Polyphenolic compounds of Phyllanthus amarus Schum & Thonn. (1827) and diabetes-related activity of an aqueous extract as affected by in vitro gastrointestinal digestion.

ETHNOPHARMACOLOGICAL RELEVANCE: Extracts of the aerial part of Phyllanthus amarus have been extensively used in several countries to cure diabetes. No data is available on the impact of gastrointestinal digestion of such crude extracts on their antidiabetic activity. AIM OF THE STUDY: The aim of this study was to identify active fractions and compounds of fresh aerial parts of P. amarus extracted by an infusion method that are responsible for antidiabetic effects occurring at the level of glucose homeostasis. MATERIALS AND METHODS: An aqueous extract was obtained by an infusion method and its polyphenolic composition was analysed by reverse phase UPLC-DAD-MS. The influence of in vitro gastrointestinal digestion was evaluated both on the chemical composition and on the antidiabetic effect of P. amarus infusion extract using glucose-6-phosphatase enzyme inhibition and stimulation of glucose uptake. RESULTS: Analysis of the chemical composition of the crude extract revealed the presence of polysaccharides and various families of polyphenols such as phenolic acids, tannins, flavonoids and lignans. After simulated digestion, the total content of polyphenols decreased by about 95%. Caffeoylglucaric acid derivates and lignans exhibited strong stimulation of glucose uptake similar to metformin with an increase of 35.62 ± 6.14% and 34.74 ± 5.33% respectively. Moreover, corilagin, geraniin, the enriched polysaccharides fraction and the bioaccessible fraction showed strong anti-hyperglycemic activity with about 39-62% of glucose-6-phosphatase inhibition. CONCLUSION: Caffeoylglucaric acid isomers, tannin acalyphidin M1 and lignan demethyleneniranthin were reported for the first time in the species. After in vitro gastroinstestinal digestion, the composition of the extract changed. The dialyzed fraction showed strong glucose-6-phosphatase inhibition.

"Ficus johannis Boiss. leaves ethanolic extract ameliorate streptozotocin-induced diabetes in rats by upregulating the expressions of GCK, GLUT4, and IGF and downregulating G6P".

The leaves of Ficus johannis Boiss (F. johannis), commonly known as Fig tree, Anjir, and Teen, are used by the folk medicinal practitioners in Iran for controlling hyperglycemia in diabetic patients. This study investigated the pharmacological basis for antidiabetic effect of the ethanolic extract of F. johannis leaves using in vitro and in vivo experimental models. Qualitative screening of phytochemicals, estimation of total phenolic and flavonoid contents, and in vitro antioxidant and α-amylase inhibition assays were performed. Moreover, the High-performance liquid chromatography (HPLC) quantification, acute toxicity, glucose tolerance, and in vivo antidiabetic effect along with the evaluation of gene expressions involved in diabetes mellitus were carried out. Significant quantities of phenolic (71.208 ± 2.89 mgg-1 GAE) and flavonoid (26.38 ± 3.53 mgg-1 QE) were present. Inhibitory concentration (IC50) of the plant extract exhibited an excellent in vitro antioxidant (IC50 = 33.81 µg/mL) and α-amylase (IC50 = 12.18 µg/mL) inhibitory potential. The HPLC analysis confirmed the gallic acid (257.79 mgg-1) as main constituent of the extract followed by kaempferol (22.86 mgg-1), myricetin (0.16 mgg-1), and quercetin (3.22 mgg-1). Ethanolic extract displayed glucose tolerance in normo-glycemic rats. Streptozotocin-induced hyperglycemia declined dose dependently in the extract treated rats with improvement in lipid profile and liver and renal function biomarkers. The F. johannis-treated groups showed an increase in mRNA expressions of glucose transporter 4 (GLUT-4), glucokinase, insulin growth like factor 1 and peroxisomal proliferator activating receptor gamma in pancreas. However, the Glucose-6-phosphatase was downregulated. Present study suggests that the ethanolic extract of F. johannis leaves demonstrates a good anti-diabetic profile by improving insulin sensitivity, GLUT-4 translocation, and carbohydrate metabolism while inhibiting lipogenesis.

Organic chromium derived from the chelation of Ganoderma lucidum polysaccharide and chromium (III) alleviates metabolic syndromes and intestinal microbiota dysbiosis induced by high-fat and high-fructose diet.

