Hepatic Gluconeogenesis Research Articles

Oxyberberine Inhibits Hepatic Gluconeogenesis via AMPK-Mediated Suppression of FoxO1 and CRTC2 Signaling Axes.

Oxyberberine (OBB), a natural metabolite of berberine, has been shown to exhibit inhibitory effects on gluconeogenesis in our previous work. This work was designed to investigate the potential effects and underlying mechanisms of OBB on hepatic gluconeogenesis. Our work found that OBB significantly inhibited the expressions of glucose 6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK), and decreased the glucose production in palmitic acid-induced HepG2 cells. Then, AMPK/Akt/FoxO1 and AMPK/CRTC2 signaling pathways were confirmed by transcriptomics and network pharmacology analyses. It was shown that AMPK activation may phosphorylate and promote nuclear exclusion of FoxO1 and CRTC2, two key regulators of hepatic gluconeogenesis transcriptional pathways, resulting in the inhibition of gluconeogenesis under OBB administration. Afterwards, AMPK/Akt/FoxO1, AMPK/CRTC2 signaling pathways were evidenced by western blot, immunoprecipitation and confocal immunofluorescence, and the targeted inhibitor (Compound C) and siRNA of AMPK were applied for further mechanism verification. Moreover, it was found that OBB treatment activated AMPK/Akt/FoxO1 and AMPK/CRTC2 signaling pathways to decrease hepatic gluconeogenesis in db/db mice. Similarly, the invivo inhibitory effects of OBB on gluconeogenesis were also diminished by AMPK inhibition. Our work demonstrated that OBB can inhibit hepatic gluconeogenesis invitro and invivo, and its underlying mechanisms were associated with AMPK-mediated suppression of FoxO1 and CRTC2 signaling axes.

A detailed review on some effects of turmeric curcuminoids on inflammation in obese individuals

Turmeric, derived from Curcuma longa, contains curcuminoids, notably curcumin, renowned for its anti-inflammatory and antioxidant properties. This review explores turmeric curcuminoids, focusing on curcumin, as potential remedies for obesity-related inflammation and associated disorders. The urgency to address obesity-related health risks is emphasized, with elevated BMI correlating with increased morbidity and mortality. Current obesity management strategies involve dietary changes, physical activity, and, sometimes, pharmacotherapy. Research suggests curcumin's role in significant weight loss and lean tissue mass augmentation, inhibiting adipogenesis-related proteins and increasing basal metabolic rate. The intricate connection between obesity and type 2 diabetes is examined, highlighting curcumin's impact on glucose homeostasis, hepatic gluconeogenesis, and lipid metabolism. Additionally, curcumin's anti-inflammatory effects, including modulation of pro-inflammatory cytokines and the NFkB pathway, demonstrate therapeutic potential. Clinical studies indicate curcumin's positive effects in reducing inflammatory markers and rebalancing adipokines in overweight and obese individuals, showing promise for addressing obesity-related inflammation and associated health risks. This review aims to investigate the potential role of turmeric curcuminoids, particularly curcumin, as remedies for obesity-related inflammation and associated disorders in obese individuals.

Advances in Research on the Anticancer Properties and Mechanisms of Metformin in Lung Cancer.

Lung cancer is a leading cause of death globally with high mortality and morbidity. Patients are often diagnosed at an advanced stage. Metformin has become a primary medication used in the clinical management of type 2 diabetes mellitus (T2DM) due to its relative safety, low cost, and effectiveness, mainly exerting its hypoglycemic effect by inhibiting hepatic gluconeogenesis and insulin resistance. Research data indicate that metformin extends the distant metastasis-free survival (DMFS) and progression-free survival (PFS) of diabetic patients with lung cancer, improving overall survival rates. Metformin lowers the risk of tumour development through various mechanisms, including the adenosine 5'-monophosphate-activated protein kinase/liver kinase B1/mechanistic target of rapamycin (AMPK/LKB1/mTOR) pathway, insulin-like growth factor-1 receptor pathway, apoptosis, and autophagy. However, research findings are not entirely consistent. This article reviews the research progress of metformin in terms of lung cancer treatment within the past few years, aiming to provide a more comprehensive understanding of how metformin exerts its anti-cancer impact and how it can be clinically applied, as well as provide new insights for lung cancer treatment.

