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Plastic pollution in the world is widespread and growing. The environment is swamped with nanoplastics (<100 nm), and the health consequences of these less visible pollutants are unknown. Furthermore, there is evidence that microplastics can release nanoplastics by digestive disintegration, implying that macroplastic exposure can cause direct and indirect disease via nanoplastics. The existence and impact of nanoplastics in numerous tissues from invertebrates to larger vertebrates that consume significant amounts of plastics were investigated, and histopathological techniques were utilized to determine physiological reactions and inflammation from the plastics. Nanoplastics enters an organism through the respiratory and gastro-intestinal tract where they accumulate into the liver through blood circulation via absorption, or epidermal infiltration. It is stated that macroplastics can cause damage directly at the site of exposure, whereas nanoplastics can influence the liver, causing subsequent damage to other organs. Multi-organ dysfunction is brought on by liver changes, and nanoplastics can readily enter the gut-liver axis and disturb the gut microflora. By exploring the literature and summarizing the research that has been published to date, this review article reveals the deleterious effect and mechanisms of nanoplastics on the pathophysiological functions of the hepatic system. [ABSTRACT FROM AUTHOR]

Ginsenoside Rb1, a major bioactive component of Panax ginseng C. A. Mey., exerts beneficial effects on type 2 diabetes mellitus (T2DM), but its underlying mechanism is unclear. STAT3 is a key factor regulating energy metabolism. Herein, we tested whether Rb1 regulates STAT3-controlled hepatic glucose metabolism to ameliorate T2DM. Rb1 ameliorated abnormal hepatic glucose metabolism, insulin resistance, and liver steatosis in T2DM mice. Hepatic STAT3 phosphorylation was decreased in T2DM and increased after Rb1 treatment. Moreover, Rb1 reversed the decreased expressions of glycolytic enzymes and the increased expressions of gluconeogenic enzymes in T2DM. STAT3 activation increased the expressions of glycolytic enzymes and decreased the expressions of gluconeogenic enzymes in vitro, and vice versa. Further, STAT3 inhibition reversed the changes of these enzymes induced by Rb1 in insulin-resistant cells. Taken together, Rb1 ameliorated abnormal hepatic glucose metabolism in T2DM in a STAT3-dependent manner, which provides experimental bases for Rb1 in treating T2DM.

Exposure to fine particulate matter (PM2.5) was associated with an increased incidence of liver metabolic disease. Melatonin has been shown to prevent liver glucolipid metabolism disorders. However, whether melatonin could rescue PM2.5‐induced liver metabolic abnormalities remains uncertain. This study was to evaluate the mitigating effect of melatonin on PM2.5‐accelerated hepatic glucose metabolism imbalance in vivo and in vitro. Schiff periodic acid shiff staining and other results showed that PM2.5 led to a decrease in hepatic glycogen reserve and an increase in glucose content, which was effectively alleviated by melatonin. Targeted lipidomics is used to identify lipid biomarkers associated with this process, including glycerolipids, glycerophospholipids, and sphingolipids. In addition, gene microarray and quantitative polymerase chain reaction analysis of ApoE−/− mice liver suggested that PM2.5 activated the miR‐200a‐3p and inhibited DNAJB9, and the targeting relationship was verified by luciferase reports for the first time. Further investigation demonstrated that DNAJB9 might motivate endoplasmic reticulum (ER) stress by regulating Ca2+ homeostasis, thus altering the protein expression of GSK3B, FOXO1, and PCK2. Meanwhile, melatonin effectively inhibited miR‐200a‐3p and glucose metabolism disorder. Knockout of miR‐200a‐3p in L02 cells revealed that miR‐200a‐3p is indispensable in the damage of PM2.5 and the therapeutic effect of melatonin. In summary, melatonin alleviated PM2.5‐induced liver metabolic dysregulation by regulating ER stress via miR‐200a‐3p/DNAJB9 signaling pathway. Our data provide a prospective targeted therapy for air pollution‐related liver metabolism disorders. [ABSTRACT FROM AUTHOR]

KRIT1 loss-of-function mutations underlie the pathogenesis of Cerebral Cavernous Malformation (CCM), a major vascular disease affecting the central nervous system (CNS). However, KRIT1 is also expressed outside the CNS and modulates key regulators of metabolic and oxy-inflammatory pathways, including the master transcription factor FoxO1, suggesting a widespread functional significance. Herein, we show that the KRIT1/FoxO1 axis is implicated in liver metabolic functions and antioxidative/antiglycative defenses. Indeed, by performing comparative studies in KRIT1 heterozygous (KRIT1+/−) and wild-type mice, we found that KRIT1 haploinsufficiency resulted in FoxO1 expression/activity downregulation in the liver, and affected hepatic FoxO1-dependent signaling pathways, which are markers of major metabolic processes, including gluconeogenesis, glycolysis, mitochondrial respiration, and glycogen synthesis. Moreover, it caused sustained activation of the master antioxidant transcription factor Nrf2, hepatic accumulation of advanced glycation end-products (AGEs), and abnormal expression/activity of AGE receptors and detoxifying systems. Furthermore, it was associated with an impairment of food intake, systemic glucose disposal, and plasma levels of insulin. Specific molecular alterations detected in the liver of KRIT1+/− mice were also confirmed in KRIT1 knockout cells. Overall, our findings demonstrated, for the first time, that KRIT1 haploinsufficiency affects glucose homeostasis and liver metabolic and antioxidative/antiglycative functions, thus inspiring future basic and translational studies. [ABSTRACT FROM AUTHOR]

Chunjie Su,1 Qian Cheng,2 Liyun Wang2 1Department of Gastrointestinal Surgery, Jingmen No.1 People’s Hospital, Jingmen, 448000, People’s Republic of China; 2Department of Endocrinology, Yixing People’s Hospital, Yixing, 214200, Jiangsu, People’s Republic of ChinaCorrespondence: Liyun WangDepartment of Endocrinology, Yixing People’s Hospital, No. 75, Tongzhenguan Road, Yicheng Street, Yixing, 214200, Jiangsu, People’s Republic of ChinaEmail wangliyunly@163.comBackground: Roux-en-Y gastric bypass (RYGB) is the most effective treatment for type 2 diabetes mellitus (T2DM). Previous studies have reported that silent information regulator 1 (Sirt1) closely relates to many pathological processes of glucose metabolism and insulin resistance (IR). However, it is unclear whether Sirt1 is involved in the hepatic glucose metabolism of T2DM after RYGB.Methods: T2DM rats were randomly divided into four groups: Control, DM, Diet and RYGB. Normal rats were served as the control group. Hematoxylin and eosin (H&E) staining and Masson staining assays were performed to explore the changes of liver fibrous tissue after RYGB. The effect of RYGB on the protein expression of Sirt1 was detected by the Western blotting assay and immunohistochemical assay. Next, we built the insulin resistance model of human hepatocyte cell lines (FL62891 and HHL5) using the human recombinant insulin. Western blotting assay was applied to determine the expression of Sirt1 and the expression change of IRS1/mTOR2 /PKB pathway-related proteins in FL62891 and HHL5 cells. Additionally, the effects of Sirt1 on the expression of PTP1B and FGF-21 in insulin-resistant FL62891 and HHL5 cells were investigated using Western blotting and immunofluorescence assay.Results: Our results showed that following RYGB improved the pathological changes of liver and increased the expression of Sirt1 in rats with T2DM compared with the diabetic rats. In experiments in vitro, the expression of Sirt1 was downregulated in insulin-resistance FL62891 and HHL5 cells. Moreover, overexpression of Sirt1 significantly increased the expression of FGF-21 whereas decreased the expression of PTP1B in insulin-resistance FL62891 and HHL5 cells. These above changes were alleviated in RYGB and Diet groups. Furthermore, RYGB could improve the glucose metabolism through activating IRS1/mTOR2/PKB pathways by regulating Sirt1 in rats with T2DM.Conclusion: RYGB could significantly improve hepatic glucose metabolism and increase the expression of Sirt1 in T2DM rats, which is related to the IRS1/mTOR2 /PKB pathway.Keywords: Roux-en-Y gastric bypass, RYGB, hepatic glucose metabolism, insulin resistance, Sirt1, IRS1, mTOR2, PKB

