup, triggering pro-inflammatory cascades: HIF-1α stabilization induces IL-6/VEGF, ROS from pyruvate excess activates NF-κB for TNF-α, and ammonia primes NLRP3 inflammasome for IL-1β/IL-18 release, fostering chronic inflammation. Multisystem consequences include musculoskeletal fatigue from ATP deficits, cognitive fog via neuroinflammation, atherosclerosis from endothelial dysfunction, hepatic fibrosis from urea cycle stress, and immune inflammaging impairing macrophage function. Clinical evidence reveals short-term anti-inflammatory benefits (reduced IL-6, CRP) via AMPK and microbiota effects, contrasted by long-term risks like lactic acidosis and neurodegeneration in renal-impaired or elderly patients. This review integrates physiological roles, molecular mechanisms, inflammatory pathways, systemic impacts, and clinical findings, highlighting metformin's dual-edged profile glycemic efficacy versus "inflammatory debt." Researchers are urged to explore precision interventions, such as antioxidants or biomarker-guided dosing, to optimize metformin's pleiotropic potential in T2DM and inflammaging-related disorders, redefining therapeutic paradigms.
2026-07-23 | Gut Microbiota Reshaping by Sparassis latifolia Polysaccharides Ameliorates Glucose Metabolism through Microbiota-Mediated Activation of Intestinal Gluconeogenesis.
Gut microbiota dysbiosis is a key contributor to glucose metabolism disorders. Sparassis latifolia polysaccharides (SLPs) may regulate microbiota-host metabolic interactions. Here, we evaluated the hypoglycemic effects of SLPs in mice with high-fat/high-sugar diet and streptozotocin-induced glucose metabolism disorders. SLPs improved glucose tolerance, reduced fasting blood glucose by approximately 40%, alleviated colonic injury, and restored gut microbiota-derived short-chain fatty acids (SCFAs). Metabolomics showed that SLPs mainly normalized purine metabolism, primary bile acid biosynthesis, and vitamin B6 metabolism. SLP treatment also modulated intestinal gluconeogenesis-related genes, proteins, and enzymes, Microbiota and coabundance group analyses indicated increased beneficial taxa, including Muribaculaceae and Bacteroides acidifaciens, and reduced CAG6 and CAG8 (Co-abundance group) taxa associated with impaired glucose tolerance. Cohabitation experiments suggested partial transmissibility of metabolic benefits. These findings suggest that SLPs improve glucose metabolism by remodeling gut microbiota and metabolites and enhancing PXR-SGK2-associated intestinal gluconeogenesis.
2026-06-26 | Sebacic Acid: A Multifunctional Medium-Chain Dicarboxylic Acid in Metabolic Regulation and Tissue Regeneration.
Sebacic acid (SA), a ten-carbon medium-chain dicarboxylic acid, has emerged as a multifunctional bioactive metabolite with potential applications in metabolic regulation and regenerative medicine. Evidence indicates that SA exerts anti-inflammatory effects by modulating nuclear factor kappa B (NF-kB), mitogen-activated protein kinase (MAPK), and signal transducer and activator of transcription (STAT) pathways, improves glucose homeostasis by enhancing mitochondrial function and suppressing hepatic gluconeogenesis, and contributes to lipid metabolism via peroxisomal and mitochondrial β-oxidation. Beyond metabolic regulation, SA promotes bone repair by stimulating osteoblast differentiation and inhibiting osteoclast activity, and supports muscle regeneration by enhancing energy supply, cell proliferation, and the microenvironment. SA also serves as a monomer for poly (glycerol sebacate) (PGS), enabling its use in biodegradable tissue engineering scaffolds. This review synthesizes current experimental and preclinical findings on the biological functions of SA, elucidates the underlying molecular mechanisms, and highlights its translational potential for the treatment of metabolic disorders and tissue regeneration.
proteins
2026-07-22 | Regulation and clinical manifestations of gluconeogenesis dysfunction.
The liver is the principal organ responsible for maintaining systemic glucose homeostasis through the integrated regulation of gluconeogenesis, glycogenolysis, glycogenesis, and glycolysis. As fasting progresses and hepatic glycogen stores decline, gluconeogenesis becomes the dominant source of endogenous glucose production required to preserve euglycemia. This review summarizes the regulation of gluconeogenesis and discusses the clinical manifestations, diagnostic implications, and therapeutic relevance of gluconeogenic dysfunction across diverse disease states.
2026-06-03 | Liver transcriptome data of T2DM rats treated with MOTS-C and aerobic exercise
Type 2 diabetes (T2DM) is a metabolic disease characterized by insulin resistance and liver glucose and lipid metabolism disorder. The liver, as the metabolic center of the body, plays a crucial role in the occurrence and development of T2DM. Previous studies have shown that aerobic exercise can significantly improve the metabolic status of T2DM patients, but its molecular mechanism has not been fully elucidated. In recent years, mitochondrial derived peptide MOTS-C has been shown to have the function of simulating exercise effects and regulating metabolic homeostasis. However, the combined intervention of MOTS-C and aerobic exercise on the transcriptome of T2DM liver still lacks systematic research. This project used high-fat diet combined with streptozotocin (STZ) - induced T2DM rats as a model, and administered MOTS-C intraperitoneal injection, aerobic treadmill exercise, and a combination of the two treatments. RNA seq technology was used to obtain liver transcriptome data for each group of rats. Through differential expression gene analysis, GO/KEGG enrichment analysis, and protein interaction network construction, key metabolic pathways and core genes were screened. Preliminary data shows that both MOTS-C and aerobic exercise intervention alone can partially reverse abnormal expression of gluconeogenesis, lipid synthesis, and inflammation related genes in the liver of T2DM rats; The combined intervention showed a synergistic effect, significantly enriched in the AMPK, PPAR, and insulin signaling pathways. Consistent with previous literature, exercise training can improve mitochondrial function by upregulating PGC-1 α, and this study found that MOTS-C can further enhance this effect. In addition, the combined intervention specifically regulated multiple novel long non coding RNAs, suggesting the existence of an epigenetic regulatory mechanism of motor MOTS-C cross-talk. The transcriptome data of this project provides important resources for revealing the molecular basis of MOTS-C simulation and enhancing exercise benefits, and also provides new ideas for developing "exercise mimetics" combination therapies for T2DM.
2026-05-09 | Hepatocyte estrogen-related receptor α modulates a gluconeogenic-epigenetic crosstalk counteracting MASLD/MASH progression.
Lactate has been recognized as a major fuel substrate and also a lactyl-group donor for histone lysine lactylation. Hepatocytes act as lactate-consuming cells owing the high oxidative capability especially during exercise, a primary nonpharmacological intervention for alleviating metabolic dysfunction-associated steatotic liver diseases including steatohepatitis (MASLD/MASH). However, little is known regarding how lactate links the metabolic-epigenetic axis in hepatocytes. Here we show that declined estrogen-related receptor α (ESRRA) expression occur in MASLD/MASH accompanied with elevated levels of lactate and histone lactylation, particularly H3K18la. Such dysregulation can be partially rescued by chronic exercise in aged mice or exacerbated by genetic ablation of hepatocyte ESRRA. Mechanistically, exercise-induced ESRRA/PPARGC1A facilitates lactate consumption through transcriptional regulation of lactate dehydrogenase B and glucose-6-phosphatase catalytic subunit 1, rewiring lactate from a lactyl donor to gluconeogenic precursor in hepatocytes. Hepatocyte-specific ESRRA overexpression counteracts MASLD/MASH progression in mice, rectifying aberrant H3K18la accumulation and its marked gene transcripts that are involved in liver pathology. Our findings reveal that ESRRA functions as an exercise executor linking metabolism with epigenetic modification, highlighting a gluconeogenic-epigenetic regulatory axis that could be fine-tuned to mitigate risk factors of MASLD/MASH such as aging, menopause, a sedentary lifestyle and malnutrition.
2026-01-19 | Cytosolic Phosphoenoylpyruvate Carboxykinase Deficiency: Clinical, Biochemical, and Genetic Features of Five Non-Finnish Patients.
Cytosolic phosphoenoylpyruvate carboxykinase (PEPCK-C) is an essential, rate-limiting enzyme in the gluconeogenesis pathway. PEPCK-C deficiency presents with hypoglycaemia, hyperlactataemia and hepatopathy, and was first reported in association with bi-allelic PCK1 variants in 2014. A Finnish cohort with a common homozygous variant (c.925G>A, p.(Gly309Arg)) is well-described, but few other genotypes are reported. Five non-Finnish probands with PEPCK-C deficiency with novel genotypes are presented. All five presented with hypoglycaemia (hypoketotic in three), lactic acidosis, and elevated transaminases. Age at presentation was newborn to 3 years. Two presented with hypoglycaemic seizures after overnight fasting during intercurrent infection. Prominent renal manifestations were noted in two, including proximal tubulopathy with bicarbonate wasting, and acute renal failure, respectively, with markedly elevated plasma glutamine in both. Urine organic acid analysis identified elevated lactate, dicarboxylic aciduria, and tricarboxylic acid cycle metabolites, especially fumarate which was detected in 3/5. PCK1 genotypes included homozygous missense variants c.1211C>T, p.(Ser404Leu) and c.265G>A, p.(Glu89Lys), or compound heterozygous variants including c.824del, p.(Gly275Valfs21); c.496G>A, p.(Val166Met); c.961 + 2 T>C; c.204del, p.(Leu69), and c.728A>G p.(Lys243Arg). A severe phenotype with failure to thrive, short fasting tolerance, liver dysfunction, and tubulopathy was noted in one individual harboring compound heterozygous splicing and nonsense variants. Evidence from in silico analyses and the specific phenotype supported the pathogenicity of novel missense variants. These patients reinforce the recognizable presentation of PEPCK-C deficiency while highlighting renal manifestations and expanding the genotypic spectrum.
2025-11-29 | The beneficial effect of hepatic ER stress-associated protein PDI on obesity-associated glucose dysregulation.
