Does lithium attenuate the liver damage due to oxidative stress and liver glycogen depletion in experimental common bile duct obstruction?

In extrahepatic cholestasis, the molecular mechanisms of liver damage due to bile acid accumulation remain elusive. In this study, the activation of glutamatergic receptors was hypothesized to be responsible for bile acid-induced oxidative stress and liver damage. Recent evidence showed that lithium, as an N-methyl-d-aspartate receptor (NMDAR) GluN2B subunit inhibitor, may act on the glutamate/NMDAR signaling axis. Guinea pigs were assigned to four groups, as sham laparotomy (SL), bile duct ligated (BDL), lithium-treated SL (SL + Li) and lithium-treated BDL (BDL + Li) groups. Cholestasis-induced liver injury was evaluated by aspartate aminotransferase (AST), alanine transaminase (ALT), interleukin-6 (IL-6), tissue malondialdehyde (MDA), copper­zinc superoxide dismutase and reduced glutathione levels. The liability of glutamate/NMDAR signaling axis was clarified by glutamate levels in both plasma and liver samples, with the production of nitric oxide (NO), as well as with the serum calcium concentrations. Blood glucose, glucagon, insulin levels and glucose consumption rates, in addition to tissue glycogen were measured to evaluate the liver glucose-glycogen metabolism. A high liver damage index (AST/ALT) was calculated in BDL animals in comparison to SL group. In the BDL animals, lithium reduced plasma NO and glutamate in addition to tissue glutamate concentrations, while serum calcium increased. The antioxidant capacities and liver glycogen contents significantly increased, whereas blood glucose levels unchanged and tissue MDA levels decreased 3-fold in lithium-treated cholestatic animals. It was concluded that lithium largely protects the cholestatic hepatocyte from bile acid-mediated damage by blocking the NMDAR-GluN2B subunit.

Replacing Foods with a High-Glycemic Index and High in Saturated Fat by Alternatives with a Low Glycemic Index and Low Saturated Fat Reduces Hepatic Fat, Even in Isocaloric and Macronutrient Matched Conditions.

BACKGROUND: Current guidelines aim to limit the dietary glycemic index (GI) and intake of saturated fatty acids (SFA). Several studies have shown favorable effects of low-GI or low-SFA diets on intrahepatic lipid content (IHL), but these studies were performed under overfeeding conditions or extreme differences in GI or SFA to maximize the contrast between diets. By combining changes in GI and SFA, we can mimic how people can improve their diet in a realistic setting. OBJECTIVES: We investigated the effect on liver fat content and substrate metabolism of both reducing GI and replacing SFA with polyunsaturated fat in practically realistic amounts under isocaloric conditions. DESIGN AND METHODS: In a randomized crossover study, thirteen overweight participants consumed two diets, one high in GI and SFA (high GI/SFA) and one low in GI and SFA (low GI/SFA) with identical macronutrient composition, for two weeks each. Diets were equal in caloric content, consisted of habitual food items, and had a macronutrient composition that can be easily achieved in daily life. At the end of each intervention, IHL content/composition and liver glycogen were measured by magnetic resonance spectroscopy. Additionally, fasted and postprandial hepatic de novo lipogenesis and glycemic and metabolic responses were investigated. RESULTS: IHL was significantly lower (-28%) after the two-week low-GI/SFA diet (2.4 ± 0.5% 95% CI [1.4, 3.4]) than after the two-week high-GI/SFA diet (3.3 ± 0.6% 95% CI [1.9, 4.7], p < 0.05). Although hepatic glycogen content, hepatic de novo lipogenesis, hepatic lipid composition, and substrate oxidation during the night were similar between the two diets, the glycemic response to the low-GI/SFA diet was reduced (p < 0.05). CONCLUSIONS: Changes in macronutrient quality can already have drastic effects on liver fat content and postprandial glycemia after two weeks and even when energy content and the percentage of total fat and carbohydrate remains unchanged.

Butanol fraction of Alstonia boonei De Wild. leaves ameliorate oxidative stress and modulate key hypoglycaemic processes in diabetic rats.