Association of antipsychotic drugs on type 2 diabetes mellitus risk in patients with schizophrenia: a population-based cohort and in vitro glucose homeostasis-related gene expression study

BackgroundType 2 diabetes mellitus (T2DM) and its related complications are associated with schizophrenia. However, the relationship between antipsychotic medications (APs) and T2DM risk remains unclear. In this population-based, retrospective cohort study across the country, we investigated schizophrenia and the effect of APs on the risk of T2DM, and glucose homeostasis-related gene expression.MethodsWe used information from the Longitudinal Health Insurance Database of Taiwan for individuals newly diagnosed with schizophrenia (N = 4,606) and a disease-free control cohort (N = 4,606). The differences in rates of development of T2DM between the two cohorts were assessed using a Cox proportional hazards regression model. The effects of APs on the expression of glucose homeostasis-related genes in liver and muscle cell lines were assessed using quantitative real-time PCR.ResultsAfter controlling potential associated confounding factors, the risk of T2DM was higher in the case group than that in the control group [adjusted hazard ratio (aHR), 1.80, p < 0.001]. Moreover, the likelihood of T2DM incidence in patients with schizophrenia without AP treatment (aHR, 2.83) was significantly higher than that in non-schizophrenia controls and those treated with APs (aHR ≤ 0.60). In an in vitro model, most APs did not affect the expression of hepatic gluconeogenesis genes but upregulated those beneficial for glucose homeostasis in muscle cells.ConclusionThis study demonstrates the impact of schizophrenia and APs and the risk of developing T2DM in Asian populations. Unmeasured confounding risk factors for T2DM may not have been included in the study. These findings may help psychiatric practitioners identify patients at risk of developing T2DM.

Metformin: Diverse molecular mechanisms, gastrointestinal effects and overcoming intolerance in type 2 Diabetes Mellitus: A review.

Metformin, the first line treatment for patients with type 2 diabetes mellitus, has alternative novel roles, including cancer and diabetes prevention. This narrative review aims to explore its diverse mechanisms, effects and intolerance, using sources obtained by searching Scopus, PubMed and Web of Science databases, and following Scale for the Assessment of Narrative Review Articles reporting guidelines. Metformin exerts it actions through duration influenced, and organ specific, diverse mechanisms. Its use is associated with inhibition of hepatic gluconeogenesis targeted by mitochondria and lysosomes, reduction of cholesterol levels involving brown adipose tissue, weight reduction influenced by growth differentiation factor 15 and novel commensal bacteria, in addition to counteraction of meta-inflammation alongside immuno-modulation. Interactions with the gastrointestinal tract include alteration of gut microbiota, enhancement of glucose uptake and glucagon like peptide 1 and reduction of bile acid absorption. Though beneficial, they may be linked to intolerance. Metformin related gastrointestinal adverse effects are associated with dose escalation, immediate release formulations, gut microbiota alteration, epigenetic predisposition, inhibition of organic cation transporters in addition to interactions with serotonin, histamine and the enterohepatic circulation. Potentially effective measures to overcome intolerance encompasses carefully objective targeted dose escalation, prescription of fixed dose combination, microbiome modulators and prebiotics, in addition to use of extended release formulations.

Effects of Zeaxanthin on the Insulin Resistance and Gut Microbiota of High-Fat-Diet-Induced Obese Mice.

