GLUT2 expression by glial fibrillary acidic protein-positive tanycytes is required for promoting feeding-response to fasting.

Feeding behavior is a complex process that depends on the ability of the brain to integrate hormonal and nutritional signals, such as glucose. One glucosensing mechanism relies on the glucose transporter 2 (GLUT2) in the hypothalamus, especially in radial glia-like cells called tanycytes. Here, we analyzed whether a GLUT2-dependent glucosensing mechanism is required for the normal regulation of feeding behavior in GFAP-positive tanycytes. Genetic inactivation of Glut2 in GFAP-expressing tanycytes was performed using Cre/Lox technology. The efficiency of GFAP-tanycyte targeting was analyzed in the anteroposterior and dorsoventral axes by evaluating GFP fluorescence. Feeding behavior, hormonal levels, neuronal activity using c-Fos, and neuropeptide expression were also analyzed in the fasting-to-refeeding transition. In basal conditions, Glut2-inactivated mice had normal food intake and meal patterns. Implementation of a preceeding fasting period led to decreased total food intake and a delay in meal initiation during refeeding. Additionally, Glut2 inactivation increased the number of c-Fos-positive cells in the ventromedial nucleus in response to fasting and a deregulation of Pomc expression in the fasting-to-refeeding transition. Thus, a GLUT2-dependent glucose-sensing mechanism in GFAP-tanycytes is required to control food consumption and promote meal initiation after a fasting period.

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.

Inhibition of the intestinal postprandial glucose transport by gallic acid and gallic acid derivatives.

Inhibition of glucose uptake in the intestine through sodium-dependent glucose transporter 1 (SGLT1) or glucose transporter 2 (GLUT2) may be beneficial in controlling postprandial blood glucose levels. Gallic acid and ten of its derivatives were identified in the active fractions of Terminalia chebula Retz. fructus immaturus, a popular edible plant fruit which has previously been associated with the inhibition of glucose uptake. Gallic acid derivatives (methyl gallate, ethyl gallate, pentyl gallate, 3,4,6-tri-O-galloyl-ß-d-glucose, and corilagin) showed good glucose transport inhibition with inhibitory rates of 72.1 ± 1.6%, 71.5 ± 1.4%, 79.9 ± 1.2%, 44.7 ± 1.2%, and 75.0 ± 0.7% at 5 mM d-glucose and/or 56.3 ± 2.3, 52.1 ± 3.2%, 70.2 ± 1.7%, 15.6 ± 1.6%, and 37.1 ± 0.8% at 25 mM d-glucose. However, only 3,4,6-tri-O-galloyl-ß-d-glucose and corilagin were confirmed GLUT2-specific inhibitors. Whilst some tea flavonoids demonstrated minimal glucose transport inhibition, their gallic acid derivatives strongly inhibited transport effect with GLUT2 specificity. This suggests that gallic acid structures are crucial for glucose transport inhibition. Plants, such as T. chebula, which contain high levels of gallic acid and its derivatives, show promise as natural functional ingredients for inclusion in foods and drinks designed to control postprandial glucose levels.

Fructose-rich diet and walnut supplementation differently regulate rat hypothalamic and hippocampal glucose transporters expression.

BACKGROUND: Nutritional modulations may be considered a strategy to protect mental health. Neuronal homeostasis is highly dependent on the availability of glucose, which represents the primary energy source for the brain. In this study, we evaluated the effects of walnut intake and fructose-rich diet on the expression of glucose transporters (GLUTs) in two rat brain regions: hypothalamus and hippocampus. RESULTS: Our results show that walnut supplementation of fructose-fed animals restored the hypothalamic content of GLUT1 and GLUT3 protein. Furthermore, walnut intake did not affect increased hypothalamic GLUT2 content upon fructose consumption. These effects were accompanied by distinctive alterations of hippocampal GLUTs levels. Specifically, walnut intake increased GLUT1 content, whereas GLUT2 protein was decreased within the rat hippocampus after both individual and combined treatments. CONCLUSION: Overall, our study suggests that walnut supplementation exerted modulatory effects on the glucose transporters within specific brain regions in the presence of developed metabolic disorder. © 2021 Society of Chemical Industry.

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.

Effect of Hydrolyzable Tannins on Glucose-Transporter Expression and Their Bioavailability in Pig Small-Intestinal 3D Cell Model.