The liver plays critical roles in glucose metabolism regulation. Accumulating evidence supported that endoplasmic reticulum (ER) stress in liver tissue may involve in the development of type 2 diabetes. However, the role of ER stress-associated proteins in diabetes still needs to be clarified. Genome-wide DNA methylome and proteome in the liver biopsies from patients with or without type 2 diabetes were performed and further validated by pyro-sequencing, real-time PCR and western blots. Circulating protein disulfide isomerase (PDI) levels at baseline and postoperative follow-up were measured by ELISA. The glucose tolerance, metabolic gene expression, glycogen deposition, glycogenesis and ER stress-associated proteins were detected in adeno-associated virus (AAV)-treated high fat-diet (HFD) mice. Based on methylome and proteome analysis, we identified the hypermethylation of PDI gene in liver biopsies, concomitant with decreased mRNA expression and protein levels in diabetic group compared with non-diabetic group. Circulating PDI levels were lower in patients with diabetes and elevated after metabolic surgery. The decreased PDI expression was correlated with increased gluconeogenesis and reduced glycogen synthesis in human liver tissue. Furthermore, hepatic PDI downregulation aggravated hyperglycemia, whereas PDI overexpression ameliorated glucose intolerance, decreased glycogen deposition and increased glycogenesis in HFD mice. We identified the beneficial effect of ER stress-associated protein PDI on the regulation of hepatic glucose metabolism, which is expected to be a potential therapeutic target against type 2 diabetes, and provided an important clue for better understanding ER stress in the pathogenesis of diabetes. The study was registered on ClinicalTrials.gov (NCT03296605). The online version contains supplementary material available at 10.1186/s12986-025-01041-9.
gene therapies
2026-06-22 | Holocarboxylase synthetase deficiency: pathogenesis, clinical features, diagnosis, treatment, and research prospects.
Holocarboxylase Synthetase Deficiency (HLCSD) is a rare autosomal recessive inborn error of metabolism caused by biallelic mutations in the HLCS gene. The encoded enzyme, holocarboxylase synthetase (HLCS), plays a critical role in biotin metabolism by activating five essential carboxylases, including pyruvate carboxylase (PC) and propionyl-CoA carboxylase (PCC), thereby regulating key processes such as gluconeogenesis, fatty acid synthesis, and branched-chain amino acid catabolism [1, 14]. HLCS dysfunction leads to the accumulation of toxic metabolites (e.g., 3-hydroxyisovaleric acid, methylcitric acid), resulting in severe manifestations like metabolic acidosis and hyperammonemia [6]. This review systematically consolidates current knowledge on the molecular mechanisms, clinical spectrum, diagnostic approaches, and therapeutic strategies for HLCSD. It critically addresses core controversies, including genotype-phenotype correlations and variability in biotin treatment response, and proposes a multidimensional "gene-enzyme activity-metabolic phenotype-treatment response" framework. Studies confirm that early diagnosis via newborn screening, coupled with standardized biotin supplementation, achieves biochemical normalization and clinical symptom resolution in over 85% of patients and reduces the risk of neurological sequelae [10, 33, 35]. However, biotin-unresponsive cases and rare phenotypes present ongoing diagnostic and therapeutic challenges, necessitating further exploration of novel interventions to advance the precision medicine approach for HLCSD. What is Known: • Holocarboxylase synthetase defi ciency (HLCSD) is a rare autosomal recessive metabolic disorder caused by HLCSbiallelic mutations, and biotin supplementation is the mainstream treatment for most patients. • Distinct population-specifi c HLCS mutation hotspots exist, and residual enzyme activity is closely correlated with disease severity and age of onset. What is New: • A multidimensional framework of gene-enzyme activity-metabolic phenotype-treatment response was proposed tointerpret phenotypic heterogeneity and variable biotin responsiveness in HLCSD. • This review systematically summarized rare clinical phenotypes, diagnostic pitfalls, emerging detection technologies and novel therapeutic directions including gene therapy and epigenetic intervention.
2026-06-04 | NgBR controls hepatic adiponectin signaling competence through KAT7-dependent chromatin regulation.
Adiponectin signaling is essential for hepatic glucose homeostasis, yet the molecular basis of adiponectin receptor responsiveness remains incompletely understood. Here, we identify the Nogo-B receptor (NgBR; NUS1) as a regulator of hepatic adiponectin sensitivity. Across human, cynomolgus monkey, and mouse datasets, hepatic NgBR expression is consistently reduced in obesity-associated diabetes, indicating a conserved metabolic signature. Hepatocyte-specific NgBR deletion abolishes the metabolic effects of the adiponectin agonist AdipoRon, resulting in impaired AMPK activation, persistent gluconeogenesis, and ceramide accumulation. Mechanistically, NgBR loss suppresses KAT7 expression and reduces histone acetylation at AdipoR1 and AdipoR2 promoters, thereby limiting receptor expression. Adeno-associated virus (AAV)-mediated restoration of hepatic NgBR reinstates KAT7-dependent chromatin activation, adiponectin receptor expression, and glucose homeostasis. These findings support a hepatocellular mechanism in which NgBR maintains adiponectin receptor competence and suggest a potential therapeutic strategy for restoring adiponectin responsiveness in metabolic disease.
2026-02-16 | Trial Interviews to Explore Glycogen Storage Disease Type Ia Patient Experiences Following Gene Therapy.
Glycogen storage disease type Ia (GSDIa) is a rare, inherited, autosomal recessive deficiency of glucose-6-phosphatase (G6Pase), an enzyme necessary in glycogenolysis and gluconeogenesis. To maintain normal blood glucose levels and ensure survival, individuals living with GSDIa must frequently consume complex carbohydrates (eg, uncooked cornstarch). Dietary management can result in chronic complications and significant patient burden. DTX401 (pariglasgene brecaparvovec) is an investigational adeno-associated virus serotype 8 vector (AAV8)-based gene therapy designed to restore endogenous glucose production. Patient experience interviews were conducted as part of an open-label, phase 1/2 dose-escalation trial (NCT03517085) evaluating the safety and efficacy of DTX401 in adults ≥18 years with GSDIa. Telephone interviews were conducted at Weeks 24, 52, and 104, using a semistructured interview guide. Qualitative interview data were audio recorded, transcribed, coded, and analyzed. Most (86%; n = 6/7) reported overall symptom improvement and reduced burden following DTX401 treatment. Three (43%) reported no negative outcomes following gene therapy; 4 (57%) mentioned at least one negative change attributed to instances of blood sugar instability, lifestyle, or diet adjustments. Satisfaction fluctuated across timepoints; however, most were somewhat satisfied/very satisfied with gene therapy at Weeks 24 (80%), 52 (86%), and 104 (86%). No participants reported being very dissatisfied. Following DTX401 treatment, most participants reported substantial reduction in cornstarch intake and corresponding improvements in symptoms, physical function, diet management, emotional function, self-perception, social function, sleep quality, work performance, and overall health. Few negative changes were reported. While some results regarding met expectations were mixed, most indicated they would still want gene therapy even if they had to continue cornstarch and if they had continued diet restrictions, and most reported satisfaction with treatment. While the study had limitations, interview results suggest that DTX401 helps to address aspects of the condition and treatment that patients have identified as burdensome. Most interviewees in this open-label trial of investigational DTX401 described positive experiences, including substantial reduction in burden and improved health-related quality of life following treatment throughout the trial. To optimize patient outcomes and experience with gene therapy, guidance on and close monitoring of dietary changes during implementation should be provided.
2026-01-14 | BMSC-derived extracellular vesicles affect gluconeogenesis and lipogenesis by releasing 5'-tRF-GlyCCC to improve MAFLD insulin sensitivity.
TsRNAs (tRNA-derived small RNAs) also known as tRNA-derived small RNAs, are a relatively new type of non-coding RNAs that have demonstrated promising effect in treating various liver diseases. However, the function of small extracellular vesicles (sEVs) secreted by human bone marrow mesenchymal stem cells (BMSCs) in safeguarding against metabolic-associated fatty liver disease (MAFLD) is still uncertain. In this research, we explored the effects of BMSCs sEVs on lipid metabolism using Palmitic Acid (PA)-induced HepG2 cells, both in the presence and absence of the sEVs inhibitor GW4869. Pandora sequencing and RNA sequencing were utilized to identify differentially expressed genes in sEVs and hepatocytes in vitro. Furthermore, we carried out in vivo studies involving male C57BL/6J mice that fed with high-fat diet (HFD) and either treated with an AAV 5'-tRF-GlyCCC mimic or not, through tail vein injection. Our findings revealed that BMSC-sEVs can relieve lipid accumulation in PA-caused HepG2 cells by inhibiting the formation of de novo fatty acid. We found that 5'-tRF-GlyCCC forms a direct connection with the 3' UTR of FoxO3, thereby decreasing the level of gluconeogenic genes PEPCK and G6Pase. Tail vein administration of the 5'-tRF-GlyCCC AAV alleviated liver gluconeogenesis and lipid metabolism issues in MAFLD mice by enhancing hepatic insulin sensitivity. The results imply that the 5'-tRF-GlyCCC/FoxO3 gluconeogenesis-signaling pathway could be crucial in the therapeutic benefits of BMSC sEVs on MAFLD.
2025-03-11 | Safety and Efficacy of DTX401, an AAV8-Mediated Liver-Directed Gene Therapy, in Adults With Glycogen Storage Disease Type I a (GSDIa).
Glycogen storage disease type Ia (GSDIa) is a rare, life-threatening, inherited carbohydrate metabolism disorder caused by glucose-6-phosphatase (G6Pase) deficiency, which is essential for glycogenolysis and gluconeogenesis. GSDIa management includes a strict medically prescribed diet that typically includes daily uncooked cornstarch doses, including overnight, to maintain euglycemia. DTX401 is an investigational adeno-associated virus serotype 8 vector expressing the human G6PC1 gene that encodes G6Pase. This open-label, phase 1/2, dose-escalation, 52-week gene therapy trial evaluated the safety and efficacy of a single DTX401 infusion in 12 adults with GSDIa (ClinicalTrials.gov Identifier: NCT03517085). Three participants in Cohort 1 received DTX401 2.0 × 1012 genome copies (GC)/kg, and three participants each in Cohorts 2, 3, and 4 received 6.0 × 1012 GC/kg. Corticosteroids were administered to mitigate vector‑induced inflammatory response. All participants experienced a treatment-emergent adverse event (TEAE) and a related TEAE. No participant experienced a dose-limiting toxicity, TEAE leading to study discontinuation, TEAE leading to death, or serious treatment-related TEAE. Mean (SD) time to hypoglycemia in minutes/gram of carbohydrate during a controlled fasting challenge was 5.0 (1.6) at baseline and 6.9 (2.7) at Week 52, a mean (SD) increase of 46% (72%). Mean total daily cornstarch intake was 284 g at baseline and 85 g at Week 52 in the 10 participants with available values at both time points, a mean (SD) total daily cornstarch intake reduction of 68% (20%); p < 0.001. DTX401 showed a favorable safety and efficacy profile at Week 52. Participants in all cohorts showed significant cornstarch need reductions from baseline to Week 52.
oligonucleotides
2026-08-08 | ApoC-III Antisense Oligonucleotide Therapy Used in Glycogen Storage Disease Type 1a.
