LONP1 ameliorates liver injury and improves gluconeogenesis dysfunction in acute-on-chronic liver failure / 中华医学杂志(英文版)

BACKGROUND@#Acute-on-chronic liver failure (ACLF) is a severe liver disease with complex pathogenesis. Clinical hypoglycemia is common in patients with ACLF and often predicts a worse prognosis. Accumulating evidence suggests that glucose metabolic disturbance, especially gluconeogenesis dysfunction, plays a critical role in the disease progression of ACLF. Lon protease-1 (LONP1) is a novel mediator of energy and glucose metabolism. However, whether gluconeogenesis is a potential mechanism through which LONP1 modulates ACLF remains unknown.@*METHODS@#In this study, we collected liver tissues from ACLF patients, established an ACLF mouse model with carbon tetrachloride (CCl 4 ), lipopolysaccharide (LPS), and D-galactose (D-gal), and constructed an in vitro hypoxia and hyperammonemia-triggered hepatocyte injury model. LONP1 overexpression and knockdown adenovirus were used to assess the protective effect of LONP1 on liver injury and gluconeogenesis regulation. Liver histopathology, biochemical index, mitochondrial morphology, cell viability and apoptosis, and the expression and activity of key gluconeogenic enzymes were detected to explore the underlying protective mechanisms of LONP1 in ACLF.@*RESULTS@#We found that LONP1 and the expressions of gluconeogenic enzymes were downregulated in clinical ACLF liver tissues. Furthermore, LONP1 overexpression remarkably attenuated liver injury, which was characterized by improved liver histopathological lesions and decreased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in ACLF mice. Moreover, mitochondrial morphology was improved upon overexpression of LONP1. Meanwhile, the expression and activity of the key gluconeogenic enzymes were restored by LONP1 overexpression. Similarly, the hepatoprotective effect was also observed in the hepatocyte injury model, as evidenced by improved cell viability, reduced cell apoptosis, and improved gluconeogenesis level and activity, while LONP1 knockdown worsened liver injury and gluconeogenesis disorders.@*CONCLUSION@#We demonstrated that gluconeogenesis dysfunction exists in ACLF, and LONP1 could ameliorate liver injury and improve gluconeogenic dysfunction, which would provide a promising therapeutic target for patients with ACLF.

Genetic features associated with ¹⁸F-FDG uptake in intrahepatic cholangiocarcinoma

PURPOSE: In intrahepatic cholangiocarcinoma (iCCA), genetic characteristics on ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG)-PET scans are not yet clarified. If specific genetic characteristics were found to be related to FDG uptake in iCCA, we can predict molecular features based on the FDG uptake patterns and to distinguish different types of treatments. In this purpose, we analyzed RNA sequencing in iCCA patients to evaluate gene expression signatures associated with FDG uptake patterns. METHODS: We performed RNA sequencing of 22 cases iCCA who underwent preoperative ¹⁸F-FDG-PET, and analyzed the clinical and molecular features according to the maximum standard uptake value (SUVmax). Genes and biological pathway which are associated with SUVmax were analyzed. RESULTS: Patients with SUVmax higher than 9.0 (n = 9) had poorer disease-free survival than those with lower SUVmax (n = 13, P = 0.035). Genes related to glycolysis and gluconeogenesis, phosphorylation and cell cycle were significantly correlated with SUVmax (r ≥ 0.5). RRM2, which is related to the toxicity of Gemcitabine was positively correlated with SUVmax, and SLC27A2 which is associated with Cisplastin response was negatively correlated with SUVmax. According to the pathway analysis, cell cycle, cell division, hypoxia, inflammatory, and metabolism-related pathways were enriched in high SUVmax patients. CONCLUSION: The genomic features of gene expression and pathways can be predicted by FDG uptake features in iCCA. Patients with high FDG uptake have enriched cell cycle, metabolism and hypoxic pathways, which may lead to a more rational targeted treatment approach.

