Glucose Bioavailability Research Articles

Glycolytic PFKFB3 and Glycogenic UGP2 Axis Regulates Perfusion Recovery in Experimental Hind Limb Ischemia.

Despite being in an oxygen-rich environment, endothelial cells (ECs) use anaerobic glycolysis (Warburg effect) as the primary metabolic pathway for cellular energy needs. PFKFB (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase)-3 regulates a critical enzymatic checkpoint in glycolysis and has been shown to induce angiogenesis. This study builds on our efforts to determine the metabolic regulation of ischemic angiogenesis and perfusion recovery in the ischemic muscle. Hypoxia serum starvation (HSS) was used as an in vitro peripheral artery disease (PAD) model, and hind limb ischemia by femoral artery ligation and resection was used as a preclinical PAD model. Despite increasing PFKFB3-dependent glycolysis, HSS significantly decreased the angiogenic capacity of ischemic ECs. Interestingly, inhibiting PFKFB3 significantly induced the angiogenic capacity of HSS-ECs. Since ischemia induced a significant in PFKFB3 levels in hind limb ischemia muscle versus nonischemic, we wanted to determine whether glucose bioavailability (rather than PFKFB3 expression) in the ischemic muscle is a limiting factor behind impaired angiogenesis. However, treating the ischemic muscle with intramuscular delivery of D-glucose or L-glucose (osmolar control) showed no significant differences in the perfusion recovery, indicating that glucose bioavailability is not a limiting factor to induce ischemic angiogenesis in experimental PAD. Unexpectedly, we found that shRNA-mediated PFKFB3 inhibition in the ischemic muscle resulted in an increased perfusion recovery and higher vascular density compared with control shRNA (consistent with the increased angiogenic capacity of PFKFB3 silenced HSS-ECs). Based on these data, we hypothesized that inhibiting HSS-induced PFKFB3 expression/levels in ischemic ECs activates alternative metabolic pathways that revascularize the ischemic muscle in experimental PAD. A comprehensive glucose metabolic gene qPCR arrays in PFKFB3 silenced HSS-ECs, and PFKFB3-knock-down ischemic muscle versus respective controls identified UGP2 (uridine diphosphate-glucose pyrophosphorylase 2), a regulator of protein glycosylation and glycogen synthesis, is induced upon PFKFB3 inhibition in vitro and in vivo. Antibody-mediated inhibition of UGP2 in the ischemic muscle significantly impaired perfusion recovery versus IgG control. Mechanistically, supplementing uridine diphosphate-glucose, a metabolite of UGP2 activity, significantly induced HSS-EC angiogenic capacity in vitro and enhanced perfusion recovery in vivo by increasing protein glycosylation (but not glycogen synthesis). Our data present that inhibition of maladaptive PFKFB3-driven glycolysis in HSS-ECs is necessary to promote the UGP2-uridine diphosphate-glucose axis that enhances ischemic angiogenesis and perfusion recovery in experimental PAD.

Interference of Glucose Bioavailability of Tumor by Engineered Biohybrids for Potentiating Targeting and Uptake of Antitumor Nanodrugs.

The chemotherapy efficacy of nanodrugs is restricted by poor tumor targeting and uptake. Here, an engineered biohybrid living material (designated as EcN@HPB) is constructed by integrating paclitaxel and BAY-876 bound human serum albumin nanodrugs (HPB) with Escherichia coli Nissle 1917 (EcN). Due to the inherent tumor tropism of EcN, EcN@HPB could actively target the tumor site and competitively deprive glucose through bacterial respiration. Thus, albumin would be used as an alternative nutrient source for tumor metabolism, which significantly promotes the internalization of HPB by tumor cells. Subsequently, BAY-876 internalized along with HPB nanodrugs would further depress glucose uptake of tumor cells via inhibiting glucose transporter 1 (GLUT1). Together, the decline of glucose bioavailability of tumor cells would activate and promote the macropinocytosis in an AMP-activated protein kinase (AMPK)-dependent manner, resulting in more uptake of HPB by tumor cells and boosting the therapeutic outcome of paclitaxel.

Maternal obesity: new placental paradigms unfolded.