Intestinal transepithelial transport of glucose is mediated by glucose transporters, and affects postprandial blood-glucose levels. This study investigates the effect of wood extracts rich in hydrolyzable tannins (HTs) that originated from sweet chestnut (Castanea sativa Mill.) and oak (Quercus petraea) on the expression of glucose transporter genes and the uptake of glucose and HT constituents in a 3D porcine-small-intestine epithelial-cell model. The viability of epithelial cells CLAB and PSI exposed to different HTs was determined using alamarBlue®. qPCR was used to analyze the gene expression of SGLT1, GLUT2, GLUT4, and POLR2A. Glucose uptake was confirmed by assay, and LC-MS/ MS was used for the analysis of HT bioavailability. HTs at 37 µg/mL were found to adversely affect cell viability and downregulate POLR2A expression. HT from wood extract Tanex at concentrations of 4 µg/mL upregulated the expression of GLUT2, as well as glucose uptake at 1 µg/mL. The time-dependent passage of gallic acid through enterocytes was influenced by all wood extracts compared to gallic acid itself as a control. These results suggest that HTs could modulate glucose uptake and gallic acid passage in the 3D cell model.

Hypothalamic MC4R regulates glucose homeostasis through adrenaline-mediated control of glucose reabsorption via renal GLUT2 in mice.

AIMS/HYPOTHESIS: Melanocortin 4 receptor (MC4R) mutation is the most common cause of known monogenic obesity in humans. Unexpectedly, humans and rodents with MC4R deficiency do not develop hyperglycaemia despite chronic obesity and insulin resistance. To explain the underlying mechanisms for this phenotype, we determined the role of MC4R in glucose homeostasis in the presence and absence of obesity in mice. METHODS: We used global and hypothalamus-specific MC4R-deficient mice to investigate the brain regions that contribute to glucose homeostasis via MC4R. We performed oral, intraperitoneal and intravenous glucose tolerance tests in MC4R-deficient mice that were either obese or weight-matched to their littermate controls to define the role of MC4R in glucose regulation independently of changes in body weight. To identify the integrative pathways through which MC4R regulates glucose homeostasis, we measured renal and adrenal sympathetic nerve activity. We also evaluated glucose homeostasis in adrenaline (epinephrine)-deficient mice to investigate the role of adrenaline in mediating the effects of MC4R in glucose homeostasis. We employed a graded [13C6]glucose infusion procedure to quantify renal glucose reabsorption in MC4R-deficient mice. Finally, we measured the levels of renal glucose transporters in hypothalamus-specific MC4R-deficient mice and adrenaline-deficient mice using western blotting to ascertain the molecular mechanisms underlying MC4R control of glucose homeostasis. RESULTS: We found that obese and weight-matched MC4R-deficient mice exhibited improved glucose tolerance due to elevated glucosuria, not enhanced beta cell function. Moreover, MC4R deficiency selectively in the paraventricular nucleus of the hypothalamus (PVH) is responsible for reducing the renal threshold for glucose as measured by graded [13C6]glucose infusion technique. The MC4R deficiency suppressed renal sympathetic nerve activity by 50% in addition to decreasing circulating adrenaline and renal GLUT2 levels in mice, which contributed to the elevated glucosuria. We further report that adrenaline-deficient mice recapitulated the increased excretion of glucose in urine observed in the MC4R-deficient mice. Restoration of circulating adrenaline in both the MC4R- and adrenaline-deficient mice reversed their phenotype of improved glucose tolerance and elevated glucosuria, demonstrating the role of adrenaline in mediating the effects of MC4R on glucose reabsorption. CONCLUSIONS/INTERPRETATION: These findings define a previously unrecognised function of hypothalamic MC4R in glucose reabsorption mediated by adrenaline and renal GLUT2. Taken together, our findings indicate that elevated glucosuria due to low sympathetic tone explains why MC4R deficiency does not cause hyperglycaemia despite inducing obesity and insulin resistance. Graphical abstract.

Ghrelin system is involved in improvements in glucose metabolism mediated by hyperbaric oxygen treatment in a streptozotocin­induced type 1 diabetes mouse model.

