Hepatic Glucose Metabolism Research Articles

Tailoring cell therapies for diabetic metabolic phenotypes: a comparative study on the efficacy of various umbilical cord-derived cell regimens.

Given the high heterogeneity of type 2 diabetes mellitus (T2DM), it is imperative to develop personalized stem cell infusion regimen for targeted metabolic phenotype in order to ensure optimal therapeutic efficacy. In this study, we conducted a comparative analysis of 4 infusion regimens involving single and repeated infusions of human umbilical cord Wharton's jelly-derived MSCs (hucMSCs), single infusions of umbilical cord blood mononuclear cells (UCB), and sequential infusions of hucMSCs and UCB in T2DM rats. Results showed all 4 infusion regimens exhibited comparable efficacy in lowering fasting blood glucose levels and suppressing glucagon secretion. Single and double infusions of hucMSCs exhibited a tendency to migrate to the liver, thereby better at ameliorating hepatic glucose metabolism by enhancing glycogen synthesis and storage, promoting glycolysis, inhibiting gluconeogenesis, and improving insulin signal transduction. The sequential infusion of hucMSCs and UCB demonstrated specific cell tropism toward the pancreas, leading to prolonged glucose-lowering effects following a glucose tolerance test, restoration of early-phase insulin secretion, stimulation of islet beta cell proliferation and improvement in the beta/alpha ratio. Multiple injections, regardless of cell type, reduced the expression of systemic chronic inflammatory markers such as IL-1β, IL-6, IL-17, IL-22, and IFN-γ. Finally, a single dose of UCB exhibited a greater tendency to target visceral fat and enhanced effectiveness in regulating levels of total cholesterol and triglycerides. In conclusion, our study provided personalized stem cell regimens for diverse T2DM metabolic phenotypes, thereby offering improved treatment alternatives for future clinical trials and applications.

β2-Chimaerin, a GTPase-Activating Protein for Rac1, Is a Novel Regulator of Hepatic Insulin Signaling and Glucose Metabolism.

Glucose homeostasis is a complex process regulated by multiple organs and hormones, with insulin playing a central role. Recent evidence underscores the role of small GTP-binding proteins, particularly Rac1, in regulating insulin secretion and glucose uptake. However, the role of Rac1-regulatory proteins in these processes remains largely unexplored. In this study, we investigated the role of β2-chimaerin, a Rac1-specific GTPase-activating protein (GAP), in glucose homeostasis using whole-body β2-chimaerin knockout mice. Our data revealed that β2-chimaerin deficiency results in improved glucose tolerance and enhanced insulin sensitivity in mice. These metabolic effects were associated with increased insulin-induced AKT phosphorylation in the liver and activation of downstream pathways that regulate gluconeogenesis and glycogen synthesis. We show that insulin activates Rac1 in the liver. However, β2-chimaerin deletion did not significantly alter Rac1 activation in this organ, suggesting that β2-chimaerin regulates insulin signaling via a Rac1-independent mechanism. These findings expand our understanding of Rac1 regulation in glucose metabolism, and identify β2-chimaerin as a novel modulator of hepatic insulin signaling, with potential implications for the development of insulin resistance and diabetes.

Hesperetin-copper (II) complex improves liver glucose metabolism by regulating the IRS-1/PI3K/AKT signaling pathway in T2DM mice