OBJECTIVE: The effect of Alstonia boonei fractions on glucose homeostasis was investigated via in vitro enzyme inhibition activity, ex vivo glucose uptake assay, and in vivo methods in diabetic rats. METHODOLOGY: A. boonei fractions were subjected to in vitro α-glucosidase inhibitory assay and then ex vivo glucose uptake activity. The butanol fraction of the leaves (ABBF) was picked for the in vivo assay since it showed more activity in the initial tests conducted. ABBF was administrated via oral dosing to six-weeks old fructose-fed STZ-induced type 2 diabetic rats over a 5-week experimental period. RESULTS: ABBF treatment at a low dose of 150 mg/kg bw, significantly (p < .05) reduced blood glucose level, enhanced oral glucose tolerance ability, restored insulin secretion and hepatic glycogen synthesis as well as promoted islet regeneration than the high dose (300 mg/kg bw). CONCLUSION: These results suggest that ABBF could be exploited as a therapeutic potential for treating T2D.

Blood glucose, insulin and glycogen profiles in Sprague-Dawley rats co-infected with Plasmodium berghei ANKA and Trichinella zimbabwensis.

Background: Plasmodium falciparum and tissue dwelling helminth parasites are endemic in sub-Saharan Africa (SSA). The geographical overlap in co-infection is a common phenomenon. However, there is continued paucity of information on how the co-infection influence the blood glucose and insulin profiles in the infected host. Animal models are ideal to elucidate effects of co-infection on disease outcomes and hence, blood glucose, insulin and glycogen profiles were assessed in Sprague-Dawley rats co-infected with P. berghei ANKA (Pb) and Trichinella zimbabwensis (Tz), a tissue-dwelling nematode. Methods: One-hundred-and-sixty-eight male Sprague-Dawley rats (weight range 90-150 g) were randomly divided into four separate experimental groups: Control (n = 42), Pb-infected (n = 42), Tz-infected (n = 42) and Pb- + Tz-infected group (n = 42). Measurement of Pb parasitaemia was done daily throughout the experimental study period for the Pb and the Pb + Tz group. Blood glucose was recorded every third day in all experimental groups throughout the experimental study period. Liver and skeletal muscle samples were harvested, snap frozen for determination of glycogen concentration. Results: Results showed that Tz mono-infection and Tz + Pb co-infection did not have blood glucose lowering effect in the host as expected. This points to other possible mechanisms through which tissue-dwelling parasites up-regulate the glucose store without decreasing the blood glucose concentration as exhibited by the absence of hypoglycaemia in Tz + Pb co-infection group. Hypoinsulinemia and an increase in liver glycogen content was observed in Tz mono-infection and Tz + Pb co-infection groups of which the triggering mechanism remains unclear. Conclusions: To get more insights into how glucose, insulin and glycogen profiles are affected during plasmodium-helminths co-infections, further studies are recommended where other tissue-dwelling helminths such as Taenia taeniformis which has strobilocercus as the metacestode in the liver to mimic infections such as hydatid disease in humans are used.

What Is the Evidence That Dietary Macronutrient Composition Influences Exercise Performance? A Narrative Review.

The introduction of the needle muscle biopsy technique in the 1960s allowed muscle tissue to be sampled from exercising humans for the first time. The finding that muscle glycogen content reached low levels at exhaustion suggested that the metabolic cause of fatigue during prolonged exercise had been discovered. A special pre-exercise diet that maximized pre-exercise muscle glycogen storage also increased time to fatigue during prolonged exercise. The logical conclusion was that the athlete's pre-exercise muscle glycogen content is the single most important acutely modifiable determinant of endurance capacity. Muscle biochemists proposed that skeletal muscle has an obligatory dependence on high rates of muscle glycogen/carbohydrate oxidation, especially during high intensity or prolonged exercise. Without this obligatory carbohydrate oxidation from muscle glycogen, optimum muscle metabolism cannot be sustained; fatigue develops and exercise performance is impaired. As plausible as this explanation may appear, it has never been proven. Here, I propose an alternate explanation. All the original studies overlooked one crucial finding, specifically that not only were muscle glycogen concentrations low at exhaustion in all trials, but hypoglycemia was also always present. Here, I provide the historical and modern evidence showing that the blood glucose concentration-reflecting the liver glycogen rather than the muscle glycogen content-is the homeostatically-regulated (protected) variable that drives the metabolic response to prolonged exercise. If this is so, nutritional interventions that enhance exercise performance, especially during prolonged exercise, will be those that assist the body in its efforts to maintain the blood glucose concentration within the normal range.

