Increased Plasma Glucose Concentrations Research Articles

Glucose volume of distribution affects insulin sensitivity measured by intravenous glucose tolerance test.

To determine whether glucose volume of distribution (VdGLUCOSE ) affects the diagnosis of impaired insulin sensitivity (IS) when using an intravenous glucose tolerance test (IVGTT). Individuals with distinct levels of IS underwent IVGTT after an overnight fast. The prediabetic group (Prediab; n = 33) differed from the healthy group (Healthy; n = 14) in their larger glycosylated hemoglobin (HbA1c of 5.9 ± 0.3 vs. 5.4 ± 0.1%; 41 ± 4 vs. 36 ± 1 mmol/mol; p < 0.001), percent body fat (37 ± 6 vs. 24 ± 3%; p < 0.001) and cardiovascular fitness level (VO2MAX 22 ± 5 vs. 44 ± 5 mL of O2 ·kg-1 ·min-1 ; p < 0.001). Ten minutes after intravenous infusion of the glucose bolus (i.e., 35 g in a 30% solution), VdGLUCOSE was assessed from the increases in plasma glucose concentration. IS was calculated during the next 50 min using the slope of glucose disappearance and the insulin time-response curve. VdGLUCOSE was higher in Healthy than in Prediab (230 ± 49 vs. 185 ± 21 mL·kg-1 ; p < 0.001). VdGLUCOSE was a strong predictor of IS (β standardized coefficient 0.362; p = 0.004). VO2MAX was associated with VdGLUCOSE and IS (Pearson r = 0.582 and 0.704, respectively; p < 0.001). However, body fat was inversely associated with VdGLUCOSE and IS (r = -0.548 and -0.555, respectively; p < 0.001). Since fat mass is inversely related to VdGLUCOSE and in turn, VdGLUCOSE affects the calculations of IS, the IV glucose bolus dose should be calculated based on fat-free mass rather than body weight for a more accurate diagnosis of impaired IS.

Supplementation of an organic mineral source modulated metabolic profile, insulin sensitivity, and oxidative stress in dairy calves with different birth body weights

The present study was conducted to investigate the effects of partial replacement of inorganic minerals (IM) with advanced chelated minerals (ACMS) in the starter diets of calves of different birth body weights (BBW) on metabolic indices and glucose tolerance test. Fifty-two Holstein calves were assigned to one of 4 treatments in a 2 × 2 factorial arrangement with two mineral sources (IM or ACMS) and two BBW (low or normal birth weight; LBW or NBW). Calves were weaned on day 56 and remained in the study until day 71 of the study. Blood samples for blood metabolite analysis were collected from the jugular vein on days 30, 60, and 70 of the study, and for hematology on days 36, 56, and 70. The results showed that the interaction of starter mineral sources (MS) and BBW affected the overall plasma concentration of β-hydroxybutyrate (BHB), with the highest value being obtained during treatment with LBW-ACMS. In addition, an interaction between MS and BBW was observed in plasma insulin concentrations, with LBW-IM calves having the lowest concentrations compared to the other treatments. Plasma albumin concentrations were lower in LBW calves than in NBW calves. In addition, NBW calves had greater plasma concentrations of glucose (day 60), insulin (day 30), BHB (day 30), and malondialdehyde (MDA; day 60 and the overall period) than LBW calves, while total antioxidant capacity (TAC) tended to reverse at day 70. The ACMS starter increased plasma glucose concentration at day 30 and tended to increase plasma BHB concentration in the overall period. In addition, plasma MDA concentrations were lower in calves receiving ACMS than in calves receiving IM during the overall period. NBW calves tended to have more eosinophils (day 70), basophils (day 36), and erythrocytes (RBC, day 56, and the overall period) in plasma than LBW calves. Regardless of BBW, feeding ACMS starter increased white blood cells (WBC), neutrophils, and eosinophils at day 70 and also tended to increase neutrophils during the overall period compared with the IM groups. Red blood cell concentrations were greater in calves fed ACMS than in calves fed IM during the overall period. Glucose tolerance test showed that basal glucose concentration and clearance rate (CR) of glucose tended to be lower and higher, respectively, in calves fed ACMS than in calves fed IM. ACMS supplementation increased basal concentrations and also tended to increase maximum insulin concentrations compared with IM supplementation. In addition, calves receiving ACMS starter had greater plasma insulin area under the curve (AUC) and CR compared with calves receiving IM. Feeding ACMS tended to increase the ratio CR of insulin to CR of glucose and increased the AUC of insulin to AUC of glucose compared with feeding IM. Overall, feeding ACMS resulted in a decrease in plasma MDA concentration and an increase in neutrophil concentration, suggesting that ACMS may improve immune function in these calves. A potential insulinotropic effect was noted with ACMS feeding, which was accompanied by an improvement in glucose control rate. This is likely due to higher bioavailability of chelated minerals such as Zn and should be further investigated.