KRIT1 loss-of-function mutations underlie the pathogenesis of Cerebral Cavernous Malformation (CCM), a major vascular disease affecting the central nervous system (CNS). However, KRIT1 is also expressed outside the CNS and modulates key regulators of metabolic and oxy-inflammatory pathways, including the master transcription factor FoxO1, suggesting a widespread functional significance. Herein, we show that the KRIT1/FoxO1 axis is implicated in liver metabolic functions and antioxidative/antiglycative defenses. Indeed, by performing comparative studies in KRIT1 heterozygous (KRIT1+/−) and wild-type mice, we found that KRIT1 haploinsufficiency resulted in FoxO1 expression/activity downregulation in the liver, and affected hepatic FoxO1-dependent signaling pathways, which are markers of major metabolic processes, including gluconeogenesis, glycolysis, mitochondrial respiration, and glycogen synthesis. Moreover, it caused sustained activation of the master antioxidant transcription factor Nrf2, hepatic accumulation of advanced glycation end-products (AGEs), and abnormal expression/activity of AGE receptors and detoxifying systems. Furthermore, it was associated with an impairment of food intake, systemic glucose disposal, and plasma levels of insulin. Specific molecular alterations detected in the liver of KRIT1+/− mice were also confirmed in KRIT1 knockout cells. Overall, our findings demonstrated, for the first time, that KRIT1 haploinsufficiency affects glucose homeostasis and liver metabolic and antioxidative/antiglycative functions, thus inspiring future basic and translational studies.

Iatrogenic hypoglycemia is a prominent barrier to achieving optimal glycemic control in patients with diabetes, in part due to dampened counterregulatory hormone responses. It has been demonstrated that elevated liver glycogen content can enhance these hormonal responses through signaling to the brain via afferent nerves, but the role that hypoglycemia in the brain plays in this liver glycogen effect remains unclear. During the first 4 h of each study, the liver glycogen content of dogs was increased by using an intraportal infusion of fructose to stimulate hepatic glucose uptake (HG; n = 13), or glycogen was maintained near fasting levels with a saline infusion (NG; n = 6). After a 2-h control period, during which the fructose/saline infusion was discontinued, insulin was infused intravenously for an additional 2 h to bring about systemic hypoglycemia in all animals, whereas brain euglycemia was maintained in a subset of the HG group by infusing glucose bilaterally into the carotid and vertebral arteries (HG-HeadEu; n = 7). Liver glycogen content was markedly elevated in the two HG groups (43 ± 4, 73 ± 3, and 75 ± 7 mg/g in NG, HG, and HG-HeadEu, respectively). During the hypoglycemic period, arterial plasma glucose levels were indistinguishable between groups (53 ± 2, 52 ± 1, and 51 ± 1 mg/dL, respectively), but jugular vein glucose levels were kept euglycemic (88 ± 5 mg/dL) only in the HG-HeadEu group. Glucagon and epinephrine responses to hypoglycemia were higher in HG compared with NG, whereas despite the increase in liver glycogen, neither increased above basal in HG-HeadEu. These data demonstrate that the enhanced counterregulatory hormone secretion that accompanies increased liver glycogen content requires hypoglycemia in the brain. [ABSTRACT FROM AUTHOR]

Rice germ is an abundant source of ferulic acid, which is known for its anti-oxidant activity. This study aimed to evaluate the regulatory effects of fermented rice germ extracts on hepatic glucose metabolism in C57BL/KsJ-db/db mice. Rice germ was fermented with Lactobacillus plantarum and extracted with 30% ethanol (RG_30E) or 50% ethanol (RG_50E). Mice were fed modified AIN-93 diets containing fermented rice germ extracts and ferulic acid for 8 weeks. RG_50E significantly reduced food intake as well as liver weight and RG_30E and RG_50E improved glucose homeostasis, as indicated by fasting blood glucose levels and glucose tolerance. Hepatic triglyceride and total cholesterol levels were significantly decreased in db/db mice fed RG_30E and RG_50E. The antioxidant capacity of RG_30E and RG_50E was confirmed by a decrease in malondialdehyde levels and an increase in hepatic superoxide dismutase activity. The expression of genes related to glycolysis and gluconeogenesis was significantly regulated by RG_30E and RG_50E. These results suggest that fermented rice germ extracts have the potential to regulate hypoglycemia and hepatic glucose metabolism in type 2 diabetes db/db mice. [ABSTRACT FROM AUTHOR]

Jian Li,1,* Haiyang Yu,2,* Sijian Wang,1 Wei Wang,3 Qian Chen,1 Yanmin Ma,2 Yi Zhang,1 Tao Wang1 1Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin, 2Department of Phytochemistry, Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China; 3Internal Medicine, Houston Methodist Hospital, Houston, TX, USA *These authors contributed equally to this work Abstract: Imbalanced hepatic glucose homeostasis is one of the critical pathologic events in the development of metabolic syndromes (MSs). Therefore, regulation of imbalanced hepatic glucose homeostasis is important in drug development for MS treatment. In this review, we discuss the major targets that regulate hepatic glucose homeostasis in human physiologic and pathophysiologic processes, involving hepatic glucose uptake, glycolysis and glycogen synthesis, and summarize their changes in MSs. Recent literature suggests the necessity of multitarget drugs in the management of MS disorder for regulation of imbalanced glucose homeostasis in both experimental models and MS patients. Here, we highlight the potential bioactive compounds from natural products with medicinal or health care values, and focus on polypharmacologic and multitarget natural products with effects on various signaling pathways in hepatic glucose metabolism. This review shows the advantage and feasibility of discovering multicompound–multitarget drugs from natural products, and providing a new perspective of ways on drug and functional food development for MSs. Keywords: hepatic glucose metabolism, natural products, multitarget, metabolic syndromes, drug and functional food development integrative medicine

Roux-en-Y gastric bypass surgery (RYGB) is known to improve whole-body glucose metabolism in patients with type 2 diabetes (T2D), although the mechanisms are not entirely clear and are likely multifactorial. The aim of this study was to assess fasting hepatic glucose metabolism and other markers of metabolic activity before and after RYGB in patients with and without T2D. Methods: Metabolic characteristics of patients who are obese with T2D were compared with those without the disease (non-T2D) before and 1 and 6 mo after RYGB. Fasting plasma insulin and the insulin: glucagon ratio were markedly reduced as early as 1 mo after RYGB in both patients with T2D and without T2D. Despite this reduction, endogenous glucose production and fasting plasma glucose levels were lower in both groups after RYGB, with the reductions being much larger in T2D. Plasma kisspeptin, an inhibitor of insulin secretion, was reduced only in T2D after surgery. Improved hepatic glucose metabolism and lower plasma kisspeptin in T2D after RYGB may link improved hepatic function with enhanced insulin responsiveness after surgery. NEW & NOTEWORTHY Our manuscript is the first, to the best of our knowledge, to present data showing that Roux-en-Y gastric bypass surgery (RYGB) lowers fasting kisspeptin levels in patients who are obese with type 2 diabetes. This lowering of kisspeptin is important because it could link improvements in liver glucose metabolism after RYGB with increased insulin responsiveness also seen after surgery. [ABSTRACT FROM AUTHOR]