Expected or unexpected clinical findings in liver glycogen storage disease type IX: distinct clinical and molecular variability.

OBJECTIVES: To reveal the different clinical presentations of liver glycogen storage disease type IX (GSD IX), which is a clinically and genetically heterogeneous type of glycogenosis. METHODS: The data from the electronic hospital records of 25 patients diagnosed with liver GSD IX was reviewed. Symptoms, clinical findings, and laboratory and molecular analysis were assessed. RESULTS: Of the patients, 10 had complaints of short stature in the initial presentation additionally other clinical findings. Elevated serum transaminases were found in 20 patients, and hepatomegaly was found in 22 patients. Interestingly, three patients were referred due to neurodevelopmental delay and hypotonia, while one was referred for only autism. One patient who presented with neurodevelopmental delay developed hepatomegaly and elevated transaminases during the disease later on. Three of the patients had low hemoglobin A1C and fructosamine values that were near the lowest reference range. Two patients had left ventricular hypertrophy. Three patients developed osteopenia during follow-up, and one patient had osteoporosis after puberty. The most common gene variant, PHKA2, was observed in 16 patients, 10 variants were novel and six variants were defined before. Six patients had variants in PHKG2, two variants were not defined before and four variants were defined before. PHKB variants were found in three patients. One patient had two novel splice site mutations in trans position. It was revealed that one novel homozygous variant and one defined homozygous variant were found in PHKB. CONCLUSIONS: This study revealed that GSD IX may present with only hypotonia and neurodevelopmental delay without liver involvement in the early infantile period. It should be emphasized that although liver GSDIX is thought of as a benign disease, it might present with multisystemic involvement and patients should be screened with echocardiography, bone mineral densitometry, and psychometric evaluation.

Crassocephalum rubens (Juss. Ex Jacq.) S. Moore improves pancreatic histology, insulin secretion, liver and kidney functions and ameliorates oxidative stress in fructose-streptozotocin induced type 2 diabetic rats.

Crassocephalum rubens (C. rubens) is a traditional leafy vegetables (TLV) eaten in parts of Africa for the management of symptoms of diabetes mellitus. This study was done to investigate the in vivo anti-diabetic activity of the aqueous extract of C. rubens aerial parts (CRAQ). Type 2 diabetes (T2D) was induced in male Sprague Dawley (SD) rats by feeding them with a 10% fructose solution for two weeks followed by single dose (40 mg/kg body weight) intraperitoneal injection of streptozotocin. After confirmation of T2D, animals were treated with a low and a high dose (150 and 300 mg/kg body weight) of extract for five weeks. Parameters used as markers of hyperglycemia were analyzed in the samples collected from rats. Hematoxylin-eosin staining was used in analyzing the morphological changes of the pancreas. Treatment with high dose of the extract significantly (p < 0.05) lowered blood glucose level, increased oral glucose tolerance level and pancreatic ß-cell function, while restoring the morphology of the pancreatic tissue damage. The high dose also increased insulin secretion, liver glycogen, antioxidant enzyme activities in serum and organs, and prevented liver and renal damages compared to the untreated diabetic animals. Data from this study suggest that C. rubens possesses impressive anti-diabetic activity and could be useful in ameliorating some complications associated with T2D therefore this plant can be exploited in finding new alternative therapies for the treatment of T2D.

Antidiabetic and hypolipidemic potentials of Solidago virgaurea extract in alloxan-induced diabetes type 1.