The prevalence of maternal obesity is increasing at an alarming rate, and is providing a major challenge for obstetric practice. Adverse effects on maternal and fetal health are mediated by complex interactions between metabolic, inflammatory, and oxidative stress signaling in the placenta. Endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) are common downstream pathways of cell stress, and there is evidence that this conserved homeostatic response may be a key mediator in the pathogenesis of placental dysfunction. We summarize the current literature on the placental cellular and molecular changes that occur in obese women. A special focus is cast onto placental ER stress in obese pregnancy, which may provide a novel link for future investigation.

The Pros and Cons of Low Carbohydrate and Ketogenic Diets in the Prevention and Treatment of Cancer.

Ketogenic diets are low carbohydrate (CHO), high fat diets that are currently very popular for weight loss. Since cancer cells typically consume far more glucose than normal cells, low CHO diets are currently being considered as possible therapeutic regimens to manage cancer. However, our understanding of the safety and efficacy of such CHO-restricted diets in the prevention and treatment of cancer is still in its infancy. In this perspective we provide an overview of the current state of knowledge regarding the use of low CHO diets in the prevention and treatment of cancer. We also highlight the gaps in our knowledge regarding the potential usefulness of low CHO diets in cancer. While pre-clinical rodent studies have provided convincing evidence that CHO restriction may be effective in reducing cancer growth, there has not been sufficient attention given to the effect of these low CHO diets, that are often high in fats and low in soluble fiber, on inflammation. This is important, given that different fats have distinct effects on inflammation. As well, we demonstrate that short chain fatty acids, which are produced via the fermentation of fiber by our gut microbiome, have more anti-inflammatory properties than β-hydroxybutyrate, a ketone body produced during nutritional ketosis that is touted to have anti-inflammatory activity. Since chronic inflammation is strongly associated with cancer formation, defining the type of fats in low CHO diets may contribute to our understanding of whether these diets may work simply by reducing glucose bioavailability, or via modulation of inflammatory responses.

Disrupted Mitochondrial and Metabolic Plasticity Underlie Comorbidity between Age-Related and Degenerative Disorders as Parkinson Disease and Type 2 Diabetes Mellitus.

Idiopathic Parkinson’s disease (iPD) and type 2 diabetes mellitus (T2DM) are chronic, multisystemic, and degenerative diseases associated with aging, with eventual epidemiological co-morbidity and overlap in molecular basis. This study aims to explore if metabolic and mitochondrial alterations underlie the previously reported epidemiologic and clinical co-morbidity from a molecular level. To evaluate the adaptation of iPD to a simulated pre-diabetogenic state, we exposed primary cultured fibroblasts from iPD patients and controls to standard (5 mM) and high (25 mM) glucose concentrations to further characterize metabolic and mitochondrial resilience. iPD fibroblasts showed increased organic and amino acid levels related to mitochondrial metabolism with respect to controls, and these differences were enhanced in high glucose conditions (citric, suberic, and sebacic acids levels increased, as well as alanine, glutamate, aspartate, arginine, and ornithine amino acids; p-values between 0.001 and 0.05). The accumulation of metabolites in iPD fibroblasts was associated with (and probably due to) the concomitant mitochondrial dysfunction observed at enzymatic, oxidative, respiratory, and morphologic level. Metabolic and mitochondrial plasticity of controls was not observed in iPD fibroblasts, which were unable to adapt to different glucose conditions. Impaired metabolism and mitochondrial activity in iPD may limit energy supply for cell survival. Moreover, reduced capacity to adapt to disrupted glucose balance characteristic of T2DM may underlay the co-morbidity between both diseases. Conclusions: Fibroblasts from iPD patients showed mitochondrial impairment, resulting in the accumulation of organic and amino acids related to mitochondrial metabolism, especially when exposed to high glucose. Mitochondrial and metabolic defects down warding cell plasticity to adapt to changing glucose bioavailability may explain the comorbidity between iPD and T2DM.

In vitro assessment of food-derived-glucose bioaccessibility and bioavailability in bicameral cell culture system

Abstract Background Functional foods can help prevent metabolic diseases, and it is essential to evaluate functional characteristics of foods through in vitro and in vivo experimental approaches. Objective We aimed to use the bicameral cell culture system combined with the in vitro digestion to evaluate glucose bioavailability. Materials and methods Cake, almond paste, and pudding were modified by adding fiber and replacing sugar with sweeteners and polyols. Digestion process was modeled in test tubes. Rat enterocyte cells (IEC-6) were grown in a bicameral cell culture system to mimic the physiological characteristics of the human intestine. The glucose bioaccessibility and cellular glucose efflux were measured by glucose oxidase assay. Results and discussion The glucose bioaccessibilities of modified foods were significantly lower (cake: 2.6 fold, almond paste: 9.2 fold, pudding 2.8 fold) than the controls. Cellular glucose effluxes also decreased in the modified cake, almond paste, and pudding by 2.2, 4, and 2 fold respectively compared to their controls. Conclusion Our results suggest that combining in vitro enzymatic digestion with cell culture studies can be a practical way to test in vitro glucose bioaccessibility and bioavailability in functional food development.