The metal complexes of flavonoids have attracted widespread attention because of their distinct structural and functional characteristics. Hesperetin-Cu(II) complex [Hsp-Cu(II)] showed good hypoglycemic potential, but its hypoglycemic effect and mechanism in vivo are still vague. This study aimed to investigate the hypoglycemic effect of Hsp-Cu(II) on type 2 diabetic (T2DM) mice and its underlying mechanism. The results showed that Hsp-Cu(II) (50 mg/kg) effectively improved hyperglycemia and dyslipidemia, increased the fast insulin level and HOMA-IR to alleviate the insulin resistance in the T2DM mice. Compared with the Diseased group, treatment of Hsp-Cu(II) at 50 mg/kg reduced the activities of α-amylase, phosphoenolpyruvate carboxy kinase (PEPCK) and glucose 6-phosphatase (G6Pase) by 31.7%, 45.5% and 35.1%, respectively; elevated the level of glutathione and activities of superoxide dismutase and catalase by 27.2%, 71.7% and 36.7%, respectively, and decreased the malondialdehyde content by 23.6% to improve the liver antioxidant abilities; reduced the activities of alanine aminotransferase and aspartate aminotransferase by 15.6% and 28.1%, as well as the levels of inflammatory factors to relieve liver damage. In addition, Hsp-Cu(II) activated the insulin receptor substrate-1/phosphoinositide-3-kinase/protein kinase B (IRS-1/PI3K/AKT) signaling pathway to up-regulate the protein expression levels of phospho-glycogen synthase kinase-3β (p-GSK-3β) and phospho-fork head box transcription factor O1 (p-FoxO1) and down-regulate the mRNA expression of PEPCK and G6Pase. Therefore, Hsp-Cu(II) may regulate hepatic glucose metabolism through IRS-1/PI3K/AKT‒GSK3β pathways to increase the hepatic glycogen content and IRS-1/PI3K/AKT‒FoxO1‒PEPCK/G6Pase pathways to inhibit gluconeogenesis, maintain hepatic glucose homeostasis, thus exerting the hypoglycemia effect in T2DM. These discoveries may provide a scientific basis for developing Hsp-Cu(II) as a food function factor to alleviate T2DM.

Duration of morning hyperinsulinemia determines hepatic glucose uptake and glycogen storage later in the day.

The second-meal phenomenon refers to the improvement in glucose tolerance seen following a second identical meal. We previously showed that 4 h of morning hyperinsulinemia, but not hyperglycemia, enhanced hepatic glucose uptake (HGU) and glycogen storage during an afternoon hyperinsulinemic-hyperglycemic (HIHG) clamp. Our current aim was to determine if the duration or pattern of morning hyperinsulinemia is important for the afternoon response to a HIHG clamp. To determine this, the same total amount of insulin was administered either over 2 h in the first (Ins2h-A) or second (Ins2h-B) half of the morning or over the entire 4 h (Ins4h) of the morning. In the 4-h afternoon period, all three groups had 4x-basal insulin, 2x-basal glycemia, and portal glucose infusion to expose the liver to the primary postprandial regulators of hepatic glucose metabolism. During the afternoon clamp, there was a marked increase in HGU and hepatic glycogen synthesis in the Ins4h group compared with the Ins2h-A and Ins2h-B groups, despite matched hepatic glucose loads and total insulin infusion rates. Thus, the longer duration (Ins4h) of lower hyperinsulinemia in the morning seems to be the key to much greater liver glucose uptake during the afternoon clamp.NEW & NOTEWORTHY Morning insulin exposure primes the liver for increased hepatic glucose uptake and glycogen storage during a subsequent hyperinsulinemic-hyperglycemic clamp. This study addressed whether the pattern and/or duration of insulin delivery in the morning influences insulin's ensuing priming effect. We found that despite receiving equal total doses of insulin in the morning, a prolonged, lower rate of morning insulin delivery improved afternoon liver glucose metabolism more effectively than a shorter, higher rate of delivery.

Co-Micronized Palmitoylethanolamide and Rutin Associated With Hydroxytyrosol Recover Diabesity-Induced Hepatic Dysfunction in Mice: InVitro Insights Into the Synergistic Effect.

Metabolic dysfunction-associated fatty liver disease (MAFLD) and diabesity (diabetes related to obesity) are interrelated since glucose and lipid alterations play a vital role in the development of both disorders. Due to their multi-variant metabolic features, more than one drug or natural product may be required to achieve proper therapeutic effects. This study aimed to evaluate the effectiveness of a formulation containing co-micronized palmitoylethanolamide and rutin (PEA-Rut) associated with hydroxytyrosol (HT), namely NORM3, against hepatic damage and metabolic alterations in high-fat diet (HFD)-induced diabesity in mice. NORM3 decreased the body weight and fat mass of obese mice. The formulation improved HFD-altered insulin sensitivity and hepatic glucose production and metabolism, as shown by glucose, insulin, pyruvate tolerance tests, Western blot, and real-time PCR. In the liver, NORM3 limited macro- and micro-vacuolar steatosis, as revealed by morphological analysis, and reduced the associated hepatic inflammation. NORM3 counteracted lipid dysfunctions of HFD animals, activating AMPK, a key cellular energy sensor, and normalizing the expression of carnitine palmitoyl-transferase (CPT)1, a rate-limiting enzyme of fatty acid β-oxidation, and other genes involved in lipid homeostasis. Relevantly, the hepatic antioxidant activity of NORM3 was proved (reduced ROS and increased detoxifying factors and enzymes). Finally, invitro synergistic protective effects of the components (PEA-Rut and HT) on H2O2-induced oxidative challenge in HepG2 were determined (ROS production, inflammation, and antioxidant defense). Our results show the beneficial effect of NORM3 and its potential as an innovative phytotherapeutic combination in limiting hepatic damage progression and counteracting glucose and lipid dysmetabolism associated with diabesity.