Rice germ is an abundant source of ferulic acid, which is known for its anti-oxidant activity. This study aimed to evaluate the regulatory effects of fermented rice germ extracts on hepatic glucose metabolism in C57BL/KsJ-db/db mice. Rice germ was fermented with Lactobacillus plantarum and extracted with 30% ethanol (RG_30E) or 50% ethanol (RG_50E). Mice were fed modified AIN-93 diets containing fermented rice germ extracts and ferulic acid for 8 weeks. RG_50E significantly reduced food intake as well as liver weight and RG_30E and RG_50E improved glucose homeostasis, as indicated by fasting blood glucose levels and glucose tolerance. Hepatic triglyceride and total cholesterol levels were significantly decreased in db/db mice fed RG_30E and RG_50E. The antioxidant capacity of RG_30E and RG_50E was confirmed by a decrease in malondialdehyde levels and an increase in hepatic superoxide dismutase activity. The expression of genes related to glycolysis and gluconeogenesis was significantly regulated by RG_30E and RG_50E. These results suggest that fermented rice germ extracts have the potential to regulate hypoglycemia and hepatic glucose metabolism in type 2 diabetes db/db mice.

High-fat diet-induced obesity can lead to hepatic insulin resistance (IR) and alter glucose metabolism. The decreased protein expression involved in the PI3K-Akt pathway may enhance hepatic glycogenolysis and gluconeogenesis. Obesity-associated glucose dysregulation and IR are risk factors for the development of peripheral arterial disease. Glutamine (Gln) has immunomodulatory properties and was found to attenuate IR and hyperglycemia in diabetic condition. Thus, in this study we hypothesized that Gln administration modulates hepatic glucose metabolism and improve IR via PI3K-Akt pathway in obese mice with limb ischemia. Mice were divided into a high-fat group (HC), and a high-fat Gln group (HG). Mice in the HC group were fed the high-fat diet for 8 weeks, while the HG group was initially fed the high-fat diet for 4 weeks followed by a high-fat diet with Gln for an additional 4 weeks. Part of the mice in the HC and HG groups were subjected to a limb ischemic operation and were euthanized after the operation. Liver tissues and blood samples were collected for analysis. The results showed that high-fat diet-induced obesity resulted in increased plasma glucose and insulin levels. Also, impairment of hepatic insulin signaling by downregulating PI3K-Akt pathway-associated protein expression was observed. Administration of Gln increased protein expression associated with PI3K-Akt signaling pathway, while reducing G6PC and FOXO1 expression in the hepatocytes that may promote glycogen synthesis and inhibit gluconeogenesis. These findings suggest that obese mice treated with Gln-containing high-fat diet may normalize blood glucose and improve IR in response to limb ischemia. [ABSTRACT FROM AUTHOR]

Cadmium (Cd), is a well-known reproductive toxicant. The impacts of paternal Cd exposure on offspring glucose and lipid metabolism remain unclear, despite the abundance of adverse reports following early exposure from the mother. Here, we assessed paternally acquired metabolic derailment using a mouse model. LC-MS/MS, transcriptomics and molecular experimental techniques were subsequently applied in this study to explore the potential mechanism. We found that paternal Cd exposure caused glucose intolerance, lower insulin sensitivity and abnormal hepatic glycogen storage in adult female offspring, but not in males. LC-MS/MS data showed that hepatic phospholipids accumulation was also only observed in adult female offspring after paternal Cd exposure. Gene expression data showed that the level of insulin signaling and lipid transport-related genes was decreased in Cd-treated adult female offspring livers. Meanwhile, AHR, a transcription factor that combines with phospholipids to promote insulin resistance, was increased in Cd-treated adult female offspring livers. In addition, the escalation of the afore-mentioned lipid metabolites in the liver occurred as early as fetal stages in the female pups following paternal Cd exposure, suggesting the potential for these lipid species to be selected as early markers of disease for metabolic derailment later in life. Altogether, paternal Cd exposure causes offspring glucose metabolism disorder and phospholipids accumulation in a sex-dependent manner. This study provides a theoretical framework for future understanding of paternal-originated metabolic diseases. [Display omitted] • Paternal Cd impairs glucose metabolism in adult female offspring. • Paternal Cd enhances hepatic phospholipids in adult female offspring. • Paternal Cd reduces phospholipid transport-related mRNAs in offspring livers. • Paternal Cd persistently elevated six phospholipids in fetal and adult female livers. [ABSTRACT FROM AUTHOR]

There is no previous study in the literature that has examined the relationship between circulating vitamin K1 (VK1) with glycemic status in type 2 diabetes (T2D). Moreover, scientific explanation for the beneficial role of VK1 supplementation in lowering glycemia in diabetes is yet to be determined. This study for the first time demonstrated that circulating VK1 was significantly lower in T2D patients compared to age-matched control subjects, and VK1 levels in T2D were significantly and inversely associated with fasting glucose and insulin resistance [homeostatic model assessment of insulin resistance (HOMA-IR)], which suggest that boosting plasma VK1 may reduce the fasting glucose and insulin resistance in T2D patients. Using high-fat-diet-fed T2D animal model, this study further investigated the positive effect of VK1 supplementation on glucose metabolism and examined the underlying molecular mechanism. Results showed that VK1 supplementation [1, 3, 5 μg/kg body weight (BW), 8 weeks] dose dependently improved the glucose tolerance; decreased BW gain, fasting glucose and insulin, glycated hemoglobin, HOMA-IR and cytokine secretion (monocyte chemoattractant protein-1 and interleukin-6); and regulated the signaling pathway of hepatic glucose metabolism [sirtuin 1 (SIRT1)/AMP-activated protein kinase (AMPK)/phosphoinositide 3-kinase/phosphatase and tensin homolog/glucose transporter 2/glucokinase/glucose 6 phosphatase], lipid oxidation (peroxisome proliferator-activated receptor alpha/carnitine palmitoyltransferase 1A) and inflammation (nuclear factor kappa B) in T2D mice. Comparative signal silencing studies also depicted the role of SIRT1/AMPK in mediating the effect of VK1 on glucose metabolism, lipid oxidation and inflammation in high-glucose-treated cultured hepatocytes. In conclusion, this study demonstrates that circulating VK1 has a positive effect on lowering fasting glucose and insulin resistance in T2D via regulating SIRT1/AMPK signaling pathway. [ABSTRACT FROM AUTHOR]

Under physiological conditions, nitric oxide (NO) produced by the endothelial NO synthase (eNOS) upregulates hepatic insulin sensitivity. Recently, contact sites between the endoplasmic reticulum and mitochondria named mitochondria-associated membranes (MAMs) emerged as a crucial hub for insulin signaling in the liver. As mitochondria are targets of NO, we explored whether NO regulates hepatic insulin sensitivity by targeting MAMs. In Huh7 cells, primary rat hepatocytes and mouse livers, enhancing NO concentration increased MAMs, whereas inhibiting eNOS decreased them. In vitro, those effects were prevented by inhibiting protein kinase G (PKG) and mimicked by activating soluble guanylate cyclase (sGC) and PKG. In agreement with the regulation of MAMs, increasing NO concentration improved insulin signaling, both in vitro and in vivo, while eNOS inhibition disrupted this response. Finally, inhibition of insulin signaling by wortmannin did not affect the impact of NO on MAMs, while experimental MAM disruption, using either targeted silencing of cyclophilin D or the overexpression of the organelle spacer fetal and adult testis-expressed 1 (FATE-1), significantly blunted the effects of NO on both MAMs and insulin response. Therefore, under physiological conditions, NO participates to the regulation of MAM integrity through the sGC/PKG pathway and concomitantly improves hepatic insulin sensitivity. Altogether, our data suggest that the induction of MAMs participate in the impact of NO on hepatocyte insulin response.