Organic chromium is of great interest and has become an important chromium supplement resource in recent years because of its low toxicity and easy absorption. In our previous study, we synthesized a novel organic chromium [GLP-Cr] through the chelation of Ganoderma lucidum polysaccharide and chromium (III). The purpose of this study was to investigate the beneficial effects of GLP-Cr on the improvement of metabolic syndromes (MetS) in mice fed with a high-fat and high-fructose diet (HFHFD) and its mechanism of action. The results indicated that oral administration of GLP-Cr inhibited the excessive exaltation of body weight, glucose tolerance, fasting blood glucose and lipid levels, hepatic total cholesterol (TC), triglyceride (TG) levels caused by HFHFD. Besides, 16S rRNA amplicon sequencing showed that GLP-Cr intervention evidently ameliorated intestinal microbiota dysbiosis by changing the proportions of some intestinal microbial phylotypes. In addition, correlation network-based analysis indicated that the key intestinal microbial phylotypes were closely related to biochemical parameters associated with MetS under GLP-Cr intervention. Liver metabolomics analysis suggested that GLP-Cr intervention significantly regulated the levels of some biomarkers involved in alpha-linolenic acid metabolism, fatty acid biosynthesis, steroid hormone biosynthesis, glycerophospholipid metabolism, glycerolipid metabolism, steroid hormone biosynthesis, primary bile acid biosynthesis, and so on. Moreover, GLP-Cr intervention regulated liver mRNA levels of key genes associated with glucose and lipid metabolism. The mRNA level of glucose transporter type 4 (Glut4) was markedly increased by GLP-Cr intervention, and the mRNA levels of phosphoenolpyruvate carboxykinase (Pepck) and glucose-6-phosphatase (G6Pase) in the liver were significantly decreased. Meanwhile, GLP-Cr intervention significantly decreased hepatic mRNA levels of cluster of differentiation 36 (Cd36), acetyl-CoA carboxylase 1 (Acc1) and sterol regulatory element binding protein-1c (Srebp-1c), indicating that GLP-Cr intervention inhibited the excessive accumulation of free fatty acids in the liver. These findings suggest that the prevention of hyperglycemia and dyslipidemia by GLP-Cr may be closely related to the regulation of gut microbial composition and hepatic metabolic pathways, thus GLP-Cr can be serving as a functional component in the prevention of MetS.

Novel Triterpenoids from Cassia fistula Stem Bark Depreciates STZ-Induced Detrimental Changes in IRS-1/Akt-Mediated Insulin Signaling Mechanisms in Type-1 Diabetic Rats.

Here, we identified the mechanisms of action of antidiabetic activity of novel compounds isolated from Cassia fistula stem bark in STZ-diabetic animals. Novel triterpenoid compounds (C1, C2 and C3) were treated to STZ-administered diabetic animals at a concentration of 20mg/kg body weight orally for 60 days to assess their effects on plasma glucose, plasma insulin/C-peptide, serum lipid markers and the enzymes of carbohydrate metabolism, glucose oxidation and insulin signaling molecules. Oral administration of novel triterpenoid compounds to STZ-diabetic animals significantly decreased (p < 0.05) the plasma glucose concentration on the 7th, 15th, 30th, 45th and 60th daysin a duration-dependent manner (p < 0.05). Plasma insulin (p < 0.0001)/C-peptide (p < 0.0006), tissue glycogen (p < 0.0034), glycogen phosphorylase (p < 0.005), glucose 6-phosphatase (p < 0.0001) and lipid markers were significantly increased (p < 0.0001) in diabetic rats, whereas glucokinase (p < 0.0047), glycogen synthase (p < 0.003), glucose oxidation (p < 0.001), GLUT4 mRNA (p < 0.0463), GLUT4 protein (p < 0.0475) and the insulin-signaling molecules IR mRNA (p < 0.0195), IR protein (p < 0.0001), IRS-1 mRNA (p < 0.0478), p-IRS-1Tyr612 (p < 0.0185), Akt mRNA (p < 0.0394), p-AktSer473 (p < 0.0162), GLUT4 mRNA (p < 0.0463) and GLUT4 (p < 0.0475) were decreased in the gastrocnemius muscle. In silico analysis of C1-C3 with IRK and PPAR-γ protein coincided with in vivo findings. C1-C3 possessed promising antidiabetic activity by regulating insulin signaling mechanisms and carbohydrate metabolic enzymes.

Effects of phloridzin on blood glucose and key enzyme G-6-Pase of gluconeogenesis in mice.