Decreased glucose bioavailability and elevated aspartate metabolism in prostate cancer cells undergoing epithelial-mesenchymal transition.

Prostate cancer (PCa) is a common malignancy with a high tendency for metastasis. Epithelial-mesenchymal transition (EMT) plays a crucial role in PCa metastasis. Metabolic reprogramming offers metabolic advantages for cancer development and could result in the discovery of novel targets for cancer therapy. However, the metabolic features of PCa cells undergoing EMT remain unclear. We used metabolome and transcriptome analyses and found that PCa cells undergoing EMT showed impaired glucose utilization. In vitro studies demonstrated that PCa cells undergoing EMT were less addicted to glucose than epithelial-like PCa cells. However, cells that underwent EMT had higher levels of aspartate and its downstream metabolites, indicative of upregulated aspartate metabolism. As aspartate is a contributor for EMT and metastasis in human cancer cells, we conclude that this metabolic reprogramming may play a vital role in EMT and PCa progression.

Effect of <i>Ficus capensis</i> chloroform extract and <i>Eucalyptus camaldulensis</i> n-hexane extract on blood glucose and lipids in normal Wistar rats

The present study was designed to investigate the effects of the stem bark and leaf extracts of Eucalyptus camaldulensis and Ficus capensis on the blood glucose and lipid profile in normal albino rats. Forty adult albino rats were classified into two sets (blood glucose and lipid profile determination) with five groups comprising of four animals per group. The first four groups (treatment groups) in each set were administered 100, 400, 800 and 1200 mg/kg body weight of each extract, the fifth group (control group) received 5 ml of 0.90% normal saline solution for a 7 days duration. The result showed a decrease in blood glucose concentration in a dose dependent manner but was however seen to increase at 1200 mg/kg bw when the chloroform extract of F. capensis was administered. The nhexane extract of E. camaldulensis caused a corresponding increase in blood glucose concentration in a dose dependent manner. In both determinations and in comparison, to the control group, there were statistically significant differences between the treatment groups at 95% confidence level for all lipid parameters determined. The findings of this study indicate that while the chloroform extract of F. capensis possesses anti-diabetic property, the n – hexane extract of E. camaldulensis does not have anti-diabetic effect, but rather appears to promote bioavailability of glucose in the blood. Both extracts however showed promising anti-lipidemic activity.Keywords: Eucalyptus camaldulensis; Ficus capensis; Glucose; Lipids

The Relevance of Starch and Protein Digestive Dynamics in Poultry

SUMMARY The fundamental premise of starch and protein digestive dynamics is that an ideal balance of glucose and amino acids is made available at sites of skeletal muscle protein synthesis to promote efficient growth. Digestive dynamics involve the digestion of protein and starch in the gut lumen, absorption of glucose and amino acids along the small intestine and their transition across the gut mucosa into the portal circulation. However, the post-enteral, bilateral bioavailability of glucose and amino acids is ultimately dependent on their metabolic fates in enterocytes as both may be catabolized in avian enterocytes for energy to drive digestive processes. Importantly, digestive dynamics consider rates and sites of glucose and amino acid absorption along the small intestine in addition to their extents of digestion as determined by static digestibility coefficients. There is considerable interest in the development of low-protein/high-supplemental amino acid diets but the digestive dynamics of supplemental and protein-bound amino acids are inherently different. Therefore, the relevance of starch and protein digestive dynamics in poultry will become increasingly evident if low-protein diets are to be developed successfully in the future.

A metabolic perspective on CSF-mediated neurodegeneration in multiple sclerosis.