The dynamics of energy metabolism in the tick embryo / A dinâmica do metabolismo energético em embriões de carrapato

Abstract The cattle tick Rhipicephalus (Boophilus) microplus is an ectoparasite capable of transmitting a large number of pathogens, causing considerable losses in the cattle industry, with substantial damage to livestock. Over the years, important stages of its life cycle, such as the embryo, have been largely ignored by researchers. Tick embryogenesis has been typically described as an energy-consuming process, sustaining cell proliferation, differentiation, and growth. During the embryonic stage of arthropods, there is mobilization of metabolites of maternal origin for the development of organs and tissues of the embryo. Glycogen resynthesis in late embryogenesis is considered as an effective indicator of embryonic integrity. In the cattle tick R.(B. (B.) microplus, glycogen resynthesis is sustained by protein degradation through the gluconeogenesis pathway at the end of the embryonic period. Despite recent advancements in research on tick energy metabolism at the molecular level, the dynamics of nutrient utilization during R. (B.) microplus embryogenesis is still poorly understood. The present review aims to describe the regulatory mechanisms of carbohydrate metabolism during maternal-zygotic transition and identify possible new targets for the development of novel drugs and other control measures against R. (B.) microplus infestations.

Resumo O carrapato bovino Rhipicephalus (B.) microplus é um ectoparasita capaz de transmitir diversos patógenos, sendo responsável por grandes perdas na pecuária pelos danos causados ao gado. Atualmente, muitos estudos têm negligenciado fases importantes do ciclo de vida deste parasita, como a fase embrionária. A embriogênese é classicamente descrita como um processo que demanda um consumo de energia, possibilitando a proliferação celular, diferenciação e crescimento. Além disso, em artrópodes, o estágio da embriogênese é caracterizado pela mobilização de metabolitos de origem materna para o desenvolvimento de novos tecidos e órgãos. A ressíntese de glicogênio no final da embriogênese tem sido descrita em diversas espécies de artrópodes, sendo considerada um indicador de integridade do embrião. No caso do R. (B.) microplus a ressíntese de glicogênio é sustentada pela degradação de proteínas durante a gliconeogênese, no terço final da embriogênese. Apesar dos recentes avanços, no estudo molecular e do metabolismo energético, os mecanismos envolvidos na dinâmica da utilização de diferentes substratos energéticos durante a embriogênese do carrapato R. (B.) microplus ainda é pouco entendido. Diante deste panorama, estudos que descrevam a regulação destes mecanismos e da associação do metabolismo de carboidratos com a transição materno zigótica, pode auxiliar na busca de novos alvos para o desenvolvimento de novos acaricidas e outras intervenções para o controle infestações de R. (B.) microplus.

Anti-hyperglycemic effects and signaling mechanism of Perilla frutescens sprout extract

BACKGROUND/OBJECTIVES: Perilla frutescens (L.) Britton var. (PF) sprout is a plant of the labiate family. We have previously reported the protective effects of PF sprout extract on cytokine-induced β-cell damage. However, the mechanism of action of the PF sprout extract in type 2 diabetes (T2DM) has not been investigated. The present study was designed to study the effects of PF sprout extract and signaling mechanisms in the T2DM mice model using C57BL/KsJ-db/db (db/db) mice. MATERIALS/METHODS: Male db/db mice were orally administered PF sprout extract (100, 300, and 1,000 mg/kg of body weight) or rosiglitazone (RGZ, positive drug, 1 mg/kg of body weight) for 4 weeks. Signaling mechanisms were analyzed using liver tissues and HepG2 cells. RESULTS: The PF sprout extract (300 and 1,000 mg/kg) significantly reduced the fasting blood glucose, serum insulin, triglyceride and total cholesterol levels in db/db mice. PF sprout extract also significantly improved glucose intolerance and insulin sensitivity, decreased hepatic gluconeogenic protein expression, and ameliorated histological alterations of the pancreas and liver. Levels of phosphorylated AMP-activated protein kinase (AMPK) protein expression also increased in the liver after treatment with the extract. In addition, an increase in the phosphorylation of AMPK and decrease in the phosphoenolpyruvate carboxykinase and glucose 6-phosphatase proteins in HepG2 cells were also observed. CONCLUSIONS: Our results sugges that PF sprout displays beneficial effects in the prevention and treatment of type 2 diabetes via modulation of the AMPK pathway and inhibition of gluconeogenesis in the liver.