Glycogen storage disease type 1a (GSD1a) is an autosomal recessive disorder characterized by impaired glycogenolysis and gluconeogenesis. Individuals with GSD1a manifest significant hypertriglyceridemia refractory to dietary and lipid-lowering medication therapies. Apolipoprotein C-III antisense oligonucleotide (apoCIII-ASO) therapy is approved to reduce severe hypertriglyceridemia in familial chylomicronemia syndrome but is also effective in moderate hypertriglyceridemia of varied genetic backgrounds. We describe a 22-year-old with GSD1a and hypertriglyceridemia with past pancreatitis despite fibric acid derivative, niacin, and bempedoic acid therapy in whom apoCIII-ASO was associated with triglyceride reduction from 4,951 to 1,643 mg/dL. As GSD1a-associated hypertriglyceridemia is often refractory to standard therapies, apoCIII-ASO therapy may offer promise as a treatment. This case describes the first use of apoCIII-ASO in GSD1a-related hypertriglyceridemia. GSD1a-driven hypertriglyceridemia may be treatable using apoCIII-ASO.
2026-05-15 | Galactosylated LNP-mediated hepatic Sam68 silencing improves glucose homeostasis in diabetes by suppressing gluconeogenesis.
Excessive hepatic glucose production is a key driver of the progression of type 2 diabetes (T2DM), a highly prevalent global metabolic disorder. We previously reported that Sam68 expression is upregulated in the livers of both diabetic patients and mouse models, and hepatocyte-specific knockdown of Sam68 greatly alleviates hyperglycemia and improves insulin sensitivity in diabetic mice. Here, we engineered a series of ligand-functionalized lipid nanoparticles (LNPs) and identified a galactose-decorated formulation (LNP-Gal) that enables efficient hepatocyte-selective delivery of Sam68 siRNA, thereby achieving robust Sam68 silencing and suppressing hepatic gluconeogenesis in both cellular and animal models. In both genetic and diet-induced diabetic mouse models, systemic administration of siSam68/LNP-Gal improved glycemic control and insulin responsiveness and attenuated hepatic gluconeogenic output, accompanied by suppression of the hepatic gluconeogenic program. Thus, we establish siSam68/LNP-Gal as a hepatocyte-selective siRNA delivery system that elicits a potent antihyperglycemic effect with a favorable safety profile in vitro and in vivo, providing a promising siRNA-based strategy for the treatment of T2DM and related metabolic disorders.
2025-04-11 | Identification of Shared Pathways and Molecules Between Type 2 Diabetes and Lung Adenocarcinoma and the Impact of High Glucose Environment on Lung Adenocarcinoma.
Objective: This research focused on exploring the shared pathophysiological bases of lung adenocarcinoma (LUAD) and Type 2 diabetes mellitus (T2DM). Methods: The investigation into the molecular similarities between LUAD and T2DM involved querying the Gene Expression Omnibus for pertinent data. Upon pinpointing genes exhibiting differential expression, pathway enrichment analyses were executed to discern the molecular pathways shared by both conditions. In addition, GeneMANIA was employed to establish a protein interaction network, pinpointing STK26 as a critical gene. In addition, the influence of STK26 on the immune environment of the tumor was examined using tools such as the Microenvironment Cell Populations-counter to assess levels of stromal and immune cells in cancer tissues from expression profiles. Furthermore, a lung cancer cell model enriched in glucose was developed to facilitate the knockdown of STK26 using small interfering RNA. The influence of STK26 on A549 cell functionality was assessed using CCK-8, wound healing (scratch), and colony formation (cloning) assays. Results: This will help ensure accuracy and relevance in the revised version. TGF-β, HIF-1, AGE-RAGE, extracellular matrix (ECM) components and function regulation, and cell adhesion were activated in LUAD and T2DM. WGCNA identified two main modules in LUAD, three main modules in T2DM, and 44 shared genes. ClueGO and GeneMANIA analyses focused on pathways regulating cell growth and mitosis. Our analysis revealed STK26 as a central gene that exhibits elevated expression levels in tissues affected by LUAD. Elevated expression of STK26 correlates with a diminished prognosis for LUAD patients. In patients with LUAD characterized by elevated STK26 levels, gene set enrichment analysis identified a notable upregulation in numerous metabolic pathways. These include glycolysis-gluconeogenesis, oxidative phosphorylation, and the conversion pathways between pentose and glucuronic acid, as well as the pentose phosphate pathway. Gene set variation analysis suggested that a high STK26 expression was related to glycolysis, hypoxia, MYC, oxidative phosphorylation, cell cycle, and citric acid cycle pathways. In the group exhibiting elevated levels of STK26, a marked upregulation of glycolytic pathway genes, including HK2, RPIA, IDH3G, and SORD, was noted. This upregulation indicates a correlation between STK26 expression and these pivotal glycolytic genes. MCP-counter analysis suggested that the group with a high STK26 expression level had reduced immune infiltration. Laboratory studies have demonstrated that LUAD cells thrive in a high-glucose setting, where STK26 expression notably surpasses that observed under standard conditions. In addition, suppressing STK26 using siRNA significantly curtails both the growth and movement of LUAD cells. Conclusion: The research established a shared pathogenic basis between LUAD and T2DM. TGF-β, HIF-1, AGE-RAGE, ECM components and function regulation, cell adhesion, and additional signaling pathways are intricately linked with the pathophysiological mechanisms underlying both LUAD and T2DM. Thus, STK26 may affect the development of LUAD and T2DM by regulating glucose metabolism. Suppressing STK26 in a glucose-rich setting curtailed both the expansion and mobility of LUAD cells.
2024-10-10 | Silencing the glycerol-3-phosphate acyltransferase-1 gene in the liver of mice fed a high-fat diet, enhances insulin sensitivity and glucose metabolism by promoting fatty acid beta-oxidation.
Liver plays a central role in systemic glucose and lipid metabolism. High-fat diet (HFD) and obesity are related to hepatic lipid accumulation and insulin resistance (InsR). Diacylglycerols (DAG) play a key role in the induction of InsR, however their involvement in hepatic InsR remains debated. This study aimed to clarify and confirm the role of glycero-3-phosphate acyltransferase 1 (GPAT1), a rate-limiting enzyme in DAG synthesis, in the progression of hepatic InsR in the context of HFD-induced lipid accumulation and insulin resistance in the liver. Liver-targeted GPAT1 silencing was performed using shRNA-mediated hydrodynamic gene delivery. Lipid species including LCA-CoA, sphingolipids, DAG and acyl-carnitines were quantified using UHPLC/MS/MS while insulin signalling was assessed at protein level by Western Blot. Hepatic glucose metabolism, including glucose-6-pasphate content and gluconeogenesis rate was evaluated using GC/MS. HFD-fed animals developed InsR, evidenced by increased HOMA-IR, enhanced gluconeogenesis and reduced glycogen content compared to controls. Hepatic GPAT1 silencing in HFD-fed animals resulted in a significant reduction of DAG and TAG levels, increased acyl-carnitines content and upregulated mitochondrial β-oxidation protein expression. These changes were accompanied by improved insulin signalling, enhanced glycogen storage, and reduced gluconeogenesis. Silencing GPAT1, and thereby reducing glycerolipid synthesis, promotes β-oxidation and ameliorates HFD-induced hepatic insulin resistance, confirming the enzyme's pivotal role in liver metabolic dysfunction associated with increased lipid supply.
2024-05-15 | MicroRNA-721 regulates gluconeogenesis via KDM2A-mediated epigenetic modulation in diet-induced insulin resistance in C57BL/6J mice.
Aberrant gluconeogenesis is considered among primary drivers of hyperglycemia under insulin resistant conditions, with multiple studies pointing towards epigenetic dysregulation. Here we examine the role of miR-721 and effect of epigenetic modulator laccaic acid on the regulation of gluconeogenesis under high fat diet induced insulin resistance. Reanalysis of miRNA profiling data of high-fat diet-induced insulin-resistant mice model, GEO dataset (GSE94799) revealed a significant upregulation of miR-721, which was further validated in invivo insulin resistance in mice and invitro insulin resistance in Hepa 1-6 cells. Interestingly, miR-721 mimic increased glucose production in Hepa 1-6 cells via activation of FOXO1 regulated gluconeogenic program. Concomitantly, inhibition of miR-721 reduced glucose production in palmitate induced insulin resistant Hepa 1-6 cells by blunting the FOXO1 induced gluconeogenesis. Intriguingly, at epigenetic level, enrichment of the transcriptional activation mark H3K36me2 got decreased around the FOXO1 promoter. Additionally, identifying targets of miR-721 using miRDB.org showed H3K36me2 demethylase KDM2A as a potential target. Notably, miR-721 inhibitor enhanced KDM2A expression which correlated with H3K36me2 enrichment around FOXO1 promoter and the downstream activation of the gluconeogenic pathway. Furthermore, inhibition of miR-721 in high-fat diet-induced insulin-resistant mice resulted in restoration of KDM2A levels, concomitantly reducing FOXO1, PCK1, and G6PC expression, attenuating gluconeogenesis, hyperglycemia, and improving glucose tolerance. Interestingly, the epigenetic modulator laccaic acid also reduced the hepatic miR-721 expression and improved KDM2A expression, supporting our earlier report that laccaic acid attenuates insulin resistance by reducing gluconeogenesis. Our study unveils the role of miR-721 in regulating gluconeogenesis through KDM2A and FOXO1 under insulin resistance, pointing towards significant clinical and therapeutic implications for metabolic disorders. Moreover, the promising impact of laccaic acid highlights its potential as a valuable intervention in managing insulin resistance-associated metabolic diseases.
other
2026-03-14 | PHYSIOLOGICAL ROLES OF THE LIVER AND PANCREAS: INTEGRATED FUNCTIONS IN METABOLISM, DIGESTION, ENDOCRINE REGULATION, AND DETOXIFICATION
The liver and pancreas are the two largest accessory digestive glands in the human body and among the most metabolically versatile organs. The liver, weighing approximately 1.5 kg and receiving a dual blood supply from the portal vein and hepatic artery, performs over 500 distinct physiological functions. The pancreas, a mixed exocrine–endocrine gland of approximately 80–100 g, produces digestive enzymes that hydrolyze all major macronutrients and secretes the hormones insulin, glucagon, and somatostatin that maintain blood glucose homeostasis. Dysregulation of either organ underlies some of the most common and lethal diseases encountered in clinical medicine, including non-alcoholic fatty liver disease (NAFLD), cirrhosis, diabetes mellitus, and pancreatic adenocarcinoma. Objective: To provide a comprehensive, evidence-based review of the integrated physiological roles of the liver and pancreas, including their roles in macronutrient metabolism, bile acid physiology, detoxification, endocrine regulation of glucose homeostasis, and the pathophysiological consequences of organ dysfunction. Methods: A systematic review of eight primary peer-reviewed sources was conducted, encompassing original research articles, authoritative textbooks, meta-analyses, and clinical guidelines published between 1998 and 2024. Results: Hepatocytes, the principal parenchymal cells of the liver, perform glycogenesis, gluconeogenesis, fatty acid oxidation, urea synthesis, bile acid conjugation, and phase I/II biotransformation of xenobiotics via the cytochrome P450 (CYP) enzyme system. The exocrine pancreas secretes 1.5–2.5 L of bicarbonate-rich fluid daily containing proteases (trypsinogen, chymotrypsinogen), lipases, and amylases, regulated by cholecystokinin (CCK) and secretin. Pancreatic β-cells release insulin in a biphasic pattern in response to glucose, while α-cells secrete glucagon during hypoglycemia, and δ-cells release somatostatin to modulate both. The enteroinsular axis, mediated by GLP-1 and GIP incretin hormones, amplifies postprandial insulin secretion by 50–70% of the total insulin response. Conclusion: The liver and pancreas operate as a functionally integrated unit, coordinating nutrient absorption, macronutrient metabolism, and glucose homeostasis through hormonal, neural, and paracrine signaling networks. Understanding their physiological interdependence is essential for the rational management of metabolic, digestive, and endocrine disorders.