Type 1 diabetes mellitus (T1DM) is an autoimmune disorder for which the only effective therapy is insulin replacement. Hyperbaric oxygen (HBO) therapy has demonstrated potential in improving hyperglycemia and as a treatment option for T1DM. Ghrelin and HBO have been previously reported to exert proliferative, anti­apoptotic and anti­inflammatory effects in pancreatic cells. The present study investigated the mechanism underlying HBO­ and ghrelin system­mediated regulation of glucose metabolism. Male C57BL/6 mice were intraperitoneally injected with streptozotocin (STZ; 150 mg/kg) to induce T1DM before the diabetic mice were randomly assigned into the T1DM and T1DM + HBO groups. Mice in the T1DM + HBO group received HBO (1 h; 100% oxygen; 2 atmospheres absolute) daily for 2 weeks. Significantly lower blood glucose levels and food intake were observed in mice in the T1DM + HBO group. Following HBO treatment, islet ß­cell area were increased whereas those of α­cell were decreased in the pancreas. In addition, greater hepatic glycogen storage in liver was observed, which coincided with higher pancreatic glucose transporter 2 (GLUT2) expression levels and reduced hepatic GLUT2 membrane trafficking. There were also substantially higher total plasma ghrelin concentrations and gastric ghrelin­O­acyl transferase (GOAT) expression levels in mice in the T1DM + HBO group. HBO treatment also abolished reductions in pancreatic GOAT expression levels in T1DM mice. Additionally, hepatic growth hormone secretagogue receptor­1a levels were found to be lower in mice in the T1DM + HBO group compared with those in the T1DM group. These results suggest that HBO administration improved glucose metabolism in a STZ­induced T1DM mouse model. The underlying mechanism involves improved insulin­release, glucose­sensing and regulation of hepatic glycogen storage, an observation that was also likely dependent on the ghrelin signalling system.

Inhibition of the facilitative sugar transporters (GLUTs) by tea extracts and catechins.

Tea polyphenolics have been suggested to possess blood glucose lowering properties by inhibiting sugar transporters in the small intestine and improving insulin sensitivity. In this report, we studied the effects of teas and tea catechins on the small intestinal sugar transporters, SGLT1 and GLUTs (GLUT1, 2 and 5). Green tea extract (GT), oolong tea extract (OT), and black tea extract (BT) inhibited glucose uptake into the intestinal Caco-2 cells with GT being the most potent inhibitor (IC50 : 0.077 mg/mL), followed by OT (IC50 : 0.136 mg/mL) and BT (IC50 : 0.56 mg/mL). GT and OT inhibition of glucose uptake was partial non-competitive, with an inhibitor constant (Ki ) = 0.0317 and 0.0571 mg/mL, respectively, whereas BT was pure non-competitive, Ki  = 0.36 mg/mL. Oocytes injected to express small intestinal GLUTs were inhibited by teas, but SGLT1 was not. Furthermore, catechins present in teas were the predominant inhibitor of glucose uptake into Caco-2 cells, and gallated catechins the most potent: CG > ECG > EGCG ≥ GCG when compared to the non-gallated catechins (C, EC, GC, and EGC). In Caco-2 cells, individual tea catechins reduced the SGLT1 gene, but not protein expression levels. In contrast, GLUT2 gene and protein expression levels were reduced after 2 hours exposure to catechins but increased after 24 hours. These in vitro studies suggest teas containing catechins may be useful dietary supplements capable of blunting postprandial glycaemia in humans, including those with or at risk to Type 2 diabetes mellitus.

Coloured Rice Phenolic Extracts Increase Expression of Genes Associated with Insulin Secretion in Rat Pancreatic Insulinoma ß-cells.

Glucose-induced oxidative stress is associated with the overproduction of reactive oxygen species (ROS), which may dysregulate the expression of genes controlling insulin secretion leading to ß-cell dysfunction, a hallmark of type 2 diabetes mellitus (T2DM). This study investigated the impact of coloured rice phenolic extracts (CRPEs) on the expression of key genes associated with ß-cell function in pancreatic ß-cells (INS-1E). These genes included glucose transporter 2 (Glut2), silent mating type information regulation 2 homolog 1 (Sirt1), mitochondrial transcription factor A (Tfam), pancreatic/duodenal homeobox protein 1 (Pdx-1) and insulin 1 (Ins1). INS-1E cells were cultured in high glucose (25 mM) to induce glucotoxic stress conditions (HGSC) and in normal glucose conditions (NGC-11.1 mM) to represent normal ß-cell function. Cells were treated with CRPEs derived from two coloured rice cultivars, Purple and Yunlu29-red varieties at concentrations ranged from 50 to 250 µg/mL. CRPEs upregulated the expression of Glut2, Sirt1 and Pdx-1 significantly at 250 µg/mL under HGSC. CRPEs from both cultivars also upregulated Glut2, Sirt1, Tfam, Pdx-1 and Ins1 markedly at 250 µg/mL under NGC with Yunlu29 having the greatest effect. These data suggest that CRPEs may reduce ß-cell dysfunction in T2DM by upregulating the expression of genes involved in insulin secretion pathways.