Obesity-induced insulin resistance (IR) can precipitate metabolic disorders such as diabetes. Zeaxanthin, a crucial member of the carotenoid family, has been found to mitigate the damage caused by obesity. However, reports on the effects of zeaxanthin on obesity-induced IR are lacking. Our objective was to examine the metabolic regulatory impacts of zeaxanthin on mice subjected to a high-fat diet (HFD) that triggered IR and to explore their influence on gut microbiota regulation. This study constructed a mouse model of metabolic dysfunction caused by lipid-rich nutritional patterns to investigate physiological and biochemical indices, liver pathway expression, and the intestinal microbiota. The mechanisms by which zeaxanthin improved both IR and glucose metabolic disorders were elucidated. The results demonstrate that zeaxanthin effectively suppressed obesity. The fasting blood glucose, area under curve of oral glucose tolerance test and insulin tolerance test, and homeostatic model assessment-insulin resistance (HOMA-IR) indices in the HFDZEA group decreased by 14.9%, 25.2%, 28.9%, and 29.8%. Additionally, zeaxanthin improved the lipid metabolism and alleviated damage to the liver and pancreas while also activating the PI3K/Akt pathway, regulating hepatic gluconeogenesis and the glycogen metabolism. The number of OTUs in the HFDZEA group increased by 29.04%. Zeaxanthin improved the structure and profile of the gastrointestinal microbiome and enhanced its diversity, increasing probiotics abundance, decreasing pathogen abundance, and thereby ameliorating the dysbiosis of enteric microbial communities in rodents with obesity resulting from excessive fat consumption. The outcomes of our analysis provide a rational basis for advancing zeaxanthin-based nutritional products.

Metformin restores autophagic flux and mitochondrial function in late passage myoblast to impede age-related muscle loss

Sarcopenia, which refers to age-related muscle loss, presents a significant challenge for the aging population. Age-related changes that contribute to sarcopenia include cellular senescence, decreased muscle stem cell number and regenerative capacity, impaired autophagy, and mitochondrial dysfunction. Metformin, an anti-diabetic agent, activates AMP-activated protein kinase (AMPK) and affects various cellular processes in addition to reducing hepatic gluconeogenesis, lowering blood glucose levels, and improving insulin resistance. However, its effect on skeletal muscle cells remains unclear. This study aimed to investigate the effects of metformin on age-related muscle loss using a late passage C2C12 cell model. The results demonstrated that metformin alleviated hallmarks of cellular senescence, including SA-β-gal activity and p21 overexpression. Moreover, treatment with pharmacological concentrations of metformin restored the reduced differentiation capacity in late passage cells, evident through increased myotube formation ability and enhanced expression of myogenic differentiation markers such as MyoD, MyoG, and MHC. These effects of metformin were attributed to enhanced autophagic activity, normalization of mitochondrial membrane potential, and improved mitochondrial respiratory capacity. These results suggest that pharmacological concentrations of metformin alleviate the hallmarks of cellular senescence, restore differentiation capacity, and improve autophagic flux and mitochondrial function. These findings support the potential use of metformin for the treatment of sarcopenia.

BCKDH kinase promotes hepatic gluconeogenesis independent of BCKDHA

Elevated circulating branched-chain amino acids (BCAAs) are tightly linked to an increased risk in the development of type 2 diabetes mellitus. The rate limiting enzyme of BCAA catabolism branched-chain α-ketoacid dehydrogenase (BCKDH) is phosphorylated at E1α subunit (BCKDHA) by its kinase (BCKDK) and inactivated. Here, the liver-specific BCKDK or BCKDHA knockout mice displayed normal glucose tolerance and insulin sensitivity. However, knockout of BCKDK in the liver inhibited hepatic glucose production as well as the expression of key gluconeogenic enzymes. No abnormal gluconeogenesis was found in mice lacking hepatic BCKDHA. Consistent with the vivo results, BT2-mediated inhibition or genetic knockdown of BCKDK decreased hepatic glucose production and gluconeogenic gene expressions in primary mouse hepatocytes while BCKDK overexpression exhibited an opposite effect. Whereas, gluconeogenic gene expressions were not altered in BCKDHA-silenced hepatocytes. Mechanistically, BT2 treatment attenuated the interaction of cAMP response element binding protein (CREB) with CREB-binding protein and promoted FOXO1 protein degradation by increasing its ubiquitination. Our findings suggest that BCKDK regulates hepatic gluconeogenesis through CREB and FOXO1 signalings, independent of BCKDHA-mediated BCAA catabolism.