The effects of phloridzin (PHL), main component of Malus hupehensis (MH) tea leaves, on blood glucose (BG) and glucose-6-phosphatase (G-6-Pase) were investigated to provide a basis for finding a scheme of stabilizing BG. Glucose uptake of insulin resistant HepG2 cells was measured by glucose oxidase method. Glucose tolerance, fasting BG (FBG) and postprandial BG (PBG) were determined by BG test strips. The expression of G-6-Pase was detected by Western blot. The results showed that glucose uptake was enhanced and the expression of G-6-Pase was inhibited by PHL in insulin resistant HepG2 cells. Glucose tolerance was enhanced, FBG level was increased and PBG level was decreased by PHL in mice. The expression of G-6-Pase in the liver was enhanced under fasting state, and was inhibited by the low and medium dose under postprandial state. It indicated that PHL has a positive effect on stabilizing BG in mice, which is related to bidirectional regulation of G-6-Pase activity. PRACTICAL APPLICATIONS: Malus hupehensis, edible and medicinal plant, which has been proved by long-term application and experiments that it has a good effect on stabilizing blood glucose, preventing diabetes and adjuvant treatment. Its effect is closely related to its main component PHL. Thus, MH can be used as a dietary regulating drink for daily life to maintain blood glucose. Its main ingredient is PHL, which can be developed as a candidate drug for diabetes treatment.

Growth hormone promotes hepatic gluconeogenesis by enhancing BTG2-YY1 signaling pathway.

Growth hormone (GH) is one of the critical factors in maintaining glucose metabolism. B-cell translocation gene 2 (BTG2) and yin yang 1 (YY1) are key regulators of diverse metabolic processes. In this study, we investigated the link between GH and BTG2-YY1 signaling pathway in glucose metabolism. GH treatment elevated the expression of hepatic Btg2 and Yy1 in primary mouse hepatocytes and mouse livers. Glucose production in primary mouse hepatocytes and serum blood glucose levels were increased during GH exposure. Overexpression of hepatic Btg2 and Yy1 induced key gluconeogenic enzymes phosphoenolpyruvate carboxykinase 1 (PCK1) and glucose-6 phosphatase (G6PC) as well as glucose production in primary mouse hepatocytes, whereas this phenomenon was markedly diminished by knockdown of Btg2 and Yy1. Here, we identified the YY1-binding site on the Pck1 and G6pc gene promoters using reporter assays and point mutation analysis. The regulation of hepatic gluconeogenic genes induced by GH treatment was clearly linked with YY1 recruitment on gluconeogenic gene promoters. Overall, this study demonstrates that BTG2 and YY1 are novel regulators of GH-dependent regulation of hepatic gluconeogenic genes and glucose production. BTG2 and YY1 may be crucial therapeutic targets to intervene in metabolic dysfunction in response to the GH-dependent signaling pathway.

Increased insulin and GLUT2 gene expression and elevated glucokinase activity in ß-like cells of islets of langerhans differentiated from human haematopoietic stem cells on treatment with Costus igneus leaf extract.

In the quest to understand lost ß-cells regeneration in the diabetic condition, we have demonstrated successful differentiation of human haematopoietic stem cells (HSCs) to functional ß-like cells. Costus igneus (Ci) leaf extract is known to exhibit anti-diabetic properties by lowering the blood glucose level as demonstrated in mice models. To establish the anti-diabetic properties of Ci leaf extract on human subjects, we studied the effect of Ci on these differentiated ß-like cells. Ci leaf extract showed its anti-diabetic property through elevated glucokinase activity which catalyzes the rate-limiting step of glucose catabolism in ß-like cells and acts as a sensor for insulin production while decreasing the glucose-6-phosphatase activity. Upon increasing the concentrations of Ci leaf extract (25, 65, 105, 145, 185 µg/ml) and glucose concentrations (5.5, 11.1, and 25 mM) Ci leaf extract treated ß-like cells showed enhanced glucokinase and decreased glucose-6-phosphatase activities and an exponential rise in gene expressions of INS and GLUT2 was observed. The present study shows enhanced INS and GLUT2 gene expression and elevated glucokinase activity in ß-like cells differentiated from HSCs upon treatment with Ci leaf extract explain the anti-diabetic property of Ci leaf extract. This extract can be effectively used in the management of diabetes.

