Glycogen Depletion Research Articles

The ups and downs of low-carbohydrate diets in the management of Type 1 diabetes: a review of clinical outcomes.

Dietary management has been a mainstay of care in Type 1 diabetes since before the discovery of insulin when severe carbohydrate restriction was advocated. The use of insulin facilitated re-introduction of carbohydrate into the diet. Current management guidelines focus on a healthy and varied diet with consideration of glycaemic load, protein and fat. As a result of frustration with glycaemic outcomes, low-carbohydrate diets have seen a resurgence in popularity. To date, low-carbohydrate diets have not been well studied in the management of Type 1 diabetes. Studies looking at glycaemic outcomes from low-carbohydrate diets have largely been cross-sectional, without validated dietary data and with a lack of control groups. The participants have been highly motivated self-selected individuals who follow intensive insulin management practices, including frequent blood glucose monitoring and additional insulin corrections with tight glycaemic targets. These confounders limit the ability to determine the extent of the impact of dietary carbohydrate restriction on glycaemic outcomes. Carbohydrate-containing foods including grains, fruit and milk are important sources of nutrients. Hence, low-carbohydrate diets require attention to vitamin and energy intake to avoid micronutrient deficiencies and growth issues. Adherence to restricted diets is challenging and can have an impact on social normalcy. In individuals with Type 1 diabetes, adverse health risks such as diabetic ketoacidosis, hypoglycaemia, dyslipidaemia and glycogen depletion remain clinical concerns. In the present paper, we review studies published to date and provide clinical recommendations for ongoing monitoring and support for individuals who choose to adopt a low-carbohydrate diet. Strategies to optimize postprandial glycaemia without carbohydrate restriction are presented.

Inhibition of pyruvate dehydrogenase kinase-4 by l-glutamine protects pregnant rats against fructose-induced obesity and hepatic lipid accumulation

ObjectiveAccumulation of lipids in non-adipose tissues particularly the liver is a feature of tissue insulin resistance. Hepatic glycogen depletion reflects counter glucoregulation in an insulin-resistant state and/or obesity. The effect of l-glutamine on fructose-induced increased hepatic lipid accumulation and depleted glycogen content, particularly in pregnancy, is not known. We therefore aimed at investigating the effect of glutamine on fructose-induced weight gain, hepatic lipids and glycogen contents in pregnant rats and also tested the hypothesis that hepatoprotective role of l-glutamine is through suppression of PDK-4. MethodsEleven-week-old pregnant Wistar rats were allotted into the Control, Glutamine, Fructose and Fructose plus Glutamine groups (6 rats/group). The groups received distilled water (vehicle, p.o.), 1 g/kg bwl-glutamine (p.o.), 10% Fructose (w/v) and 10% Fructose (w/v) plus 1 g/kg bwl-glutamine (p.o.) respectively, daily for 19 days. Biochemical analysis and histology of the liver were performed. ResultsData showed that fructose intake caused insulin resistance, hyperglycemia, hyperlipidemia, increased body weight gain, visceral fat mass, hepatic mass, lactate production, uric acid production, lipid peroxidation and decreased pancreatic β-cell function and hepatic glycogen synthesis. These alterations were accompanied by elevated pyruvate dehydrogenase kinase-4 (PDK-4). However, the fructose-induced dysmetabolism were improved by l-glutamine. ConclusionOur results demonstrate that obesity and hepatic lipid accumulation induced by fructose in pregnant rats is accompanied by increased PDK-4. The findings also suggest that l-glutamine would protect against obesity and hepatic lipid accumulation by suppression of PDK-4.

No evidence of direct association between GLUT4 and glycogen in human skeletal muscle.

Previous studies have demonstrated that exercise increases whole body and skeletal muscle insulin sensitivity that is linked with increased GLUT4 at the plasma membrane following insulin stimulation and associated with muscle glycogen depletion. To assess the potential direct association between muscle glycogen and GLUT4, seven untrained, male subjects exercised for 60 min at ~75% VO2 peak, with muscle samples obtained by percutaneous needle biopsy immediately before and after exercise. Exercise reduced muscle glycogen content by ~43%. An ultracentrifugation protocol resulted in a ~2‐3‐fold enriched glycogen fraction from muscle samples for analysis. Total GLUT4 content was unaltered by exercise and we were unable to detect any GLUT4 in glycogen fractions, either with or without amylase treatment. In skinned muscle fiber segments, there was very little, if any, GLUT4 detected in wash solutions, except following exposure to 1% Triton X‐100. Amylase treatment of single fibers did not increase GLUT4 in the wash solution and there were no differences in GLUT4 content between fibers obtained before or after exercise for any of the wash treatments. Our results indicate no direct association between GLUT4 and glycogen in human skeletal muscle, before or after exercise, and suggest that alterations in GLUT4 translocation associated with exercise‐induced muscle glycogen depletion are mediated via other mechanisms.