The phytochemical, menthol, has been reported to play many beneficial roles. However, under diabetic conditions, there is no detail mechanism of its beneficial action in the glucose homeostasis. The present study, we investigated to explore the role of menthol, on the glucose metabolic enzymes and pancreatic islet cell apoptosis of streptozotocin–nicotinamide (STZ–NA) induced diabetes in rats. Diabetes was induced by single intraperitoneal (i.p.) injection of STZ (50 mg/kg/b.w.) and NA (110 mg/kg/b.w.). Diabetic rats were treated with different dose of menthol (25, 50, and 100 mg/kg/b.w.) and glibenclamide (600 μg/kg/b.w.) daily for 45 days. The result of our study shows that menthol significantly reduced the blood glucose and glycosylated hemoglobin levels and significantly increased the total hemoglobin, plasma insulin and liver glycogen levels in diabetic rats. The altered activities of hepatic glucose metabolic enzymes, serum biomarkers of liver damage were restored to near normal. The pathological abnormalities in hepatic and pancreatic islets of diabetic rats were significantly ameliorated by menthol intervention. These effects were mediated by suppressing pancreatic β-cells apoptosis and were associated with increased anti-apoptotic Bcl-2 expression and reduced pro-apoptotic Bax expression. Findings from the current study consent us to conclude that menthol alleviates STZ–NA-induced hyperglycemia via modulating glucose metabolizing enzymes, suppression of pancreatic β-cells apoptosis and altered hepatic, pancreatic morphology. This exclusivity and dearth of any noticeable adverse efficacy proposes the opportunity of using this monoterpene as an efficient adjuvant in the management diabetes mellitus. [ABSTRACT FROM AUTHOR]

[Display omitted] • Ginsenoside Rb1 improves type 2 diabetes mellitus. • Rb1 ameliorates the abnormal hepatic glucose metabolism in T2DM mice. • Rb1 promotes glycolysis and inhibits gluconeogenesis to improve hepatic glucose metabolism. • Rb1 meliorates the abnormal hepatic glucose metabolism in a STAT3-dependent manner. Ginsenoside Rb1, a major bioactive component of Panax ginseng C. A. Mey., exerts beneficial effects on type 2 diabetes mellitus (T2DM), but its underlying mechanism is unclear. STAT3 is a key factor regulating energy metabolism. Herein, we tested whether Rb1 regulates STAT3-controlled hepatic glucose metabolism to ameliorate T2DM. Rb1 ameliorated abnormal hepatic glucose metabolism, insulin resistance, and liver steatosis in T2DM mice. Hepatic STAT3 phosphorylation was decreased in T2DM and increased after Rb1 treatment. Moreover, Rb1 reversed the decreased expressions of glycolytic enzymes and the increased expressions of gluconeogenic enzymes in T2DM. STAT3 activation increased the expressions of glycolytic enzymes and decreased the expressions of gluconeogenic enzymes in vitro , and vice versa. Further, STAT3 inhibition reversed the changes of these enzymes induced by Rb1 in insulin-resistant cells. Taken together, Rb1 ameliorated abnormal hepatic glucose metabolism in T2DM in a STAT3-dependent manner, which provides experimental bases for Rb1 in treating T2DM. [ABSTRACT FROM AUTHOR]

Background: Fibroblast growth factor (FGF) 15/19, which is expressed in and secreted from the distal ileum, can regulate hepatic glucose metabolism in an endocrine manner. The levels of both bile acids (BAs) and FGF15/19 are elevated after bariatric surgery. However, it is unclear whether the increase in FGF15/19 is induced by BAs. Moreover, it remains to be understood whether FGF15/19 elevations contribute to improvements in hepatic glucose metabolism after bariatric surgery., Aim: To investigate the mechanism of improvement of hepatic glucose metabolism by elevated BAs after sleeve gastrectomy (SG)., Methods: By calculating and comparing the changes of body weight after SG with SHAM group, we examined the weight-loss effect of SG. The oral glucose tolerance test (OGTT) test and area under the curve of OGTT curves were used to assess the anti-diabetic effects of SG. By detecting the glycogen content, expression and activity of glycogen synthase as well as the glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (Pepck), we evaluated the hepatic glycogen content and gluconeogenesis activity. We examined the levels of total BA (TBA) together with the farnesoid X receptor (FXR)-agonistic BA subspecies in systemic serum and portal vein at week 12 post-surgery. Then the histological expression of ileal FXR and FGF15 and hepatic FGF receptor 4 (FGFR4) with its corresponding signal pathways involved in glucose metabolism were detected., Results: After surgery, food intake and body weight gain of SG group was decreased compare with the SHAM group. The hepatic glycogen content and glycogen synthase activity was significantly stimulated after SG, while the expression of the key enzyme for hepatic gluconeogenesis: G6Pase and Pepck, were depressed. TBA levels in serum and portal vein were both elevated after SG, the FXR-agonistic BA subspecies: Chenodeoxycholic acid (CDCA), lithocholic acid (LCA) in serum and CDCA, DCA, LCA in portal vein were all higher in SG group than that in SHAM group. Consequently, the ileal expression of FXR and FGF15 were also advanced in SG group. Moreover, the hepatic expression of FGFR4 was stimulated in SG-operated rats. As a result, the activity of its corresponding pathway for glycogen synthesis: FGFR4-Ras-extracellular signal regulated kinase pathway was stimulated, while the corresponding pathway for hepatic gluconeogenesis: FGFR4- cAMP regulatory element-binding protein- peroxisome proliferator-activated receptor γ coactivator-1α pathway was suppressed., Conclusion: Elevated BAs after SG induced FGF15 expression in distal ileum by activating their receptor FXR. Furthermore, the promoted FGF15 partly mediated the improving effects on hepatic glucose metabolism of SG., Competing Interests: Conflict-of-interest statement: The authors declare that they have no competing interests., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

The present study investigated the effect of 1-Deoxynojirimycin (DNJ) on liver injury and hepatic glucose metabolism in db/db mice. Mice were divided into five groups: normal control, db/db control, DNJ-20 (DNJ 20 mg. kg-1. day-1), DNJ-40 (DNJ 40 mg-1 kg-1. day-1) and DNJ-80 (DNJ 80 mg. kg-1. day-1). All doses were treated intravenously by tail vein for four weeks. DNJ was observed to significantly reduce the levels of serum triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and liver TG, as well as activities of serum alanine aminotransferase (ALT), and aspartate transaminase (AST); DNJ also alleviated macrovesicular steatosis and decreased tumor necrosis factor α (TNF-α), interleukin-1 (IL-1), interleukin-6 (IL-6) levels in liver tissue. Furthermore, DNJ treatment significantly increased hepatic glycogen content, the activities of hexokinase (HK), pyruvate kinase (PK) in liver tissue, and decreased the activities of glucose-6-phosphatase (G6Pase), glycogen phosphorylase (GP), and phosphoenolpyruvate carboxykinase (PEPCK). Moreover, DNJ increased the phosphorylation of phosphatidylinositol 3 kinase (PI3K) on p85, protein kinase B (PKB) on Ser473, glycogen synthase kinase 3β (GSK-3β) on Ser9, and inhibited phosphorylation of glycogen synthase (GS) on Ser645 in liver tissue of db/db mice. These results demonstrate that DNJ can increase hepatic insulin sensitivity via strengthening of the insulin-stimulated PKB/GSK-3β signal pathway and by modulating glucose metabolic enzymes in db/db mice. Moreover, DNJ also can improve lipid homeostasis and attenuate hepatic steatosis in db/db mice. [ABSTRACT FROM AUTHOR]