Adaptations in hepatic glucose metabolism after chronic social defeat stress in mice

Chronic stress has been shown to induce hyperglycemia in both peripheral blood and the brain, yet the detailed mechanisms of glucose metabolism under stress remain unclear. Utilizing 13C6-labeled glucose to trace metabolic pathways, our study investigated the impact of stress by chronic social defeat (CSD) on glucose metabolites in the liver and brain one week post-stress. We observed a reduction in 13C6-enrichment of glucose metabolites in the liver, contrasting with unchanged levels in the brain. Notably, hepatic glycogen levels were reduced while lactate concentrations were elevated, suggesting lactate as an alternative energy source during stress. Long-term effects were also examined, revealing normalized blood glucose levels and restored glycogen stores in the liver three weeks post-CSD, despite sustained increases in food intake. This normalization is hypothesized to result from diminished glucagon levels leading to reduced glycogen phosphorylase activity. Our findings highlight a temporal shift in glucose metabolism, with hyperglycemia and glycogen depletion in the liver early after CSD, followed by a later phase of metabolic stabilization. These results underscore the liver’s critical role in adapting to CSD and provide insights into the metabolic adjustments that maintain glucose homeostasis under prolonged stress conditions.

Untargeted metabolomic analysis reveals a time-course hepatic metabolism disorder induced by short-term 6PPD exposure in rats

The tire antioxidant 6PPD has garnered extensive attention due to its widespread presence in the environment and the harmful effects of its transformation products on aquatic organisms. 6PPD has been detected in airborne dust, and it can enter mammals through inhalation exposure. While the toxic effects of 6PPD exposure have been reported in mammals, its effects on hepatic metabolism still remain poorly understood. Here, we collected the serum and liver samples at 1, 6, and 72 h following a single oral exposure of 100 mg/kg body weight (bw) 6PPD, respectively. We also investigated changes in serum and hepatic physiological indicators and metabolites, correspondingly. Results indicated that single time oral exposure a high dose of 6PPD did not significantly affect the physiological indexes of rats within a short time frame. However, untargeted metabolomics analysis of the metabolites in the liver at 1, 6, and 72 h revealed that the number of differential expression metabolites gradually increased over time and the most affected substances were lipids and lipid-like molecules. Interestingly, the KEGG pathway enrichment analysis indicated that 6PPD disrupted the riboflavin metabolism, leading to a significant decrease in FMN levels at all time points. In addition, the hepatic glucose metabolism was significantly affected at 6 and 72 h after oral administration. Taken together, short-term exposure to 6PPD disturbed lipid and riboflavin metabolism and gradually affected glucose metabolism in the liver of rats. These findings revealed the impacts of 6PPD on the hepatic metabolism in animals, and also offered some important insights into its toxicology and health risk.

Retinoid X receptor heterodimers in hepatic function: structural insights and therapeutic potential.

Nuclear receptors (NRs) are key regulators of multiple physiological functions and pathological changes in the liver in response to a variety of extracellular signaling changes. Retinoid X receptor (RXR) is a special member of the NRs, which not only responds to cellular signaling independently, but also regulates multiple signaling pathways by forming heterodimers with various other NR. Therefore, RXR is widely involved in hepatic glucose metabolism, lipid metabolism, cholesterol metabolism and bile acid homeostasis as well as hepatic fibrosis. Specific activation of particular dimers regulating physiological and pathological processes may serve as important pharmacological targets. So here we describe the basic information and structural features of the RXR protein and its heterodimers, focusing on the role of RXR heterodimers in a number of physiological processes and pathological imbalances in the liver, to provide a theoretical basis for RXR as a promising drug target.