Effect of Caralluma tuberculata on regulation of carbohydrate metabolizing genes in alloxan-induced rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Caralluma tuberculata (C. tuberculata) has traditionally been used in Pakistan and other parts of the world as a folk treatment for diabetes mellitus. A few studies indicated its antihyperglycemic effect, however, the mystery remained unfolded as how did it modify the pathophysiological condition. AIM OF STUDY: Hence, this study aimed to explore underlying mechanism(s) for its hypoglycemic activity at biochemical and molecular levels. MATERIALS AND METHODS: Methanol extract (ME) of C. tuberculata as well as its hexane (HF) and aqueous (AF) fractions were explored for their effect on total glycogen in liver and skeletal muscle of alloxan-induced rats by spectroscopy. Moreover, the expression of genes related to hepatic carbohydrate metabolizing enzymes was quantified. At molecular level, mRNA expression of glucose transporter 2 (GLUT-2), glycogen synthase (GS), glucokinase (GK), hexokinase 1 (HK-1), pyruvate kinase (PK), glucose 6 phosphate dehydrogenase (G-6-PDH), pyruvate carboxylase (PC), phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6 phosphatase (G-6-Pase) was determined by using quantitative real time polymerase chain reaction (qRT-PCR) after administration of ME (350 mg), HF(3 mg), AF (10 mg) and metformin (500 mg). The doses were administered twice daily according to per kg of body weight. RESULTS: A significant reduction in hepatic and skeletal muscle glycogen content was exhibited. The data of qRT-PCR revealed that gene's expression of GLUT-2 was significantly decreased after treatment with ME and HF, whilst it was unaltered by AF, however, a significant decrease was observed in genes corresponding to GS, GK and HK-1 after treatment with ME. Similarly, there was a significant decrease in expression of genes corresponding to GS, GK and HK-1 following treatment with HF. Surprisingly, post-treatment with AF didn't modify the gene's expression of GS and GK, whilst it caused a profound decrease in expression of HK-1 gene. Contrarily, the expression of gene related to PK was significantly up-regulated post-administration with ME, HF and AF. The expression levels of G-6-PDH, however, remained unaltered after treatment with the experimental extract and fractions of the plant. In addition, HF and AF did not cause any modification in PEPCK, whereas ME caused a significant down-regulation of the gene. Treatment with all the extract and fractions of the plant caused a substantial decrease in the gene's expression of PC, while there was a significant increase in the expression of gene related to G-6-Pase. CONCLUSION: The three experimental extract and fractions caused a substantial decrease in glycogen content in liver and skeletal muscle tissues. The analysis by qRT-PCR showed that glucose transport via GLUT-2 was profoundly declined by ME and HF. The expression of genes related to various metabolic pathways involved in metabolism of carbohydrate in hepatocytes revealed explicitly that the ME, HF and AF decreased the phenomena of glycogenesis and gluconeogenesis. Contrarily, all the extract and fractions of the plant activated glycogenolysis and glycolysis but did not modify the pentose phosphate shunt pathway.

Supercritical carbon dioxide extracts of small cardamom and yellow mustard seeds have fasting hypoglycaemic effects: diabetic rat, predictive iHOMA2 models and molecular docking study.

In the present investigation, the supercritical carbon dioxide (SC-CO2) extracts of small cardamom (SC) and yellow mustard (YM) seeds have been investigated for their efficacies in combating type 2 diabetes in streptozotocin-induced Wistar albino rats. Fasting blood glucose (FBG) levels in the rats were monitored on days 8, 15 and 21. On day 15, FBG level reduced appreciably by 31·49 % in rats treated with SC seed extract and by 32·28 % in rats treated with YM seed extract, comparable to metformin (30·70 %) and BGR-34 (a commercial polyherbal drug) (31·81 %) administered rats. Either extract exhibited desirable effects on hepatic glucose-6-phosphatase, glucose-6-phosphate dehydrogenase (G6PD) and catalase activities in controlling diabetes. A molecular docking exercise was conducted to identify specific compounds in the extracts which possessed augmenting effect on G6PD. The results revealed that all the bioactive compounds in the extracts have binding affinities with the enzyme and contributed to the antidiabetic efficacies of the extracts as G6PD augmenters. The effects of the extracts on insulin sensitivity and glucose uptake were investigated using non-invasive modelling by iHOMA2 software. This in vitro approach indicated that extract administration resulted in increased both insulin sensitivity of the liver and glucose uptake in the gut. The findings of the present study attest these SC-CO2 extracts of the spices as safe alternatives of metformin and BGR-34 in combating type 2 diabetes and could be safely subjected to clinical studies. These extracts could also be employed in designing proactive food supplements in mitigating the metabolic disorder.