Sleep and Wake Affect Glycogen Content and Turnover at Perisynaptic Astrocytic Processes.

Astrocytic glycogen represents the only form of glucose storage in the brain, and one of the outcomes of its breakdown is the production of lactate that can be used by neurons as an alternative energetic substrate. Since brain metabolism is higher in wake than in sleep, it was hypothesized that glycogen stores are depleted during wake and replenished during sleep. Furthermore, it was proposed that glycogen depletion leads to the progressive increase in adenosine levels during wake, providing a homeostatic signal that reflects the buildup of sleep pressure. However, previous studies that measured glycogen dynamics across the sleep/wake cycle obtained inconsistent results, and only measured glycogen in whole tissue. Since most energy in the brain is used to sustain synaptic activity, here we employed tridimensional electron microscopy to quantify glycogen content in the astrocytic processes surrounding the synapse. We studied axon-spine synapses in the frontal cortex of young mice after ~7 h of sleep, 7–8 h of spontaneous or forced wake, or 4.5 days of sleep restriction. Relative to sleep, all wake conditions increased the number of glycogen granules around the synapses to a similar extent. However, progressively longer periods of wake were associated with progressively smaller glycogen granules, suggesting increased turnover. Despite the increased number of granules, in all wake conditions the estimated amount of glucose within the granules was lower than in sleep, indicating that sleep may favor glucose storage. Finally, chronic sleep restriction moved glycogen granules closer to the synaptic cleft. Thus, both short and long wake lead to increased glycogen turnover around cortical synapses, whereas sleep promotes glycogen accumulation.

ANTICOAGULATION INDEPENDENT EFFECTS OF ORAL ANTICOAGULANTS: ON THE SEARCH FOR THE VASCULO-PROTECTIVE EFFECT OF RIVAROXABAN

Because optimising therapy for the management of diabetes mellitus remains challenging, the study investigated the effects of salmon calcitonin (Sct) and/or omega-3 fatty acids (N-3 – eicosapentaenoic acid and docosahexaenoic acid-3:2), compared to metformin, on selected biochemical parameters in male Wistar rats, in an experimental model of diabetes. Forty rats were used for this study. They were divided into eight groups of five rats each, which included: Normal control; Diabetic (D) control; D + N-3; D + low dose Sct (Sct. Lw); D + high dose Sct (Sct. Hi); D + N-3 + Sct.Lw; D + N-3 + Sct.Hi; and D + metformin. Diabetes was induced in overnight fasted rats by the administration of streptozotocin (65 mg/kg b.w., i.p.), 15 min after the administration of nicotinamide (110 mg/kg b.w., i.p.). Nine days later, Sct was administered at 2.5 and 5.0 IU/kg b.w./day (i.m.), while N-3 and metformin were administered at 200 and 180 mg/kg b.w./day (p.o.) respectively, for four weeks. Sct, N-3, and metformin significantly reduced total cholesterol, LDL-C, cortisol, c-telopeptide of type 1 collagen, and collagen type 2 alpha-1. The combined administration of Sct and N-3 had more favorable effects on triglyceride and HDL-C than either monotherapy. Unlike metformin and Sct. Hi, N-3 significantly reduced alkaline phosphatase activity. Moreover, N-3 significantly suppressed the hypocalcaemic, hyperglycaemic, and insulin resistance provoking actions of Sct. Furthermore, N-3 contradicted the hepatic glycogen depletion and inhibition of nitric oxide synthesis brought about by Sct. In conclusion, N-3 demonstrated antagonistic and non-additive actions with Sct. Moreover, the effects of the combined administration of Sct and N-3 were comparable to that of metformin; therefore, they might be considered as therapeutic alternatives in diabetes.