Glucose metabolism in the perfused liver did not improve with resistance training in male Swiss mice under caloric restriction

Context: Energy homeostasis is a primary factor for the survival of mammals. Many tissues and organs, among which is the liver, keep this homeostasis in varied circumstances, including caloric restriction (CR) and physical activity. Objective: This study investigated glucose metabolism using the following groups of eight-week-old male Swiss mice: CS, sedentary and fed freely; RS, sedentary and RT, trained, both under 30% CR (n = 20–23 per group). Results: Organs and fat depots of groups RS and RT were similar to CS, although body weight was lower. CR did not impair training performance nor affected systemic or hepatic glucose metabolism. Training combined with CR (group RT) improved in vivo glucose tolerance and did not affect liver gluconeogenesis. Conclusions: The mice tolerated the prolonged moderate CR without impairment of their well-being, glucose homeostasis, and resistance training performance. But the higher liver gluconeogenic efficiency previously demonstrated using this training protocol in mice was not evidenced under CR.

In vivo mapping of postprandial hepatic glucose metabolism using dynamic magnetic resonance spectroscopy combined with stable isotope flux analysis in Roux-en-Y gastric bypass adults and non-operated controls: A case-control study.

Roux-en-Y gastric bypass (RYGB) surgery alters postprandial glucose profiles, causing post-bariatric hypoglycaemia (PBH) in some individuals. Due to the liver's central role in glucose homeostasis, hepatic glucose handling might differ in RYGB-operated patients with PBH compared to non-operated healthy controls (HC). We enrolled RYGB-operated adults with PBH and HCs (n = 10 each). Participants ingested 60 g of [6,6'-2H2]-glucose (d-glucose) after an overnight fast. Deuterium metabolic imaging (DMI) with interleaved 13C magnetic resonance spectroscopy was performed before and until 150 min post-d-glucose intake, with frequent blood sampling to quantify glucose enrichment and gluco-regulatory hormones until 180 min. Glucose fluxes were assessed by mathematical modelling. Outcome trajectories were described using generalized additive models. In RYGB subjects, the hepatic d-glucose signal increased early, followed by a decrease, whereas HCs exhibited a gradual increase and consecutive stabilization. Postprandial hepatic glycogen accumulation and the suppression of endogenous glucose production were lower in RYGB patients than in HCs, despite higher insulin exposure, indicating lower hepatic insulin sensitivity. The systemic rate of ingested d-glucose was faster in RYGB, leading to a higher, earlier plasma glucose peak and increased insulin secretion. Postprandial glucose disposal increased in RYGB patients, without between-group differences in peripheral insulin sensitivity. Exploiting DMI with stable isotope flux analysis, we observed distinct postprandial hepatic glucose trajectories and parameters of glucose-insulin homeostasis in RYGB patients with PBH versus HCs. Despite altered postprandial glucose kinetics and higher insulin exposure, there was no evidence of impaired hepatic glucose uptake or output predisposing to PBH in RYGB patients.

Antidiabetic Effect of Bifidobacterium animalis TISTR 2591 in a Rat Model of Type 2 Diabetes.

This study investigated the beneficial effects of probiotic Bifidobacterium animalis TISTR 2591 on the regulation of blood glucose and its possible mechanisms in a rat model of type 2 diabetes. The type 2 diabetic-Sprague Dawley rats were established by the combination of a high-fat diet and a low dose of streptozotocin. After 4weeks of treatment with 2 × 108CFU/ml of B. animalis TISTR 2591, fasting blood glucose (FBG), oral glucose tolerance, serum insulin, and pancreatic and hepatic histopathology were determined. Liver lipid accumulation, glycogen content, and gluconeogenic protein expression were evaluated. Oxidative stress and inflammatory status were determined. B. animalis TISTR 2591 significantly reduced FBG levels and improved glucose tolerance and serum insulin in the diabetic rats. Structural damage of the pancreas and liver was ameliorated in the B. animalis TISTR 2591-treated diabetic rats. In addition, significant decreases in hepatic fat accumulation, glycogen content, and phosphoenolpyruvate carboxykinase-1 protein expression were found in the diabetic rats treated with B. animalis TISTR 2591. The diabetic rats showed a significant reduction of inflammation following B. animalis TISTR 2591 supplementation, as demonstrated by decreasing hepatic NF-κB protein expression and serum and liver TNF-α levels. The B. animalis TISTR 2591 significantly decreased MDA levels and increased antioxidant SOD and GPx activities in the diabetic rats. In conclusion, B. animalis TISTR 2591 was shown to be effective in controlling glucose homeostasis and improving glucose tolerance in the diabetic rats. These beneficial activities were attributed to reducing oxidative and inflammatory status and modulating hepatic glucose metabolism.