211-OR: Plasma Insulin Is Required for the Increase in Plasma ANGPTL8 Concentration following Glucose Ingestion

Aim: ANGPTL8 plays an important role in regulating lipoprotein lipase activity. Its plasma level is increased following nutrient ingestion. Its not well characterized whether insulin or glucose drive the increased ANGPTL8 after food uptake. To address this, we examined the dynamic relationship between plasma insulin level, ANGPTL8 concentration and glucose following glucose ingestion. Methods: 30 healthy subjects with impaired fasting glucose (IFG) (n=14) and normal glucose tolerance (NGT) (n=16) received 75-glucose OGTT, multistep euglycemic hyperinsulinemic clamp and pancreatic clamp. ANGPTL8 level was measured during the fasting state, OGTT and the clamp studies. Results: Subjects with IFG had significantly higher ANGPTL8 during the fasting state (80±5.6 pmol/L VS 68±4.9 pmol/L respectively, p&amp;lt;0.05) . During the OGTT, plasma ANGPTL8 level increased by 62% above the fasting level (from 81±8 pmol/L to 131±pmol/L, p&amp;lt;0.0001) . During the insulin clamp, insulin infusion caused a dose-dependent increase in ANGPTL8 level (figure 1) . Conversely, during the pancreatic clamp and in the absence of an increase in plasma insulin, the increase in plasma glucose concentration failed to cause a significant increase in plasma ANGPTL8 concentration. Conclusion: The increased ANGPTL8 expression in circulation after glucose ingestion was driven by increased insulin and not glucose. Disclosure M.Abu-farha: None. R.A.Defronzo: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Intarcia Therapeutics, Inc., Novo Nordisk, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Merck &amp; Co., Inc., Speaker's Bureau; AstraZeneca. M.Abdul-ghani: None. J.Abubaker: None. I.Al khairi: None. P.T.Cherian: None. C.Agyin: None. S.Abdelgani: None. E.S.Alozairi: None. J.M.Adams: None. F.Almulla: None. Funding Kuwait Foundation for the Advancement of Sciences

195-OR: A Novel 13C5 Glutamine Tracer Method (Q Flux) Reveals a Key Role of Succinyl CoA Anaplerosis in Promoting Increased Rates of Hepatic Gluconeogenesis during Hyperglucagonemia

Hyperglucagonemia is a hallmark of type 2 diabetes mellitus (T2DM) and contributes to increased rates of endogenous glucose production (EGP) , mostly through increased rates of hepatic gluconeogenesis (GNG) , but the anaplerotic pathways and respective substrates that support this process are unclear. To address this question, we developed a novel and extensively validated 13C5 glutamine-based in vivo metabolic flux analysis method (Q Flux) , which allows for quantitation of both the relative and absolute rates of hepatic gluconeogenesis from pyruvate (via pyruvate carboxylase [PC]) , succinyl CoA (via methylmalonyl CoA mutase [MUT]) , glutamine (via glutaminase [GLS2]) , and glycerol. Male Sprague-Dawley rats (∼300 g) were infused for 90 minutes with either low-dose (LD) glucagon (1.25 ng/[kg-min]) or high-dose (HD) glucagon (ng/[kg-min]) , plus insulin (0.5 mU/[kg-min]) , somatostatin (4 μg/[kg-min]) , and 13C5 glutamine (3 μmol/[kg-min]) after a 16-hour fast to deplete hepatic glycogen. HD animals displayed significantly increased plasma glucose concentrations and EGP relative to LD controls. Analyses of liver tissues collected at sacrifice revealed that in LD animals, 70% of mitochondrial GNG was from pyruvate, 15% from succinyl CoA, and 15% from glutamine. In HD animals, 59% of mitochondrial GNG was derived from pyruvate (p=0.vs. LD) , 26% from succinyl CoA (p=0.0vs. LD) , and 15% from glutamine (p=0.99 vs. LD) . Conclusion: We find an unexpected role for succinyl CoA anaplerosis and methylmalonyl CoA mutase flux in supporting increased rates of mitochondrial GNG during hyperglucagonemia. Furthermore, relative contributions of glutamine to hepatic gluconeogenesis were unchanged, contrary to previous reports. Taken together, these results identify novel targets to reduce hyperglucagonemia-induced increases in rates of gluconeogenesis and hyperglycemia in T2DM. Disclosure B.T.Hubbard: None. G.I.Shulman: Advisory Panel; 89bio, Inc., AstraZeneca, Equator Therapeutics, Inc., Janssen Research &amp; Development, LLC, Merck &amp; Co., Inc., Consultant; DiCerna Pharmaceuticals, Inc. , Novo Nordisk, Other Relationship; Generian Pharmaceuticals, iMetabolic Biopharma Corporation, Maze Therapeutics, The Liver Company, Stock/Shareholder; Levels Health, Inc. .