A Journey to Understand Glucose Homeostasis: Starting from Rat Glucose Transporter Type 2 Promoter Cloning to Hyperglycemia

My professional journey to understand the glucose homeostasis began in the 1990s, starting from cloning of the promoter region of glucose transporter type 2 (GLUT2) gene that led us to establish research foundation of my group. When I was a graduate student, I simply thought that hyperglycemia, a typical clinical manifestation of type 2 diabetes mellitus (T2DM), could be caused by a defect in the glucose transport system in the body. Thus, if a molecular mechanism controlling glucose transport system could be understood, treatment of T2DM could be possible. In the early 70s, hyperglycemia was thought to develop primarily due to a defect in the muscle and adipose tissue; thus, muscle/adipose tissue type glucose transporter (GLUT4) became a major research interest in the diabetology. However, glucose utilization occurs not only in muscle/adipose tissue but also in liver and brain. Thus, I was interested in the hepatic glucose transport system, where glucose storage and release are the most actively occurring.

A possible relationship between gluconeogenesis and glycogen metabolism in rabbits during myocardial ischemia

ABSTRACT Ischemia is responsible for many metabolic abnormalities in the heart, causing changes in organ function. One of modifications occurring in the ischemic cell is changing from aerobic to anaerobic metabolism. This change causes the predominance of the use of carbohydrates as an energy substrate instead of lipids. In this case, the glycogen is essential to the maintenance of heart energy intake, being an important reserve to resist the stress caused by hypoxia, using glycolysis and lactic acid fermentation. In order to study the glucose anaerobic pathways utilization and understand the metabolic adaptations, New Zealand white rabbits were subjected to ischemia caused by Inflow occlusion technique. The animals were monitored during surgery by pH and lactate levels. Transcription analysis of the pyruvate kinase, lactate dehydrogenase and phosphoenolpyruvate carboxykinase enzymes were performed by qRT-PCR, and glycogen quantification was determined enzymatically. Pyruvate kinase transcription increased during ischemia, followed by glycogen consumption content. The gluconeogenesis increased in control and ischemia moments, suggesting a relationship between gluconeogenesis and glycogen metabolism. This result shows the significant contribution of these substrates in the organ energy supply and demonstrates the capacity of the heart to adapt the metabolism after this injury, sustaining the homeostasis during short-term myocardial ischemia.

NUCB2/Nesfatin-1: a potent meal regulatory hormone and its role in diabetes

Background: Nesfatin-1, a newly discovered calcium and DNA binding peptide, originate from nucle-obindin 2 [NUCB2] precursors and expressed by central and peripheral nervous system, and peripheral tissues such as digestive organs and adipose tissues. It has the astonishingly large number of chemical messengers for full appetite and introduced as a potential anorectic factor with ability to modulate body weight and probably, energy homeostasis

Nesfatin-1/NUCB2 level in the circulation is elevated after meal intake and decreased during a fast. Its food intake suppression effect is independent from the leptin pathway, and act via the melanocortin signaling. On the other hand, Nesfatin-1 colocalizes with insulin in pancreatic beta islet cells and has been shown to increase insulin secretion

Methodology: PubMed databases were searched for [NUCB2 or nesfatin-1 or nucleobindin] with the combination of [diabetes mellitus]

Included papers were further searched manually for additional studies

The databases were searched up to 2015. Fifty one articles were selected for full text review

Result: Centrally controlled Nesfatin-1 was stated to raise peripheral and hepatic insulin sensitivity by reducing gluconeogenesis and stimulating peripheral glucose uptake in vivo

Conclusion: Nesfatin-1 has gain attention as a new target to generate, drug for treatment of endocrine nutritional and metabolic disorders like obesity and type 2 diabetes mellitus

Glycolysis and gluconeogenesis in the liver of catfish fed with different concentrations of proteins, lipids and carbohydrates / Glicólise e gliconeogênese no fígado de jundiá alimentado com diferentes concentrações de proteínas, lipídeos e carboidratos