Antidiabetic activities of alkaloids isolated from medicinal plants

Diabetes mellitus is a metabolic disorder affecting a great part of population around the world. It is the fifth leading death causing disease in the world and its cases are increasing day by day. Traditional medicine is thought to have promising future in the treatment of diabetes mellitus. In contrast to synthetic drugs phytochemicals are considered to be free from side effects. As one of the main class of natural products, alkaloids and their derivatives have been widely used as sources of pharmacological agents against a variety of medical problems. Many studies confirmed the role of alkaloids in the management of diabetes and numerous alkaloids isolated from different medicinal plants were found active against diabetes. Like other natural products, alkaloids regulate glucose metabolism either by inhibiting or inducing multiple candidate proteins including AMP-activated protein kinase, glucose transporters, glycogen synthase kinase-3, sterol regulatory element-binding proteins 1, glucokinase, glucose-6-phosphatase, acetyl-CoA carboxylase among the others. A comprehensive review of alkaloids reported in the literature with anti-diabetic activities and their target enzymes is conducted, with the aim to help in exploring the use of alkaloids as anti-diabetic agents. Future work should focus on rigorous clinical studies of the alkaloids, their development and relevant drug targets.

Therapeutic Effects of Morinda citrifolia Linn. (Noni) Aqueous Fruit Extract on the Glucose and Lipid Metabolism in High-Fat/High-Fructose-Fed Swiss Mice.

The aim of this study was to evaluate the therapeutic effects of two different doses (250 and 500 mg/kg) of Morinda citrifolia fruit aqueous extract (AE) in high-fat/high-fructose-fed Swiss mice. The food intake, body weight, serum biochemical, oral glucose tolerance test (OGTT), and enzyme-linked immunosorbent assay (ELISA), as well as histological analyses of the liver, pancreatic, and epididymal adipose tissue, were used to determine the biochemical and histological parameters. The chemical profile of the extract was determined by ultra-fast liquid chromatography-diode array detector-tandem mass spectrometry (UFLC-DAD-MS), and quantitative real-time PCR (qRT-PCR) was used to evaluate the gene expressions involved in the lipid and glucose metabolism, such as peroxisome proliferative-activated receptors-γ (PPAR-γ), -α (PPAR-α), fatty acid synthase (FAS), glucose-6-phosphatase (G6P), sterol regulatory binding protein-1c (SREBP-1c), carbohydrate-responsive element-binding protein (ChREBP), and fetuin-A. Seventeen compounds were tentatively identified, including iridoids, noniosides, and the flavonoid rutin. The higher dose of AE (AE 500 mg/kg) was demonstrated to improve the glucose tolerance; however, both doses did not have effects on the other metabolic and histological parameters. AE at 500 mg/kg downregulated the PPAR-γ, SREBP-1c, and fetuin-A mRNA in the liver and upregulated the PPAR-α mRNA in white adipose tissue, suggesting that the hypoglycemic effects could be associated with the expression of genes involved in de novo lipogenesis.

The effects of prepartum energy intake and peripartum rumen-protected choline supplementation on hepatic genes involved in glucose and lipid metabolism.

Nutritional interventions, either by controlling dietary energy (DE) or supplementing rumen-protected choline (RPC) or both, may mitigate negative postpartum metabolic health outcomes. A companion paper previously reported the effects of DE density and RPC supplementation on production and health outcomes. The objective of this study was to examine the effects of DE and RPC supplementation on the expression of hepatic oxidative, gluconeogenic, and lipid transport genes during the periparturient period. At 47 ± 6 d relative to calving (DRTC), 93 multiparous Holstein cows were randomly assigned in groups to dietary treatments in a 2 × 2 factorial of (1) excess energy (EXE) without RPC supplementation (1.63 Mcal of NEL/kg of dry matter; EXE-RPC); (2) maintenance energy (MNE) without RPC supplementation (1.40 Mcal of NEL/kg dry matter; MNE-RPC); (3) EXE with RPC supplementation (EXE+RPC); and (4) MNE with RPC supplementation (MNE+RPC). To achieve the objective of this research, liver biopsy samples were collected at -14, +7, +14, and +21 DRTC and analyzed for mRNA expression (n = 16/treatment). The interaction of DE × RPC decreased glucose-6-phosphatase and increased peroxisome proliferator-activated receptor α in MNE+RPC cows. Expression of cytosolic phosphoenolpyruvate carboxykinase was altered by the interaction of dietary treatments with reduced expression in EXE+RPC cows. A dietary treatment interaction was detected for expression of pyruvate carboxylase although means were not separated. Dietary treatment interactions did not alter expression of carnitine palmitoyltransferase 1A or microsomal triglyceride transfer protein. The 3-way interaction of DE × RPC × DRTC affected expression of carnitine palmitoyltransferase 1A, glucose-6-phosphatase, and peroxisome proliferator-activated receptor α and tended to affect cytosolic phosphoenolpyruvate carboxykinase. Despite previously reported independent effects of DE and RPC on production variables, treatments interacted to influence hepatic metabolism through altered gene expression.