NO SIGNALLING: THE PROCESSES ON THE CONSCIOUS AND UNCONSCIOUS LEVELS

Because optimising therapy for the management of diabetes mellitus remains challenging, the study investigated the effects of salmon calcitonin (Sct) and/or omega-3 fatty acids (N-3 – eicosapentaenoic acid and docosahexaenoic acid-3:2), compared to metformin, on selected biochemical parameters in male Wistar rats, in an experimental model of diabetes. Forty rats were used for this study. They were divided into eight groups of five rats each, which included: Normal control; Diabetic (D) control; D + N-3; D + low dose Sct (Sct. Lw); D + high dose Sct (Sct. Hi); D + N-3 + Sct.Lw; D + N-3 + Sct.Hi; and D + metformin. Diabetes was induced in overnight fasted rats by the administration of streptozotocin (65 mg/kg b.w., i.p.), 15 min after the administration of nicotinamide (110 mg/kg b.w., i.p.). Nine days later, Sct was administered at 2.5 and 5.0 IU/kg b.w./day (i.m.), while N-3 and metformin were administered at 200 and 180 mg/kg b.w./day (p.o.) respectively, for four weeks. Sct, N-3, and metformin significantly reduced total cholesterol, LDL-C, cortisol, c-telopeptide of type 1 collagen, and collagen type 2 alpha-1. The combined administration of Sct and N-3 had more favorable effects on triglyceride and HDL-C than either monotherapy. Unlike metformin and Sct. Hi, N-3 significantly reduced alkaline phosphatase activity. Moreover, N-3 significantly suppressed the hypocalcaemic, hyperglycaemic, and insulin resistance provoking actions of Sct. Furthermore, N-3 contradicted the hepatic glycogen depletion and inhibition of nitric oxide synthesis brought about by Sct. In conclusion, N-3 demonstrated antagonistic and non-additive actions with Sct. Moreover, the effects of the combined administration of Sct and N-3 were comparable to that of metformin; therefore, they might be considered as therapeutic alternatives in diabetes.

PATHOGENIC ROLE OF AUTONOMIC DYSFUNCTION IN COLD INTOLERANCE IN MULTIPLE SCLEROSIS PATIENTS

Because optimising therapy for the management of diabetes mellitus remains challenging, the study investigated the effects of salmon calcitonin (Sct) and/or omega-3 fatty acids (N-3 – eicosapentaenoic acid and docosahexaenoic acid-3:2), compared to metformin, on selected biochemical parameters in male Wistar rats, in an experimental model of diabetes. Forty rats were used for this study. They were divided into eight groups of five rats each, which included: Normal control; Diabetic (D) control; D + N-3; D + low dose Sct (Sct. Lw); D + high dose Sct (Sct. Hi); D + N-3 + Sct.Lw; D + N-3 + Sct.Hi; and D + metformin. Diabetes was induced in overnight fasted rats by the administration of streptozotocin (65 mg/kg b.w., i.p.), 15 min after the administration of nicotinamide (110 mg/kg b.w., i.p.). Nine days later, Sct was administered at 2.5 and 5.0 IU/kg b.w./day (i.m.), while N-3 and metformin were administered at 200 and 180 mg/kg b.w./day (p.o.) respectively, for four weeks. Sct, N-3, and metformin significantly reduced total cholesterol, LDL-C, cortisol, c-telopeptide of type 1 collagen, and collagen type 2 alpha-1. The combined administration of Sct and N-3 had more favorable effects on triglyceride and HDL-C than either monotherapy. Unlike metformin and Sct. Hi, N-3 significantly reduced alkaline phosphatase activity. Moreover, N-3 significantly suppressed the hypocalcaemic, hyperglycaemic, and insulin resistance provoking actions of Sct. Furthermore, N-3 contradicted the hepatic glycogen depletion and inhibition of nitric oxide synthesis brought about by Sct. In conclusion, N-3 demonstrated antagonistic and non-additive actions with Sct. Moreover, the effects of the combined administration of Sct and N-3 were comparable to that of metformin; therefore, they might be considered as therapeutic alternatives in diabetes.

Potentiating effect of acetaminophen and carbon tetrachloride-induced hepatotoxicity is mediated by activation of receptor interaction protein in mice

When multiple drugs or chemicals are used in combination, it is important to understand the risk of their interactions and predict potential additive effects. The aim of the current study was to investigate the molecular mechanism(s) accounting for the additive/synergistic effect of combination treatment with acetaminophen (APAP) and carbon tetrachloride (CCl4). Mice were intraperitoneally administered vehicle or 100 mg/kg (5 mL/kg) APAP and 30 min after vehicle or 15 mg/kg (5 mL/kg) CCl4. Sixteen hours after treatment, mice from each group were sacrificed and the livers were removed. CCl4 administration caused slight glycogen depletion; this effect was more pronounced following co-administration of APAP and CCl4. ATP and NADPH levels showed the same trend as glycogen levels. The levels of receptor interacting protein 1 and 3 increased following combination treatment with APAP and CCl4. In contrast, levels of the glutamate cysteine ligase catalytic subunit and glutamate cysteine ligase modifier subunits were not significantly affected by combination treatment. APAP and CCl4 co-administration potentiated the phosphorylation of c-Jun N-terminal kinase and p38 kinases, although phosphorylated activation of extracellular signal-regulated kinase was not changed. Our results suggest that APAP and CCl4 co-administration potentiates hepatotoxicity in an additive/synergistic manner via receptor interacting protein activation.