Fibroblast growth factor 1 (FGF1) improves glucose homeostasis, modulates gut microbial composition, and reduces inflammatory responses in rainbow trout (Oncorhynchus mykiss) fed a high-fat diet

High-fat diets (HFDs) are widely used in aquaculture due to their lipid and protein-conserving effects, thereby reducing feed costs. However, prolonged feeding of HFD often leads to metabolic disorders in fish, such as disruption of hepatic lipid homeostasis, liver injury, and disruption of glucose homeostasis. Fibroblast growth factor 1 (FGF1) plays an essential role in controlling glucose levels in the body and dampening immune reactions. However, its impact on teleosts remains poorly researched. The therapeutic potential of recombinant FGF1 (rFGF1) was examined in a 6-week culture experiment involving rainbow trout (Oncorhynchus mykiss) that were fed an HFD. The results revealed that rFGF1 significantly reduced serum glucose levels and hepatic PEPCK and G6PC activities, but improved hepatic glycogen (P < 0.05), compared to the HFD + PBS group. Further experiments indicated that the inhibitory effect of rFGF1 on hepatic gluconeogenesis was mediated by the cAMP signaling pathway and was dependent on the high expression of PDE4D. In addition, rFGF1 increased hepatic glycogen content, which involves the AKT-GSK3β axis. Despite this increase, rFGF1 did not lead to glycogen storage disease, as shown by reduced hepatic inflammation as a result of decreased GOT (glutamic oxaloacetic transaminase), GPT (glutamic pyruvic transaminase), and elevated SOD (superoxide dismutase) in the rFGF1-treated group, accompanied by decreased il-1β, il-6, and xbp-1, and elevated nrf2 and number of hepatocyte autophagosomes. Alterations in gut microbes and short-chain fatty acids (SCFAs) were noted, indicating that rFGF1 caused a notable rise in intestinal Lactobacillus, acetic acid, and butyric acid levels. This study investigated the molecular mechanisms of rFGF1 on glucose metabolism and inflammatory responses in an HFD-fed rainbow trout model, providing new insights to improve the regulation of glucose metabolism in carnivorous fish.

Hypoxanthine ameliorates diet-induced insulin resistance by improving hepatic lipid metabolism and gluconeogenesis via AMPK/mTOR/PPARα pathway

AimInsulin resistance (IR) is a pivotal metabolic disorder associated with type 2 diabetes and metabolic syndrome. This study investigated the potential of hypoxanthine (Hx), a purine metabolite and uric acid precursor, in ameliorating IR and regulating hepatic glucose and lipid metabolism. MethodsWe utilized both in vitro IR-HepG2 cells and in vivo diet-induced IR mice to investigate the impact of Hx. The HepG2 cells were treated with Hx to evaluate its effects on glucose production and lipid deposition. Activity-based protein profiling (ABPP) was applied to identify Hx-target proteins and the underlying pathways. In vivo studies involved administration of Hx to IR mice, followed by assessments of IR-associated indices, with explores on the potential regulating mechanisms on hepatic glucose and lipid metabolism. Key findingsHx intervention significantly reduced glucose production and lipid deposition in a dose-dependent manner without affecting cell viability in IR-HepG2 cells. ABPP identified key Hx-target proteins engaged in fatty acid and pyruvate metabolism. In vivo, Hx treatment reduced IR severities, as evidenced by decreased HOMA-IR, fasting blood glucose, and serum lipid profiles. Histological assessments confirmed reduced liver lipid deposition. Mechanistic insights revealed that Hx suppresses hepatic gluconeogenesis and fatty acid synthesis, and promotes fatty acid oxidation via the AMPK/mTOR/PPARα pathway. SignificanceThis study delineates a novel role of Hx in regulating hepatic metabolism, offering a potential therapeutic strategy for IR and associated metabolic disorders. The findings provide a foundation for further investigation into the role of purine metabolites in metabolic regulation and their clinical implications.