2025-03-12 | Adipose stromal cells increase insulin sensitivity and decrease liver gluconeogenesis in a mouse model of type 1 diabetes mellitus.
Diabetic ketoacidosis (DKA) is a serious complication of hyperglycemic emergency caused by insulin deficiency through accelerated liver gluconeogenesis and glycogenolysis. DKA is most common in type 1 diabetes (T1D). Transplantation of islet cells and pancreas is an alternative to insulin injection for treating T1D. However, this alternative is only suitable for some patients. This study investigated the effects and mechanisms of adipose stromal vascular fraction (SVF) cells on liver gluconeogenesis and insulin sensitivity in an insulin-dependent T1D animal model. SVF cells were obtained from wild-type inguinal adipose tissue and transplanted into the peritoneal cavity of type I diabetic Akita (Ins2Akita) mice. We found that transplantation of 5 × 106 SVF cells from wild-type adipose tissue significantly downregulated proinflammatory genes of TNF-α, IL-1β, IL-33, iNOS, and DPP4 in the liver and upregulated anti-inflammatory factors IL-10 and FOXP3 in blood serum and liver tissue 7 days after injection. Moreover, we found that the expression levels of G6pc and Pck1 were significantly decreased in the Akita mice livers. Furthermore, the intraperitoneal insulin tolerance test assay showed that diabetic Akita mice significantly had increased insulin sensitivity, reduced fasting blood glucose, and restored glucose-responsive C-peptide expression compared with the control Akita group. This result was noted 14 days after administration of 5 × 106 or 1 × 107 SVF cells from wild-type adipose tissue into diabetic Akita mice. Together, these findings suggest that adipose tissue-derived SVF cells could suppress liver inflammation, regulate liver gluconeogenesis, and improve insulin sensitivity in an animal model with T1D. Therefore, adipose SVF cells may be novel cellular therapeutic alternatives to maintain steady liver gluconeogenesis in T1D.
2024-12-09 | MicroRNAs Dependent G-ELNs Based Intervention Improves Glucose and Fatty Acid Metabolism While Protecting Pancreatic β-Cells in Type 2 Diabetic Mice.
Metabolic disorders such as Type 2 diabetes mellitus (T2DM) imposes a significant global health burden. Plant-derived exosome like nanoparticles (P-ELNs) have emerged as a promising therapeutic alternate for various diseases. Present data demonstrates that treatment with Ginger-derived exosome like nanoparticles (G-ELNs) enhance insulin dependent glucose uptake, downregulate gluconeogenesis and oxidative stress in insulin resistant HepG2 cells. Furthermore, oral administration of G-ELNs in T2DM mice decreases fasting blood glucose levels and improves glucose tolerance as effectively as metformin. These improvements are attributed to the enhanced phosphorylation of Protein kinase B (Akt-2), the phosphatidylinositol 3-kinase at serine 474 which consequently leads to increase in hepatic insulin sensitivity, improvement in glucose homeostasis and decrease in ectopic fat deposition. Oral administration of G-ELNs also exerts protective effect on Streptozotocin (STZ)-induced pancreatic β-cells damage, contributing to systemic amelioration of T2DM. Further, as per computational tools, miRNAs present in G-ELNs modulate the phosphatidylinositol 3-kinase (PI3K)/Akt-2 pathway and exhibit strong interactions with various target mRNAs responsible for hepatic gluconeogenesis, ectopic fat deposition and oxidative stress. Furthermore, synthetic mimic of G-ELNs miRNA effectively downregulates its target mRNA in insulin resistant HepG2 cells. Overall, the results indicate that the miRNAs present in G-ELNs target hepatic metabolism thus, exerting therapeutic effects in T2DM.
2024-10-29 | VEGFB ameliorates insulin resistance in NAFLD via the PI3K/AKT signal pathway.
Non-alcoholic fatty liver disease (NAFLD) is one of the most universal liver diseases with complicated pathogenesis throughout the world. Insulin resistance is a leading risk factor that contributes to the development of NAFLD. Vascular endothelial growth factor B (VEGFB) was described by researchers as contributing to regulating lipid metabolic disorders. Here, we investigated VEGFB as a main target to regulate insulin resistance and metabolic syndrome. In this study, bioinformatics, transcriptomics, morphological experiments, and molecular biology were used to explore the role of VEGFB in regulating insulin resistance in NAFLD and its molecular mechanism based on human samples, animal models, and cell models. RNA-seq was performed to analyze the signal pathways associated with VEGFB and NAFLD; Palmitic acid and High-fat diet were used to induce insulin-resistant HepG2 cells model and NAFLD animal model. Intracellular glucolipid contents, glucose uptake, hepatic and serum glucose and lipid levels were examined by Microassay and Elisa. Hematoxylin-eosin staining, Oil Red O staining, and Periodic acid-schiff staining were used to analyze the hepatic steatosis, lipid droplet, and glycogen content in the liver. Western blot and quantitative real-time fluorescent PCR were used to verify the expression levels of the VEGFB and insulin resistance-related signals PI3K/AKT pathway. We observed that VEGFB is genetically associated with NAFLD and the PI3K/AKT signal pathway. After VEGFB knockout, glucolipids levels were increased, and glucose uptake ability was decreased in insulin-resistant HepG2 cells. Meanwhile, body weight, blood glucose, blood lipids, and hepatic glucose of NAFLD mice were increased, and hepatic glycogen, glucose tolerance, and insulin sensitivity were decreased. Moreover, VEGFB overexpression reduced glucolipids and insulin resistance levels in HepG2 cells. Specifically, VEGFB/VEGFR1 activates the PI3K/AKT signals by activating p-IRS1Ser307 expression, inhibiting p-FOXO1pS256 and p-GSK3Ser9 expressions to reduce gluconeogenesis and glycogen synthesis in the liver. Moreover, VEGFB could also enhance the expression level of GLUT2 to accelerate glucose transport and reduce blood glucose levels, maintaining glucose homeostasis. Our studies suggest that VEGFB could present a novel strategy for treating NAFLD as a positive factor.
2024-10-14 | A rare case of fructose-1, 6-bisphosphatase deficiency: Clinical features in a pediatric patient.
Fructose-1, 6- bisphosphatase deficiency is a rare autosomal recessive inborn error of fructose metabolism which mainly affects gluconeogenesis. It often presents with ketotic hypoglycemia and lactic acidosis, with hyperventilation. The disease has a high mortality rate when undiagnosed. Here we report a case of this rare disorder, referred to our hospital in Western Nepal, diagnosed originally as pneumonia. The patient presented in respiratory distress with severe metabolic acidosis and dehydration. She also demonstrated hypoglycemia, hypernatremia, coagulation dysfunction and albuminuria, all of which gradually improved, though her lactate remained consistently elevated. This led to investigation of urinary ketones which were positive suggesting a defect in the metabolism of carbohydrates. Urine organic acid profile and whole exome sequencing finally confirmed the diagnosis of Fructose-1, 6- bisphosphatase deficiency. To our knowledge this is the first case report of this disease diagnosed in Nepal.
small molecules
2026-08-11 | High-Protein Diet Ameliorates Cardiomyopathy in a Cardiac-Specific AGL Knockout Mouse Model: Association With Upregulated Hepatic Gluconeogenesis.
Glycogen storage disease type IIIa (GSDIIIa) causes progressive cardiomyopathy, and current high-fat dietary strategies lack consensus regarding long-term cardiovascular safety. We evaluated the efficacy and safety of high-protein versus high-fat diets in a novel cardiac-specific AGL knockout (CKO; AGLflox/flox/MHC-Cre) mouse model to specifically assess isolated cardiac responses. CKO mice were randomized at weaning to High-Protein (HPD), High-Protein High-Fat (HPHFD), or Low-Protein (LPD) diets, with approximate protein/fat/carbohydrate distributions of 40%/4%/50%, 40%/50%/10%, and 10%/4%/80%, respectively; CKO mice on normal diet (ND) and AGLflox/flox mice served as controls. Cardiac phenotypes and hepatic gluconeogenic enzymes were evaluated longitudinally up to 24 weeks. CKO-ND mice developed progressive cardiomyopathy with elevated myocardial glycogen at 24 weeks (32.01 ± 3.22 vs. 5.90 ± 2.21 mg/g in controls, p < 0.001), reduced left ventricular ejection fraction, and elevated serum creatine kinase. Both HPD and HPHFD significantly reduced myocardial glycogen burden (12.82 ± 3.58 and 15.07 ± 4.40 mg/g, p < 0.001), restored systolic function, and normalized hypertrophy. However, HPHFD induced distinct hyperlipidemia, whereas HPD maintained a stable lipid profile. Furthermore, therapeutic benefits in high-protein groups were associated with upregulated hepatic rate-limiting gluconeogenic enzymes (FBP2, PCK1). In this cardiac-specific AGL knockout model, a high-protein, non-high-fat diet attenuated cardiac glycogen accumulation and systolic dysfunction without the hyperlipidemia observed with the high-fat regimen. These preclinical findings support further evaluation of high-protein dietary strategies for GSDIIIa cardiomyopathy and suggest a possible liver-heart metabolic axis involving hepatic gluconeogenesis.
2026-08-04 | Hepatic Neu1 deficiency drives metabolic dysregulation via GCGR desialylation-dependent cAMP-PKA signaling and inflammatory response in old mice.