Effects of feeding 25-hydroxyvitamin D3 with an acidogenic diet during the prepartum period in dairy cows: Mineral metabolism, energy balance, and lactation performance of Holstein dairy cows

Our objective was to determine the effects of feeding 25-hydroxyvitamin D3 [25(OH)D3], or vitamin D3 (cholecalciferol) on plasma, mineral, and metabolite concentrations, mineral balance, mineral excretion, rumination, energy balance, and milk production of dairy cows. We hypothesized that supplementing 3 mg/d of 25(OH)D3 during the prepartum period would be more effective than supplementing vitamin D3 at the National Research Council (2001) levels to minimize calcium imbalance during the transition period and improve milk production of dairy cows. Forty multiparous, pregnant nonlactating-Holstein cows were enrolled in this study. Body weight, body condition score, parity, and milk yield in the previous lactation (mean ± standard deviation) were 661 ± 59.2, 3.46 ± 0.35, 1.79 ± 0.87, and 33.2 ± 6.43 kg/d, respectively. Cows were enrolled into the blocks (n = 20 for each treatment) at 30 d of the expected day of calving to receive an acidogenic diet (373 g/kg of neutral detergent fiber and 136 g/kg of crude protein, dry matter basis; -110 mEq/kg) associated with the treatments: (1) control (CTRL), vitamin D3 at 0.625 mg/d (equivalent to 25,000 IU of vitamin D3/d) or (2) 25(OH)D3 at 3 mg/d (equivalent to 120,000 IU of vitamin D3/d). All cows were fed with the base ration for 49 d after calving. Blood samples were taken on d 7, 0, 1, 2, 21, and 42, relative to calving. No effect of treatment was observed for prepartum dry matter intake or body condition score. A trend for increase of ionized Ca was observed for the cows fed 25(OH)D3, compared with the CTRL, but no effect of treatment was detected for total Ca or total P. Feeding 25(OH)D3 increased colostrum yield. The plasmatic concentration of 25-hydroxyvitamin D3 was increased with 25(OH)D3 supplementation. 25-Hydroxyvitamin D3 supplementation increased plasma glucose concentration at parturition. The postpartum dry matter intake was not influenced by treatments. Feeding 25(OH)D3 increases milk yield, 3.5% fat-corrected milk, and energy-corrected milk and improves milk yield components in early lactation. Overall, these findings suggest that 25(OH)D3 at 3 mg/d can improve the energy metabolism and lactation performance, compared with the current-feeding practice of supplementing vitamin D3 at 0.625 mg/d.

Effect of milk replacer feeding rate and frequency of preweaning dairy calves in the southeastern United States: Glucose metabolism