ZBED3 exacerbates hyperglycemia by promoting hepatic gluconeogenesis through CREB signaling

BackgroundElevated hepatic glucose production (HGP) is a prominent manifestation of impaired hepatic glucose metabolism in individuals with diabetes. Increased hepatic gluconeogenesis plays a pivotal role in the dysregulation of hepatic glucose metabolism and contributes significantly to fasting hyperglycemia in diabetes. Previous studies have identified zinc-finger BED domain-containing 3 (ZBED3) as a risk gene for type 2 diabetes (T2DM), and its single nucleotide polymorphism (SNPs) is closely associated with the fasting blood glucose level, suggesting a potential correlation between ZBED3 and the onset of diabetes. This study primarily explores the effect of ZBED3 on hepatic gluconeogenesis and analyzes the relevant signaling pathways that regulate hepatic gluconeogenesis. MethodsThe expression level of ZBED3 was assessed in the liver of insulin-resistant (IR)-related disease. RNA-seq and bioinformatics analyses were employed to examine the ZBED3-related pathway that modulated HGP. To investigate the role of ZBED3 in hepatic gluconeogenesis, the expression of ZBED3 was manipulated by upregulation or silencing using adeno-associated virus (AAV) in mouse primary hepatocytes (MPHs) and HHL-5 cells. In vivo, hepatocyte-specific ZBED3 knockout mice were generated. Moreover, AAV8 was employed to achieve hepatocyte-specific overexpression and knockdown of ZBED3 in C57BL/6 and db/db mice. Immunoprecipitation and mass spectrometry (IP-MS) analyses were employed to identify proteins that interacted with ZBED3. Co-immunoprecipitation (co-IP), glutathione S-transferase (GST) - pulldown, and dual-luciferase reporter assays were conducted to further elucidate the underlying mechanism of ZBED3 in regulating hepatic gluconeogenesis. ResultsThe expression of ZBED3 in the liver of IR-related disease models was found to be increased. Under the stimulation of glucagon, ZBED3 promoted the expression of hepatic gluconeogenesis-related genes PGC1A, PCK1, G6PC, thereby increasing HGP. Consistently, the rate of hepatic gluconeogenesis was found to be elevated in mice with hepatocyte-specific overexpression of ZBED3 and decreased in those with ZBED3 knockout. Additionally, the knockdown of ZBED3 in the liver of db/db mice resulted in a reduction in hepatic gluconeogenesis. Moreover, the study revealed that ZBED3 facilitated the nuclear translocation of protein arginine methyltransferases 5 (PRMT5) to influence the regulation of PRMT5-mediated symmetrical dimethylation of arginine (s-DMA) of cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), which in turn affects the phosphorylation of CREB and ultimately promotes HGP. ConclusionsThis study indicates that ZBED3 promotes hepatic gluconeogenesis and serves as a critical regulator of the progression of diabetes.

Dissociation between liver fat content and fasting metabolic markers of selective hepatic insulin resistance in humans.

Fasting hyperglycemia and hypertriglyceridemia are characteristic of insulin resistance (IR) and rodent work has suggested this may be due to selective hepatic IR; defined by increased hepatic gluconeogenesis and de novo lipogenesis (DNL), but this has not been shown in humans. Cross-sectional study in men and women across a range of adiposity. Medication-free participants (n=177) were classified as normoinsulinemic (NI) or hyperinsulinemic (HI) and as having low (LF) or high (HF) liver fat content measured by magnetic resonance spectroscopy. Fractional gluconeogenesis (frGNG) and hepatic DNL were measured using stable isotope tracer methodology following an overnight fast. Although HI and HF groups had higher fasting plasma glucose and triglyceride concentrations when compared to NI and LF groups respectively, there was no difference in frGNG. However, HF participants tended to have lower frGNG than LF participants. HI participants had higher DNL compared to NI participants but there was no difference observed between liver fat groups. Taken together, we found no metabolic signature of selective hepatic IR in fasting humans. DNL may contribute to hypertriglyceridemia in individuals with HI but not those with HF. Glycogenolysis and systemic glucose clearance may have a larger contribution to fasting hyperglycemia than gluconeogenesis, especially in those with HF and these pathways should be considered for therapeutic targeting.