The activities of enzymes from a number of metabolic pathways have been used as a tool to evaluate the best use of nutrients on fish performance. In the present study the catfish Rhamdia quelen was fed with diets containing crude protein-lipid-carbohydrate (%) as follows: treatment (T) T1: 19-19-44; T2: 26-15-39; T3: 33-12-33; and T4: 40-10-24. The fish were held in tanks of re-circulated, filtered water with controlled temperature and aeration in 2000L experimental units. The feeding experiment lasted 30 days. The following enzymes of the carbohydrate metabolism were determined: Glucokinase (GK), Phosphofructokinase 1 (PFK-1), Pyruvate kinase (PK), Fructose-1,6-biphosphatase 1 (FBP-1). The activities of 6 phosphogluconate dehydrogenase (6PGDH) and glucose 6 phosphate dehydrogenase (G6PDH) were also assayed. The influence of nutrient levels on the enzyme activities is reported. The increase of dietary protein plus reduction of carbohydrates and lipids attenuates the glycolytic activity and induces hepatic gluconeogenesis as a strategy to provide metabolic energy from amino acids. The fish performance was affected by the concentrations of protein, lipid and carbohydrates in the diet. The greatest weight gain was obtained in fish fed diet T4 containing 40.14% of crude protein, 9.70% of lipids, and 24.37% of carbohydrate, respectively.(AU)

As atividades de enzimas das vias metabólicas têm sido utilizadas como uma ferramenta para avaliar a melhor utilização dos nutrientes e o desempenho dos peixes. No presente estudo, o jundiá foi alimentado com rações contendo diferentes concentrações de proteína bruta, lipídeos e carboidratos (%), da seguinte forma: tratamento (T) T1: 19-19-44; T2: 26-15-39; T3: 33-12-33; e T4: 40-10-24. Os peixes foram mantidos em tanques de recirculação, com água filtrada, temperatura controlada e aeração em unidades experimentais de 2.000L. O período experimental foi de 30 dias. Foram aferidas as atividades das enzimas glicoquinase (GK), fosfofrutoquinase 1 (PFK-1), piruvato quinase (PK) e frutose-1,6-difosfatase (FBP-1). Também foram aferidas as atividades da 6-fosfogluconato desidrogenase (6PGDH) e glicose-6-fosfato desidrogenase (G6PDH) da via das pentoses. É relatado que níveis de nutrientes influenciam as atividades enzimáticas das vias metabólicas. No presente estudo, o aumento da proteína da dieta e a redução de hidratos de carbono e lipídeos reduziram a atividade glicolítica e induziram a gliconeogênese hepática como uma estratégia para fornecer energia pelos aminoácidos. O desempenho dos peixes foi afetado pelas concentrações de proteínas, lipídeos e carboidratos na dieta. O maior ganho de peso foi obtido em peixes alimentados com dieta T4 contendo 40,14% de proteína bruta, 9,70% de lipídeos, e 24,37% de carboidratos, respectivamente.(AU)

Gynura procumbens extract improves insulin sensitivity and suppresses hepatic gluconeogenesis in C57BL/KsJ-db/db mice

BACKGROUND/OBJECTIVES: This study was designed to investigate whether Gynura procumbens extract (GPE) can improve insulin sensitivity and suppress hepatic glucose production in an animal model of type 2 diabetes. MATERIALS/METHODS: C57BL/Ksj-db/db mice were divided into 3 groups, a regular diet (control), GPE, and rosiglitazone groups (0.005 g/100 g diet) and fed for 6 weeks. RESULTS: Mice supplemented with GPE showed significantly lower blood levels of glucose and glycosylated hemoglobin than diabetic control mice. Glucose and insulin tolerance test also showed the positive effect of GPE on increasing insulin sensitivity. The homeostatic index of insulin resistance was significantly lower in mice supplemented with GPE than in the diabetic control mice. In the skeletal muscle, the expression of phosphorylated AMP-activated protein kinase, pAkt substrate of 160 kDa, and PM-glucose transporter type 4 increased in mice supplemented with GPE when compared to that of the diabetic control mice. GPE also decreased the expression of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase in the liver. CONCLUSIONS: These findings demonstrate that GPE might improve insulin sensitivity and inhibit gluconeogenesis in the liver.

Glycemic Management of Patients Undergoing Dialysis / 임상당뇨병

Diabetes mellitus is the leading cause of end-stage renal disease in Korea. The management of glycemic control in patients undergoing dialysis is challenging due to the complexity of the treatment and the lack of convincing data supporting the benefits of tight glycemic control. When kidney function decreased, glucose homeostasis changed. Increased insulin resistance due to uremia and decreased insulin secretion resulted in hyperglycemia, and decreased counter-regulatory hormone and renal gluconeogenesis led to hypoglycemia. Moreover, glycosylated hemoglobin is affected by various factors in patients undergoing dialysis, so it is difficult to monitor for glycemic control. Decreased kidney function changes the pharmacokinetics of drugs. Some oral hypoglycemic agents are used for patients undergoing dialysis, but the main treatment for glycemic control is insulin. Considering these factors, the management of glycemic control for patients undergoing dialysis is delicate and should be individualized based on the patient's risk profile.