The objective of this experiment was to examine the effect of milk replacer (MR) feeding rate (FR) and frequency (FF) on glucose metabolism before and after weaning during summer and winter in the subtropical climate of the southeastern United States. Holstein calves (n = 48/season) were enrolled at 8 d of age (DOA) in the summer (June to August, body weight = 40.6 ± 0.7 kg) and winter (November to January, body weight = 41.9 ± 0.8 kg). In each season, calves were randomly assigned to 1 of 4 treatments in a 2 × 2 factorial arrangement including 2 FR [0.65 (low) or 0.76 kg of solids/d (high) of a 26% CP and 17% fat MR] and 2 FF [2× (0700 and 1600 h) or 3× (0700, 1600, and 2200 h)]. Calves were managed similarly and housed in polyethylene hutches bedded with sand. Milk replacer (12.5%) was fed based on treatments until 42 DOA when FR was reduced by half and offered 1×/d (0700 h) for 7 d. Plasma was collected weekly at 1400 h for analyses of glucose and insulin concentrations in all calves. Pre- and postprandial glucose and insulin concentrations of a subset of calves (n = 10/treatment per season) were measured on 20 DOA. A subset of calves (n = 8/treatment per season) was subjected to an intravenous glucose tolerance test (GTT) on 27 and 57 DOA and insulin challenge on 28 and 58 DOA at 1030 h. Average ambient temperature was 26.1 ± 2.2°C in summer and 12.9 ± 5.4°C in winter. During the preweaning period in both seasons, feeding high increased plasma glucose concentrations compared with low, and increasing FF reduced basal insulin concentrations. Compared with 2×, feeding 3× did not affect postprandial glucose but lowered insulin in the summer, whereas in the winter, increased glucose from 30 to 180 min but lowered insulin from 240 to 420 min after MR feeding. Following GTT before weaning in both seasons, 3× reduced insulin increment and area under the curve compared with 2× without affecting glucose disposal. After weaning, treatment did not affect glucose disposal or insulin responses after GTT during winter, but calves fed 3× had faster glucose disposal and stronger insulin responses than 2× during summer. In both summer and winter, preweaned calves fed 3× had greater decrement and area under the curve of plasma glucose after insulin challenge, suggesting enhanced peripheral tissue insulin response compared with 2×. This effect persisted after weaning only during summer. Increasing FR had no effect on metabolic responses in both seasons. In conclusion, increasing MR FF from 2 to 3 times per day reduced insulin secretion but enhanced insulin response on peripheral tissues of preweaned calves regardless of season.

146 Nutritional Advances in Fetal and neonatal development: effect of fatty acid supplementation

Abstract Data from a series of experiments demonstrates that maternal supply of polyunsaturated fatty acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), during late gestation affects offspring growth. The increase in growth is independent on the fatty acid supplemented during the growing or finishing phase of the offspring; but it is sex dependent. Dam PUFA supplementation increases wether growth. Supplementation with EPA and DHA to pregnant ewes and to their offspring after weaning showed a treatment interaction in mRNA concentration of hypothalamic neuropeptides associated with dry matter intake (DMI) regulation. A dose increased in EPA and DHA in pregnant ewe diets shows a linear increase in growth, but a quadratic change in DMI or feed efficiency; growth was associated with a linear increase in plasma glucose concentration and a linear decrease in plasma ghrelin concentration. In lambs born from ewes supplemented with different sources of FA during a glucose tolerance test; males’ plasma insulin concentration increased as FA unsaturation degree increased in the dam diet, the opposite happened with females’ plasma insulin concentration. Recent data from our lab showed that the supplementation with EPA and DHA during the last third of gestation to pregnant ewes increased liver and small intestine global DNA methylation and small intestine transporters for amino acids in the fetus. Despite EPA and DHA during late gestation increase growth in the offspring; when EPA and DHA were supplemented in early gestation, offspring growth was lesser that lambs born from ewes supplemented a saturated and monounsaturated lipid. The reason for the difference in results it is not clear. However, more studies focusing in some aspect of the biology will help to understand what specific fatty acid needs to be supplemented at different stages of gestation to improve offspring growth.

A four-week high fat diet does not alter plasma glucose or metabolic physiology in wild-caught mourning doves (Zenaida macroura)

The aim of this study was to determine the metabolic effects of a four-week 60% high-fat (HF) diet on mourning doves. Plasma glucose concentrations are, on average, 1.5–2 times higher in birds than in mammals of similar body mass, but birds have innate mechanisms that protect them from high blood glucose-associated pathologies normally developed in mammals. Elucidating these mechanisms may help develop therapeutics for treatment of human diabetes-related complications. A high fat (HF) diet is commonly used in rodents to investigate metabolic disease. We hypothesized that this diet in doves would elevate plasma glucose and alter metabolic physiology compared to the control (CON) diet. Following the four-week long diets, doves were euthanized, and we collected blood, liver, pectoralis muscles, and kidney samples. Contrary to the rodent-models, HF-fed birds did not have increased plasma glucose concentrations relative to CON-fed birds. Metabolomic analyses revealed no group differences in plasma, liver, pectoralis muscle, or kidney metabolites (FDR q-value>0.05 for all). Principal component analysis score plots of metabolites showed no separation between groups, and pathway analyses revealed no significantly altered metabolic pathways between groups (191 pathways across tissues, FDR q-value>0.05). Body mass, plasma uric acid, glucose, and insulin as well as liver and pectoralis muscle glycogen and triglycerides did not differ between groups (p > 0.05 for all). In conclusion, a four-week long high fat diet did not alter plasma glucose concentrations or metabolic physiology in mourning doves, indicating that these birds have mechanisms that allow them to avoid high fat diet-induced pathologies seen in mammals.