Iodine in excess in the alterations of carbohydrate and lipid metabolic pattern as well as histomorphometric changes in associated organs.

Background Iodine is a nonpareil constituent of thyroid hormones (THs) and a prime regulator of thyroid gland functioning. Although essential at recommended levels for the prevention of iodine deficiency disorders (IDDs), exposure to excess iodine reportedly causes hypothyroidism, hyperthyroidism, and several other emerging deleterious impacts. The objective of the present study is to explore the influence of excess iodide exposure on carbohydrate and lipid metabolism along with the histoarchitecture of certain associated organs such as the pancreas, liver, kidney, and skeletal and cardiac muscle because information on those aspects was found to be scanty. Methods Twelve rats were taken, six were fed with iodine through gavage at a dose of 3.5 mg potassium iodide (KI)/100-g body weight, which corresponded to 500 times of the physiological daily dosage of iodide for a period of 60 days, while the other six formed the control group. Results KI-treated rats presented high body weight and urinary iodine with low TH levels, suggesting a primary thyroid dysfunction. There was an increase in blood glucose, cholesterol, triglycerides, low density lipoprotein (LDL), and very low density lipoprotein (VLDL), while high density lipoprotein (HDL) levels decreased. Tissue glycogen content in the liver and skeletal muscle was decreased and was increased in the heart and kidney. Histological sections of the pancreas showed a complete disruption with hardly recognizable histoarchistructure. Treated liver sections displayed the broadened central vein with degenerated hepatocytes, while skeletal muscle sections showed dissolution of muscle fibre cells linked with loss of glycogen from these organs. Histological changes in the heart include features similar to those of a fatty heart with cardiac muscles mutilation, while that of the kidney shows an increase in glomerular tuft size and Bowman's space expansion with general deterioration. Conclusions It may thus be concluded that excess iodine exposure for a long duration causes the development of a biochemical state of hypothyroidism. The developed hypothyroidism was found responsible for the hyperglycaemic and hypercholestromic status evident by high blood glucose and cholesterol levels and the depletion of glycogen at its storage sites in the liver and skeletal muscle but the extra deposition in the cardiac muscle and kidney; histomicrophotographs showed severe destruction of the pancreatic structure. All these alterations are conducive for the pathogenesis of cardiovascular and kidney diseases.

Empagliflozin effects on ischemic contracture and I/R injury in isolated mouse hearts perfused with or without insulin

Background: Activation of sodium hydrogen exchanger (NHE) contributes to cardiac ischemia reperfusion (I/R) injury. We recently reported NHE inhibition properties of the diabetic drug SGLT2 inhibitor empagliflozin (EMPA). Classic NHE inhibitors delay ischemic contracture and reduce I/R injury in the heart, dependent on the degree of ischemic glycogen depletion. We examined in normal-/low-glycogen hearts whether EMPA delays ischemic contracture and reduces I/R injury.

Skeletal Muscle Glycogen Content at Rest and During Endurance Exercise in Humans: A Meta-Analysis.