OBJECTIVES: The aim of the current study is to investigate the antidiabetic and hypolipidemic potentials of Solidago virgaurea extract in alloxan-induced diabetic rats. MATERIALS AND METHODS: Alloxan-induced diabetic rats were orally administered a dose of Solidago virgaurea extract (250 mg/kg body weight) daily for 15 days. Then blood glucose, insulin, serum lipid profile, amylase, tumour necrosis factor-α (TNF- α), and liver glycogen were determined. Besides, superoxide dismutase (SOD), catalase activities, and malondialdehyde (MDA) levels in pancreatic tissue were assessed. RESULTS: Solidago virgaurea extract significantly reduced blood glucose level, serum amylase activity, TNF-α level, and pancreatic MDA level as well as increasing the serum insulin, liver glycogen level, pancreatic SOD, and catalase activities in comparison with their corresponding diabetic rats, p < .05. CONCLUSION: The findings of this study support the ethnomedicinal use of Solidago virgaurea extract as an antidiabetic and antihyperlipidemic in the management of diabetes mellitus.

O-GlcNAcylation increases PYGL activity by promoting phosphorylation.

O-GlcNAcylation is a post-translational modification that links metabolism with signal transduction. High O-GlcNAcylation appears to be a general characteristic of cancer cells. It promotes the invasion, metastasis, proliferation and survival of tumor cells, and alters many metabolic pathways. Glycogen metabolism increases in a wide variety of tumors, suggesting that it is an important aspect of cancer pathophysiology. Herein we focused on the O-GlcNAcylation of liver glycogen phosphorylase (PYGL)-an important catabolism enzyme in the glycogen metabolism pathway. PYGL expressed in both HEK 293T and HCT116 was modified by O-GlcNAc. And both PYGL O-GlcNAcylation and phosphorylation of Ser15 (pSer15) were decreased under glucose and insulin, whereas increased under glucagon and Na2S2O4 (hypoxia) conditions. Then, we identified the major O-GlcNAcylation site to be Ser430, and demonstrated that pSer15 and Ser430 O-GlcNAcylation were mutually reinforced. Lastly, we found that Ser430 O-GlcNAcylation was fundamental for PYGL activity. Thus, O-GlcNAcylation of PYGL positively regulated pSer15 and therefore its enzymatic activity. Our results provided another molecular insight into the intricate post-translational regulation network of PYGL.

Characterization of liver GSD IX γ2 pathophysiology in a novel Phkg2-/- mouse model.

INTRODUCTION: Liver Glycogen Storage Disease IX is a rare metabolic disorder of glycogen metabolism caused by deficiency of the phosphorylase kinase enzyme (PhK). Variants in the PHKG2 gene, encoding the liver-specific catalytic γ2 subunit of PhK, are associated with a liver GSD IX subtype known as PHKG2 GSD IX or GSD IX γ2. There is emerging evidence that patients with GSD IX γ2 can develop severe and progressive liver disease, yet research regarding the disease has been minimal to date. Here we characterize the first mouse model of liver GSD IX γ2. METHODS: A Phkg2-/- mouse model was generated via targeted removal of the Phkg2 gene. Knockout (Phkg2-/-, KO) and wild type (Phkg2+/+, WT) mice up to 3 months of age were compared for morphology, Phkg2 transcription, PhK enzyme activity, glycogen content, histology, serum liver markers, and urinary glucose tetrasaccharide Glcα1-6Glcα1-4Glcα1-4Glc (Glc4). RESULTS: When compared to WT controls, KO mice demonstrated significantly decreased liver PhK enzyme activity, increased liver: body weight ratio, and increased glycogen in the liver, with no glycogen accumulation observed in the brain, quadricep, kidney, and heart. KO mice demonstrated elevated liver blood markers as well as elevated urine Glc4, a commonly used biomarker for glycogen storage disease. KO mice demonstrated features of liver structural damage. Hematoxylin & Eosin and Masson's Trichrome stained KO mice liver histology slides revealed characteristic GSD hepatocyte architectural changes and early liver fibrosis, as have been reported in liver GSD patients. DISCUSSION: This study provides the first evidence of a mouse model that recapitulates the liver-specific pathology of patients with GSD IX γ2. The model will provide the first platform for further study of disease progression in GSD IX γ2 as well as for the evaluation of novel therapeutics.