Selenium Supplementation Increases Hepatic Glucose-6-Phosphatase and Peroxisome Proliferator Activated Receptor Gamma Coactivator-1α Activity in Male Wistar Rats.

Increased selenium supplementation has been implicated in diabetes mellitus via peroxisome-proliferator-activated-receptor-gamma-coactivator-1-alpha (PGC-1α) associated pathways. This study was designed to investigate the effect of selenium supplementation on PGC-1α and glucose-6-phosphatase (G6Pase) as well its likely hepato toxicity in male Wistar rats. Animals were randomly divided into 3 groups (n=10/group) and treated orally with water (0.2ml - group 1) or selenium (25µg/day -group 2; 50µg/day - group 3) for 28 and 56days, respectively. Thereafter, blood samples were collected and estimated for glucose, alkaline-phosphate (ALP), gamma-glutamyltransferase (GGT) and aspartate-aminotransferase (AST). Liver homogenates were analyzed for PGC-1α and G6Pase activity. Significant dose-dependent increases in blood glucose, hepatic PGC-1α and G6Pase activities were observed on days 28 and 56 in selenium groups compared to group 1. Serum GGT activity increased in both selenium groups on day 28 however, on day 56 values in group 2 were reduced and increased in group 3, respectively. Compared to control ALP reduced in selenium groups while AST was not significantly different. This study suggests that selenium supplementation increases hepatic peroxisome-proliferator-activated-receptor-gamma-coactivator-1α and glucose-6-phosphatase activity leading to a likely increase in hepatic glucose output. It also shows that though selenium supplementation at the doses used maybe nontoxic to hepatocytes, it may however exert potential toxicity on the biliary tract.

Effect of feeding type 2 diabetes mellitus rats with synbiotic yogurt sweetened with monk fruit extract on serum lipid levels and hepatic AMPK (5' adenosine monophosphate-activated protein kinase) signaling pathway.

Monk fruit extract (MFE) is a natural sweetener that has been used as an ingredient of food and pharmaceutical products. The effects of feeding synbiotic yogurt fortified with MFE to rats with type 2 diabetes induced by high-fat diet and streptozotocin on serum lipid levels and hepatic AMPK signaling pathway were evaluated. Results showed that oral administration of the synbiotic yogurt fortified with MFE could improve serum lipid levels, respiratory exchange rate, and heat level in type 2 diabetic rats. Transcriptome analysis showed that synbiotic yogurt fortified with MFE may affect the expression of genes involved in binding, catalytic activity, and transporter activity. The Kyoto Encyclopedia of Genes and Genomes enrichment analysis revealed that these differentially expressed genes were related to AMPK signaling pathway, linoleic acid metabolism, and α-linolenic acid metabolism. Western blotting confirmed that synbiotic yogurt fortified with MFE could activate AMPK signaling and improve the protein level of the hepatic gluconeogenic enzyme G6Pase in diabetic rats. The results indicated that MFE could be a novel sweetener for functional yogurt and related products.

Effects of Anthocyanin Extracts from Bilberry (Vaccinium myrtillus L.) and Purple Potato (Solanum tuberosum L. var. 'Synkeä Sakari') on the Plasma Metabolomic Profile of Zucker Diabetic Fatty Rats.

This study compared the effects of the nonacylated and acylated anthocyanin-rich extracts on plasma metabolic profiles of Zucker diabetic fatty rats. The rats were fed with the nonacylated anthocyanin extract from bilberries (NAAB) or the acylated anthocyanin extract from purple potatoes (AAPP) at daily doses of 25 and 50 mg/kg body weight for 8 weeks. 1H NMR metabolomics was used to study the changes in plasma metabolites. A reduced fasting plasma glucose level was seen in all anthocyanin-fed groups, especially in the groups fed with NAAB. Both NAAB and AAPP decreased the levels of branched-chain amino acids and improved lipid profiles. AAPP increased the glutamine/glutamate ratio and decreased the levels of glycerol and metabolites involved in glycolysis, suggesting improved insulin sensitivity, gluconeogenesis, and glycolysis. AAPP decreased the hepatic TBC1D1 and G6PC messenger RNA level, suggesting regulation of gluconeogenesis and lipogenesis. This study indicated that AAPP and NAAB affected the plasma metabolic profile of diabetic rats differently.