Multiple sclerosis is an autoimmune demyelinating disorder of the CNS, characterized by inflammatory lesions and an underlying neurodegenerative process, which is more prominent in patients with progressive disease course. It has been proposed that mitochondrial dysfunction underlies neuronal damage, the precise mechanism by which this occurs remains uncertain. To investigate potential mechanisms of neurodegeneration, we conducted a functional screening of mitochondria in neurons exposed to the CSF of multiple sclerosis patients with a relapsing remitting (n = 15) or a progressive (secondary, n = 15 or primary, n = 14) disease course. Live-imaging of CSF-treated neurons, using a fluorescent mitochondrial tracer, identified mitochondrial elongation as a unique effect induced by the CSF from progressive patients. These morphological changes were associated with decreased activity of mitochondrial complexes I, III and IV and correlated with axonal damage. The effect of CSF treatment on the morphology of mitochondria was characterized by phosphorylation of serine 637 on the dynamin-related protein DRP1, a post-translational modification responsible for unopposed mitochondrial fusion in response to low glucose conditions. The effect of neuronal treatment with CSF from progressive patients was heat stable, thereby prompting us to conduct an unbiased exploratory lipidomic study that identified specific ceramide species as differentially abundant in the CSF of progressive patients compared to relapsing remitting multiple sclerosis. Treatment of neurons with medium supplemented with ceramides, induced a time-dependent increase of the transcripts levels of specific glucose and lactate transporters, which functionally resulted in progressively increased glucose uptake from the medium. Thus ceramide levels in the CSF of patients with progressive multiple sclerosis not only impaired mitochondrial respiration but also decreased the bioavailability of glucose by increasing its uptake. Importantly the neurotoxic effect of CSF treatment could be rescued by exogenous supplementation with glucose or lactate, presumably to compensate the inefficient fuel utilization. Together these data suggest a condition of 'virtual hypoglycosis' induced by the CSF of progressive patients in cultured neurons and suggest a critical temporal window of intervention for the rescue of the metabolic impairment of neuronal bioenergetics underlying neurodegeneration in multiple sclerosis patients.

Insulin-responsive autonomic neurons in rat medulla oblongata.

Low blood glucose activates brainstem adrenergic and cholinergic neurons, driving adrenaline secretion from the adrenal medulla and glucagon release from the pancreas. Despite their roles in maintaining glucose homeostasis, the distributions of insulin-responsive adrenergic and cholinergic neurons in the medulla are unknown. We fasted rats overnight and gave them insulin (10 U/kg i.p.) or saline after 2 weeks of handling. Blood samples were collected before injection and before perfusion at 90 min. We immunoperoxidase-stained transverse sections of perfused medulla to show Fos plus either phenylethanolamine N-methyltransferase (PNMT) or choline acetyltransferase (ChAT). Insulin injection lowered blood glucose from 4.9 ± 0.3 mmol/L to 1.7 ± 0.2 mmol/L (mean ± SEM; n = 6); saline injection had no effect. In insulin-treated rats, many PNMT-immunoreactive C1 neurons had Fos-immunoreactive nuclei, with the proportion of activated neurons being highest in the caudal part of the C1 column. In the rostral ventrolateral medulla, 33.3% ± 1.4% (n = 8) of C1 neurons were Fos-positive. Insulin also induced Fos in 47.2% ± 2.0% (n = 5) of dorsal medullary C3 neurons and in some C2 neurons. In the dorsal motor nucleus of the vagus (DMV), insulin evoked Fos in many ChAT-positive neurons. Activated neurons were concentrated in the medial and middle regions of the DMV beneath and just rostral to the area postrema. In control rats, very few C1, C2, or C3 neurons and no DMV neurons were Fos-positive. The high numbers of PNMT-immunoreactive and ChAT-immunoreactive neurons that express Fos after insulin treatment reinforce the importance of these neurons in the central response to a decrease in glucose bioavailability.

Aerobic respiration of mineral-bound organic carbon in a soil

Associations with minerals can potentially augment soil organic carbon (SOC) stability by reducing the bioavailability and degradation of SOC. However, few studies have directly measured aerobic respiration of mineral-bound SOC. In this study, we investigated the microbial aerobic respiration and bioavailability of ferrihydrite-sorbed glucose (Fh-GLU) and ferrihydrite-sorbed formic acid (Fh-FA) by adding 13C-labeled compounds to a soil. During an 11-day incubation, 30.2% of free, non-Fh-sorbed glucose (GLU) and 61.8% of free formic acid (FA) were respired, whereas 4.2% and 27.9% of Fh-GLU and Fh-FA were respired, respectively. Our results demonstrated that Fh-bound GLU/FA had lower bioavailability compared to free organic compounds. Associations with Fh led to greater inhibition in the bioavailability of GLU than that for FA. The priming effects of added compounds on the respiration of native SOC were decreased by their association with Fh. Our results demonstrated that the bioavailability and priming effect of organic compounds depend on their interactions with minerals.