Neuraminidase 1 (Neu1) plays a crucial role in the removal of sialic acid from glycoproteins and glycolipids, significantly influencing hepatic glycolipid metabolism. However, its precise contributions to liver gluconeogenesis and bile acid metabolism are not well defined. Although the sialylation of the hepatic glucagon receptor (GCGR) has been linked to the regulation of hepatic glucose homeostasis, the impact of Neu1 on hepatic gluconeogenesis through the desialylation of GCGR remains to be elucidated. To explore the physiological function of Neu1 in liver glycolipid metabolism, we constructed liver-specific Neu1 knockout mice. Glucagon induced HepG2 cells were used to assess the role of Neu1 in gluconeogenesis. Phenotypic analysis indicated that these knockout mice exhibited a late-onset glycolipid metabolism disorder. Mechanistically, Neu1 deficiency caused the upregulation of key gluconeogenic genes, with cAMP-PKA signaling and the sialylation mediated activation of GCGR influencing the Akt-FoxO1 pathway, contributing to the disruption of hepatic glucose metabolism in 21-month-old Neu1 deficient mice. Transcriptomic analysis revealed an increase in lipogenesis and bile acid synthesis pathways in the livers of aged Neu1 knockout mice. Notably, there were significant alterations in steroid hormone biosynthesis, with elevated levels of lithocholic acid and allolithocholic acid detected in the Neu1 deficient mice. Additionally, the activation of inflammatory responses and reduced lipolysis seemed to correlate with the observed abnormalities in glycolipid metabolism. These results indicate that Neu1 is essential for GCGR-dependent gluconeogenesis, suggesting that Neu1 could be a potential therapeutic target for addressing hepatic glycolipid metabolism disorders associated with aging.
2026-08-03 | Metformin's disruption of gluconeogenesis in type 2 diabetes impairments of the cori and alanine cycles as hidden drivers of metabolic waste accumulation, NF-κBHIF-1α-mediated low-grade inflammation, and multisystem dysfunction.
Gluconeogenesis, a dual-purpose pathway in type 2 diabetes mellitus (T2DM), not only synthesizes glucose but also clears metabolic waste via the Cori cycle (lactate recycling through LDH, PC, PEPCK) and Alanine cycle (nitrogen disposal via ALT, GDH, urea cycle), preventing acidosis, ROS accumulation, and ammonia toxicity. Metformin, the cornerstone T2DM therapy, inhibits gluconeogenesis by targeting mitochondrial complex I, elevating AMP/ATP ratios, and activating AMPK-PKCι/λ signaling to repress CREB-CRTC2-driven PEPCK/G6Pase expression, disrupting these cycles. This leads to lactate, pyruvate, and ammonia buildup, triggering pro-inflammatory cascades: HIF-1α stabilization induces IL-6/VEGF, ROS from pyruvate excess activates NF-κB for TNF-α, and ammonia primes NLRP3 inflammasome for IL-1β/IL-18 release, fostering chronic inflammation. Multisystem consequences include musculoskeletal fatigue from ATP deficits, cognitive fog via neuroinflammation, atherosclerosis from endothelial dysfunction, hepatic fibrosis from urea cycle stress, and immune inflammaging impairing macrophage function. Clinical evidence reveals short-term anti-inflammatory benefits (reduced IL-6, CRP) via AMPK and microbiota effects, contrasted by long-term risks like lactic acidosis and neurodegeneration in renal-impaired or elderly patients. This review integrates physiological roles, molecular mechanisms, inflammatory pathways, systemic impacts, and clinical findings, highlighting metformin's dual-edged profile glycemic efficacy versus "inflammatory debt." Researchers are urged to explore precision interventions, such as antioxidants or biomarker-guided dosing, to optimize metformin's pleiotropic potential in T2DM and inflammaging-related disorders, redefining therapeutic paradigms.
2026-07-23 | Gut Microbiota Reshaping by Sparassis latifolia Polysaccharides Ameliorates Glucose Metabolism through Microbiota-Mediated Activation of Intestinal Gluconeogenesis.
Gut microbiota dysbiosis is a key contributor to glucose metabolism disorders. Sparassis latifolia polysaccharides (SLPs) may regulate microbiota-host metabolic interactions. Here, we evaluated the hypoglycemic effects of SLPs in mice with high-fat/high-sugar diet and streptozotocin-induced glucose metabolism disorders. SLPs improved glucose tolerance, reduced fasting blood glucose by approximately 40%, alleviated colonic injury, and restored gut microbiota-derived short-chain fatty acids (SCFAs). Metabolomics showed that SLPs mainly normalized purine metabolism, primary bile acid biosynthesis, and vitamin B6 metabolism. SLP treatment also modulated intestinal gluconeogenesis-related genes, proteins, and enzymes, Microbiota and coabundance group analyses indicated increased beneficial taxa, including Muribaculaceae and Bacteroides acidifaciens, and reduced CAG6 and CAG8 (Co-abundance group) taxa associated with impaired glucose tolerance. Cohabitation experiments suggested partial transmissibility of metabolic benefits. These findings suggest that SLPs improve glucose metabolism by remodeling gut microbiota and metabolites and enhancing PXR-SGK2-associated intestinal gluconeogenesis.
2026-06-26 | Sebacic Acid: A Multifunctional Medium-Chain Dicarboxylic Acid in Metabolic Regulation and Tissue Regeneration.
Sebacic acid (SA), a ten-carbon medium-chain dicarboxylic acid, has emerged as a multifunctional bioactive metabolite with potential applications in metabolic regulation and regenerative medicine. Evidence indicates that SA exerts anti-inflammatory effects by modulating nuclear factor kappa B (NF-kB), mitogen-activated protein kinase (MAPK), and signal transducer and activator of transcription (STAT) pathways, improves glucose homeostasis by enhancing mitochondrial function and suppressing hepatic gluconeogenesis, and contributes to lipid metabolism via peroxisomal and mitochondrial β-oxidation. Beyond metabolic regulation, SA promotes bone repair by stimulating osteoblast differentiation and inhibiting osteoclast activity, and supports muscle regeneration by enhancing energy supply, cell proliferation, and the microenvironment. SA also serves as a monomer for poly (glycerol sebacate) (PGS), enabling its use in biodegradable tissue engineering scaffolds. This review synthesizes current experimental and preclinical findings on the biological functions of SA, elucidates the underlying molecular mechanisms, and highlights its translational potential for the treatment of metabolic disorders and tissue regeneration.
proteins
2026-07-22 | Regulation and clinical manifestations of gluconeogenesis dysfunction.
The liver is the principal organ responsible for maintaining systemic glucose homeostasis through the integrated regulation of gluconeogenesis, glycogenolysis, glycogenesis, and glycolysis. As fasting progresses and hepatic glycogen stores decline, gluconeogenesis becomes the dominant source of endogenous glucose production required to preserve euglycemia. This review summarizes the regulation of gluconeogenesis and discusses the clinical manifestations, diagnostic implications, and therapeutic relevance of gluconeogenic dysfunction across diverse disease states.
2026-06-03 | Liver transcriptome data of T2DM rats treated with MOTS-C and aerobic exercise
Type 2 diabetes (T2DM) is a metabolic disease characterized by insulin resistance and liver glucose and lipid metabolism disorder. The liver, as the metabolic center of the body, plays a crucial role in the occurrence and development of T2DM. Previous studies have shown that aerobic exercise can significantly improve the metabolic status of T2DM patients, but its molecular mechanism has not been fully elucidated. In recent years, mitochondrial derived peptide MOTS-C has been shown to have the function of simulating exercise effects and regulating metabolic homeostasis. However, the combined intervention of MOTS-C and aerobic exercise on the transcriptome of T2DM liver still lacks systematic research. This project used high-fat diet combined with streptozotocin (STZ) - induced T2DM rats as a model, and administered MOTS-C intraperitoneal injection, aerobic treadmill exercise, and a combination of the two treatments. RNA seq technology was used to obtain liver transcriptome data for each group of rats. Through differential expression gene analysis, GO/KEGG enrichment analysis, and protein interaction network construction, key metabolic pathways and core genes were screened. Preliminary data shows that both MOTS-C and aerobic exercise intervention alone can partially reverse abnormal expression of gluconeogenesis, lipid synthesis, and inflammation related genes in the liver of T2DM rats; The combined intervention showed a synergistic effect, significantly enriched in the AMPK, PPAR, and insulin signaling pathways. Consistent with previous literature, exercise training can improve mitochondrial function by upregulating PGC-1 α, and this study found that MOTS-C can further enhance this effect. In addition, the combined intervention specifically regulated multiple novel long non coding RNAs, suggesting the existence of an epigenetic regulatory mechanism of motor MOTS-C cross-talk. The transcriptome data of this project provides important resources for revealing the molecular basis of MOTS-C simulation and enhancing exercise benefits, and also provides new ideas for developing "exercise mimetics" combination therapies for T2DM.
2026-05-09 | Hepatocyte estrogen-related receptor α modulates a gluconeogenic-epigenetic crosstalk counteracting MASLD/MASH progression.
Lactate has been recognized as a major fuel substrate and also a lactyl-group donor for histone lysine lactylation. Hepatocytes act as lactate-consuming cells owing the high oxidative capability especially during exercise, a primary nonpharmacological intervention for alleviating metabolic dysfunction-associated steatotic liver diseases including steatohepatitis (MASLD/MASH). However, little is known regarding how lactate links the metabolic-epigenetic axis in hepatocytes. Here we show that declined estrogen-related receptor α (ESRRA) expression occur in MASLD/MASH accompanied with elevated levels of lactate and histone lactylation, particularly H3K18la. Such dysregulation can be partially rescued by chronic exercise in aged mice or exacerbated by genetic ablation of hepatocyte ESRRA. Mechanistically, exercise-induced ESRRA/PPARGC1A facilitates lactate consumption through transcriptional regulation of lactate dehydrogenase B and glucose-6-phosphatase catalytic subunit 1, rewiring lactate from a lactyl donor to gluconeogenic precursor in hepatocytes. Hepatocyte-specific ESRRA overexpression counteracts MASLD/MASH progression in mice, rectifying aberrant H3K18la accumulation and its marked gene transcripts that are involved in liver pathology. Our findings reveal that ESRRA functions as an exercise executor linking metabolism with epigenetic modification, highlighting a gluconeogenic-epigenetic regulatory axis that could be fine-tuned to mitigate risk factors of MASLD/MASH such as aging, menopause, a sedentary lifestyle and malnutrition.
2026-01-19 | Cytosolic Phosphoenoylpyruvate Carboxykinase Deficiency: Clinical, Biochemical, and Genetic Features of Five Non-Finnish Patients.