The Mediator complex kinase module is necessary for fructose regulation of liver glycogen levels through induction of glucose-6-phosphatase catalytic subunit (G6pc).

OBJECTIVE: Liver glycogen levels are dynamic and highly regulated by nutrient availability as the levels decrease during fasting and are restored during the feeding cycle. However, feeding in the presence of fructose in water suppresses glycogen accumulation in the liver by upregulating the expression of the glucose-6-phosphatase catalytic subunit (G6pc) gene, although the exact mechanism is unknown. We generated liver-specific knockout MED13 mice that lacked the transcriptional Mediator complex kinase module to examine its effect on the transcriptional activation of inducible target gene expression, such as the ChREBP- and FOXO1-dependent control of the G6pc gene promoter. METHODS: The relative changes in liver expression of lipogenic and gluconeogenic genes as well as glycogen levels were examined in response to feeding standard low-fat laboratory chow supplemented with water or water containing sucrose or fructose in control (Med13fl/fl) and liver-specific MED13 knockout (MED13-LKO) mice. RESULTS: Although MED13 deficiency had no significant effect on constitutive gene expression, all the dietary inducible gene transcripts were significantly reduced despite the unchanged insulin sensitivity in the MED13-LKO mice compared to that in the control mice. G6pc gene transcription displayed the most significant difference between the Med13 fl/fl and MED13-LKO mice, particularly when fed fructose. Following fasting that depleted liver glycogen, feeding induced the restoration of glycogen levels except in the presence of fructose. MED13 deficiency rescued the glycogen accumulation defect in the presence of fructose. This resulted from the suppression of G6pc expression and thus G6PC enzymatic activity. Among two transcriptional factors that regulate G6pc gene expression, FOXO1 binding to the G6pc promoter was not affected, whereas ChREBP binding was dramatically reduced in MED13-LKO hepatocytes. In addition, there was a marked suppression of FOXO1 and ChREBP-ß transcriptional activities in MED13-LKO hepatocytes. CONCLUSIONS: Taken together, our data suggest that the kinase module of the Mediator complex is necessary for the transcriptional activation of metabolic genes such as G6pc and has an important role in regulating glycogen levels in the liver through altering transcription factor binding and activity at the G6pc promoter.

Anti-fatigue Effects of Santé Premium Silver Perch Essence on Exhaustive Swimming Exercise Performance in Rats.

Aim: Fish soup is a traditional Chinese food usually offered as a healthy supplement to elders, pregnant women and persons who just had surgery. Silver perch (Santé premium silver perch essence, SPSPE) extract contains various quality proteins, collagen, minerals, trace elements, and branch chain amino acids (BCAA) that could help individuals recover from exhaustion and control body weight. However, there are very limited studies exploring the effects of fish extracts on exercise performance and fatigue, and relevant physiological mechanisms. Therefore, the purpose of this study was to investigate the effects of chronic SPSPE administration on exhaustive exercise performance. Method: Male Wistar rats weighing around 250 g were divided into 4 groups: Control, 1X SPSPE (6.2 ml/kg), 2X SPSPE (12.4 ml/kg) and 5X SPSPE (31.0 ml/kg). Rats were administrated SPSPE by oral gavage feeding every day for 33 days. Their body weight were measured every week. Before and after the exhaustive swimming test, the blood was collected for circulating lactate, glucose, ammonia, hormones, and myoglobin analysis. Rats were sacrificed after performing an exhaustive swimming exercise test. The liver tissues were collected for glycogen content and H&E staining. Results: After the administration of 1X and 5X SPSPE, swimming fatigue was significantly delayed (p = 0.024). There was no difference in the hormone plasma level between the control and SPSPE groups. The induction of plasma corticosterone and TBARS by exhaustive swimming exercise could be decreased by SPSPE administration. The increased plasma myoglobin concentration from exhaustive swimming exercise was weakened by SPSPE supplementation. The higher glycogen sparing contained in liver tissue was observed in SPSPE-treated groups (p < 0.05). Conclusion: SPSPE could efficiently delay swimming fatigue through sparing of liver glycogen and attenuation of plasma TBARS, myoglobin induction by exhaustive exercise. Our findings provide a scientific-based fundamental information and better understanding for developing a fish extract-based anti-fatigue supplement.