Capsaicinoid nonivamide improves nonalcoholic fatty liver disease in rats fed a high-fat diet.

Nonalcoholic fatty liver disease (NAFLD) is a chronic disease that causes morbidity associated with metabolic syndrome. NAFLD is a worldwide problem and represents a major cause of liver injury, which can lead to liver cell death. We investigated the effects of nonivamide (pelargonic acid vanillylamide, PAVA; 1 mg/kg) and rosuvastatin (RSV; 10 mg/kg) on hepatic steatosis induced by a high-fat diet (HFD). Male Sprague-Dawley rats were fed a HFD for 16 weeks then received PAVA or RSV for 4 additional weeks. We examined the metabolic parameters, function, fat content, histological alterations, reactive oxygen species production, and apoptotic cell death of the liver, in addition to the expression of the following important molecules: transient receptor potential cation channel subfamily V member 1 (TRPV1) phosphorylation of sterol regulatory element binding protein (pSREBP-1c/SREBP-1c), total and membrane glucose transporter 2 (GLUT2), 4-hydroxynonenal (4-HNE), and cleaved caspase-3. HFD-induced hepatic steatosis was associated with significantly increased morphological disorganization, injury markers, oxidative stress, lipid peroxidation, and apoptosis. However, metabolic dysfunction and hepatic injury were reduced by RSV and PAVA treatment. PAVA regulated lipid deposition, improved insulin resistance, and decreased oxidative stress and apoptotic cell death. Therefore, PAVA represents a promising therapeutic approach for treating metabolic disorders in patients with NAFLD.

Necrostatin-1 supplementation enhances young porcine islet maturation and in vitro function.

BACKGROUND: Necroptosis has been demonstrated to be a primary mechanism of islet cell death. This study evaluated whether the supplementation of necrostatin-1 (Nec-1), a potent inhibitor of necroptosis, to islet culture media could improve the recovery, maturation, and function of pre-weaned porcine islets (PPIs). METHODS: PPIs were isolated from pre-weaned Yorkshire piglets (8-15 days old) and either cultured in control islet culture media (n = 6) or supplemented with Nec-1 (100 µM, n = 5). On days 3 and 7 of culture, islets were assessed for recovery, insulin content, viability, cellular composition, GLUT2 expression in beta cells, differentiation of pancreatic endocrine progenitor cells, function, and oxygen consumption rate. RESULTS: Nec-1 supplementation induced a 2-fold increase in the insulin content of PPIs on day 7 of culture. When compared to untreated islets, Nec-1 treatment doubled the beta- and alpha-cell composition and accelerated the development of delta cells. Additionally, beta cells of Nec-1-treated islets had a significant upregulation in GLUT2 expression. The enhanced development of major endocrine cells and GLUT2 expression after Nec-1 treatment subsequently led to a significant increase in the amount of insulin secreted in response to in vitro glucose challenge. Islet recovery, viability, and oxygen consumption rate were unaffected by Nec-1. CONCLUSION: This study underlines the importance of necroptosis in islet cell death after isolation and demonstrates the novel effects of Nec-1 to increase islet insulin content, enhance pancreatic endocrine cell development, facilitate GLUT2 upregulation in beta cells, and augment insulin secretion. Nec-1 supplementation to culture media significantly improves islet quality prior to xenotransplantation.

Suppressive effect of ghrelin on nicotine-induced clock gene expression in the mouse pancreas.