Iron exerts significant influences on glucose metabolism. However, the regulatory mechanisms underlying disordered glucose response remains largely unclear. The aim of this study was to examine the impact of dietary iron on hepatic gluconeogenesis in mice and in rat liver-derived cells. High iron models of C57BL/6J mice were fed with 1.25 g Fe/kg diets for 9 weeks, and high-iron BRL-3A cell models were treated with 250 μmol/L FeSO4 for 12 h and 24 h. Our data showed that higher iron intake resulted in higher hepatic iron without iron toxicity, and reduced body weight gain with no difference of food intakes. High dietary iron significantly increased 61% of hepatic glycogen deposition, but exhibited impairment in glucose responses in mice. Moreover, high dietary iron suppressed hepatic gluconeogenesis by repressing the expression of key gluconeogenic enzymes, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. Meanwhile, mice fed with higher iron diets exhibited both decreased AMP-activated protein kinase (AMPK) activity and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) protein levels. Furthermore, in BRL-3A cells, iron treatment increased cellular glucose uptake, and altered gluconeogenesis rhythmically by regulating the activation of AMPK and expression of PGC-1α successively. This study demonstrated that dietary high iron was able to increase hepatic glycogen deposition by enhancement of glucose uptake, and suppress hepatic gluconeogenesis by regulation of AMPK and PGC-1α. [ABSTRACT FROM AUTHOR]

Mulberry leaf is a traditional medicine used to treat diabetes in the clinic. The aim of this study was to determine the mechanisms by which mulberry leaf polysaccharide (MLPII), improves hepatic glucose metabolism and insulin resistance in rats with type 2 diabetes induced by high fat and streptozotocin (STZ). MLPII was administered for 6 weeks after establishment of type 2 diabetes in Wistar rats. At the end of the experiment, oral glucose tolerance, liver glycogen content, glucose synthase (GS) activity and insulin resistance were determined. Expression patterns of proteins and genes associated with insulin signaling as well as biomarkers of oxidative stress and antioxidant enzyme activities were assayed. Compared with normal control rats, MLPII treatment significantly improved oral glucose tolerance ( P < 0.01) and restored the glycogen level ( P < 0.01) and GS activity ( P < 0.05) in diabetic rats. Insulin resistance was improved in MLPII-treated diabetic rats ( P < 0.01). Furthermore, expression levels of insulin receptor substrate 2 (IRS2), phosphatidylinositol 3-kinase (PI3K) and protein kinase B (PKB/AKT) involved in insulin signaling were significantly increased ( P < 0.01), while protein–tyrosine phosphatase 1B (PTP1B) expression was markedly reduced ( P < 0.01). The levels of 8-hydroxy-2-deoxyguanosine (8-OHdG) and malondialdehyde (MDA) in livers of the MLPII-treated group were significantly reduced ( P < 0.01), while activities of the antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), were significantly increased ( P < 0.01, P < 0.01, P < 0.01, respectively). The results clearly indicate that MLPII treatment effectively normalizes hepatic glucose metabolism and insulin signaling by inhibiting the expression of PTP1B, activating the PI3K–AKT pathway and mitigating oxidative stress in the livers of rats with type 2 diabetes induced by high fat and STZ. [ABSTRACT FROM AUTHOR]

Summary: Background: Insulin resistance is highly prevalent in patients with chronic hepatitis C (CHC) and to some extent accounts for fibrosis and reducing viral eradication. Activated cannabinoid 1 receptor (CB1R) signaling has been implicated in the development of phenotypes associated with insulin resistance and steatosis. We investigated the role of the endocannabinoid system in glucose metabolism disorders induced by hepatitis C virus (HCV) replication. Methods: Human hepatic stellate cells (HSC; LX-2 cells) were co-cultured with Huh-7.5 cells or Huh-7.5 cells harboring HCV replicon (replicon cells). Endocannabinoid levels were then measured by liquid chromatography/mass spectrometry. The expression of CB1R and its downstream glucose metabolism genes in hepatocytes were determined by real-time PCR and Western blot. Glucose uptake by hepatocytes and glucose production were measured. Glucose metabolism tests and measurements of HCV RNA levels and nonstructural protein 5A (NS5A) levels were taken after treatment with CB1R agonist arachidonyl-2-chloroethanolamide (ACEA) or antagonist AM251. Results: Compared to the co-culture with Huh-7.5 cells, the level of 2-arachidonoylglycerol (2-AG) and the CB1R mRNA and protein levels increased in the co-culture of LX-2 cells with replicon cells. The activation of CB1R decreased AMP-activated protein kinase (AMPK) phosphorylation, inhibited cell surface expression of glucose transporter 2 (GLUT2), and suppressed cellular glucose uptake; furthermore, it increased cyclic AMP response element-binding protein H (CREBH), then up-regulated phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) genes and down-regulated the glucokinase (GK) gene, thus promoting glucose production. Interferon treatment restored the aforementioned changes. CB1R antagonist improved glucose metabolism disorders by an increase in glucose uptake and a decrease in glucose production, and inhibited HCV replication. Conclusions: HCV replication may not only increase the 2-AG content, but may also up-regulate the expression of CB1R of hepatocytes, then change the expression profile of glucose metabolism-related genes, thereby causing glucose metabolism disorders of hepatocytes and promoting HCV replication. Treatment with CB1R antagonist improved glucose metabolism disorders and inhibited viral genome replication. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Excessive hepatic glucose production is a hallmark of insulin resistance in type 2 diabetes. The cAMP responsive transcription factor cAMP responsive element binding protein (CREB), thought to be a key activator of the hepatic gluconeogenic gene regulation programme, has been suggested as a therapeutic target to reduce glucose output by the liver. Here, we test directly the requirement for hepatocytic CREB for the maintenance of glucose homeostasis. Methods: We derived mice with a Creb (also known as Creb1) loxP allele for conditional, cell-type specific gene ablation. Hepatocyte-specific deletion of Creb was induced by injecting Creb mice with Cre recombinase expression adeno-associated virus. Results: Strikingly, we found no difference in fed and fasted glucose levels, or in glucose, insulin and glucagon tolerance in mice fed a normal chow or a high-fat diet. In addition, mRNA levels of liver-specific genes, including several CREB target genes involved in gluconeogenesis, were not affected by CREB deficiency in the liver. Conclusion/interpretation: Our data show that CREB has no non-redundant functions in hepatic glucose metabolism, and is therefore not likely to be a useful target for the development of glucose-lowering drugs. [ABSTRACT FROM AUTHOR]