Glucagon-like peptide-2: A potential role in equine insulin dysregulation.

Equine insulin dysregulation (ID) is a common and poorly understood disorder that increases the risk of laminitis. Recent data show that the condition may be associated with alteration of the enteroinsular axis and enhanced glucose bioavailability. Upregulation of glucagon-like peptide-2 (GLP-2), an intestinotrophic peptide, leads to enhanced nutrient uptake and metabolic dysfunction in other species. The study aimed to 1) determine whether GLP-2 is differentially expressed in insulin-dysregulated ponies, compared with healthy ponies, and 2) confirm intestinal expression of the GLP-2 receptor in horses (eGLP-2R). Cohort study. Fasting and post-prandial GLP-2 concentrations were measured in archived plasma samples obtained from 25 mixed-breed ponies during two feeding studies. Measurements were undertaken with an ELISA that was validated for equine use as part of the current study. Ponies were designated as healthy or insulin-dysregulated based on an oral glucose test, and the results were compared between groups. The gene expression of the eGLP-2R was determined with polymerase chain reaction. Basal, fasted plasma GLP-2 concentrations were higher in ponies with ID, compared with healthy ponies. Grazing increased GLP-2 in healthy, but not in insulin-dysregulated, ponies. The eGLP-2R gene was expressed in the small intestine and pancreas. The study was performed with a relatively small sample size. The specificity of the GLP-2 assay could not be determined due to the lack of equine-specific assay standards. This study has demonstrated that GLP-2 may be important in the pathogenesis of equine ID and suggests that the eGLP-2R may be a novel therapeutic target for the treatment of equine ID.

The DEAL trial: A diet and exercise intervention in (pre)-diabetics during treatment for non-muscle invasive bladder cancer.

473 Background: Patients with diabetes are at greater risk for bladder cancer (BC) as well as disease recurrence and progression. Even after controlling for clinical and pathologic risk factors, DM confers a 2x greater risk of recurrence and 9x greater risk of progression. We hypothesize that utilizing a carbohydrate restricted (CR) diet ( < 130 grams/day) to decrease the bioavailability of glucose in patients with DM and BC, a “Warburg-like” tumor, has potential therapeutic benefit. We designed a study to assess the feasibility of a CR diet in patients with (pre)diabetes and non-muscle invasive bladder cancer receiving BCG therapy. Methods: This is a pilot study of 5 (pre)diabetic patients (defined as HgbA1c > 5.7) with NMIBC receiving BCG and maintenance. A CR diet ( < 130 g/day) was supplied for the first 12 weeks through a meal delivery service. Patients received weekly coaching with a nutritionist for 6 weeks during induction BCG and at the 3 month surveillance cystoscopy with dietary and activity goals implemented. Patients had laboratory evaluation at baseline and at 3 month intervals. Patients tracked their diet. Two (1 weekday, 1 weekend day) unannounced 24 hour diet recalls were obtained to monitor compliance. Dietary compliance was defined as < 130 grams/day of carbohydrate intake. Results: Between 09/2016 and 05/2017, 5 patients were enrolled. Mean age was 66.2 years (Range 59-74). Three patients had diabetes and two patients had pre-diabetes. Two patients had CIS, 1 patient had high-grade Ta, and 2 patients had high-grade T1 disease. Mean baseline hemoglobin A1c was 7.6% (Range 5.9-11.8). Mean bodyweight and BMI were 92 kg (Range 66-105) and 28.2 (Range 23.1- 31.3) respectively. Regarding compliance, 4/5 (80%) patients completed dietary logs and weekly labs. Three patients (60%) achieved their goal of < 130 grams carbohydrates/day on 24-hour dietary recall. Average 3-month HbA1c improved from 7.6% to 6.6% (Range 5.6-7.9). Conclusions: Eighty percent of patients completed dietary logs for the first three months of the trial; 60% achieved compliance with the CR diet. These data demonstrate the feasibility of a dietary intervention utilizing CR in patients with high-grade NMIBC undergoing BCG. Clinical trial information: NCT02716623.