Those who smoke nicotine-based cigarettes have elevated plasma levels of ghrelin, a hormone secreted from the stomach. Ghrelin has various physiological functions and has recently been shown to be involved in regulating biological rhythms. Therefore, in this study, in order to clarify the significance of the plasma ghrelin increase in smokers, we sought to clarify how nicotine and ghrelin affect the expression dynamics of clock genes using a mouse model. A single dose of nicotine administered intraperitoneally increased plasma ghrelin concentrations transiently, whereas continuous administration of nicotine with an osmotic minipump did not induce any change in the plasma ghrelin concentration. Single administration of nicotine resulted in a transient increase in ghrelin gene expression in the pancreas but not in the stomach, which is the major producer of ghrelin. In addition, in the pancreas, the expression of clock genes was also increased temporarily. Therefore, in order to clarify the interaction between nicotine-induced ghrelin gene expression and clock gene expression in the pancreas, nicotine was administered to ghrelin gene-deficient mice. Administration of nicotine to ghrelin-gene deficient mice increased clock gene expression in the pancreas. However, upon nicotine administration to mice pretreated with octanoate to upregulate ghrelin activity, expression levels of nicotine-inducible clock genes in the pancreas were virtually the same as those in mice not administered nicotine. Thus, our findings indicate that pancreatic ghrelin may suppress nicotine-induced clock gene expression in the pancreas.

Inhibition of GLUT2 transporter by geraniol from Cymbopogon martinii: a novel treatment for diabetes mellitus in streptozotocin-induced diabetic rats.

OBJECTIVE: To isolate and identify the bioactive component from Cymbopogon martinii having GLUT2 transporter inhibitory activity - towards development of a novel strategy for treatment of diabetes mellitus. METHOD: Isolation of bioactive component was carried out using differential solvent extraction, HPTLC and HPLC, and identification was done by GC-MS. In-vitro studies on intestine, liver, kidney and in-vivo assessment by OGTT and long-term treatment on diabetic rats were carried out. KEY FINDINGS: Geraniol was isolated and identified as bioactive component. Intestinal glucose absorption demonstrated 60.28% inhibition of transport at 648.34 µm of geraniol. It was found to inhibit glucose release from liver on adrenaline challenge by 89.82% at 324.17 µm/ml. Kidney glycogen content doubled using 648.34 µm of geraniol as compared to control. Geraniol demonstrated 2.14 times higher renal glucose output than diabetic control. OGTT demonstrated prevention of postprandial spikes. Prolonged treatment for 60 days with 29.37 mm/kg B.W. twice a day of geraniol improved the lipid profile, HbA1C levels and renal parameters. In mRNA studies for 10 days, over expression of GLUT2 was prevented by geraniol. CONCLUSIONS: Inhibition of GLUT2 by geraniol has the potential to reduce hyperglycaemia and prevent secondary complications in diabetes.

Nocturnal enteral nutrition is therapeutic for growth failure in Fanconi-Bickel syndrome.

Fanconi-Bickel syndrome (FBS) is a rare autosomal recessive disorder characterised by impaired glucose liver homeostasis and proximal renal tubular dysfunction. It is caused by pathogenic variants in SLC2A2 coding for the glucose transporter GLUT2. Main clinical features include hepatomegaly, fasting hypoglycaemia, postprandial hyperglycaemia, Fanconi-type tubulopathy occasionally with rickets, and a severe growth disorder. While treatment for renal tubular dysfunction is well established, data regarding optimal nutritional therapy are scarce. Similarly, detailed clinical evaluation of treated FBS patients is lacking. These unmet needs were an incentive to conduct the present pilot study. We present clinical findings, laboratory parameters and molecular genetic data on 11 FBS patients with emphasis on clinical outcome under various nutritional interventions. At diagnosis, the patients' phenotypic severity could be classified into two categories: a first group with severe growth failure and rickets, and a second group with milder signs and symptoms. Three patients were diagnosed early and treated because of family history. All patients exhibited massive glucosuria at diagnosis and some in both groups had fasting hypoglycaemic episodes. Growth retardation improved drastically in all five patients treated by intensive nutritional intervention (nocturnal enteral nutrition) and uncooked cornstarch with final growth parameters in the normal range. The four severely affected patients who were treated with uncooked cornstarch alone did not catch up growth. All patients received electrolytes and l-carnitine supplementation to compensate for the tubulopathy. This is one of the largest series of FBS on therapeutic management with evidence that nocturnal enteral nutrition rescues growth failure.

The effects of chromium picolinate on glucose and lipid metabolism in running rats.