Skeletal muscle glycogen is an important energy source for muscle contraction and a key regulator of metabolic responses to exercise. Manipulation of muscle glycogen is therefore a strategy to improve performance in competitions and potentially adaptation to training. However, assessing muscle glycogen in the field is impractical, and there are no normative values for glycogen concentration at rest and during exercise. The objective of this study was to meta-analyse the effects of fitness, acute dietary carbohydrate (CHO) availability and other factors on muscle glycogen concentration at rest and during exercise of different durations and intensities. PubMed was used to search for original articles in English published up until February 2018. Search terms included muscle glycogen and exercise, filtered for humans. The analysis incorporated 181 studies of continuous or intermittent cycling and running by healthy participants, with muscle glycogen at rest and during exercise determined by biochemical analysis of biopsies. Resting muscle glycogen was determined with a meta-regression mixed model that included fixed effects for fitness status [linear, as maximal oxygen uptake ([Formula: see text]O2max) in mL·kg-1·min-1] and CHO availability (three levels: high, ≥ 6g·kg-1 of CHO per day for ≥ 3days or ≥ 7g·kg-1 CHO per day for ≥ 2days; low, glycogen depletion and low-CHO diet; and normal, neither high nor low, or not specified in study). Muscle glycogen during exercise was determined with a meta-regression mixed model that included fixed effects for fitness status, resting glycogen [linear, in mmol·kg-1 of dry mass (DM)], exercise duration (five levels, with means of 5, 23, 53 and 116min, and time to fatigue), and exercise intensity (linear, as percentage of [Formula: see text]O2max); intensity, fitness and resting glycogen were interacted with duration, and there were also fixed effects for exercise modes, CHO ingestion, sex and muscle type. Random effects in both models accounted for between-study variance and within-study repeated measurement. Inferences about differences and changes in glycogen were based on acceptable uncertainty in standardised magnitudes, with thresholds for small, moderate, large and very large of 25, 75, 150 and 250mmol·kg-1 of DM, respectively. The resting glycogen concentration in the vastus lateralis of males with normal CHO availability and [Formula: see text]O2max (mean ± standard deviation, 53 ± 8mL·kg-1·min-1) was 462 ± 132mmol·kg-1. High CHO availability was associated with a moderate increase in resting glycogen (102, ± 47mmol·kg-1; mean ± 90% confidence limits), whereas low availability was associated with a very large decrease (- 253, ± 30mmol·kg-1). An increase in [Formula: see text]O2max of 10mL·kg-1·min-1 had small effects with low and normal CHO availability (29, ± 44 and 67, ± 15mmol·kg-1, respectively) and a moderate effect with high CHO availability (80, ± 40mmol·kg-1). There were small clear increases in females and the gastrocnemius muscle. Clear modifying effects on glycogen utilisation during exercise were as follows: a 30% [Formula: see text]O2max increase in intensity, small (41, ± 20mmol·kg-1) at 5min and moderate (87-134mmol·kg-1) at all other timepoints; an increase in baseline glycogen of 200mmol·kg-1, small at 5-23min (28-59mmol·kg-1), moderate at 116min (104, ± 15mmol·kg-1) and moderate at fatigue (143, ± 33mmol·kg-1); an increase in [Formula: see text]O2max of 10mL·kg-1·min-1, mainly clear trivial effects; exercise mode (intermittent vs. continuous) and CHO ingestion, clear trivial effects. Small decreases in utilisation were observed in females (vs. males: - 30, ± 29mmol·kg-1), gastrocnemius muscle (vs. vastus lateralis: - 31, ± 46mmol·kg-1) and running (vs. cycling: - 70, ± 32mmol·kg-1). Dietary CHO availability and fitness are important factors for resting muscle glycogen. Exercise intensity and baseline muscle glycogen are important factors determining glycogen use during exercise, especially with longer exercise duration. The meta-analysed effects may be useful normative values for prescription of endurance exercise.

Glycogen at the Crossroad of Stress Resistance, Energy Maintenance, and Pathophysiology of Aging.

Glycogen is synthesized and stored to maintain postprandial blood glucose homeostasis and to ensure an uninterrupted energy supply between meals. Although the regulation of glycogen turnover has been well studied, the effects of glycogen on aging and disease development have been largely unexplored. In Caenorhabditis elegans fed a high sugar diet, glycogen potentiates resistance to oxidants, but paradoxically, shortens lifespan. Depletion of glycogen by oxidants or inhibition of glycogen synthesis extends the lifespan of worms by an AMPK-dependent mechanism. Thus, glycogen is not merely an inert storage molecule, but also an active regulator of energy balance and aging. Its depletion by oxidants may be beneficial in the treatment of hyperglycemia and glycogen-related diseases.

Acute modulation in dietary behavior following glycogen depletion and postexercise supplementation in trained cyclists.

We investigated the influence of immediate postexercise dietary supplementation on the subsequent food consumption pattern and endurance exercise performance in physically trained individuals. On 2 occasions, trained male cyclists performed a glycogen-depleting exercise bout followed by a 2-h nutritional supplementation period, 28 h of free-living recovery, and a subsequent 40-km cycling time trial. During the 2-h postexercise supplementation, the subjects consumed equal volumes of reduced-fat chocolate milk (CM) or a sports beverage (SB) in a single-blind, randomized design. Thereafter, the cyclists maintained a food log during the free-living recovery period. Dietary and exercise performance parameters were compared between the treatment beverage visits. No differences in total caloric and macronutrient intakes were detected between the CM and SB trials over the course of the free-living recovery. However, a significant interaction (treatment × time) was detected for caloric and macronutrient intakes during the early phase of free-living recovery, such that significantly larger proportions were consumed shortly after SB as compared with CM. No difference was observed in completion time of the 40-km cycling time trial (CM: 66.9 ± 4.1 vs SB: 66.9 ± 3.7 min). Hence, the cyclists achieved similar levels of recovery during the prolonged, free-living period despite the different acute, postexercise nutrient intake rates. We suggest that given adequate time, athletes appear to subconsciously modify their food consumption in response to varied postexercise supplementation such that subsequent-day exercise performance is equivalent.