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

BackgroundLiver 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. MethodsLiver-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. ResultsHFD-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. ConclusionsSilencing 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.

Effects of artificial diets on lipid and glucose metabolism, antioxidative capacity, and inflammation in the liver of mandarin fish (Siniperca chuatsi)

The mandarin fish (Siniperca chuatsi) is a typical carnivorous fish, which has been able to consume artificial diets after domestication in recent years. However, the potential health consequences of artificial diets in mandarin fish remain unclear. This study aimed to elucidate the molecular mechanisms underlying these concerns. Fish (initial weight: 25.1 ± 0.1 g) were fed with natural (CON group) or artificial diets (AF group) for 8 weeks. Each diet was randomly distributed to sextuplicate circular tanks (300 L) with 40 fish in each tank. The transcriptome analysis revealed significant changes in metabolism-related pathways, particularly those involved in lipid and carbohydrate metabolism. Further investigation confirmed that the artificial diets significantly increased hepatic triglyceride content and fatty acid synthase activity. The artificial diets also significantly increased hepatic glycogen and glucose-6-phosphatase activity. Furthermore, the artificial diets significantly increased hepatic malondialdehyde levels, indicating increased oxidative stress. Antioxidant defense enzyme activities and the expression of antioxidant stress-related genes were significantly decreased. Additionally, the artificial diets significantly increased the expression of proinflammatory genes, including interleukin 1 beta and interferon-gamma. These findings collectively demonstrated that the artificial diets disrupted hepatic lipid and glucose metabolism, leading to oxidative stress and inflammation, thus affecting the health status of mandarin fish.

Ameliorative effects of Penthorum chinense Pursh on insulin resistance and oxidative stress in diabetic obesity db/db mice.

Penthorum chinense Pursh (PCP), a medicinal and edible plant, has been reported to protect against liver damage by suppressing oxidative stress. Type 2 diabetes mellitus (T2DM) is associated with liver dysfunction and oxidative stress. In the present study, we aim to investigate the hypoglycemic effect of PCP on db/db mice and further explore the underlying mechanisms. Thirty-two db/db mice were randomized into four groups, including a diabetic model control group (MC) and three diabetic groups treated with low (LPCP, 300 mg/kg/d), medium (MPLP, 600 mg/kg/d), and high doses of PCP (HPCP, 1200 mg/kg/d), and the normal control group (NC) of eight db/m mice were included. Mice in the NC and MC groups received the ultrapure water. After four weeks of intervention, parameters of fasting blood glucose (FBG), insulin resistance (IR), blood lipid levels, hepatic oxidative stress, and enzymes related to hepatic glucose metabolism were compared in the groups. PCP administration significantly reduced FBG and IR in diabetic db/db mice, and improved hepatic glucose metabolism by increasing glucose transporter 2 (GLUT2) and glucokinase (GCK) protein expression. Meanwhile, PCP supplementation ameliorated hepatic oxidative stress by decreasing malonaldehyde content and increasing the activities of superoxide dismutase and glutathione peroxidase in db/db mice. Furthermore, PCP treatment reduced obesity and food intake in db/db mice, and improved dyslipidemia demonstrated by increasing high-density lipoprotein cholesterol (HDL-C) while decreasing total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (HDL-C). All doses of PCP treatment decreased the values of LDL-C/HDL-C in a dose-response relationship. PCP significantly alleviated hyperglycemia, hyperinsulinemia, hyperlipidemia, and obesity, inhibited hepatic oxidative stress, and enhanced hepatic glucose transport in T2DM mice. Based on the above findings, the hypoglycemic effect of PCP may be attributed to the activation of the GLUT2/GCK expression in the liver and the reduction of hepatic oxidative stress.