The impact of the GLP-1 receptor agonist lixisenatide on postprandial glucose disposition was examined in conscious dogs to identify mechanisms for its improvement of meal tolerance in humans and examine the tissue disposition of meal-derived carbohydrate. Catheterization for measurement of hepatic balance occurred ≈16 days before study. After being fasted overnight, dogs received a subcutaneous injection of 1.5g/kg lixisenatide or vehicle (saline, control; n = 6/group). Thirty minutes later, they received an oral meal feeding (93.4 kJ; 19% protein, 71% glucose polymers, and 10% lipid). Acetaminophen was included in the meal in four control and five lixisenatide dogs for assessment of gastric emptying. Observations continued for 510 min; absorption was incomplete in lixisenatide at that point. The plasma acetaminophen area under the curve (AUC) in lixisenatide was 65% of that in control (P < 0.05). Absorption of the meal began within 15 min in control but was delayed until ≈30-45 min in lixisenatide. Lixisenatide reduced (P < 0.05) the postprandial arterial glucose AUC ≈54% and insulin AUC ≈44%. Net hepatic glucose uptake did not differ significantly between groups. Nonhepatic glucose uptake tended to be reduced by lixisenatide (6,151 ± 4,321 and 10,541 ± 1,854 μmol·kg-1·510 min-1 in lixisenatide and control, respectively; P = 0.09), but adjusted (for glucose and insulin concentrations) values did not differ (18.9 ± 3.8 and 19.6 ± 7.9 l·kg-1·pmol-1·l-1, lixisenatide and control, respectively; P = 0.94). Thus, lixisenatide delays gastric emptying, allowing more efficient disposal of the carbohydrate in the feeding without increasing liver glucose disposal. Lixisenatide could prove to be a valuable adjunct in treatment of postprandial hyperglycemia in impaired glucose tolerance or type 2 diabetes. [ABSTRACT FROM AUTHOR]

Exposure to fine particulate matter (PM 2.5 ) was associated with an increased incidence of liver metabolic disease. Melatonin has been shown to prevent liver glucolipid metabolism disorders. However, whether melatonin could rescue PM 2.5 -induced liver metabolic abnormalities remains uncertain. This study was to evaluate the mitigating effect of melatonin on PM 2.5 -accelerated hepatic glucose metabolism imbalance in vivo and in vitro. Schiff periodic acid shiff staining and other results showed that PM 2.5 led to a decrease in hepatic glycogen reserve and an increase in glucose content, which was effectively alleviated by melatonin. Targeted lipidomics is used to identify lipid biomarkers associated with this process, including glycerolipids, glycerophospholipids, and sphingolipids. In addition, gene microarray and quantitative polymerase chain reaction analysis of ApoE -/- mice liver suggested that PM 2.5 activated the miR-200a-3p and inhibited DNAJB9, and the targeting relationship was verified by luciferase reports for the first time. Further investigation demonstrated that DNAJB9 might motivate endoplasmic reticulum (ER) stress by regulating Ca 2+ homeostasis, thus altering the protein expression of GSK3B, FOXO1, and PCK2. Meanwhile, melatonin effectively inhibited miR-200a-3p and glucose metabolism disorder. Knockout of miR-200a-3p in L02 cells revealed that miR-200a-3p is indispensable in the damage of PM 2.5 and the therapeutic effect of melatonin. In summary, melatonin alleviated PM 2.5 -induced liver metabolic dysregulation by regulating ER stress via miR-200a-3p/DNAJB9 signaling pathway. Our data provide a prospective targeted therapy for air pollution-related liver metabolism disorders., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Incretins improve glucose metabolism through multiple mechanisms. It remains unclear whether direct hepatic effects are an important part of exenatide's (Ex-4) acute action. Therefore, the objective of this study was to determine the effect of intraportal delivery of Ex-4 on hepatic glucose production and uptake. Fasted conscious dogs were studied during a hyperglycemic clamp in which glucose was infused into the hepatic portal vein. At the same time, portal saline (control; n = 8) or exenatide was infused at low (0.3 pmol·kg-1·min-1, Ex-4-low; n = 5) or high (0.9 pmol·kg-1·min-1, Ex-4-high; n = 8) rates. Arterial plasma glucose levels were maintained at 160 mg/dl during the experimental period. This required a greater rate of glucose infusion in the Ex-4-high group (1.5 ± 0.4, 2.0 ± 0.7, and 3.7 ± 0.7 mg·kg-1·min-1 between 30 and 240 min in the control, Ex-4-low, and Ex-4-high groups, respectively). Plasma insulin levels were elevated by Ex-4 (arterial: 4,745 ± 428, 5,710 ± 355, and 7,262 ± 1,053 μU/ml; hepatic sinusoidal: 14,679 ± 1,700, 15,341 ± 2,208, and 20,445 ± 4,020 μU/ml, 240 min, area under the curve), whereas the suppression of glucagon was nearly maximal in all groups. Although glucose utilization was greater during Ex-4 infusion (5.92 ± 0.53, 6.41 ± 0.57, and 8.12 ± 0.54 mg·kg-1·min-1), when indices of hepatic, muscle, and whole body glucose uptake were expressed relative to circulating insulin concentrations, there was no indication of insulin-independent effects of Ex-4. Thus, this study does not support the notion that Ex-4 generates acute changes in hepatic glucose metabolism through direct effects on the liver. [ABSTRACT FROM AUTHOR]

Increased hepatic glucose output is one of the major causes of fasting hyperglycemia in diabetic patients. In this study, we investigated the mechanism of action of coagulanolide on hepatic glucose, regulating enzymes in type 2 diabetic C57BL/KsJ-db/db (db/db) mice. Coagulanolide is an active component of Withania coagulans fruit. Oral administration of coagulanolide for 3 weeks decreases fasting blood glucose and plasma insulin significantly, and it improves glucose tolerance in the db/db mice group. The enzyme activity and protein expression of glucokinase and pyruvate kinase was significantly enhanced in coagulanolide-treated db/db group when compared with untreated one. On the other hand, activities and protein expression of fructose-1,6-bisphosphatase, glucose 6-phosphatase, phosphoenolpyruvate carboxykinase, and glycogen phosphorylase enzymes were significantly lowered in treated group. The treatment with coagulanolide also normalizes the concentrations of plasma cholesterol, triglyceride, free fatty acid, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol in the db/db mice. These findings suggested that the coagulanolide is useful in the control of fasting hyperglycemia in type 2 diabetes by regulating the production of hepatic glucose. [ABSTRACT FROM AUTHOR]