BACKGROUND: Chromium picolinate (CrPic) is commonly used to reduce muscle fatigue after exercise. We aimed to elucidate the effects of CrPic on glucose and lipid metabolism and the expression of glucose transporters in exercised rats. METHODS: Forty-two male Wistar rats (8-week-old) were distributed into six groups (n = 7) as follows: Control, CrPic, Chronic Exercise (CEx), CEx + CrPic, Acute Exercise (AEx), and AEx + CrPic. CEx consists of 30 m/min, 30 min/day, and 5 days/week for 6 weeks. CrPic was supplemented at 400 µg elemental Cr/kg of diet for 6 weeks. In the AEx groups, animals were run on the treadmill at 30 m/min until exhaustion. RESULTS: CEx significantly lowered blood glucose (BG), total cholesterol (TC) and triglyceride (TG) levels, but elevated insulin concentration (IC), compared with control (P < 0.05). CEx significantly decreased the level of malondialdehyde (MDA) in the serum, liver, and muscle while AEx elevated it (P < 0.001 for all). CrPic significantly decreased BG, TC, TG levels, and increased IC with a remarkable effect in CEx rats (P < 0.01). CrPic also significantly reduced serum, liver, and muscle MDA levels (P < 0.001). Both AEx and CEx increased the expression of liver glucose transporter 2 (GLUT-2) and muscle GLUT-4 with the highest level in CEx rats (P < 0.05). Moreover, CrPic supplementation significantly elevated GLUT-2 and GLUT-4 expressions in the liver and muscle of sedentary and exercise-treated rats (P < 0.05). CONCLUSION: CrPic improves various metabolic parameters and reduces oxidative stress in CEx and AEx rats by decreasing BG, TC, TG, MDA levels in serum and elevating GLUT-2 and GLUT-4 expression in the liver and muscle samples. The efficacy of CrPic was more pronounced in CEx rats.

Effect of Marantodes pumilum Blume (Kuntze) var.alata on ß-cell function and insulin signaling in ovariectomised diabetic rats.

BACKGROUND: Oestrogen deficiency leads to metabolic disturbances such as insulin resistance and impairment of adipose tissue or lipid metabolism. Marantodes pumilum (Blume) Kuntze (Primulaceae) is believed to have phytoestrogenic properties and is claimed to have beneficial effects in the treatment of diabetes mellitus (DM), but the mechanism behind its phytoestrogenic effects on estrogen-deficient diabetic condition have not been fully examined. PURPOSE: The present study investigated the effects of oral treatment with M. pumilum var. alata (MPA) extracts on the estrogen receptor, metabolic characteristics and insulin signaling pathway in pancreas and liver of ovariectomised nicotidamide streptozotocin-induced diabetes in female rats. MATERIALS AND METHODS: Ovariectomised diabetic (OVXS) Sprague-Dawley rats were orally administered with either aqueous leaf extract and ethanol (50%) stem-root extract of MPA (50 or 100 mg/kg) respectively for 28 days. Metabolic parameters were evaluated by measuring fasting blood glucose, serum insulin, oral glucose and insulin tolerance test. Distribution and expression level of insulin, oxidative stress and inflammatory marker in the pancreatic islets and liver were evaluated by immunohistochemistry and western blot, respectively. RESULTS: Oral treatment with aqueous leaf and ethanol (50%) stem-root extracts of MPA (100 mg/kg) significantly reversed the elevated fasting blood glucose, impaired glucose and insulin tolerance. The protein expression of insulin, glucose transporter (GLUT-2 and GLUT-4) increased in the pancreatic islets and liver. Furthermore, marked improvement in the tissue morphology following treatment with MPA was observed. Similarly, the western blots analysis denotes improved insulin signaling in the liver and decreased reactive oxygen species producing enzymes, inflammatory and pro-apoptotic molecules with MPA treatment. CONCLUSIONS: Taken together, this work demonstrate that 100 mg/kg of aqueous leaf extract and ethanol (50%) stem-root extract of MPA improves ß-cell function and insulin signaling in postmenopausal diabetes through attenuation of oxidative stress and partially mediated by oestrogen receptor stimulation.

The ameliorative effect of the Pyracantha fortuneana (Maxim.) H. L. Li extract on intestinal barrier dysfunction through modulating glycolipid digestion and gut microbiota in high fat diet-fed rats.