Ground-glass hepatocellular inclusions are associated with polypharmacy.

Ground-glass (GG) hepatocytes are classically associated with chronic hepatitis B (HBV) infection, storage disorders, or cyanamide therapy. In a subset of cases, an exact etiology cannot be identified. In this study, we sought to characterize the clinical, histological, and ultrastructural findings associated with HBV-negative GG hepatocytes. Our institutional laboratory information system was searched from 2000 to 2019 for all cases of ground-glass hepatocytes. Ten liver biopsies with GG hepatocellular inclusions and negative HBV serology, no known history of storage disorders, or cyanamide therapy were reviewed. Half of the patients had history of organ transplantation and/or malignancy. These patients took on average 8.1 medications (range: 3-14) with the most common medications being immunosuppressive and health supplements. Histologically, GG hepatocytes show either peri-portal or centrizonal distribution. The inclusions are PAS-positive and diastase sensitive. Electron microscopy showed intracytoplasmic granular inclusions with low electron density, consistent with unstructured glycogen. In summary, GG hepatocytes are a rare finding in liver biopsies, but are more common in patients with hepatitis B. They can also be seen in HBV-negative patients who have polypharmacy. In these cases, they are the result of unstructured glycogen accumulation putatively due to altered cell metabolism.

Energy Metrics of Red-Sided Garter Snakes (Thamnophis sirtalis parietalis) Vary with Sex but Not Life-History Stage.

Because reproduction is energetically expensive, an organism's energy stores are likely involved in mediating transitions between reproductive and self-maintenance activities. We investigated whether body condition index, adipocyte follicle size, and liver glycogen differ with the life-history transition from reproduction to migration and foraging in red-sided garter snakes (Thamnophis sirtalis parietalis). Females primarily investing in mating behavior located at the den had a significantly higher body condition index than females migrating to summer feeding grounds. The body condition index of male snakes did not differ between snakes located at the den and those migrating to summer feeding grounds. Neither adipocyte follicle area nor liver glycogen stores differed significantly between snakes performing mating activities at the den and those migrating to summer feeding grounds. We did find a sexual dimorphism in that female red-sided garter snakes had significantly larger adipocyte follicles and higher liver glycogen compared with males. Our findings support the across-species phenomenon of females and males displaying a sexual dimorphism in stored energy substrates. Conversely, we did not find evidence to suggest that red-sided garter snakes primarily utilize fatty acids to fuel the initiation of migration, a finding that is not consistent with other long-distance migrators, such as birds. Because we did not find evidence to suggest that stored energy metrics influence the decision to migrate, a physiological mechanism that induces migration in red-sided garter snakes remains elusive.

Diurnal variation in the glycogen content of the human liver using 13 C MRS.

Glycogen in tissues functions not only as carbohydrate reserves, but also as molecular sensors capable of activating signaling pathways in response to physical activity. While glycogen in the skeletal muscles is mainly a local energy substrate, glycogen in the liver serves as a glucose reserve to maintain normal blood glucose levels in the body, even during the sleep state. The aim of this study is to compare the diurnal variation of glycogen in the muscle and liver of human subjects under normal conditions. The glycogen content was measured in the muscle and liver of 10 young, healthy, male volunteers using 13 C MRS, a non-invasive technique. The subjects remained sedentary, and glycogen concentration was measured six times daily. Experimental meals were provided to achieve individual energy balance, estimated according to the energy requirement guideline for patients from Japan. The largest variation in muscle glycogen compared with 1 h after supper (20:00 on Day 1) was 3.1 ± 8.2 mmol/L (16:00 on Day 2). In the liver, however, the glycogen content decreased by 80.6 ± 40.4 mmol/L through the overnight fasting period (07:00 on Day 2). This study demonstrated that the glycogen content in the liver was significantly lower in the morning, while the glycogen content in the calf muscles underwent minimal diurnal variation. The overnight fast is a characteristic daily condition, in which liver glycogen content is low, whereas muscle glycogen content is relatively unaffected.