The effect of candesartan on chronic stress induced imbalance of glucose homeostasis

ObjectiveTo explore whether chronic stress induces imbalance of glucose homeostasis, and to investigate the possible involvement of the renin-angiotensin system (RAS). MethodsMale Sprague-Dawley rats were divided into four groups: control, chronic stress, chronic stress plus low dose candesartan (an angiotensin II receptor-1 blocker, ARB, 5 mg/kg/d, i.p.), chronic stress plus high dose candesartan (15 mg/kg/d, i.p.). Rats were received restraint stress for 14 days. Glucose transporter 2 (GLUT2) mRNA was quantified in liver by real-time polymerase chain reaction. The concentration of glucokinase (GK), glucose-6-phosphatase (G-6-P), glycogen synthase (GS), insulin receptor (ISR), glucocorticoid receptor (GR)-alpha and -beta in liver, hexokinase (HK), lactate dehydrogenase (LDH) and succinate dehydrogenase (SDH) in muscle, and serum insulin were measured by ELISA. Body weights, systolic blood pressure, heart rate and fasting blood glucose were monitored. Glucose tolerance test were performed after 14 days restraint stress. ResultsAfter 14 days restraint stress, systolic blood pressure, increase of plasma glucose concentration at 15 minutes were higher and the fasting plasma concentration of glucose was lower compared with control group (P < 0.05), which were reversed by high dose ARB treatment (P < 0.05). In addition, chronic stress decreased expression of GLUT2 and increased expression of GR beta in liver. High dose ARB treatment normalized GLUT2 and GR beta expressions in liver. ConclusionsOur present data indicate chronic stress induces the imbalance of glucose homeostasis and RAS contributes to the imbalance of glucose homeostasis induced by chronic stress.

A four-week white bread diet does not alter plasma glucose concentrations, metabolic or vascular physiology in mourning doves, Zenaida macroura

Birds are an enigma: their plasma glucose concentration is 1.5–2 times higher than similar-sized mammals, yet they do not normally exhibit symptoms of diabetes. We hypothesized that feeding adult mourning doves a refined carbohydrate diet (white bread: WB) for four weeks would raise plasma glucose concentrations and alter metabolic pathways and endothelial function when compared to birds receiving a nutritionally-balanced diet (bird seeds: SD). Following the four-week long diets, birds were euthanized, and cardiac blood, liver, and pectoralis muscles were collected for metabolomics analyses and biochemical assays. Cranial tibial arteries were dissected to measure acetylcholine-mediated vasodilation. Contrary to the hypothesis, WB-fed birds did not have increased plasma glucose concentrations. Principle component analysis score plots suggest minimal differences between groups. However, we identified 15 changes in individual metabolite concentrations between diet groups that, although not statistically significant, are highly predictive (area under receive operating curve, AUROC>0.90; number of highly predictive metabolites: 5 of 123 in plasma, 4 of 92 in liver, and 6 of 92 in pectoralis muscle). Moreover, pathway analyses revealed no significantly altered metabolic pathways between groups. Biochemical assays revealed no significant group differences in plasma uric acid and insulin, or pectoralis muscle glycogen concentrations. However, hepatic glycogen concentration was 2.12-fold higher in the WB group than in control doves (p = .015). Diet type did not influence vasodilation. In conclusion, a four-week long white bread diet increased liver glycogen but did not alter plasma glucose concentrations, metabolic or vascular physiology in mourning doves.

Milk yield and composition from ewes fed diets containing narasin and their lambs' performance.