Mechanisms and Future Perspectives of Curcumin in Diabetes Management

Background: Diabetes is a chronic metabolic disorder that leads to significant damage to vital organs due to prolonged high blood glucose levels. These complications include cardiovascular disease, peripheral neuropathy, retinopathy (eye damage), nephropathy (kidney damage), myopathy, and foot infections. Type 2 diabetes mellitus (T2DM) is the most common form of diabetes, primarily affecting adults when the body becomes resistant to insulin or when insulin production by the pancreas is insufficient. Turmeric (Curcuma longa), a spice widely used around the world, has been traditionally recognized for its numerous health benefits, including antidiabetic, antioxidant, antibacterial, hepatoprotective, and anticancer properties. Among its active compounds, curcumin, a polyphenolic curcuminoid, has garnered significant attention for its potential role in managing diabetes and its complications. Methods: Data for this review were obtained from databases including PubMed, Elsevier, ScienceDirect, and Google Scholar. Search terms utilized included "diabetes," "type 2 diabetes," "diabetic complications," "turmeric," "curcumin," "oxidative stress and curcumin," "curcumin and nephropathy," "curcumin and retinopathy," "curcumin and neuropathy," "curcumin and cardiovascular diseases," "curcumin and cardiomyopathy," “curcumin and pyroptosis,” "curcumin and diabetic foot ulcer," and "curcumin and erectile dysfunction." Results: This review highlights the promising role of curcumin in transforming diabetes treatment and management. The findings demonstrate that curcumin offers protective effects against diabetic complications by modulating key signaling pathways, such as NF-κB, AMPK, MAPK, and AP-1. Its anti-inflammatory properties, inhibition of hepatic gluconeogenesis, and reduction of oxidative stress through antioxidant activity present a strong case for its therapeutic potential in diabetes care. Conclusion: This review provides an in-depth explanation of curcumin's mechanisms of action, detailing its medicinal effects on diabetes-related complications and key outcomes from preclinical and clinical studies supporting its potential benefits. It also outlines future directions for research into curcumin's role in diabetes treatment.

The mitochondrial dicarboxylate carrier mediates in vivo hepatic gluconeogenesis.

Hepatic gluconeogenesis (GNG) is essential for maintaining euglycemia during prolonged fasting. However, GNG becomes pathologically elevated and drives chronic hyperglycemia in type 2 diabetes (T2D). Lactate/pyruvate is a major GNG substrate known to be imported into mitochondria for GNG. Yet, the subsequent mitochondrial carbon export mechanisms required to supply the extra-mitochondrial canonical GNG pathway have not been genetically delineated. Here, we evaluated the role of the mitochondrial dicarboxylate carrier (DiC) in mediating GNG from lactate/pyruvate. We generated liver-specific DiC knockout (DiC LivKO) mice. During lactate/pyruvate tolerance tests, DiC LivKO decreased plasma glucose excursion and 13C-lactate/-pyruvate flux into hepatic and plasma glucose. In a Western diet (WD) feeding model of T2D, acute DiC LivKO after induction of obesity decreased lactate/pyruvate-driven GNG, hyperglycemia, and hyperinsulinemia. Our results show that mitochondrial carbon export through the DiC mediates GNG and that the DiC contributes to impaired glucose homeostasis in a mouse model of T2D.