Glucocorticoid-dependent REDD1 expression reduces muscle metabolism to enable adaptation under energetic stress

BackgroundSkeletal muscle atrophy is a common feature of numerous chronic pathologies and is correlated with patient mortality. The REDD1 protein is currently recognized as a negative regulator of muscle mass through inhibition of the Akt/mTORC1 signaling pathway. REDD1 expression is notably induced following glucocorticoid secretion, which is a component of energy stress responses.ResultsUnexpectedly, we show here that REDD1 instead limits muscle loss during energetic stresses such as hypoxia and fasting by reducing glycogen depletion and AMPK activation. Indeed, we demonstrate that REDD1 is required to decrease O2 and ATP consumption in skeletal muscle via reduction of the extent of mitochondrial-associated endoplasmic reticulum membranes (MAMs), a central hub connecting energy production by mitochondria and anabolic processes. In fact, REDD1 inhibits ATP-demanding processes such as glycogen storage and protein synthesis through disruption of the Akt/Hexokinase II and PRAS40/mTORC1 signaling pathways in MAMs. Our results uncover a new REDD1-dependent mechanism coupling mitochondrial respiration and anabolic processes during hypoxia, fasting, and exercise.ConclusionsTherefore, REDD1 is a crucial negative regulator of energy expenditure that is necessary for muscle adaptation during energetic stresses. This present study could shed new light on the role of REDD1 in several pathologies associated with energetic metabolism alteration, such as cancer, diabetes, and Parkinson’s disease.

In vivo investigation on the chronic hepatotoxicity induced by sertraline

Although sertraline is widely prescribed as relatively safe antidepressant drug, hepatic toxicity was reported in some patients with sertraline treatment. The present study was conducted to investigate the morphometric, hepatotoxicity, and change in gene expression of drug metabolizing enzymes. Male healthy adult rabbits (Oryctolagus cuniculus) ranging from 1050 to 1100 g were exposed to oral daily doses of sertraline (0, 1, 2, 4, 8 mg/kg) for 9 weeks. The animals were subjected to morphometric, hepatohistological, histochemical and quantitative real-time polymerase chain reaction analyses. Sertraline chronic exposure induced morphometric changes and provoked histological and histochemical alterations including: hepatocytes hydropic degeneration, necrosis, nuclear alteration, sinusoidal dilation, bile duct hyperplasia, inflammatory cells infiltration, portal vessel congestion, Kupffer cells hyperplasia, portal fibrosis and glycogen depletion. In addition, the gene expression of drug and arachidonic acid metabolizing enzymes were reduced significantly (p value <0.05). The most affected genes were cyp4a12, ephx2, cyp2d9 and cyp1a2, demonstrating 5 folds or more down-regulation. These findings suggest that chronic sertraline treatment induced toxic histological alterations in the hepatic tissues and reduced the gene expression of drug metabolizing enzymes. Patients on chronic sertraline treatment may be on risk of hepatotoxicity with reduced capacity to metabolize drugs and fatty acids.

Effect Of Progressive Fatigue On Session Rpe

INTRODUCTION: The Session Rating of Perceived Exertion (sRPE) is an accepted surrogate measure of exercise intensity. The purpose of this study was to examine the effect of progressive fatigue from heavier than normal training on sRPE. METHODS: Twelve moderately fit college age students completed 30-min or 60-min interval workouts on a cycle ergometer, with the sequence of sessions designed to test the hypothesis that sRPE for a given exercise bout would increase with progressive fatigue, whether from a longer bout, or from successive days of harder than usual bouts. The workouts were Monday through Thursday for two weeks. The first week was three 30-min sessions (e.g. normal training) followed by a 60-min session (30-min session repeated 2x) (e.g. heavier than usual training). The second week was three 60-min sessions followed by a 30-min session. sRPE was measured 30-min post exercise, and RPE and HLa were measured at 10 min intervals during exercise. RESULTS: The 30-min sessions in week 1 had sRPE that was significantly less than the 60-min session (4.3+1.7, 4.3+1.4, 4.5+1.7 & 5.3+1.8). During week 2 the 60-min sessions became progressively harder, before the recovery 30- min session on day 4 (5.3+1.4, 5.9+1.6, 6.0+2.1 & 4.5+1.6). The mean RPE/HLa during the exercise bouts, a potential index of glycogen depletion mediated fatigue, followed a relatively constant course in week 1 (0.7+0.2, 0.9+0.4, 0.8+0.4 & 0.9+0.4) and an increasing course in week 2 (0.8+0.4, 0.9+0.4, 1.0+0.4 & 0.9+0.4). CONCLUSION: The results suggest that in addition to being a surrogate of exercise intensity, sRPE reflects accumulated fatigue during periods of increased training.