Cytosolic phosphoenoylpyruvate carboxykinase (PEPCK-C) is an essential, rate-limiting enzyme in the gluconeogenesis pathway. PEPCK-C deficiency presents with hypoglycaemia, hyperlactataemia and hepatopathy, and was first reported in association with bi-allelic PCK1 variants in 2014. A Finnish cohort with a common homozygous variant (c.925G>A, p.(Gly309Arg)) is well-described, but few other genotypes are reported. Five non-Finnish probands with PEPCK-C deficiency with novel genotypes are presented. All five presented with hypoglycaemia (hypoketotic in three), lactic acidosis, and elevated transaminases. Age at presentation was newborn to 3 years. Two presented with hypoglycaemic seizures after overnight fasting during intercurrent infection. Prominent renal manifestations were noted in two, including proximal tubulopathy with bicarbonate wasting, and acute renal failure, respectively, with markedly elevated plasma glutamine in both. Urine organic acid analysis identified elevated lactate, dicarboxylic aciduria, and tricarboxylic acid cycle metabolites, especially fumarate which was detected in 3/5. PCK1 genotypes included homozygous missense variants c.1211C>T, p.(Ser404Leu) and c.265G>A, p.(Glu89Lys), or compound heterozygous variants including c.824del, p.(Gly275Valfs21); c.496G>A, p.(Val166Met); c.961 + 2 T>C; c.204del, p.(Leu69), and c.728A>G p.(Lys243Arg). A severe phenotype with failure to thrive, short fasting tolerance, liver dysfunction, and tubulopathy was noted in one individual harboring compound heterozygous splicing and nonsense variants. Evidence from in silico analyses and the specific phenotype supported the pathogenicity of novel missense variants. These patients reinforce the recognizable presentation of PEPCK-C deficiency while highlighting renal manifestations and expanding the genotypic spectrum.
2025-11-29 | The beneficial effect of hepatic ER stress-associated protein PDI on obesity-associated glucose dysregulation.
The liver plays critical roles in glucose metabolism regulation. Accumulating evidence supported that endoplasmic reticulum (ER) stress in liver tissue may involve in the development of type 2 diabetes. However, the role of ER stress-associated proteins in diabetes still needs to be clarified. Genome-wide DNA methylome and proteome in the liver biopsies from patients with or without type 2 diabetes were performed and further validated by pyro-sequencing, real-time PCR and western blots. Circulating protein disulfide isomerase (PDI) levels at baseline and postoperative follow-up were measured by ELISA. The glucose tolerance, metabolic gene expression, glycogen deposition, glycogenesis and ER stress-associated proteins were detected in adeno-associated virus (AAV)-treated high fat-diet (HFD) mice. Based on methylome and proteome analysis, we identified the hypermethylation of PDI gene in liver biopsies, concomitant with decreased mRNA expression and protein levels in diabetic group compared with non-diabetic group. Circulating PDI levels were lower in patients with diabetes and elevated after metabolic surgery. The decreased PDI expression was correlated with increased gluconeogenesis and reduced glycogen synthesis in human liver tissue. Furthermore, hepatic PDI downregulation aggravated hyperglycemia, whereas PDI overexpression ameliorated glucose intolerance, decreased glycogen deposition and increased glycogenesis in HFD mice. We identified the beneficial effect of ER stress-associated protein PDI on the regulation of hepatic glucose metabolism, which is expected to be a potential therapeutic target against type 2 diabetes, and provided an important clue for better understanding ER stress in the pathogenesis of diabetes. The study was registered on ClinicalTrials.gov (NCT03296605). The online version contains supplementary material available at 10.1186/s12986-025-01041-9.
gene therapies
2026-06-22 | Holocarboxylase synthetase deficiency: pathogenesis, clinical features, diagnosis, treatment, and research prospects.
Holocarboxylase Synthetase Deficiency (HLCSD) is a rare autosomal recessive inborn error of metabolism caused by biallelic mutations in the HLCS gene. The encoded enzyme, holocarboxylase synthetase (HLCS), plays a critical role in biotin metabolism by activating five essential carboxylases, including pyruvate carboxylase (PC) and propionyl-CoA carboxylase (PCC), thereby regulating key processes such as gluconeogenesis, fatty acid synthesis, and branched-chain amino acid catabolism [1, 14]. HLCS dysfunction leads to the accumulation of toxic metabolites (e.g., 3-hydroxyisovaleric acid, methylcitric acid), resulting in severe manifestations like metabolic acidosis and hyperammonemia [6]. This review systematically consolidates current knowledge on the molecular mechanisms, clinical spectrum, diagnostic approaches, and therapeutic strategies for HLCSD. It critically addresses core controversies, including genotype-phenotype correlations and variability in biotin treatment response, and proposes a multidimensional "gene-enzyme activity-metabolic phenotype-treatment response" framework. Studies confirm that early diagnosis via newborn screening, coupled with standardized biotin supplementation, achieves biochemical normalization and clinical symptom resolution in over 85% of patients and reduces the risk of neurological sequelae [10, 33, 35]. However, biotin-unresponsive cases and rare phenotypes present ongoing diagnostic and therapeutic challenges, necessitating further exploration of novel interventions to advance the precision medicine approach for HLCSD. What is Known: • Holocarboxylase synthetase defi ciency (HLCSD) is a rare autosomal recessive metabolic disorder caused by HLCSbiallelic mutations, and biotin supplementation is the mainstream treatment for most patients. • Distinct population-specifi c HLCS mutation hotspots exist, and residual enzyme activity is closely correlated with disease severity and age of onset. What is New: • A multidimensional framework of gene-enzyme activity-metabolic phenotype-treatment response was proposed tointerpret phenotypic heterogeneity and variable biotin responsiveness in HLCSD. • This review systematically summarized rare clinical phenotypes, diagnostic pitfalls, emerging detection technologies and novel therapeutic directions including gene therapy and epigenetic intervention.
2026-06-04 | NgBR controls hepatic adiponectin signaling competence through KAT7-dependent chromatin regulation.
Adiponectin signaling is essential for hepatic glucose homeostasis, yet the molecular basis of adiponectin receptor responsiveness remains incompletely understood. Here, we identify the Nogo-B receptor (NgBR; NUS1) as a regulator of hepatic adiponectin sensitivity. Across human, cynomolgus monkey, and mouse datasets, hepatic NgBR expression is consistently reduced in obesity-associated diabetes, indicating a conserved metabolic signature. Hepatocyte-specific NgBR deletion abolishes the metabolic effects of the adiponectin agonist AdipoRon, resulting in impaired AMPK activation, persistent gluconeogenesis, and ceramide accumulation. Mechanistically, NgBR loss suppresses KAT7 expression and reduces histone acetylation at AdipoR1 and AdipoR2 promoters, thereby limiting receptor expression. Adeno-associated virus (AAV)-mediated restoration of hepatic NgBR reinstates KAT7-dependent chromatin activation, adiponectin receptor expression, and glucose homeostasis. These findings support a hepatocellular mechanism in which NgBR maintains adiponectin receptor competence and suggest a potential therapeutic strategy for restoring adiponectin responsiveness in metabolic disease.
2026-02-16 | Trial Interviews to Explore Glycogen Storage Disease Type Ia Patient Experiences Following Gene Therapy.
Glycogen storage disease type Ia (GSDIa) is a rare, inherited, autosomal recessive deficiency of glucose-6-phosphatase (G6Pase), an enzyme necessary in glycogenolysis and gluconeogenesis. To maintain normal blood glucose levels and ensure survival, individuals living with GSDIa must frequently consume complex carbohydrates (eg, uncooked cornstarch). Dietary management can result in chronic complications and significant patient burden. DTX401 (pariglasgene brecaparvovec) is an investigational adeno-associated virus serotype 8 vector (AAV8)-based gene therapy designed to restore endogenous glucose production. Patient experience interviews were conducted as part of an open-label, phase 1/2 dose-escalation trial (NCT03517085) evaluating the safety and efficacy of DTX401 in adults ≥18 years with GSDIa. Telephone interviews were conducted at Weeks 24, 52, and 104, using a semistructured interview guide. Qualitative interview data were audio recorded, transcribed, coded, and analyzed. Most (86%; n = 6/7) reported overall symptom improvement and reduced burden following DTX401 treatment. Three (43%) reported no negative outcomes following gene therapy; 4 (57%) mentioned at least one negative change attributed to instances of blood sugar instability, lifestyle, or diet adjustments. Satisfaction fluctuated across timepoints; however, most were somewhat satisfied/very satisfied with gene therapy at Weeks 24 (80%), 52 (86%), and 104 (86%). No participants reported being very dissatisfied. Following DTX401 treatment, most participants reported substantial reduction in cornstarch intake and corresponding improvements in symptoms, physical function, diet management, emotional function, self-perception, social function, sleep quality, work performance, and overall health. Few negative changes were reported. While some results regarding met expectations were mixed, most indicated they would still want gene therapy even if they had to continue cornstarch and if they had continued diet restrictions, and most reported satisfaction with treatment. While the study had limitations, interview results suggest that DTX401 helps to address aspects of the condition and treatment that patients have identified as burdensome. Most interviewees in this open-label trial of investigational DTX401 described positive experiences, including substantial reduction in burden and improved health-related quality of life following treatment throughout the trial. To optimize patient outcomes and experience with gene therapy, guidance on and close monitoring of dietary changes during implementation should be provided.
2026-01-14 | BMSC-derived extracellular vesicles affect gluconeogenesis and lipogenesis by releasing 5'-tRF-GlyCCC to improve MAFLD insulin sensitivity.
TsRNAs (tRNA-derived small RNAs) also known as tRNA-derived small RNAs, are a relatively new type of non-coding RNAs that have demonstrated promising effect in treating various liver diseases. However, the function of small extracellular vesicles (sEVs) secreted by human bone marrow mesenchymal stem cells (BMSCs) in safeguarding against metabolic-associated fatty liver disease (MAFLD) is still uncertain. In this research, we explored the effects of BMSCs sEVs on lipid metabolism using Palmitic Acid (PA)-induced HepG2 cells, both in the presence and absence of the sEVs inhibitor GW4869. Pandora sequencing and RNA sequencing were utilized to identify differentially expressed genes in sEVs and hepatocytes in vitro. Furthermore, we carried out in vivo studies involving male C57BL/6J mice that fed with high-fat diet (HFD) and either treated with an AAV 5'-tRF-GlyCCC mimic or not, through tail vein injection. Our findings revealed that BMSC-sEVs can relieve lipid accumulation in PA-caused HepG2 cells by inhibiting the formation of de novo fatty acid. We found that 5'-tRF-GlyCCC forms a direct connection with the 3' UTR of FoxO3, thereby decreasing the level of gluconeogenic genes PEPCK and G6Pase. Tail vein administration of the 5'-tRF-GlyCCC AAV alleviated liver gluconeogenesis and lipid metabolism issues in MAFLD mice by enhancing hepatic insulin sensitivity. The results imply that the 5'-tRF-GlyCCC/FoxO3 gluconeogenesis-signaling pathway could be crucial in the therapeutic benefits of BMSC sEVs on MAFLD.