The changes promoted by feed additives in ruminal fermentation, especially increasing the availability of propionate, can improve the energy balance of an animal, which is of great importance in the lactation period. This trial aimed to evaluate the inclusion of narasin in the diet of lactating ewes on milk yield, composition, dry matter intake (DMI), and plasma metabolites of the ewes and growth rate of lambs. Thirty-two lactating ewes (59.0 ± 2.42 kg) were assigned to a randomized complete block design. The experimental diets contained 500 g/kg of dry matter (DM) of coast cross (Cynodon dactylon (L.) Pers) hay and 500 g/kg DM of concentrate, and the treatments were: N0—no narasin inclusion; N13—inclusion of 13 mg of narasin/kg DM. Once a week, from week 2 to 10 of lactation, ewes were separated from their lambs, injected with oxytocin, and milked mechanically to empty the udder. After 3 h, the milk production was recorded, using the same procedure, and sampled to evaluate the composition. The blood samples were taken weekly, 4 h after feeding. The average daily gain (ADG) and starter DMI of the lambs were evaluated weekly from week 2 to 12 of age. The inclusion of narasin did not affect (P = 0.93) DMI of ewes; however, it increased milk production (P < 0.01) and feed efficiency (P = 0.02; FE). Ewes fed N13 had a greater milk fat (P < 0.01), protein (P < 0.01), lactose (P = 0.04), and total solids production (P < 0.01). Narasin inclusion in ewe’s diet increased plasma glucose concentration (P = 0.05) at weeks 8, 9 and 10; however, there was no effect on plasma urea concentration (P = 0.96). The lambs of N0 ewes had a greater starter DMI (P < 0.01) at weeks 7, 8, 9, and 10; however, the ADG and body weight at weaning and after weaning were similar between treatments (P > 0.05). The results showed that the inclusion of 13 mg of narasin/kg DM improved the milk production and FE of the ewes without altering the composition of the milk. The lower initial consumption of concentrate by N13 lambs before weaning was caused by the higher production of milk. The results obtained in the present study demonstrate the possible productive gain with the inclusion of narasin in diets for lactating ewes.

Hyperlipidimia, Hyperleptinemia and Insulin Resistance Intercorrelation with Obesity

The present study has shown a parallel increase of triacylglycerol, cholesterol, and low density lipoprotein (LDL) along with an increase in body mass and BMI of human obese subjects. Conversely a fall in HDL concentration was observed. Plasma leptin level increased proportionately with increase of body weight as obesity advanced from obese to morbid type. A positive correlation was observed between leptin and insulin concentrations in obese subjects. A parallel increase of plasma glucose concentration was followed with decreased expression of insulin receptor, measured in adipose tissue, with the progress of obesity. The decreased insulin receptor concentration might be the reason for seen insulin resistance and increased insulin level which marked the positive correlation with associated liptin level in obese subjects.

Growth performance, blood parameters and metabolic-enzyme gene expression of finishing pigs as affected by dietary level of methionine + cystine supplemented with vitamin B6

Context Methionine (Met) is an essential amino acid in pig diets. However, high blood homocysteine concentration, a risk factor for cardiovascular disease, can arise from high dietary Met intake and may indicate an imbalance in the Met cycle. Vitamin B6 acts as a cofactor for enzymes associated with the trans-sulfuration pathway, considered the major elimination route of excess homocysteine. Aims We evaluated the effects of different levels of dietary Met and vitamin B6 supplementation and their interaction with respect to growth performance, blood parameters and metabolic-enzyme gene expression of finishing pigs. Methods Fifty-six crossbred barrows, averaging 75.11 ± 1.84 kg bodyweight (BW), were assigned in a completely randomised block design arranged in a 2 × 4 factorial with two levels of vitamin B6 supplementation (1.58 and 3.58 mg/kg) and four levels of standardised ileal digestible (SID) Met + cystine (Cys) (0.35%, 0.45%, 0.55 and 0.65%), with seven replicates and one animal per pen, for an average duration of 26 days. BW of each pig and quantity of experimental diets on-offer and consumed were recorded at the beginning and end of the experiment. Plasma concentrations of glucose, urea, total proteins, creatinine and triacylglycerol were determined by the colourimetric method, and serum homocysteine by chemiluminescence. Gene expression was measured by quantitative real-time polymerase chain reaction. Key results No interactions (P > 0.05) between vitamin B6 supplementation and SID Met + Cys levels were observed for growth performance, blood parameters or metabolic-enzyme gene expression. Higher vitamin B6 supplementation (3.58 mg/kg) improved (P = 0.05) the feed : growth ratio. Treatments did not affect (P > 0.05) expression of the enzymes methionine synthase or cystathionine γ-lyase, and there was a linear increase (P = 0.01) in serum homocysteine levels with increasing dietary Met + Cys. Increasing vitamin B6 supplementation (3.58 mg/kg) in finishing pig diets increased plasma glucose concentration (P = 0.05), but did not mitigate the increase in homocysteine concentration. Conclusions Overall, a dietary SID Met + Cys intake of 10.46 g/day (corresponding to 0.35%) was sufficient for the growth of finishing barrows from 75 to 100 kg BW. Vitamin B6 supplementation at 3.58 mg/kg improved the feed : growth ratio but was not effective for metabolising the increasing homocysteine concentration via the trans-sulfuration pathway. Implications This study provides much needed empirical data on the dietary SID Met + Cys requirements for finishing pigs, and the metabolism of these amino acids.