Essential Roles of Lactate in Müller Cell Survival and Function.

Müller cells are pivotal in sustaining retinal ganglion cells, and an intact energy metabolism is essential for upholding Müller cell functions. The present study aimed to investigate the impact of lactate on Müller cell survival and function. Primary mice Müller cells and human Müller cell lines (MIO-M1) were treated with or without lactate (10 or 20mM) for 2 and 24 hours. Simultaneously, Müller cells were incubated with or without 6mM of glucose. L-lactate exposure increased Müller cell survival independently of the presence of glucose. This effect was abolished by the addition of the monocarboxylate inhibitor 4-cinnamic acid to the treatment media, whereas survival continued to increase in response to addition of D-lactate during glucose restriction. ATP levels decreased over time in MIO-M1 cells and remained stable over time in primary Müller cells. Lactate was preferably metabolized in MIO-M1 cells compared to glucose, and 10mM of L-Lactate exposure prevented complete glycogen depletion in MIO-M1 cells. Glutamate uptake increased after 2hours and decreased after 24 hours in glucose-restricted Müller cells compared to cells with glucose supplement. The addition of 10mM of lactate to the treatment media increased glutamate uptake in glucose supplemented and restricted cells. In conclusion, lactate is a key component in maintaining Müller cell survival and function. Hence, lactate administration may be of great future interest, ultimately leading to novel therapies to rescue retinal ganglion cells.

REDD1 Reduces Muscle Metabolism to Foster Adaptation under Fasting

Aims and backgroundRegulated in Development and DNA Damage 1 (REDD1) is a stress‐induced protein responsible for the inhibition of the Akt/mTORC1 pathway. This pathway integrates energetic status and oxygen availability to promote protein and glycogen synthesis as well as mitochondrial biogenesis. REDD1 is expressed in response to exercise, hypoxia or fasting and has been observed in the mitochondrial fraction in vitro. Our aim is to characterize the role of REDD1 in skeletal muscle under energetic challenge.Methods and resultsWild‐type (WT) and REDD1 knockout (KO) mice were deprived of food for 16h and immediately killed before gastrocnemius and tibialis anterior muscles sampling. We observed an overactivation of the metabolic sensor AMPK and a greater glycogen depletion in skeletal muscle of REDD1 KO mice after fasting. In addition, REDD1 deficient mice displayed exacerbation of skeletal muscle atrophy in response to food deprivation compared to WT animals. We then used dexamethasone treatment to induce REDD1 protein expression and showed for the first time that REDD1 is (partly) localized at the mitochondrial‐associated endoplasmic reticulum membranes (MAM) of skeletal muscle fibers, where it is able to inhibit the Akt/mTORC1 pathway. Indeed, REDD1 binds to and reduces the interaction of MAM protein components, resulting in decreased mitochondrial O2 consumption and protein synthesis.ConclusionsSustained activity of the Akt/mTORC1 pathway is known to promote anabolic processes and therefore to increase ATP consumption. Our results supports that REDD1 deletion contribute to maintain high fuel demand that in turn leads to skeletal muscle atrophy under fasting. We propose here that a physiological role for REDD1 is to foster skeletal muscle acclimatization during energetic challenges via reduction of O2 and ATP consumption assigned to synthesis processes.Support or Funding InformationThis work was supported by the Agence Française de Lutte contre le Dopage (grant #4299).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Small molecule inhibition of protein phosphatase 2A in vivo does not disrupt glucose homeostasis in mice.