2025-03-11 | Safety and Efficacy of DTX401, an AAV8-Mediated Liver-Directed Gene Therapy, in Adults With Glycogen Storage Disease Type I a (GSDIa).
Glycogen storage disease type Ia (GSDIa) is a rare, life-threatening, inherited carbohydrate metabolism disorder caused by glucose-6-phosphatase (G6Pase) deficiency, which is essential for glycogenolysis and gluconeogenesis. GSDIa management includes a strict medically prescribed diet that typically includes daily uncooked cornstarch doses, including overnight, to maintain euglycemia. DTX401 is an investigational adeno-associated virus serotype 8 vector expressing the human G6PC1 gene that encodes G6Pase. This open-label, phase 1/2, dose-escalation, 52-week gene therapy trial evaluated the safety and efficacy of a single DTX401 infusion in 12 adults with GSDIa (ClinicalTrials.gov Identifier: NCT03517085). Three participants in Cohort 1 received DTX401 2.0 × 1012 genome copies (GC)/kg, and three participants each in Cohorts 2, 3, and 4 received 6.0 × 1012 GC/kg. Corticosteroids were administered to mitigate vector‑induced inflammatory response. All participants experienced a treatment-emergent adverse event (TEAE) and a related TEAE. No participant experienced a dose-limiting toxicity, TEAE leading to study discontinuation, TEAE leading to death, or serious treatment-related TEAE. Mean (SD) time to hypoglycemia in minutes/gram of carbohydrate during a controlled fasting challenge was 5.0 (1.6) at baseline and 6.9 (2.7) at Week 52, a mean (SD) increase of 46% (72%). Mean total daily cornstarch intake was 284 g at baseline and 85 g at Week 52 in the 10 participants with available values at both time points, a mean (SD) total daily cornstarch intake reduction of 68% (20%); p < 0.001. DTX401 showed a favorable safety and efficacy profile at Week 52. Participants in all cohorts showed significant cornstarch need reductions from baseline to Week 52.
oligonucleotides
2026-08-08 | ApoC-III Antisense Oligonucleotide Therapy Used in Glycogen Storage Disease Type 1a.
Glycogen storage disease type 1a (GSD1a) is an autosomal recessive disorder characterized by impaired glycogenolysis and gluconeogenesis. Individuals with GSD1a manifest significant hypertriglyceridemia refractory to dietary and lipid-lowering medication therapies. Apolipoprotein C-III antisense oligonucleotide (apoCIII-ASO) therapy is approved to reduce severe hypertriglyceridemia in familial chylomicronemia syndrome but is also effective in moderate hypertriglyceridemia of varied genetic backgrounds. We describe a 22-year-old with GSD1a and hypertriglyceridemia with past pancreatitis despite fibric acid derivative, niacin, and bempedoic acid therapy in whom apoCIII-ASO was associated with triglyceride reduction from 4,951 to 1,643 mg/dL. As GSD1a-associated hypertriglyceridemia is often refractory to standard therapies, apoCIII-ASO therapy may offer promise as a treatment. This case describes the first use of apoCIII-ASO in GSD1a-related hypertriglyceridemia. GSD1a-driven hypertriglyceridemia may be treatable using apoCIII-ASO.
2026-05-15 | Galactosylated LNP-mediated hepatic Sam68 silencing improves glucose homeostasis in diabetes by suppressing gluconeogenesis.
Excessive hepatic glucose production is a key driver of the progression of type 2 diabetes (T2DM), a highly prevalent global metabolic disorder. We previously reported that Sam68 expression is upregulated in the livers of both diabetic patients and mouse models, and hepatocyte-specific knockdown of Sam68 greatly alleviates hyperglycemia and improves insulin sensitivity in diabetic mice. Here, we engineered a series of ligand-functionalized lipid nanoparticles (LNPs) and identified a galactose-decorated formulation (LNP-Gal) that enables efficient hepatocyte-selective delivery of Sam68 siRNA, thereby achieving robust Sam68 silencing and suppressing hepatic gluconeogenesis in both cellular and animal models. In both genetic and diet-induced diabetic mouse models, systemic administration of siSam68/LNP-Gal improved glycemic control and insulin responsiveness and attenuated hepatic gluconeogenic output, accompanied by suppression of the hepatic gluconeogenic program. Thus, we establish siSam68/LNP-Gal as a hepatocyte-selective siRNA delivery system that elicits a potent antihyperglycemic effect with a favorable safety profile in vitro and in vivo, providing a promising siRNA-based strategy for the treatment of T2DM and related metabolic disorders.
2025-04-11 | Identification of Shared Pathways and Molecules Between Type 2 Diabetes and Lung Adenocarcinoma and the Impact of High Glucose Environment on Lung Adenocarcinoma.
Objective: This research focused on exploring the shared pathophysiological bases of lung adenocarcinoma (LUAD) and Type 2 diabetes mellitus (T2DM). Methods: The investigation into the molecular similarities between LUAD and T2DM involved querying the Gene Expression Omnibus for pertinent data. Upon pinpointing genes exhibiting differential expression, pathway enrichment analyses were executed to discern the molecular pathways shared by both conditions. In addition, GeneMANIA was employed to establish a protein interaction network, pinpointing STK26 as a critical gene. In addition, the influence of STK26 on the immune environment of the tumor was examined using tools such as the Microenvironment Cell Populations-counter to assess levels of stromal and immune cells in cancer tissues from expression profiles. Furthermore, a lung cancer cell model enriched in glucose was developed to facilitate the knockdown of STK26 using small interfering RNA. The influence of STK26 on A549 cell functionality was assessed using CCK-8, wound healing (scratch), and colony formation (cloning) assays. Results: This will help ensure accuracy and relevance in the revised version. TGF-β, HIF-1, AGE-RAGE, extracellular matrix (ECM) components and function regulation, and cell adhesion were activated in LUAD and T2DM. WGCNA identified two main modules in LUAD, three main modules in T2DM, and 44 shared genes. ClueGO and GeneMANIA analyses focused on pathways regulating cell growth and mitosis. Our analysis revealed STK26 as a central gene that exhibits elevated expression levels in tissues affected by LUAD. Elevated expression of STK26 correlates with a diminished prognosis for LUAD patients. In patients with LUAD characterized by elevated STK26 levels, gene set enrichment analysis identified a notable upregulation in numerous metabolic pathways. These include glycolysis-gluconeogenesis, oxidative phosphorylation, and the conversion pathways between pentose and glucuronic acid, as well as the pentose phosphate pathway. Gene set variation analysis suggested that a high STK26 expression was related to glycolysis, hypoxia, MYC, oxidative phosphorylation, cell cycle, and citric acid cycle pathways. In the group exhibiting elevated levels of STK26, a marked upregulation of glycolytic pathway genes, including HK2, RPIA, IDH3G, and SORD, was noted. This upregulation indicates a correlation between STK26 expression and these pivotal glycolytic genes. MCP-counter analysis suggested that the group with a high STK26 expression level had reduced immune infiltration. Laboratory studies have demonstrated that LUAD cells thrive in a high-glucose setting, where STK26 expression notably surpasses that observed under standard conditions. In addition, suppressing STK26 using siRNA significantly curtails both the growth and movement of LUAD cells. Conclusion: The research established a shared pathogenic basis between LUAD and T2DM. TGF-β, HIF-1, AGE-RAGE, ECM components and function regulation, cell adhesion, and additional signaling pathways are intricately linked with the pathophysiological mechanisms underlying both LUAD and T2DM. Thus, STK26 may affect the development of LUAD and T2DM by regulating glucose metabolism. Suppressing STK26 in a glucose-rich setting curtailed both the expansion and mobility of LUAD cells.
2024-10-10 | Silencing the glycerol-3-phosphate acyltransferase-1 gene in the liver of mice fed a high-fat diet, enhances insulin sensitivity and glucose metabolism by promoting fatty acid beta-oxidation.
Liver plays a central role in systemic glucose and lipid metabolism. High-fat diet (HFD) and obesity are related to hepatic lipid accumulation and insulin resistance (InsR). Diacylglycerols (DAG) play a key role in the induction of InsR, however their involvement in hepatic InsR remains debated. This study aimed to clarify and confirm the role of glycero-3-phosphate acyltransferase 1 (GPAT1), a rate-limiting enzyme in DAG synthesis, in the progression of hepatic InsR in the context of HFD-induced lipid accumulation and insulin resistance in the liver. Liver-targeted GPAT1 silencing was performed using shRNA-mediated hydrodynamic gene delivery. Lipid species including LCA-CoA, sphingolipids, DAG and acyl-carnitines were quantified using UHPLC/MS/MS while insulin signalling was assessed at protein level by Western Blot. Hepatic glucose metabolism, including glucose-6-pasphate content and gluconeogenesis rate was evaluated using GC/MS. HFD-fed animals developed InsR, evidenced by increased HOMA-IR, enhanced gluconeogenesis and reduced glycogen content compared to controls. Hepatic GPAT1 silencing in HFD-fed animals resulted in a significant reduction of DAG and TAG levels, increased acyl-carnitines content and upregulated mitochondrial β-oxidation protein expression. These changes were accompanied by improved insulin signalling, enhanced glycogen storage, and reduced gluconeogenesis. Silencing GPAT1, and thereby reducing glycerolipid synthesis, promotes β-oxidation and ameliorates HFD-induced hepatic insulin resistance, confirming the enzyme's pivotal role in liver metabolic dysfunction associated with increased lipid supply.
2024-05-15 | MicroRNA-721 regulates gluconeogenesis via KDM2A-mediated epigenetic modulation in diet-induced insulin resistance in C57BL/6J mice.