Pyracantha fortuneana fruits are consumed as a dietary supplement in China and attenuate obesity and metabolic disorders. Obesity is known to be associated with intestinal barrier dysfunction driven by hyperglycemia and gut dysbiosis. However, whether the health benefits of P. fortuneana fruits are linked with the intestinal barrier function (IBF) remains unknown. This study aimed to evaluate the restorative effects of P. fortuneana fruit extract (PFE) on the IBF. Sprague Dawley rats were fed with a chow, a high-fat diet (HFD), or a PFE-supplemented diet for 8 weeks. Results showed that PFE intervention ameliorated HFD-induced intestinal barrier dysfunction by attenuating impaired structural integrity, reducing the elevated lactulose/mannitol ratio, and improving the mRNA and protein expression levels of tight junction proteins in HFD-fed rats. The ameliorations were associated with a beneficial effect on glycolipid homeostasis, as evidenced from the PFE decreasing intestinal absorptive capacity based on the d-xylose excretory rate, lowering the expression of GLUT2 and inhibiting digestive enzyme activities. The proanthocyanidins in the PFE showed greater in vitro inhibition on α-amylase, α-glucosidase, and lipase compared with triterpenoid saponins. Furthermore, the ameliorations on the IBF were also associated with effects on the microbial composition based on 16S rRNA gene sequence analysis. Several bacterial groups, which were linked with gut barrier integrity, were modulated after PFE administration, that is, Actinobacteria, Bacteroidaceae, Corynebacteriaceae, Lactobacillaceae, and S24-7 were elevated and the HFD-induced increase in Clostridia, Ruminococcaceae, Oscillospira, and Flexispira was restored. These data provide evidence for the ameliorative effect of the PFE on diet-induced intestinal barrier functional alternations in association with its capacity to modulate glycolipid digestion and gut microbiota in HFD-fed obese rats.

Momordica charantia reverses type II diabetes in rat.

Diabetes, a disease with abnormal production or use of insulin, is a growing concern that affects many individuals globally. Although many attempts have been made, there is no satisfactory treatment for diabetes. Recently, scientists have been exploring a promising treatment of diabetes involving herbal medicine. In this line, we show that Momordica charantia, a tendril-bearing vine belonging to the Cucurbitaceae family, permanently normalizes blood glucose levels comparable to healthy rats. Most importantly, M. charantia increases the expression of Insulin and Pdx1 genes while lowers the expression Glut2. Moreover, the number and size of the pancreatic islets have remarkably increased in treated animals. Liver ALT, AST, and ALP enzyme activities fell into normal range in treated animals suggesting the protective effect of M. charantia. These data indicate that M. Charantia improves the pancreas function by activating pancreatic beta cells and protecting liver tissue. PRACTICAL APPLICATIONS: Owing to the effectiveness of Momordica Charantia extracts in management of diabetes in STZ-induced diabetic rats, we have intention to evaluate the powder of Charantia to discover novel drug for treating diabetes. It is expected that the results could be translated in clinical trials.

Sodium Butyrate Improves Liver Glycogen Metabolism in Type 2 Diabetes Mellitus.

Liver plays a central role in modulating blood glucose level. Our most recent findings suggested that supplementation with microbiota metabolite sodium butyrate (NaB) could ameliorate progression of type 2 diabetes mellitus (T2DM) and decrease blood HbA1c in db/db mice. To further investigate the role of butyrate in homeostasis of blood glucose and glycogen metabolism, we carried out the present study. In db/db mice, we found significant hypertrophy and steatosis in hepatic lobules accompanied by reduced glycogen storage, and expression of GPR43 was significantly decreased by 59.38 ± 3.33%; NaB administration significantly increased NaB receptor G-protein coupled receptor 43 (GPR43) level and increased glycogen storage in both mice and HepG2 cells. Glucose transporter 2 (GLUT2) and sodium-glucose cotransporter 1 (SGLT1) on cell membrane were upregulated by NaB. The activation of intracellular signaling Protein kinase B (PKB), also known as AKT, was inhibited while glycogen synthase kinase 3 (GSK3) was activated by NaB in both in vivo and in vitro studies. The present study demonstrated that microbiota metabolite NaB possessed beneficial effects on preserving blood glucose homeostasis by promoting glycogen metabolism in liver cells, and the GPR43-AKT-GSK3 signaling pathway should contribute to this effect.