Regulation of glucose metabolism from a liver-centric perspective

Glucose homeostasis is tightly regulated to meet the energy requirements of the vital organs and maintain an individual's health. The liver has a major role in the control of glucose homeostasis by controlling various pathways of glucose metabolism, including glycogenesis, glycogenolysis, glycolysis and gluconeogenesis. Both the acute and chronic regulation of the enzymes involved in the pathways are required for the proper functioning of these complex interwoven systems. Allosteric control by various metabolic intermediates, as well as post-translational modifications of these metabolic enzymes constitute the acute control of these pathways, and the controlled expression of the genes encoding these enzymes is critical in mediating the longer-term regulation of these metabolic pathways. Notably, several key transcription factors are shown to be involved in the control of glucose metabolism including glycolysis and gluconeogenesis in the liver. In this review, we would like to illustrate the current understanding of glucose metabolism, with an emphasis on the transcription factors and their regulators that are involved in the chronic control of glucose homeostasis.

Glucose Metabolism in the Intestine

Few are familiar with the gluconeogenesis that occurs in the intestine under fasting or the influence of insulin. Recently, however, studies that revealed the function of intestinal gluconeogenesis as a regulatory process for glucose homeostasis and appetite were described. The intestine produces about 25% of total endogenous glucose during fasting and regulates energy homeostasis through communication with the brain. Glucose produced via intestinal gluconeogenesis is delivered to portal vein where periportal neural system senses glucose and sends a signal to the brain to regulate appetite and glucose homeostasis. Moreover, studies uncovered that intestinal gluconeogenesis contributes to the rapid metabolic improvements induced by gastric bypass surgery.

Glucose Homeostasis during Fetal and Neonatal Period / 대한주산의학회잡지

Glucose is essential for energy metabolism in human, especially in brain, and is a source of energy storage in the form of glycogen, fat and protein. During fetal life, the predominant source of energy is also glucose, which crosses the placenta by facilitated diffusion. There is very little endogenous glucose production under normal circumstances during fetal life. During labor, the fetus is exposed to physiological challenges that require metabolic adaptation. A healthy infant successfully manages the postnatal transition by mobilizing and using alternative. After birth, there is a rapid surge in catecholamine and glucagon levels, and a steady decrease in insulin, as blood glucose levels decline. These hormonal changes induce enzyme activities that lead to glycogenolysis and gluconeogenesis. During the first 24-48 hours of life, plasma glucose concentrations of neonates are typically lower than later in life. Distinguishing between transitional neonatal glucose regulation in normal neonates and hypoglycemia that persists or occurs for the first time beyond the first 72 hours of life is important for prompt diagnosis and treatment to avoid serious consequences.

D-Xylose as a sugar complement regulates blood glucose levels by suppressing phosphoenolpyruvate carboxylase (PEPCK) in streptozotocin-nicotinamide-induced diabetic rats and by enhancing glucose uptake in vitro