Aberrant gluconeogenesis is considered among primary drivers of hyperglycemia under insulin resistant conditions, with multiple studies pointing towards epigenetic dysregulation. Here we examine the role of miR-721 and effect of epigenetic modulator laccaic acid on the regulation of gluconeogenesis under high fat diet induced insulin resistance. Reanalysis of miRNA profiling data of high-fat diet-induced insulin-resistant mice model, GEO dataset (GSE94799) revealed a significant upregulation of miR-721, which was further validated in invivo insulin resistance in mice and invitro insulin resistance in Hepa 1-6 cells. Interestingly, miR-721 mimic increased glucose production in Hepa 1-6 cells via activation of FOXO1 regulated gluconeogenic program. Concomitantly, inhibition of miR-721 reduced glucose production in palmitate induced insulin resistant Hepa 1-6 cells by blunting the FOXO1 induced gluconeogenesis. Intriguingly, at epigenetic level, enrichment of the transcriptional activation mark H3K36me2 got decreased around the FOXO1 promoter. Additionally, identifying targets of miR-721 using miRDB.org showed H3K36me2 demethylase KDM2A as a potential target. Notably, miR-721 inhibitor enhanced KDM2A expression which correlated with H3K36me2 enrichment around FOXO1 promoter and the downstream activation of the gluconeogenic pathway. Furthermore, inhibition of miR-721 in high-fat diet-induced insulin-resistant mice resulted in restoration of KDM2A levels, concomitantly reducing FOXO1, PCK1, and G6PC expression, attenuating gluconeogenesis, hyperglycemia, and improving glucose tolerance. Interestingly, the epigenetic modulator laccaic acid also reduced the hepatic miR-721 expression and improved KDM2A expression, supporting our earlier report that laccaic acid attenuates insulin resistance by reducing gluconeogenesis. Our study unveils the role of miR-721 in regulating gluconeogenesis through KDM2A and FOXO1 under insulin resistance, pointing towards significant clinical and therapeutic implications for metabolic disorders. Moreover, the promising impact of laccaic acid highlights its potential as a valuable intervention in managing insulin resistance-associated metabolic diseases.
other
2026-03-14 | PHYSIOLOGICAL ROLES OF THE LIVER AND PANCREAS: INTEGRATED FUNCTIONS IN METABOLISM, DIGESTION, ENDOCRINE REGULATION, AND DETOXIFICATION
The liver and pancreas are the two largest accessory digestive glands in the human body and among the most metabolically versatile organs. The liver, weighing approximately 1.5 kg and receiving a dual blood supply from the portal vein and hepatic artery, performs over 500 distinct physiological functions. The pancreas, a mixed exocrine–endocrine gland of approximately 80–100 g, produces digestive enzymes that hydrolyze all major macronutrients and secretes the hormones insulin, glucagon, and somatostatin that maintain blood glucose homeostasis. Dysregulation of either organ underlies some of the most common and lethal diseases encountered in clinical medicine, including non-alcoholic fatty liver disease (NAFLD), cirrhosis, diabetes mellitus, and pancreatic adenocarcinoma. Objective: To provide a comprehensive, evidence-based review of the integrated physiological roles of the liver and pancreas, including their roles in macronutrient metabolism, bile acid physiology, detoxification, endocrine regulation of glucose homeostasis, and the pathophysiological consequences of organ dysfunction. Methods: A systematic review of eight primary peer-reviewed sources was conducted, encompassing original research articles, authoritative textbooks, meta-analyses, and clinical guidelines published between 1998 and 2024. Results: Hepatocytes, the principal parenchymal cells of the liver, perform glycogenesis, gluconeogenesis, fatty acid oxidation, urea synthesis, bile acid conjugation, and phase I/II biotransformation of xenobiotics via the cytochrome P450 (CYP) enzyme system. The exocrine pancreas secretes 1.5–2.5 L of bicarbonate-rich fluid daily containing proteases (trypsinogen, chymotrypsinogen), lipases, and amylases, regulated by cholecystokinin (CCK) and secretin. Pancreatic β-cells release insulin in a biphasic pattern in response to glucose, while α-cells secrete glucagon during hypoglycemia, and δ-cells release somatostatin to modulate both. The enteroinsular axis, mediated by GLP-1 and GIP incretin hormones, amplifies postprandial insulin secretion by 50–70% of the total insulin response. Conclusion: The liver and pancreas operate as a functionally integrated unit, coordinating nutrient absorption, macronutrient metabolism, and glucose homeostasis through hormonal, neural, and paracrine signaling networks. Understanding their physiological interdependence is essential for the rational management of metabolic, digestive, and endocrine disorders.
2025-03-12 | Adipose stromal cells increase insulin sensitivity and decrease liver gluconeogenesis in a mouse model of type 1 diabetes mellitus.
Diabetic ketoacidosis (DKA) is a serious complication of hyperglycemic emergency caused by insulin deficiency through accelerated liver gluconeogenesis and glycogenolysis. DKA is most common in type 1 diabetes (T1D). Transplantation of islet cells and pancreas is an alternative to insulin injection for treating T1D. However, this alternative is only suitable for some patients. This study investigated the effects and mechanisms of adipose stromal vascular fraction (SVF) cells on liver gluconeogenesis and insulin sensitivity in an insulin-dependent T1D animal model. SVF cells were obtained from wild-type inguinal adipose tissue and transplanted into the peritoneal cavity of type I diabetic Akita (Ins2Akita) mice. We found that transplantation of 5 × 106 SVF cells from wild-type adipose tissue significantly downregulated proinflammatory genes of TNF-α, IL-1β, IL-33, iNOS, and DPP4 in the liver and upregulated anti-inflammatory factors IL-10 and FOXP3 in blood serum and liver tissue 7 days after injection. Moreover, we found that the expression levels of G6pc and Pck1 were significantly decreased in the Akita mice livers. Furthermore, the intraperitoneal insulin tolerance test assay showed that diabetic Akita mice significantly had increased insulin sensitivity, reduced fasting blood glucose, and restored glucose-responsive C-peptide expression compared with the control Akita group. This result was noted 14 days after administration of 5 × 106 or 1 × 107 SVF cells from wild-type adipose tissue into diabetic Akita mice. Together, these findings suggest that adipose tissue-derived SVF cells could suppress liver inflammation, regulate liver gluconeogenesis, and improve insulin sensitivity in an animal model with T1D. Therefore, adipose SVF cells may be novel cellular therapeutic alternatives to maintain steady liver gluconeogenesis in T1D.
2024-12-09 | MicroRNAs Dependent G-ELNs Based Intervention Improves Glucose and Fatty Acid Metabolism While Protecting Pancreatic β-Cells in Type 2 Diabetic Mice.
Metabolic disorders such as Type 2 diabetes mellitus (T2DM) imposes a significant global health burden. Plant-derived exosome like nanoparticles (P-ELNs) have emerged as a promising therapeutic alternate for various diseases. Present data demonstrates that treatment with Ginger-derived exosome like nanoparticles (G-ELNs) enhance insulin dependent glucose uptake, downregulate gluconeogenesis and oxidative stress in insulin resistant HepG2 cells. Furthermore, oral administration of G-ELNs in T2DM mice decreases fasting blood glucose levels and improves glucose tolerance as effectively as metformin. These improvements are attributed to the enhanced phosphorylation of Protein kinase B (Akt-2), the phosphatidylinositol 3-kinase at serine 474 which consequently leads to increase in hepatic insulin sensitivity, improvement in glucose homeostasis and decrease in ectopic fat deposition. Oral administration of G-ELNs also exerts protective effect on Streptozotocin (STZ)-induced pancreatic β-cells damage, contributing to systemic amelioration of T2DM. Further, as per computational tools, miRNAs present in G-ELNs modulate the phosphatidylinositol 3-kinase (PI3K)/Akt-2 pathway and exhibit strong interactions with various target mRNAs responsible for hepatic gluconeogenesis, ectopic fat deposition and oxidative stress. Furthermore, synthetic mimic of G-ELNs miRNA effectively downregulates its target mRNA in insulin resistant HepG2 cells. Overall, the results indicate that the miRNAs present in G-ELNs target hepatic metabolism thus, exerting therapeutic effects in T2DM.
2024-10-29 | VEGFB ameliorates insulin resistance in NAFLD via the PI3K/AKT signal pathway.
Non-alcoholic fatty liver disease (NAFLD) is one of the most universal liver diseases with complicated pathogenesis throughout the world. Insulin resistance is a leading risk factor that contributes to the development of NAFLD. Vascular endothelial growth factor B (VEGFB) was described by researchers as contributing to regulating lipid metabolic disorders. Here, we investigated VEGFB as a main target to regulate insulin resistance and metabolic syndrome. In this study, bioinformatics, transcriptomics, morphological experiments, and molecular biology were used to explore the role of VEGFB in regulating insulin resistance in NAFLD and its molecular mechanism based on human samples, animal models, and cell models. RNA-seq was performed to analyze the signal pathways associated with VEGFB and NAFLD; Palmitic acid and High-fat diet were used to induce insulin-resistant HepG2 cells model and NAFLD animal model. Intracellular glucolipid contents, glucose uptake, hepatic and serum glucose and lipid levels were examined by Microassay and Elisa. Hematoxylin-eosin staining, Oil Red O staining, and Periodic acid-schiff staining were used to analyze the hepatic steatosis, lipid droplet, and glycogen content in the liver. Western blot and quantitative real-time fluorescent PCR were used to verify the expression levels of the VEGFB and insulin resistance-related signals PI3K/AKT pathway. We observed that VEGFB is genetically associated with NAFLD and the PI3K/AKT signal pathway. After VEGFB knockout, glucolipids levels were increased, and glucose uptake ability was decreased in insulin-resistant HepG2 cells. Meanwhile, body weight, blood glucose, blood lipids, and hepatic glucose of NAFLD mice were increased, and hepatic glycogen, glucose tolerance, and insulin sensitivity were decreased. Moreover, VEGFB overexpression reduced glucolipids and insulin resistance levels in HepG2 cells. Specifically, VEGFB/VEGFR1 activates the PI3K/AKT signals by activating p-IRS1Ser307 expression, inhibiting p-FOXO1pS256 and p-GSK3Ser9 expressions to reduce gluconeogenesis and glycogen synthesis in the liver. Moreover, VEGFB could also enhance the expression level of GLUT2 to accelerate glucose transport and reduce blood glucose levels, maintaining glucose homeostasis. Our studies suggest that VEGFB could present a novel strategy for treating NAFLD as a positive factor.
2024-10-14 | A rare case of fructose-1, 6-bisphosphatase deficiency: Clinical features in a pediatric patient.
Fructose-1, 6- bisphosphatase deficiency is a rare autosomal recessive inborn error of fructose metabolism which mainly affects gluconeogenesis. It often presents with ketotic hypoglycemia and lactic acidosis, with hyperventilation. The disease has a high mortality rate when undiagnosed. Here we report a case of this rare disorder, referred to our hospital in Western Nepal, diagnosed originally as pneumonia. The patient presented in respiratory distress with severe metabolic acidosis and dehydration. She also demonstrated hypoglycemia, hypernatremia, coagulation dysfunction and albuminuria, all of which gradually improved, though her lactate remained consistently elevated. This led to investigation of urinary ketones which were positive suggesting a defect in the metabolism of carbohydrates. Urine organic acid profile and whole exome sequencing finally confirmed the diagnosis of Fructose-1, 6- bisphosphatase deficiency. To our knowledge this is the first case report of this disease diagnosed in Nepal.
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