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.

Activity and phosphatidylcholine transfer protein interactions of skeletal muscle thioesterase Them2 enable hepatic steatosis and insulin resistance

Thioesterase superfamily member 2 (Them2), a long-chain fatty acyl-CoA thioesterase that is highly expressed in oxidative tissues, interacts with phosphatidylcholine transfer protein (PC-TP) to regulate hepatic lipid and glucose metabolism and to suppress insulin signaling. High-fat diet (HFD)-fed mice lacking Them2 globally or specifically in skeletal muscle, but not liver, exhibit reduced hepatic steatosis and insulin resistance. Here, we report that the capacity of Them2 in skeletal muscle to promote hepatic steatosis and insulin resistance depends on both its catalytic activity and interaction with PC-TP. Two residues of Them2 catalytic site were mutated (N50A/D65A) to produce the inactive enzyme while maintaining its homotetrameric structure and interaction with PC-TP. Restoration of skeletal muscle expression in Them2-/- mice using recombinant adeno-associated virus revealed that wild-type (WT), but not N50A/D65A Them2, promoted HFD-induced weight gain and hepatic steatosis. This was accompanied by greater impairment of insulin sensitivity in WT compared with N50A/D65A Them2. Pharmacological inhibition or genetic ablation of PC-TP attenuated these effects. In reductionist experiments, conditioned medium collected from WT primary cultured myotubes promoted excess lipid accumulation in oleic acid-treated primary cultured hepatocytes relative to Them2-/- myotubes, which was attributable to secreted extracellular vesicles (EV). Reconstitution of Them2 expression in Them2-/- myotubes affirmed the requirements for catalytic activity and PC-TP interactions for EV to promote lipid accumulation in hepatocytes. These studies provide valuable mechanistic insights whereby Them2 in skeletal muscle promotes hepatic steatosis and establish both Them2 and PC-TP as represent attractive targets for managing metabolic dysfunction-associated steatotic liver disease.