Research priorities for liver glycogen storage disease: An international priority setting partnership with the James Lind Alliance.

The international liver glycogen storage disease (GSD) priority setting partnership (IGSDPSP) was established to identify the top research priorities in this area. The multiphase methodology followed the principles of the James Lind Alliance (JLA) guidebook. An international scoping survey in seven languages was distributed to patients, carers, and healthcare professionals to gather uncertainties, which were consolidated into summary questions. The existing literature was reviewed to ensure that the summary questions had not yet been answered. A second survey asked responders to prioritize these summary questions. A final shortlist of 22 questions was discussed during an international multi-stakeholder workshop, and a consensus was reached on the top 11 priorities using an adapted nominal group technique.In the first survey, a total of 1388 questions were identified from 763 responders from 58 countries. These original uncertainties were refined into 72 summary questions for a second prioritization survey. In total 562 responders from 58 countries answered the second survey. From the second survey, the top 10 for patients, carers and healthcare professionals was identified and this shortlist of 22 questions was taken to the final workshop. During the final workshop, participants identified the worldwide top 11 research priorities for liver GSD. In addition, a top three research priorities per liver GSD subtype was identified.This unique priority setting partnership is the first international, multilingual priority setting partnership focusing on ultra-rare diseases. This process provides a valuable resource for researchers and funding agencies to foster interdisciplinary and transnational research projects with a clear benefit for patients.

Post-Stress Fructose and Glucose Ingestion Exhibit Dissociable Behavioral and Physiological Effects.

An acute traumatic event can lead to lifelong changes in stress susceptibility and result in psychiatric disease such as Post-Traumatic Stress Disorder (PTSD). We have previously shown that access to a concentrated glucose solution for 24 hours beginning immediately after trauma decreased stress-related pathology in the learned helplessness model of PTSD and comorbid major depression. The current study sought to investigate the peripheral physiological effects of post-stress glucose consumption. We exposed 128 male Sprague-Dawley rats to inescapable and unpredictable 1-milliamp electric tail shocks or simple restraint in the learned helplessness procedure. Rats in each stress condition had access to a 40% glucose solution, 40% fructose solution, or water. Blood and liver tissue were extracted and processed for assay. We assessed corticosterone, corticosteroid-binding globulin (CBG), glucose, and liver glycogen concentrations at various time points following stress. We found that rats given access to glucose following exposure to traumatic shock showed a transient rise in blood glucose and an increase in liver glycogen repletion compared to those that received water or fructose following exposure to electric shock. We also found that animals given glucose following shock exhibited reduced free corticosterone and increased CBG compared to their water-drinking counterparts. However, this difference was not apparent when glucose was compared to fructose. These data suggest that post-stress glucose prophylaxis is likely not working via modulation of the HPA axis, but rather may provide its benefit by mitigating the metabolic challenges of trauma exposure.

Cycling time trial performance is improved by carbohydrate ingestion during exercise regardless of a fed or fasted state.