Postpartum supplementation with fermented ammoniated condensed whey altered nutrient partitioning to support hepatic metabolism.

Our previously published paper demonstrated that fermented ammoniated condensed whey (FACW) supplementation improved feed efficiency and metabolic profile in postpartum dairy cows. The objective of this study was to further explore the effects of FACW supplementation on liver triglyceride content, hepatic gene expression and protein abundance, and plasma biomarkers related to liver function, inflammation, and damage. Individually fed multiparous Holstein cows were blocked by calving date and randomly assigned to postpartum (1 to 45 d in milk, DIM) isonitrogenous treatments: control diet (n = 20) or diet supplemented with FACW (2.9% dry matter of diet as GlucoBoost; Fermented Nutrition, Luxemburg, WI, replacing soybean meal; n = 19). Liver biopsies were performed at 14 and 28 DIM for analysis of mRNA expression, protein abundance, and liver triglyceride content. There was marginal evidence for a reduction in liver triglyceride content at 14 DIM in FACW-supplemented cows compared with the control group. Cows supplemented with FACW had greater mRNA expression of glucose-6-phosphatase at 14 DIM relative to control. Supplementation with FACW increased mRNA expression of pyruvate carboxylase (PC), but did not alter cytosolic phosphoenolpyruvate carboxykinase (PCK1), resulting in a 2.4-fold greater PC:PCK1 ratio for FACW-supplemented cows compared with control. There was no evidence for a FACW effect on mRNA expression of propionyl-CoA carboxylase nor on mRNA expression or protein abundance of lactate dehydrogenase A or B. Cows supplemented with FACW had lower plasma urea nitrogen compared with control. Plasma l-lactate was greater for FACW-supplemented cows compared with control at 2 h before feeding time at 21 DIM. There was no evidence for altered expression of IL1B or IL10, or blood biomarkers related to liver function and damage. Greater glucose-6-phosphatase and PC gene expression, together with greater blood glucose and similar milk lactose output, suggests that FACW increased the supply of glucose precursors, resulting in greater gluconeogenesis between 3 and 14 DIM. Greater hepatic PC:PCK1 ratio, together with previously reported decreased plasma ß-hydroxybutyrate and the marginal evidence for lower liver triglyceride content at 14 DIM, suggests greater hepatic capacity for complete oxidation of fatty acids in FACW-supplemented cows compared with control. Overall, improvements in metabolite profile and feed efficiency observed with postpartum supplementation of FACW may be attributed to increased gluconeogenic and anaplerotic precursors, most likely propionate, due to modulated rumen fermentation.

Metabolomics study of polysaccharide extracts from Polygonatum sibiricum in mice based on 1 H NMR technology.

BACKGROUND: Polygonatum sibiricum Liliaceae perennial herb, as a commonly used medicine and food homologous plant, has been widely used in clinical practice of Chinese medicine since ancient times, with a history of 2000 years. As the main active ingredient, P. sibiricum polysaccharides have important pharmacological effects in blood sugar reduction and antitumor, antioxidant and liver protection. RESULTS: Mouse models of P. sibiricum polysaccharides were used in combination with 1 H NMR to investigate the metabolic regulation mechanism in mouse tissue and blood. The metabolite maps of the control group and the drug group in the liver had significant changes. The main differential metabolites were glucose 6-phosphate, inositol, lactose, glutamylglycine, galactose, rhamnose, cis-aconitic acid and histidine, indicating that there was definite correlation between the metabolic detection based on 1 H NMR and the metabolic characteristics of P. sibiricum. The common differential metabolites obtained by overall metabolism analysis were 3-hydroxybutyric acid, d-ribose, adenosine phosphate, inositol, fructose 6-phosphate, histidine, aspartic acid and cis-aconitic acid. CONCLUSIONS: This work forms the basis for identification of metabolic states combined with metabolic pathways, which could be used as diagnostic and prognostic indicators, providing therapeutic targets for new diseases. © 2020 Society of Chemical Industry.

Ficus deltoidea extract down-regulates protein tyrosine phosphatase 1B expression in a rat model of type 2 diabetes mellitus: a new insight into its antidiabetic mechanism.