8396 Growth Hormone Secretion after Glucagon Stimulation is Increased in Individuals with History of Bariatric Surgery

Abstract Disclosure: L. Pei: None. C. Cummings: None. H. Saeed: None. M. Farahmandsadr: None. A. Amore: None. A. Sheehan: None. R. Ferraz-Bannitz: None. D.C. Simonson: Stock Owner; Self; GI Windows. Other; Self; wife owns Phase V Technologies. M. Patti: Advisory Board Member; Self; data and safety monitoring board on Fractyl Health. Consulting Fee; Self; AstraZeneca, Hamni, MBX Biosciences. Grant Recipient; Self; Receive investigator-initiated research funding from Dexcom. Background: Growth hormone (GH) is an important counterregulatory hormone and regulator of hepatic glucose metabolism. Previous studies demonstrated increased plasma GH and reduced plasma growth hormone receptor (GHR) after bariatric surgery in both rodents and humans. Moreover, plasma GHR was identified as mediator of improved glycemic control after Roux-en-Y gastric bypass (RYGB). We now test the hypothesis that altered GH and/or GHR levels contribute to post-bariatric hypoglycemia (PBH). Methods: Cross-sectional studies were performed at a single academic institution. GH secretion was assessed after 1mg IV glucagon (GCG) and during hyperinsulinemic-hypoglycemic clamp in 3 groups: 1) post-RYGB without hypoglycemia symptoms (RnonH) (20F, age 51±11 (mean±SD) y, BMI 35±8 kg/m2, HbA1c 5.2±0.3%, 10.6±5.3 years post-surgery), 2) PBH (18F/2M, age 54±12y, BMI 30.5±4.6 kg/m2, HbA1c 5.2±0.3%, 9.4±6.0 years post-surgery), 3) weight-similar controls without upper GI surgery (CON) (6F/4M, age 47.1±13.1y, BMI 31.9±5.7 kg/m2, HbA1c 5.4±0.3%). Plasma GHR and GH were measured via ELISA. Results: Fasting GH did not differ between groups (mean±SE, CON: 285±78, RnonH: 860±179, PBH: 980±284 pg/mL, P=0.16). Peak incremental glucose response to GCG, ranging from 46-59 mg/dL, did not differ between groups. At 120 min after GCG, GH was significantly higher in both PBH and RnonH vs. CON (PBH: 3018±678, RnonH: 2521±656, CON: 481±137 pg/mL, ANOVA P= 0.012, PBH vs. CON P=0.003, RnonH vs. CON P=0.02). Peak GH in PBH was significantly higher vs. CON (3431± 655 vs. 547±153 pg/mL, P=0.03), but did not differ in RnonH vs. PBH. Peak GH was inversely correlated with postoperative duration in PBH only (r=-0.49, P=0.03), with BMI in both surgical groups (PBH: r=-0.49, P=0.03, RnonH: r=-0.57, P=0.009) and with percent body fat (impedance plethysmography) in the combined surgical group (r=-0.51, P=0.0007). In contrast, GH during hyperinsulinemic hypoglycemia did not differ between groups (CON: 9660 ±2588, RnonH: 7759±1751, PBH: 7309±1549 pg/mL, P=0.3) at similar degrees of hypoglycemia (CON: 54.8±1.5, RnonH: 50.7±1.0, PBH: 50.9±1.4 mg/dL). Fasting plasma GHR did not differ (CON: 23.3±3.8, RnonH: 19.4±2.8, PBH: 13.8±2.1 ng/mL, P=0.10). GHR was correlated with percent fat mass in the combined surgical group (r=0.56, P=0.0003) but not in CON. Conclusion: Plasma GH did not differ as a function of prior RYGB, with or without hypoglycemia, in the fasting state or in response to insulin-induced hypoglycemia. However, GCG-stimulated GH levels were 5-6-fold higher in individuals with history of RYGB, numerically higher in PBH, and inversely related to body fat and postop duration. Together these results suggest that reduced GH is not likely driving hypoglycemia in PBH, but that alterations in glucagon-mediated GH secretion and/or action may contribute to observed metabolic effects of RYGB. Presentation: 6/1/2024

7657 Single Cell RNAseq And Omics Revealed Novel Role Of Liver Group 2 Innate Lymphocytes In Regulation Of Hepatic Gluconeogenesis

Abstract Disclosure: M. Fujimoto: None. T. Tanaka: None. Background: The liver is an important organ that maintains homeostasis of glucose metabolism in the body through gluconeogenesis. It is considered that gluconeogenesis in hepatocytes is particularly active around the portal vein. However, since excessive gluconeogenesis aggravates the pathogenesis of diabetes, it is necessary to elucidate the regulatory mechanism of gluconeogenesis. Although several studies revealed that group 2 innate lymphocytes (ILC2) contribute to blood glucose maintenance in adipose and pancreatic tissues, the contribution of liver ILC2s to glucose metabolism is unknown. This study aims to elucidate the contribution of liver ILC2s to glucose metabolism and its molecular mechanism. Methods: We administered IL-33, an endogenous ILC2 activator, to BALB/c and NSG mice, and measured fasting blood glucose levels and blood glucose elevation by gluconeogenic substrate pyruvate, and blood glucose levels in liver ILC2s transplanted NSG mice. Molecular mechanisms were analyzed by single cell-RNAseq (scRNA-seq) of liver ILC2s, lung ILC2s and hepatocytes, GATA3 transcription complex, ATAC-seq, GATA3-ChIP-seq, and Metabolomics of primary hepatocytes. Results: IL-33 strongly induced IL-13 production by liver ILC2s, lowered fasting blood glucose, and suppressed pyruvate-induced glucose elevation; these effects were not observed in NSG mice lacking immune cells including ILC2s. A hypoglycemic effect of IL-33 was observed in liver ILC2-transplanted NSG mice, but not in mice transplanted with IL-13-deficient ILC2s, suggesting the effect is IL-13-dependent. scRNA-seq results showed that liver ILC2s showed higher IL-13 expression than lung ILC2s, and IL-33 treatment suppressed the expression of gluconeogenic enzymes in the G6pc-high hepatocyte population. The interaction between liver ILC2s and G6pc-high hepatocytes via IL-13/IL-13 receptors was also demonstrated; co-culture of ILC2s with primary cultured hepatocytes resulted in decreased expression of hepatocyte gluconeogenic enzymes and accumulation of multiple gluconeogenic substrates. In addition, IL-13 neutralizing antibody treatment attenuated the effect of the decreased expression of gluconeogenic enzymes in hepatocytes. Transcription factor GATA3 complex analysis and GATA3-ChIPseq suggested binding of GATA3 of the AP-1 family (JunB) in liver ILC2s. Overexpression, knockdown, and scRNA-seq results suggest that AP1 may act in a GATA3-repressive manner in liver ILC2s. Discussion The functional characteristics of liver ILC2s, hepatocyte heterogeneity and subcluster were demonstrated by scRNA-seq, suggesting that liver ILC2s may directly suppress hepatocyte gluconeogenesis via IL-13. This may play a novel role in the homeostasis of hepatic glucose metabolism. Presentation: 6/1/2024