Identifying new targets for therapeutic intervention that might attenuate cardiovascular complications associated with type 2 diabetes is needed. Earlier we reported that mice treated with a potent and selective small molecule inhibitor (LB1; Lixte Biotechnology Holdings, Inc., East Setauket, NY; 1 mg/kg IP) of protein phosphatase 2A (PP2A) for the last 14 days of an obesogenic diet (12 weeks of fat‐feeding) did not display vascular PP2A hyperactivation, endothelial dysfunction, or hypertension that otherwise developed in fat‐fed mice treated with vehicle (Bharath et al, Diabetes, 2015). We concluded that PP2A hyperactivation should be considered further as a therapeutic target for intervention. Results from another laboratory group indicated that 2 mg/kg LB1 IP (3 hours) evoked hyperglycemia, glucose intolerance, and hepatic glycogen depletion in chow‐fed and fat‐fed (3 days) rats. The authors concluded that targeting PP2A hyperactivation should not be considered as a therapeutic intervention. Based on the incongruent conclusions from the two studies we tested the hypotheses that LB1 treatment for 14‐days impairs: (i) peripheral glucose homeostasis; (ii) hepatic glycogen content; and (iii) insulin‐mediated signal transduction in the liver. To test the first two hypotheses, 7‐week old male C57BL/6J mice consumed standard (Con) or high fat (HF) chow for 12 weeks. Subgroups of Con and HF mice received 1 mg/kg LB1 or saline (Veh) IP for the last 14 days. First, glucose and insulin tolerance testing indicated that LB1 treatment does not impair peripheral glucose homeostasis in Con mice or HF mice. Second, LB1 treatment did not lower hepatic glycogen content, p‐Akt2S474/Akt2, p‐Gsk3ɑS21/Gsk3ɑβ, or p‐GSS641/GS, in lean or obese mice under basal, random‐fed conditions. To test the third hypothesis, age‐matched male mice that consumed standard chow were treated with LB1 or Veh for 14 days. On day 15, after a 6 h fast, insulin or saline was administered (i.v.) to anesthetized mice, and segments of liver were collected to assess p‐Akt2S474/Akt2, p‐GSK3ɑS21/GSK3ɑ, and p‐GSS641/GS. Insulin‐mediated signal transduction in the liver was similar regardless of LB1 treatment. We conclude that LB1 treatment in mice for 14‐days does not impair: (i) peripheral glucose homeostasis; (ii) hepatic glycogen content; or (iii) insulin‐mediated signal transduction in the liver.Support or Funding InformationAmerican Diabetes Association (ADA: 1‐12‐BS‐208, ADA 7‐08‐RA‐164) and National Institutes of Health (NIH: 2R15HL091493) to JDSThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Empagliflozin effects on ischemic contracture and I/R injury in isolated mouse hearts perfused with or without insulin

IntroductionThe kidney‐targeted Empagliflozin (EMPA) has shown large unexpected cardiovascular benefits, which cannot be explained by general cardiovascular risk factors. We recently reported that EMPA has sodium hydrogen exchanger (NHE) inhibition properties in isolated cardiomyocytes. Classic NHE inhibitors such as Cariporide (CARI) delay ischemic contracture onset and reduce ischemia reperfusion (I/R) injury in the heart. Here we examined whether EMPA delays contracture onset and reduces I/R injury. Both normal‐ and low‐glycogen hearts were used, because the rate of glycogen depletion during ischemia affects contracture onset and IR injury.Methods/ResultsIsolated mouse hearts were perfused with and without 50 mU/L insulin, to create normal‐ and low‐glycogen hearts respectively, and subjected to 25 min I and 120 min R. 1μM EMPA, 10μM cariporide (CARI; positive control) or vehicle was administered prior to ischemia until 10 minutes post‐reperfusion. In normal‐glycogen hearts, EMPA and CARI did not change ischemic contracture (in seconds, vehicle 1056±56, EMPA 900±44, CARI 880±84) and IR injury (infarct size (%): vehicle 59±6, Empa 62±10, Cari 68±4), however in low‐glycogen hearts, both EMPA and CARI delayed ischemic contracture onset (vehicle 459±25, EMPA 559±22, CARI 588±31). Higher EMPA concentration further delayed contracture onset. Only CARI reduced I/R injury (from 51±6 to 34±5). The presence of insulin (same concentration used) did not alter NHE activity, nor the ability of CARI or EMPA to inhibit NHE, in isolated cardiomyocytes. The increased IR injury in normal‐glycogen hearts was associated with increased end‐ischemic lactate and glucose‐6‐phosphate accumulation, and consequently decreased mitochondrial hexokinase ll.ConclusionEMPA does not protect against I/R injury in isolated hearts, yet EMPA delayed ischemic contracture onset in low‐glycogen hearts, suggesting a direct cardiac, ATP preserving, effect of EMPA during ischemia. Cardiac glycogen content interferes with the effects of NHE inhibitors on I/R injury in isolated hearts. These data indicate that empagliflozin and cariporide may inhibit NHE in different manners.Support or Funding InformationNone.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.