A sucrose-rich diet (SRD) induces insulin resistance and dyslipidemia with impaired hepatic glucose production and gluconeogenesis, accompanied by altered post-receptor insulin signaling steps. The aim of this study was to examine the effectiveness of fish oil (FO) to reverse or improve the impaired hepatic glucose metabolism once installed in rats fed 8 months a SRD. In the liver of rats fed SRD in which FO replaced corn-oil during the last 2 months, as dietary fat, several key enzyme activities and metabolites involved in glucose metabolisms (phosphorylation, glycolysis, gluconeogenesis and oxidative and non oxidative glucose pathway) were measured. The protein mass levels of IRS-1 and αp85 PI-3K at basal conditions were also analyzed. FO improved the altered activities of some enzymes involved in the glycolytic and oxidative pathways observed in the liver of SRD fed rats but was unable to restore the impaired capacity of glucose phosphorylation. Moreover, FO reversed the increase in PEPCK and G-6-Pase and reduced the G-6-Pase/GK ratio. Glycogen concentration and GSa activity returned to levels similar to those observed in the liver of the control-fed rats. Besides, FO did not modify the altered protein mass levels of IRS-1 and αp85 PI-3K. Finally, dietary FO was effective in reversing or improving the impaired activities of several key enzymes of hepatic carbohydrate metabolism contributing, at least in part, to the normalization of plasma glucose levels in the SRD-fed rats. However, these positive effects of FO were not observed under basal conditions in the early steps of insulin signaling transduction. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: The mechanisms by which transcription factor 7-like 2 (TCF7L2) regulates the pathways that are important in the pathogenesis of type 2 diabetes are unknown. We therefore examined the role of TCF7L2 in hepatic glucose production (HGP) in vitro and characterised the whole-genome chromatin occupancy of TCF7L2 in hepatocytes. Methods: We investigated the effect of TCF7L2 silencing and overexpression on HGP from gluconeogenic precursors and used chromatin-immunoprecipitation (ChIP) combined with massively parallel DNA sequencing (ChIP-Seq) to investigate the DNA binding patterns of TCF7L2 across the whole genome. Results: Silencing of TCF7L2 induced a marked increase in basal HGP, which was accompanied by significant increases in the expression of the gluconeogenic genes Fbp1, Pck1 and G6pc. Overexpression of Tcf7l2 reversed this phenotype and significantly reduced HGP. TCF7L2 silencing did not affect the half-maximal inhibitory concentration of insulin or metformin, but HGP remained elevated in TCF7L2-silenced cells due to the increased baseline HGP. Using ChIP-Seq, we detected 2,119 binding events across the genome. Pathway analysis demonstrated that diabetes genes were significantly over-represented in the dataset. Our results indicate that TCF7L2 binds directly to multiple genes that are important in regulation of glucose metabolism in the liver, including Pck1, Fbp1, Irs1, Irs2, Akt2, Adipor1, Pdk4 and Cpt1a. Conclusions/interpretation: TCF7L2 is an important regulator of HGP in vitro and binds directly to genes that are important in pathways of glucose metabolism in the liver. These data highlight the possibility that TCF7L2 may affect fasting and postprandial hyperglycaemia in carriers of at-risk TCF7L2 genetic polymorphisms. [ABSTRACT FROM AUTHOR]

Aim: Orally delivered insulin is predicted to bear therapeutic advantages in diabetes management when compared to injectable insulin, because of its ability to mimic the natural route of endogenous insulin secreted by the pancreas into the portal vein and directly to the liver. Oramed Pharmaceuticals is developing an oral insulin product which consists of unmodified recombinant human insulin combined with adjuvants that protect it from enzymatic degradation in the gastrointestinal tract and promote its absorption from the gut. The aim was to determine the optimal adjuvants to insulin ratio which can provide for the best pharmacodynamic profile, while maintaining the safety of the product. Methods: Eight healthy, male volunteers participated in this open-label study which included five independent visits. During each visit, subjects were administered one of the five encapsulated oral insulin formulations which contained equal amounts of insulin but varying proportions of adjuvants. Parameters measured included safety, Cmax and Tmax for insulin and Cmin, Tmin and area under the curve (AUC) for glucose and c-peptide. Comparisons were made between formulations and between post-treatment time periods within each visit. Results: All five oral insulin formulations were well tolerated and no serious adverse events were reported. All formulations resulted in a significant response in the response period (60–300 min) in comparison to baseline (0–60 min); this was captured both in the c-peptide response and the glucose response (all five formulations p < 0.05). However, none of the formulations turned out significantly different in response over the other. Formulation 5 showed the most profound reduction in c-peptide when AUC0–60 (baseline) was compared to AUC60–300 (p < 0.007). Conclusions: All five oral insulin formulations resulted in glucose and c-peptide reductions, where formulation 5 demonstrated the most pronounced effect on c-peptide concentration reduction. This formulation was deemed the lead formulation to be advanced to future clinical studies. This study also reinforces the notion that oral insulin can maintain its biological activity after delivery, suggesting a potential role for this product in management of diabetes. [ABSTRACT FROM AUTHOR]

Glucokinase (GCK) is a key enzyme involved in hepatic glucose metabolism as well as in glucose homeostasis regulation. In mammals, GCK is regulated in vivo by a regulatory protein (GCKR) through a nucleus-to-cytoplasm translocation enhanced by fructose 1-phosphate and counteracted by fructose 6-phosphate. There were no previous evidences in literature regarding the presence of GCKR in livers of other vertebrates like fish and bird. Accordingly, in the present study we assessed GCKR presence in chicken, trout, carp, and goldfish hepatic homogenates. The results obtained demonstrate for the first time the presence of a GCKR-like protein in the liver of those species, with molecular weight (68 kDa) and biochemical properties similar to those described in mammals. Several of the biochemical properties of rainbow trout GCKR-like protein were closer to the mammalian model whereas those of chicken protein were specific. We also compared the presence and properties of GCKR-like protein in livers of different teleost species that exhibit different tolerances to glucose such as rainbow trout (intolerant) and goldfish and common carp (tolerant). The results showed that the most powerful GCKR-like protein was found in the most intolerant species, whereas the inhibition exerted by GCKR-like protein in tolerant species was closer to chicken than to rat. Furthermore, the response of GCKR-like protein in liver of rainbow trout fed with a diet rich in carbohydrates was compared with the rat model under extreme glycemic conditions. We found that despite trout GCKR-like protein was less active and expressed than in rat, the response against glycemic changes took place in the same direction, and the ratio GCKR-like protein:GCK was affected in a similar way. [ABSTRACT FROM AUTHOR]

Thyrotoxicosis increases endogenous glucose production (EGP) and induces hepatic insulin resistance. We have recently shown that these alterations can be modulated by selective hepatic sympathetic and parasympathetic denervation, pointing to neurally mediated effects of thyroid hormone on glucose metabolism. Here, we investigated the effects of central triiodothyronine (T3) administration on EGP. We used stable isotope dilution to measure EGP before and after i.c.v. bolus infusion of T3 or vehicle in euthyroid rats. To study the role of hypothalamic preautonomic neurons, bilateral T3 microdialysis in the paraventricular nucleus (PVN) was performed for 2 h. Finally, we combined T3 microdialysis in the PVN with selective hepatic sympathetic denervation to delineate the involvement of the sympathetic nervous system in the observed metabolic alterations. T3 microdialysis in the PVN increased EGP by 11 ± 4% (P = 0.020), while EGP decreased by 5 ± 8% (ns) in vehicle-treated rats (T3 vs. Veh, P = 0.030). Plasma glucose increased by 29 ± 5% (P = 0.0001) after T3 microdialysis versus 8 ± 3% in vehicle-treated rats (T3 vs. Veh, P = 0.003). Similar effects were observed after i.c.v. T3 administration. Effects of PVN T3 microdialysis were independent of plasma T3, insulin, glucagon, and corticosterone. However, selective hepatic sympathectomy completely prevented the effect of T3 microdialysis on EGP. We conclude that stimulation of T3-sensitive neurons in the PVN of euthyroid rats increases EGP via sympathetic projections to the liver, independently of circulating glucoregulatory hormones. This represents a unique central pathway for modulation of hepatic glucose metabolism by thyroid hormone. [ABSTRACT FROM AUTHOR]