Food Stabilizing Antioxidants Increase Nutrient Bioavailability in the in Vitro Model

ABSTRACTObjective: We investigated whether antioxidants may enhance bioavailability of lipids and carbohydrates and therefore increase the risk of obesity development.Methods: We tested how supplementation with antioxidants (0.01% butylated hydroxytoluene [BHT], α-tocopherol, and green tea catechins) of a diet containing butter and wheat bread affects bioavailability of fats and carbohydrates. The absorption of the in vitro digested diet was estimated in the intestinal epithelia model of the Caco-2 cells cultured in Transwell chambers.Results: In the case of the antioxidant-supplemented diets, we observed increased bioavailability of glucose, cholesterol, and lipids, as well as elevated secretion of the main chylomicron protein apoB-48 to the basal compartment. Importantly, we did not detect any rise in the concentrations of lipid peroxidation products (malondialdehyde, MDA) in the control samples prepared without antioxidants.Conclusions: Addition of antioxidants (in particular BHT) to the diet increases bioavailability of lipids and carbohydrates, which consequently may increase the risk of obesity development. The dose of antioxidants is a factor of fundamental importance, particularly for catechins: low doses increase absorption of lipids, whereas high doses exert the opposite effect.

0261 MOOD MEDIATES THE RELATIONSHIP BETWEEN GLUCOSE AND PERFORMANCE DURING SLEEP LOSS

Sleep loss disrupts how the body utilizes glucose, and glucose bioavailability influences attention and cognitive self-control. Recent results from our lab demonstrated that 15 grams of glucose in solution sustained psychomotor vigilance during 40 hours of continuous wakefulness. The time course of this effect, relative performance sustainment for seven hours, went beyond expectations for direct neuronal nutrition. Mood, glucose, and performance are also mechanistically tied in various literatures. Therefore, we tested a mediation model of supplemental glucose on performance during sleep loss via self-reported mood. 20 college students stayed awake for 40 hours. Cognitive performance and mood were quantified while rested, then every three hours across the sleep deprivation period. Participants received 15 grams of glucose solution or an equivalent sucralose placebo at hours 18 and 36. Participant mood and cognitive function were analyzed by group across time using a bootstrapping mediation model. As observed in previous results, participants in the sucralose condition committed an average of 2.83 more lapses than the glucose condition 7 hours post-dose, 22 hours into continuous wakefulness (path C, p < .05). However, sucralose participants also reported 10.17 more subjective fatigue units than glucose participants at the same time point (path A), while their subjective fatigue score predicted their lapse rate (path B). When paths A and B are added to the original path C, the effect disappears (path C’ = .99), indicating a near complete mediation of that effect by subjective fatigue, z = 2.26, p < .05, K2=.40. Strategic glucose supplementation can temporarily sustain performance during total sleep deprivation within certain parameters. Specifically, performance sustainment is achieved via prevention of negative mood development (subjective fatigue). Glucose prevents the development of negative mood, which optimizes conditions for positive motivation. Positive motivation provides a small but measurable boost in performance as quantified by continuous engagement with the psychomotor vigilance task. Additional analyses to understand the magnitude and reach of this effect are underway. This work was completed as part of contract N62645-14-P-2046 under direction of the Naval Medical Research Unit - Dayton.

Radiosynthesis and validation of (±)-[18F]-3-fluoro-2-hydroxypropionate ([18F]-FLac) as a PET tracer of lactate to monitor MCT1-dependent lactate uptake in tumors.

Cancers develop metabolic strategies to cope with their microenvironment often characterized by hypoxia, limited nutrient bioavailability and exposure to anticancer treatments. Among these strategies, the metabolic symbiosis based on the exchange of lactate between hypoxic/glycolytic cancer cells that convert glucose to lactate and oxidative cancer cells that preferentially use lactate as an oxidative fuel optimizes the bioavailability of glucose to hypoxic cancer cells. This metabolic cooperation has been described in various human cancers and can provide resistance to anti-angiogenic therapies. It depends on the expression and activity of monocarboxylate transporters (MCTs) at the cell membrane. MCT4 is the main facilitator of lactate export by glycolytic cancer cells, and MCT1 is adapted for lactate uptake by oxidative cancer cells. While MCT1 inhibitor AZD3965 is currently tested in phase I clinical trials and other inhibitors of lactate metabolism have been developed for anticancer therapy, predicting and monitoring a response to the inhibition of lactate uptake is still an unmet clinical need. Here, we report the synthesis, evaluation and in vivo validation of (±)-[18F]-3-fluoro-2-hydroxypropionate ([18F]-FLac) as a tracer of lactate for positron emission tomography. [18F]-FLac offers the possibility to monitor MCT1-dependent lactate uptake and inhibition in tumors in vivo.