BACKGROUND/OBJECTIVES: Type 2 diabetes (T2D) is more frequently diagnosed and is characterized by hyperglycemia and insulin resistance. D-Xylose, a sucrase inhibitor, may be useful as a functional sugar complement to inhibit increases in blood glucose levels. The objective of this study was to investigate the anti-diabetic effects of D-xylose both in vitro and stretpozotocin (STZ)-nicotinamide (NA)-induced models in vivo. MATERIALS/METHODS: Wistar rats were divided into the following groups: (i) normal control; (ii) diabetic control; (iii) diabetic rats supplemented with a diet where 5% of the total sucrose content in the diet was replaced with D-xylose; and (iv) diabetic rats supplemented with a diet where 10% of the total sucrose content in the diet was replaced with D-xylose. These groups were maintained for two weeks. The effects of D-xylose on blood glucose levels were examined using oral glucose tolerance test, insulin secretion assays, histology of liver and pancreas tissues, and analysis of phosphoenolpyruvate carboxylase (PEPCK) expression in liver tissues of a STZ-NA-induced experimental rat model. Levels of glucose uptake and insulin secretion by differentiated C2C12 muscle cells and INS-1 pancreatic beta-cells were analyzed. RESULTS: In vivo, D-xylose supplementation significantly reduced fasting serum glucose levels (P < 0.05), it slightly reduced the area under the glucose curve, and increased insulin levels compared to the diabetic controls. D-Xylose supplementation enhanced the regeneration of pancreas tissue and improved the arrangement of hepatocytes compared to the diabetic controls. Lower levels of PEPCK were detected in the liver tissues of D-xylose-supplemented rats (P < 0.05). In vitro, both 2-NBDG uptake by C2C12 cells and insulin secretion by INS-1 cells were increased with D-xylose supplementation in a dose-dependent manner compared to treatment with glucose alone. CONCLUSIONS: In this study, D-xylose exerted anti-diabetic effects in vivo by regulating blood glucose levels via regeneration of damaged pancreas and liver tissues and regulation of PEPCK, a key rate-limiting enzyme in the process of gluconeogenesis. In vitro, D-xylose induced the uptake of glucose by muscle cells and the secretion of insulin cells by beta-cells. These mechanistic insights will facilitate the development of highly effective strategy for T2D.

Hyperinsulinemic Hypoglycemia Caused by Acute Reduction of Renal Function on an Eldery Patient Without Diabetes

In patient with renal failure, hypoglycemia may develop because of decreased caloric intake, diminished renal insulin degradation and clearance, reduced renal gluconeogenesis and hepatic glucose production, impaired release of counter-regulatory hormone such as glucagon and epinephrine. We report here on a 80-year-old female patient with hypoglycemia due to endogenous hyperinsulinemia with acute kidney injury. She had chronic kidney disease and had no history of diabetes mellitus or insulin use. She had experienced recurrent hypoglycemia despite of intravenous dextrose injection and eventually generalized tonic clonic seizure occurred as a result of hypoglycemia. As serum creatinine level decreases, serum insulin and C-peptide level decreased and hypoglycemia was not occurred. We present this case along with a review of the literature.

Anti-bacterial activity of Achatina CRP and its mechanism of action.

The physiological role of C-reactive protein (CRP), the classical acute-phase protein, is not well documented, despite many reports on biological effects of CRP in vitro and in model systems in vivo. It has been suggested that CRP protects mice against lethal toxicity of bacterial infections by implementing immunological responses. In Achatina fulica CRP is a constitutive multifunctional protein in haemolymph and considered responsible for their survival in the environment for millions of years. The efficacy of Achatina CRP (ACRP) was tested against both Salmonella typhimurium and Bacillus subtilis infections in mice where endogenous CRP level is negligible even after inflammatory stimulus. Further, growth curves of the bacteria revealed that ACRP (50 µg/mL) is bacteriostatic against gram negative salmonellae and bactericidal against gram positive bacilli. ACRP induced energy crises in bacterial cells, inhibited key carbohydrate metabolic enzymes such as phosphofructokinase in glycolysis, isocitrate dehydrogenase in TCA cycle, isocitrate lyase in glyoxylate cycle and fructose-1,6-bisphosphatase in gluconeogenesis. ACRP disturbed the homeostasis of cellular redox potential as well as reduced glutathione status, which is accompanied by an enhanced rate of lipid peroxidation. Annexin V-Cy3/CFDA dual staining clearly showed ACRP induced apoptosis-like death in bacterial cell population. Moreover, immunoblot analyses also indicated apoptosis-like death in ACRP treated bacterial cells, where activation of poly (ADP-ribose) polymerase-1 (PARP) and caspase-3 was noteworthy. It is concluded that metabolic impairment by ACRP in bacterial cells is primarily due to generation of reactive oxygen species and ACRP induced anti-bacterial effect is mediated by metabolic impairment leading to apoptosis-like death in bacterial cells.