Beyond weight loss: the potential of glucagon-like peptide-1 receptor agonists for treating heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome with various phenotypes, and obesity is one of the most common and clinically relevant phenotypes of HFpEF. Obesity contributes to HFpEF through multiple mechanisms, including sodium retention, neurohormonal dysregulation, altered energy substrate metabolism, expansion of visceral adipose tissue, and low-grade systemic inflammation. Glucagon-like peptide-1 (GLP-1) is a hormone in the incretin family. It is produced by specialized cells called neuroendocrine L cells located in the distal ileum and colon. GLP-1 reduces blood glucose levels by promoting glucose-dependent insulin secretion from pancreatic β cells, suppressing glucagon release from pancreatic α cells, and blocking hepatic gluconeogenesis. Recent evidence suggests that GLP-1 receptor agonists (GLP-1 RAs) can significantly improve physical activity limitations and exercise capacity in obese patients with HFpEF. The possible cardioprotective mechanisms of GLP-1 RAs include reducing epicardial fat tissue thickness, preventing activation of the renin-angiotensin-aldosterone system, improving myocardial energy metabolism, reducing systemic inflammation and cardiac oxidative stress, and delaying the progression of atherosclerosis. This review examines the impact of obesity on the underlying mechanisms of HFpEF, summarizes the trial data on cardiovascular outcomes of GLP-1 RAs in patients with type 2 diabetes mellitus, and highlights the potential cardioprotective mechanisms of GLP-1 RAs to give a pathophysiological and clinical rationale for using GLP-1 RAs in obese HFpEF patients.

Korean Red Ginseng Extract Powder Mitigates Fasting And Postprandial Hyperglycemia in Type 2 Diabetic Mice.

Type 2 diabetes mellitus (T2DM) involves insulin resistance and elevated blood sugar levels, causing complications. Red ginseng extract powder (RGEP) from Panax ginseng Meyer shows promise for diabetes treatment. However, its efficacy in managing T2DM remains unclear. Therefore, this study aims to evaluate the effectiveness of RGEP in a mouse model of T2DM. The efficacy of RGEP in treating T2DM was assessed in db/db mice. Mice were divided into seven groups: control, db/db, metformin, and RGEP at 50, 100, 200, and 400 mg/kg. Administered orally for 9 weeks, RGEP effects on glucose regulation and insulin sensitivity were assessed through various metabolic parameters. In addition, mRNA expression levels of genes associated with hepatic gluconeogenesis and insulin sensitivity were examined. Fasting blood sugar showed a significant decrease in all RGEP concentration groups, but OGTT and insulin tolerance test showed a significant decrease at the RGEP concentration of 400 mg/kg, indicating enhanced glycemic control. Moreover, RGEP dose-dependently decreased serum glucose, HbA1c levels, and homeostatic model assessment of insulin resistance values, suggesting its effectiveness in reducing insulin resistance in db/db mice. Furthermore, RGEP downregulated mRNA expression of key components in the gluconeogenesis pathway (G6Pase, FOXO1, GLUT4, and PEPCK), insulin sensitivity (leptin, insulin1, PTP1B, GLP-1, and DPP-4), and mitochondria energy metabolism (PGC1) in either the liver or pancreas, while simultaneously upregulating GLP-1 expression. In conclusion, these findings highlight the potential of RGEP as a complementary therapy for T2DM, indicating therapeutic efficacy in managing diabetic complications through improved metabolic parameters.

The deubiquitinase OTUB1 inhibits gluconeogenesis by stabilizing YWHAB

Hepatic gluconeogenesis plays a crucial role in maintaining glucose homeostasis and serves as a potential therapeutic target for type 2 diabetes, while its underlying mechanisms are not fully understood. This study elucidates the role of the deubiquitinase OTU domain-containing ubiquitin aldehyde binding protein 1 (OTUB1) in gluconeogenesis. We found that hepatic OTUB1 expression is reduced in both db/db mice and patients with type 2 diabetes. Deletion of hepatic OTUB1 significantly elevates fasting blood glucose levels and increases the expression of key gluconeogenic genes. Conversely, overexpression of OTUB1 in hepatocytes mitigates diabetic hyperglycemia and enhances insulin sensitivity. It is known that the tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein β (YWHAB) functions as an inhibitor of hepatic gluconeogenesis by interacting with forkhead box protein O (FOXO1) and glucagon receptor (GPCR), but its own modification mechanism remains unclear. Our findings indicate that OTUB1 interacts with YWHAB and deubiquitinates it through a catalytic process, which in turn suppresses gluconeogenesis. Therefore, OTUB1 plays a pivotal role in inhibiting hepatic gluconeogenesis, highlighting its potential as a therapeutic target for type 2 diabetes.