A Systematic Review of the Beneficial Effects of Berry Extracts on Non-Alcoholic Fatty Liver Disease in Animal Models.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in Western countries and is strongly associated with several metabolic disorders. Plant-derived bioactive extracts, such as berry extracts, with high antioxidant capacity have been used for the treatment and prevention of this pathology. Moreover, they promote circular economy and sustainability. To study the beneficial effects of extracts from different parts of berry plants in animal models of NAFLD. A systematic research of the MEDLINE (via PubMed), Cochrane, and Scopus databases was conducted to identify relevant studies published after January 2011. In vivo animal studies of NAFLD were included in which berry extracts of different parts of the plant were administered and significantly improved altered biomarkers related to the pathology, such as lipid metabolism and hepatic steatosis, glucose and glycogen metabolism, and antioxidant and anti-inflammatory biomarkers. Of a total of 203 articles identified, 31 studies were included after implementation of the inclusion and exclusion criteria. Most of the studies showed a decrease in steatosis and a stimulation of genes related to β-oxidation and downregulation of lipogenic genes, with administration of berry extracts. Berry extracts also attenuated inflammation and oxidative stress. Administration of berry extracts seems to have promising potential in the design of enriched foodstuffs or nutraceuticals for the treatment of NAFLD.

Effect of Dipeptidyl Peptidase-4 Inhibitors Supplementation on Non-Alcoholic Steatohepatitis in Adolescents with Type 1 Diabetes Mellitus

Abstract Background Many patients with type 1 diabetes mellitus (T1DM) had histological evidence of steatosis and met the histological criteria for non-alcoholic steatohepatitis (NASH). Accumulating data suggested that dipeptidyl peptidase-4 (DDP-4) enzyme is involved in the development of various chronic liver diseases. Some studies showed the beneficial effect of DDP-4 inhibitors in liver injury for their ability in modulating fatty acid oxidation, decreasing lipogenesis and improving hepatic glucose metabolism. Objectives Therefore, we performed a randomized-controlled trial to assess the effect of the oral DPP- 4 inhibitor vildagliptin as an add-on therapy on NASH in adolescents with T1DM as well as its effect on glycemic control, lipid profile. Methods This study included 60 adolescents with T1DM and NASH. Patients were randomly assigned into two groups; intervention group who received oral vildagliptin (50 mg daily). The other group did not receive any supplementation and served as a control group. Both groups were followed- up for six months with assessment of fasting and 2 hours post-prandial blood glucose levels, HbA1c, liver function tests, fasting lipid profile and hepatic steatosis index. Results Supplementation with oral DPP-4 inhibitor vildagliptin was safe and well-tolerated. After six months, Vildagliptin adjuvant therapy for the intervention group resulted in a significant decrease of systolic and diastolic blood pressure as well as insulin dose (p < 0.001). Blood glucose levels, HbA1c, liver enzymes, triglycerides, total cholesterol and hepatic steatosis index were significantly lower after vildagliptin therapy compared with baseline levels and compared with the control group (p < 0.001). Conclusions The DDP-4 inhibitor vildagliptin in a once daily dose of 50 mg orally for six months as an add-on therapy for adolescents with T1DM and NASH was safe and improved glycemic control and dyslipidemia while decreasing steatosis; hence, preventing disease progression.