PURPOSE: We tested the hypothesis that carbohydrate ingestion during exercise improves time trial (TT) performance and that this carbohydrate-induced improvement is greater when carbohydrates are ingested during exercise in a fasted rather than a fed state. METHODS: Nine males performed 105 minutes of constant-load exercise (50% of the difference between the first and second lactate thresholds), followed by a 10-km cycling TT. Exercise started at 9 am, 3 hours after either breakfast (FED, 824 kcal, 67% carbohydrate) or a 15-hour overnight fast (FAST). Before exercise, after every 15 minutes of exercise and at 5 km of the TT, participants ingested 2 mL kg-1 body mass of a non-caloric sweetened solution containing either carbohydrate (8% of maltodextrin, CHO) or placebo (0% carbohydrate, PLA). RESULTS: Irrespective of the fasting state, when carbohydrate was ingested during exercise, the rating of perceived exertion (RPE) was lower throughout the constant-load exercise, while the plasma glucose concentration and carbohydrate oxidation were higher during the last stages of the constant-load exercise (P < 0.05). Consequently, TT performance was faster when carbohydrate was ingested during exercise (18.5 ± 0.3 and 18.7 ± 0.4 minutes for the FEDCHO and FASTCHO conditions, respectively) than when the placebo was ingested during exercise (20.2 ± 0.8 and 21.7 ± 1.4 minutes for the FEDPLA and FASTPLA conditions, respectively), regardless of fasting. CONCLUSION: These findings indicate that even when breakfast is provided before exercise, carbohydrate ingestion during exercise is still beneficial for exercise performance. However, ingesting carbohydrate during exercise can overcome a lack of breakfast.

Anti diabetic property of aqueous extract of Stevia rebaudiana Bertoni leaves in Streptozotocin-induced diabetes in albino rats.

BACKGROUND: Stevia (Stevia rebaudiana) natural, non-caloric sugar substitute is rich source of pharmacologically important glycoside stevioside that is linked to the pathology and complications of diabetes. METHODS: The current research was carried out to explore the anti-diabetic effect of aqueous extract of Stevia rebaudiana leaves in albino rats. For this purpose, diabetes was induced by administration of streptozotocin (40 mg/kg body weight, intraperitoneally). The diabetic rats were administered with aqueous stevia extract at different dose levels (200, 300, 400 and 500 ppm/kg b.w) for 8 weeks; the control rats were fed basal diet during this period. RESULTS: Stevia aqueous extract improved caloric management and weight control by decreasing the feed intake and body weight gain. Furthermore, intake of stevia extract resulted in significant (P < 0.05) decrease in the random blood glucose level (- 73.24%) and fasting blood glucose (- 66.09%) and glycosylated (HbA1c) hemoglobin (5.32%) while insulin (17.82 µIU/mL) and liver glycogen (45.02 mg/g) levels significantly improved in the diabetic rats, compared with the diabetic and non-diabetic control rats after 8 weeks study period. CONCLUSIONS: It is concluded that aqueous extact of stevia has anti-diabetic effects in albino rats, and therefore could be promising nutraceutical therapy for the management of diabetes and its associated complications.

Melatonin attenuates smoking-induced hyperglycemia via preserving insulin secretion and hepatic glycogen synthesis in rats.

Epidemiology survey indicated that cigarette smoking is a risk factor of diabetes. However, the precise mechanisms remain to be clarified. In this study, we found that smoking caused metabolic malfunctions on pancreas and liver in experimental animal model. These were indicated by hyperglycemia, increased serum hemoglobin A1c level and decreased insulin secretion, inhibition of liver glycogen synthase (LGS), and hepatic glycogen synthesis. Mechanistic studies revealed that all these alterations were caused by the inflammatory reaction and reactive oxygen species (ROS) induced by the smoking. Melatonin treatment significantly preserved the functions of both pancreas and liver by reducing ß cell apoptosis, CD68-cell infiltration, ROS production, and caspase-3 expression. The siRNA-knockdown model identified that the protective effects of melatonin were mediated by melatonin receptor-2 (MT2). This study uncovered potentially underlying mechanisms related to the association between smoking and diabetes. In addition, it is, for first time, to report that melatonin effectively protects against smoking-induced glucose metabolic alterations and the signal transduction pathway of melatonin is mainly mediated by its MT2 receptor. These observations provide solid evidence for the clinically use of melatonin to reduce smoking-related diabetes, and the therapeutic regimens are absent currently.