The metabolic fate of hepatic glucose can be best studied using invasive techniques such as tracer infusions and frequent blood sampling which have been revealed to be impractical in the pediatric age group. The aim of this study was to develop a non-invasive method based on indirect calorimetry and expired 13CO2 monitoring in order to gain insight into the mechanisms leading to impaired glucose tolerance in children and teenagers. As a first step, net glucose oxidation (NGO) and energy expenditure (EE) were measured in 47 subjects (range 7.5–17.3 years) of whom 18 were prepubertal (P1), 11 in early puberty (P2–P3) and 18 in late puberty (P4–P5) after 3-hourly loads of 180 mg/kg of oral maize glucose containing naturally enriched 13C. Isotope analysis allowed to calculate exogenous and endogenous glucose oxidation (EXGO, ENGO) and, hence, to derive TGS and NGS, that is glycogen turnover. NGO and EE decreased significantly with pubertal progression, reflecting higher metabolism at younger ages, whereas EXGO remained constant. TGS did not change significantly whereas NGS showed a significant negative correlation with pubertal progression: this can be explained by the fact that glycogenolysis exceeded glycogen synthesis in this experimental setting. This non-invasive method appears to be a promising tool to study the fate of hepatic glucose and therefore glycogen turnover in children at risk of developing glucose intolerance and/or type 2 diabetes. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Our objective is to understand the low metabolic utilization of dietary carbohydrates in fish. We compared the regulation of gluconeogenic enzymes at a molecular level in two fish species, the common carp (Cyprinus carpio) and gilthead seabream (Sparus aurata), known to be relatively tolerant to dietary carbohydrates. After cloning of partial cDNA sequences for three key gluconeogenic enzymes (glucose-6-phosphatase (G6Pase), fructose biphosphatase (FBPase) and phosphoenolpyruvate carboxykinase (PEPCK) in the two species, we analyzed gene expressions of these enzymes 6 and 24 h after feeding with (20%) or without carbohydrates. Our data show that there is at least one gluconeogenic enzyme strongly regulated (decreased expression after feeding) in the two fish species, i.e. the PEPCK for common carp and G6Pase/FBPase for gilthead seabream. In these fish species, the regulation seems to be similar to the mammals at least at the molecular level. [Copyright &y& Elsevier]

Liver insulin resistance and glucagon-stimulated hepatic glucose production are characteristics of the diabetic state. To determine the potential role of glucose toxicity in these abnormalities, we examined whether phlorizin treatment of streptozotocin-diabetic rats resulted in altered expression of genes involved in key steps of hepatic glucose metabolism. By inhibiting renal tubular glucose reabsorption, phlorizin infusion to diabetic rats induced normoglycaemia, did not significantly alter low circulating insulinaemia, but caused a marked decrease in hyperglucagonaemia. Glucokinase and L-type pyruvate kinase mRNA levels were reduced respectively by 90% and 70% in fed diabetic rats, in close correlation with changes in enzyme activities. Eighteen days of phlorizin infusion partially restored glucokinase mRNA and activity (40% of control levels), but had no effect on L-type pyruvate kinase mRNA and activity. In contrast to the glycolytic enzymes, mRNA and activity of the gluconeogenic enzyme, phospoenolpyruvate carboxykinase were increased (10- and 2.2-fold, respectively) in fed diabetic rats. Phlorizin administration decreased phospoenolpyruvate carboxykinase mRNA to values not different from those in control rats, while phospoenolpyruvate carboxykinase activity remained 50% higher than that in control rats. The 50% rise in liver glucose transporter (GLUT 2) mRNA and protein, produced by diabetes, was also corrected by phlorizin treatment. In conclusion, we propose that phlorizin treatment of diabetic rats may induce a partial shift of the predominating gluconeogenesis, associated with hepatic glucose overproduction, into glycolysis, by correction of impaired pre-translational regulatory mechanisms. This could be essentially mediated through improved pancreatic alpha-cell function and subsequent lowering of hyperglucagonaemia. These observations suggest that glucagon-stimulated hepatic glucose production may result, in part, from glucose toxicity. [ABSTRACT FROM AUTHOR]

Sexual dimorphism is associated not only with somatic and behavioral differences between men and women, but also with physiological differences reflected in organ metabolism. Genes regulated by sex hormones differ in expression in various tissues, which is especially important in the case of liver metabolism, with the liver being a target organ for sex hormones as its cells express estrogen receptors (ERs: ERα, also known as ESR1 or NR3A; ERβ; GPER (G protein-coupled ER, also known as GPR 30)) and the androgen receptor (AR) in both men and women. Differences in sex hormone levels and sex hormone-specific gene expression are mentioned as some of the main variations in causes of the incidence of hepatic diseases; for example, hepatocellular carcinoma (HCC) is more common in men, while women have an increased risk of autoimmune liver disease and show more acute liver failure symptoms in alcoholic liver disease. In non-alcoholic fatty liver disease (NAFLD), the distinction is less pronounced, but increased incidences are suggested among men and postmenopausal women, probably due to an increased tendency towards visceral fat accumulation.

Under physiological conditions, nitric oxide (NO) produced by the endothelial NO synthase (eNOS) upregulates hepatic insulin sensitivity. Recently, contact sites between the endoplasmic reticulum and mitochondria named mitochondria-associated membranes (MAMs) emerged as a crucial hub for insulin signaling in the liver. As mitochondria are targets of NO, we explored whether NO regulates hepatic insulin sensitivity by targeting MAMs. In Huh7 cells, primary rat hepatocytes and mouse livers, enhancing NO concentration increased MAMs, whereas inhibiting eNOS decreased them. In vitro, those effects were prevented by inhibiting protein kinase G (PKG) and mimicked by activating soluble guanylate cyclase (sGC) and PKG. In agreement with the regulation of MAMs, increasing NO concentration improved insulin signaling, both in vitro and in vivo, while eNOS inhibition disrupted this response. Finally, inhibition of insulin signaling by wortmannin did not affect the impact of NO on MAMs, while experimental MAM disruption, using either targeted silencing of cyclophilin D or the overexpression of the organelle spacer fetal and adult testis-expressed 1 (FATE-1), significantly blunted the effects of NO on both MAMs and insulin response. Therefore, under physiological conditions, NO participates to the regulation of MAM integrity through the sGC/PKG pathway and concomitantly improves hepatic insulin sensitivity. Altogether, our data suggest that the induction of MAMs participate in the impact of NO on hepatocyte insulin response. [ABSTRACT FROM AUTHOR]

Whether vitamin A (VA) has a role in the development of metabolic abnormalities associated with intake of a high-fat diet (HFD) is unclear. Sprague-Dawley rats after weaning were fed an isocaloric VA sufficient HFD (VAS-HFD) or a VA deficient HFD (VAD-HFD) for 8 weeks. Body mass, food intake, liver and adipose tissue mass, and the hepatic expression levels of key proteins for metabolism were determined. VAD-HFD rats had lower body, liver, and epididymal fat mass than VAS-HFD rats. VAD-HFD rats had lower hepatic protein expression levels of cytochrome P450 26A1, glucokinase, and phosphoenolpyruvate carboxykinase than VAS-HFD rats. VAD-HFD rats had higher protein levels of glycogen synthase kinase (GSK)-3α and lower levels of GSK-3β, but not glycogen synthase, than VAS-HFD rats. VAD-HFD rats had higher hepatic levels of insulin receptor substrate-1 (IRS-1), insulin receptor β-subunit, mitogen-activated protein kinase proteins, and peroxisome proliferator-activated receptor-gamma coactivator 1α mRNA, and lower level of IRS-2 protein than VAS-HFD rats. These results indicate that in a HFD setting, VA deficiency attenuated HFD-induced obesity, and VA status altered the expression levels of proteins required for glucose metabolism and insulin signaling. We conclude that VA status contributes to the regulation of hepatic glucose and lipid metabolism in a HFD setting, and may regulate hepatic carbohydrate metabolism.