The Role of the Kidney in Glucose Metabolism / 임상당뇨병

It is well known that the kidney is important for maintaining glucose homeostasis in vivo. However, the physiological role of the kidney in glucose metabolism is typically underestimated. Recently, a new class of anti-diabetic medications that affect the renal glucose regulatory mechanism was introduced into the market, sparking the interest of many researchers to better understand this mechanism. In this article, I briefly describe the role of the kidney in glucose metabolism and the changes of its function in patients with diabetes mellitus.

Roles of Protein Arginine Methyltransferases in the Control of Glucose Metabolism

Glucose homeostasis is tightly controlled by the regulation of glucose production in the liver and glucose uptake into peripheral tissues, such as skeletal muscle and adipose tissue. Under prolonged fasting, hepatic gluconeogenesis is mainly responsible for glucose production in the liver, which is essential for tissues, organs, and cells, such as skeletal muscle, the brain, and red blood cells. Hepatic gluconeogenesis is controlled in part by the concerted actions of transcriptional regulators. Fasting signals are relayed by various intracellular enzymes, such as kinases, phosphatases, acetyltransferases, and deacetylases, which affect the transcriptional activity of transcription factors and transcriptional coactivators for gluconeogenic genes. Protein arginine methyltransferases (PRMTs) were recently added to the list of enzymes that are critical for regulating transcription in hepatic gluconeogenesis. In this review, we briefly discuss general aspects of PRMTs in the control of transcription. More specifically, we summarize the roles of four PRMTs: PRMT1, PRMT 4, PRMT 5, and PRMT 6, in the control of hepatic gluconeogenesis through specific regulation of FoxO1- and CREB-dependent transcriptional events.

Effect of homocysteine on gluconeogenesis in mice / 南方医科大学学报

<p><b>OBJECTIVE</b>To investigate the expressions of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) in the liver of mice with hyperhomocysteinemia (HHcy) and explore the mechanism of gluconeogenesis induced by homocysteine.</p><p><b>METHODS</b>Fifty mice were randomly divided into normal control group (n=25) and HHcy group (n=25) and fed with normal food and food supplemented with 1.5% methionine, respectively. After 3 months of feeding, the fasting blood glucose and insulin levels were determined, and HOMA insulin resistance index (HOMA-IR) was calculated. The expressions of G6Pase and PEPCK in the liver of mice were detected using RT-PCR and Western blotting.</p><p><b>RESULTS</b>The fasting blood glucose and insulin levels and HOMA-IR were significantly higher in HHcy group than in the control group (P<0.05). RT-PCR and Western blotting showed that the hepatic expressions of G6Pase and PEPCK mRNA and proteins increased significantly in HHcy group compared with those in the control group (P<0.05).</p><p><b>CONCLUSION</b>Homocysteine promotes gluconeogenesis to enhance glucose output and contribute to the occurrence of insulin resistance.</p>

Betaine Alleviates Hypertriglycemia and Tau Hyperphosphorylation in db/db Mice

Betaine supplementation has been shown to alleviate altered glucose and lipid metabolism in mice fed a high-fat diet or a high-sucrose diet. We investigated the beneficial effects of betaine in diabetic db/db mice. Alleviation of endoplasmic reticulum (ER) and oxidative stress was also examined in the livers and brains of db/db mice fed a betaine-supplemented diet. Male C57BL/KsJ-db/db mice were fed with or without 1% betaine for 5 wk (referred to as the db/db-betaine group and the db/db group, respectively). Lean non-diabetic db/+ mice were used as the control group. Betaine supplementation significantly alleviated hyperinsulinemia in db/db mice. Betaine reduced hepatic expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha, a major transcription factor involved in gluconeogenesis. Lower serum triglyceride concentrations were also observed in the db/db-betaine group compared to the db/db group. Betaine supplementation induced hepatic peroxisome proliferator-activated receptor alpha and carnitine palmitoyltransferase 1a mRNA levels, and reduced acetyl-CoA carboxylase activity. Mice fed a betaine-supplemented diet had increased total glutathione concentrations and catalase activity, and reduced lipid peroxidation levels in the liver. Furthermore, betaine also reduced ER stress in liver and brain. c-Jun N-terminal kinase activity and tau hyperphosphorylation levels were lower in db/db mice fed a betaine-supplemented diet, compared to db/db mice. Our findings suggest that betaine improves hyperlipidemia and tau hyperphosphorylation in db/db mice with insulin resistance by alleviating ER and oxidative stress.