Ficus deltoidea var. deltoidea Jack (FD) is a well-known plant used in Malay folklore medicine to lower blood glucose in diabetic patients. For further research of the antihyperglycemic mechanisms, the protein tyrosine phosphatase 1B (PTP1B)-inhibitory effect of FD was analysed both in vitro and in vivo. To optimise a method for FD extraction, water, 50, 70, 80, 90 and 95 % ethanol extracts were prepared and determined for their total phenolic and triterpene contents, and PTP1B-inhibition capacity. Among the tested extracts, 70 % ethanol FD extract showed a significant PTP1B inhibition (92·0 % inhibition at 200 µg/ml) and high phenolic and triterpene contents. A bioassay-guided fractionation of the 70 % ethanol extract led to the isolation of a new triterpene (3ß,11ß-dihydroxyolean-12-en-23-oic acid; F3) along with six known compounds. In vivo, 4 weeks' administration of 70 % ethanol FD extract (125, 250 and 500 mg/kg/d) to streptozotocin-nicotinamide-induced type 2 diabetic rats reversed the abnormal changes of blood glucose, insulin, total Hb, GLUT2, lipid profile, and oxidative stress in liver and pancreas. Moreover, FD reduced the mRNA expression of the key gluconeogenic enzymes (phosphoenolpyruvate carboxykinase and glucose 6-phosphatase) and restored insulin receptor and GLUT2 encoding gene (Slc2a2) expression. In addition, FD significantly down-regulated the hepatic PTP1B gene expression. These results revealed that FD could potentially improve insulin sensitivity, suppress hepatic glucose output and enhance glucose uptake in type 2 diabetes mellitus through down-regulation of PTP1B. Together, our findings give scientific evidence for the traditional use of FD as an antidiabetic agent.

Antihyperglycaemia and related gene expressions of aqueous extract of Gongronema latifolium leaf in alloxan-induced diabetic rats.

Context: Gongronema latifolium Benth (Asclepiadaceae) has been highly utilized in controlling diabetes mellitus traditionally in the eastern part of Nigeria. Objectives: Antihyperglycaemic and related gene expressions of aqueous extract of Gongronema latifolium leaf in alloxan-induced diabetic rats. Materials and methods: Forty-eight female Wistar rats were induced intraperitoneally using alloxan (150 mg/kg body weight). The rats were separated into six groups (n = 8) as follows: non-diabetic control, diabetic control, diabetic rats administered 5 mg/kg body weight of metformin, and diabetic rats administered 6.36, 12.72 and 25.44 mg/kg body weight (ethnobotanical doses) of G. latifolium orally daily. On the 14th day, the animals were sacrificed and different antihyperglycaemic parameters were evaluated as well as its related gene expressions. Results: Diabetic rats administered three doses of aqueous extract of G. latifolium significantly (p < 0.05) lowered the fasting blood glucose, glycated haemoglobin, serum lipid profiles, lipid peroxidation (5.62-1.2 µ/mg protein) levels, as well as gene expression of glucose-6-phosphatase in alloxan-induced diabetic rats. There was a significant (p < 0.05) increase in the liver glycogen content (16.23-112.5 mg glucose/2 g), antioxidant enzymes activities, glucose transporter (GLUT-2 and GLUT-4) levels and relative gene expression of hexokinase in diabetic rats administered different doses of aqueous extract of G. latifolium. Discussion and conclusions: It can be deduced that the aqueous extract of G. latifolium leaf at these doses may be useful in managing diabetes mellitus and its associated complications. Therefore, this extract may be a potent antidiabetic agent in clinical therapy in the future.

Baicalein improves glucose metabolism in insulin resistant HepG2 cells.

Insulin resistance (IR) is the primary pathogenesis of Type 2 diabetes mellitus (T2DM). Scutellaria baicalensis Georgi is a traditional Chinese herbal medicine, often used in the clinical treatment of T2DM. Baicalein which is considered to have anti-IR effects is one of its active ingredients. IR-induced HepG2 cells were used to investigate the effect of baicalein on glucose metabolism and insulin-signaling pathway, using metformin as a positive control. We found that the use of both baicalein and metformin increased the glucose consumption of IR cells, as well as increasing the pyruvate kinase (PK) and glucokinase (GCK) activity. Also increased was the expression levels of insulin receptor (InsR), insulin receptor substrate-1 (IRS-1), phosphoinositide 3-kinase (PI3K), protein kinase B (AKT) pathway and glucose transporter 2 (GLUT2). Reduced expression levels were found in that of glucose 6 phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) mRNA. The results confirmed that baicalein (10-6 and 10-5 mol/L) promotes glucose uptake and glycolysis, inhibits gluconeogenesis of hepatocytes to improve glucose metabolism, and may be as a result from regulation of InsR/IRS-1/PI3K/AKT pathway. Additionally, baicalein has large concentration range on inhibiting IR, and at lower concentrations has strong anti-IR hepatocyte activity.