Hepatic gluconeogenesis and regulatory mechanisms in lactating ruminants: A literature review

Hepatic gluconeogenesis and regulatory mechanisms in lactating ruminants: A literature review

Effective Extracorporeal Treatment of Metformin-Associated Lactic Acidosis using Continuous Venovenous Hemodiafiltration.

The prevalence of type 2 diabetes mellitus has surged globally. Metformin is recommended as the first-line oral treatment. However, metformin-associated lactic acidosis (MALA) is recognized as a rare but potentially dangerous complication. The pathogenesis of MALA is multifactorial, primarily resulting from the interference of metformin with mitochondrial function and hepatic gluconeogenesis, leading to lactate accumulation. Risk of MALA escalates with impaired kidney function, poorly controlled diabetes, fasting, and liver dysfunction. A 57-year-old woman with diabetes and hypertension presented with prolonged gastrointestinal symptoms. During this episode she continued using metformin. She had severe metabolic acidosis and acute kidney injury. Continuous venovenous hemodiafiltration was initiated, resulting in significant clinical improvement and normalized arterial blood gas parameters within 16 hours. The pharmacokinetic properties of metformin facilitate efficient elimination via hemodialysis and/or hemofiltration. Continuous venovenous hemodiafiltration emerges as effective for MALA treatment. In the case described the calculated metformin clearance during continuous venovenous hemodiafiltration was notably higher than reported values, possibly due to residual renal clearance. Clinical improvement occurred despite elevated metformin levels, suggesting a lack of correlation between metformin levels and patient outcomes. Comorbidities rather than metformin levels guide treatment decisions in MALA. This case underscores the efficacy of continuous venovenous hemodiafiltration in the treatment of MALA, suggesting its potential as a standard therapeutic approach. However, further research is needed to elucidate the complex interplay between metformin levels, clinical presentation, (extracorporeal) treatment modalities and outcome in MALA. Continuous venovenous hemodiafiltration seems to be an efficient and effective treatment to eliminate metformin in patients with metformin-associated lactic acidosis.The metformin level does not seem to correlate with the clinical condition of the patient.For a comparison between the effectiveness of different renal replacement therapies in metformin-associated lactic acidosis, more research is needed.

Overview of carboxyl‑terminal modulator protein 1 and its importance in various metabolic regulations (Review).

Acyl‑coenzyme A thioesterases (ACOTs) are crucial in mediating lipid metabolic functions, including energy expenditure, hepatic gluconeogenesis and neuronal function. The two distinct types are type I and II ACOTs, the latter of which are 'hotdog' fold superfamily members. Type II ACOTs include carboxyl‑terminal modulator protein 1 (CTMP1), also termed thioesterase superfamily member 4 (THEM4), and CTMP2, also termed THEM5. Due to their similar structural features and distinct sequence homology, CTMP1 and CTMP2 stand out from other type II ACOTs. CTMP1 was initially known as a protein kinase B (PKB) inhibitor that attenuates PKB phosphorylation. PKB is the central regulator of various cellular functions, including survival, proliferation, growth and metabolism. Therefore, by inhibiting PKB, CTMP1 can affect various cellular processes. Various other functions of CTMP1 have been revealed, including functions in cancer, brain injury, mitochondrial function and lipid metabolism. CTMP2 is a paralog of CTMP1 and was first identified as a cardiolipin remodeling factor involved in the development of fatty liver. As the functions of CTMP1 and CTMP2 were discovered separately, a review to summarize and connect these findings is essential. The current review delineates the intricate complexity of CTMP regulation across different metabolic pathways and encapsulates the principal discoveries concerning CTMP until the present day.