Starch and protein digestive dynamics in low-protein diets supplemented with crystalline amino acids

Digestive dynamics of starch and protein is defined as digestion of starch and protein, absorption of glucose and amino acids from the gut lumen and their transition across enterocytes to enter the portal circulation. Digestive dynamics consider the extent, rate and site of nutrient digestion along the small intestine and the bilateral, post-enteral bioavailability of glucose and amino acids. The underlying premise is that glucose and amino acids should be made available in appropriately balanced quantities at the sites of protein synthesis for efficient protein deposition and growth performance. Previous studies have suggested that feed conversion efficiency may be enhanced by rapidly digestible protein and that crystalline amino acids could be considered sources of ‘rapid protein’. At present, crystalline lysine, methionine and threonine are routinely included in broiler diets; moreover, an increasing array of both essential and non-essential crystalline amino acids is becoming commercially available. Despite unrestricted feed access in commercial chicken-meat production systems during the period of illumination, it appears that the intermittent feed consumption patterns of broiler chickens still provide scope for asynchronies in digestion and absorption of nutrients, which affects broiler performance. A better understanding of the post-enteral, bilateral bioavailability of glucose and amino acids in low-protein diets containing high levels of synthetic amino acids is clearly desirable and this applies equally to the relationship between crystalline and protein-bound amino acids.

Modulation of Postprandial Glucose Bioavailability in a Cohort of Healthy and Pre-Diabetics Subjects during Ramadan Fasting in C&amp;amp;ocirc;te d’Ivoire

Objective: After the Ramadan fasting period, there is an increasing prevalence of diabetes in Cote d’Ivoire, in diabetes care centers. The objective of this study was to assess the consumption of sugary foods during this period and to determine the risks of diabetes in Muslim populations. Methods: Information was collected on the type and amount of sugary foods consumed. Methods for the preparation of these foods have been determined. Intake frequencies and postprandial glycemic responses were studied. The usual statistical methods were used. Results: Between 70% and 85% of the “fasters” consume plenty of these sugary foods during this period, with an average added sugar level varying between 10% and 35% and a daily consumption of between 250 cl and 0.5 l. The added sugar leads to hyperglycemia in both healthy subjects and pre diabetics. Conclusion: Regular consumption of these sugary foods results in significant hyperglycaemia throughout the month of fasting with a significantly higher blood glucose level in pre diabetic subjects. This makes pre diabetics people more at risk of diabetes among Muslim populations during Ramadan fasting.

Equine hyperinsulinemia: investigation of the enteroinsular axis during insulin dysregulation.

Compared with some other species, insulin dysregulation in equids is poorly understood. However, hyperinsulinemia causes laminitis, a significant and often lethal disease affecting the pedal bone/hoof wall attachment site. Until recently, hyperinsulinemia has been considered a counterregulatory response to insulin resistance (IR), but there is growing evidence to support a gastrointestinal etiology. Incretin hormones released from the proximal intestine, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide, augment insulin secretion in several species but require investigation in horses. This study investigated peripheral and gut-derived factors impacting insulin secretion by comparing the response to intravenous (iv) and oral d-glucose. Oral and iv tests were performed in 22 ponies previously shown to be insulin dysregulated, of which only 15 were classified as IR (iv test). In a more detailed study, nine different ponies received four treatments: d-glucose orally, d-glucose iv, oats, and commercial grain mix. Insulin, glucose, and incretin concentrations were measured before and after each treatment. All nine ponies showed similar iv responses, but five were markedly hyperresponsive to oral d-glucose and four were not. Insulin responsiveness to oral d-glucose was strongly associated with blood glucose concentrations and oral glucose bioavailability, presumably driven by glucose absorption/distribution, as there was no difference in glucose clearance rates. Insulin was also positively associated with the active amide of GLP-1 following d-glucose and grain. This study has confirmed a functional enteroinsular axis in ponies that likely contributes to insulin dysregulation that may predispose them to laminitis. Moreover, iv tests for IR are not reliable predictors of the oral response to dietary nonstructural carbohydrate.