The influence of exogenous phytase on the post-enteral availability of amino acids in broiler chickens offered wheat-based diets

To investigate the influence of exogenous phytase inclusions in poultry diets on the post-enteral availability of amino acids, wheat-soybean meal diets containing 0, 500, 1000 and 2000 phytase units (FTU)/kg were offered to eight replicate cages (six birds per cage) or a total of 192 male Ross 308 chicks from 7 to 28 days post-hatch. The parameters determined included growth performance, nutrient utilisation, bone mineralization, parameters of gizzard functionality, apparent ileal digestibility coefficients and disappearance rates (g/bird/day) of amino acids, plus concentrations of amino acids, glucose and ammonia in plasma from the portal circulation (anterior mesenteric vein). The inclusion of 500 FTU/kg significantly improved weight gain by 8.39% (1485 versus 1370 g/bird) and feed conversion ratio (FCR) by 5.10% (1.397 versus 1.472 g/g) in comparison to the control. Phytase inclusions significantly increased gizzard pH but not toe ash. The 2000 FTU/kg phytase inclusion significantly increased digestibility of 15 from 16 amino acids by an average of 5.29% (0.716 versus 0.680) and significantly increased apparent metabolisable energy (AME) by 0.45 MJ (12.43 versus 12.88 MJ) and N-corrected AME (AMEn) by 0.45 MJ (11.43 versus 11.88 MJ) relative to the control. The 500 FTU/kg phytase inclusion significantly increased free concentrations of seven amino acids (isoleucine, leucine, lysine, phenylalanine, tryptophan, valine and serine) in plasma from the anterior mesenteric vein based on pairwise comparisons and numerically increased concentrations of a further six amino acids. Phytase inclusions linearly reduced concentrations of glutamic acid and glutamine in the portal circulation, and there was a logarithmic relationship between phytase inclusions and increased plasma glucose concentrations. Reductions in the ratio of glutamate plus glutamine to glucose concentrations in portal plasma were significantly related to improvements in FCR. The outcomes of this study indicate that phytase can positively influence the post-enteral availability of amino acids. The inference is that phytase is manipulating the metabolic fates of amino acids and glucose in the gut mucosa and consideration is given to the possible responsible mechanisms for the observed outcomes.

Physiological responses to central and peripheral injections of compound 48/80 and histamine in chicks

Mast cells are a type of immune cell widely distributed in the body of vertebrates. Mast cells have many granules that contain several bioactive molecules such as histamine, and these molecules are released through degranulation when the mast cell receives certain stimuli. Because the number of mast cells increases during infection in chickens (Gallus gallus), the activity of mast cells might be related to non-specific symptoms such as anorexia under an infectious condition. Therefore, the purpose of the present study was to investigate whether intraperitoneal (IP) and intracerebroventricular (ICV) injections of compound 48/80, which induces degranulation of mast cells, affects feeding, voluntary activity, cloacal temperature, and the concentrations of plasma corticosterone (CORT) and glucose in chicks. The effect of histamine, which is found in mast cell granules, on these parameters was also investigated. IP injection of compound 48/80 significantly decreased food intake, voluntary activity, and cloacal temperature, and increased plasma CORT concentration in the chicks. While ICV injection of compound 48/80 also decreased food intake, it increased cloacal temperature and plasma glucose concentration. Both IP and ICV injections of histamine significantly decreased food intake, cloacal temperature, and plasma CORT concentration. However, only IP injection of histamine significantly decreased voluntary activity and increased plasma glucose concentration. The results suggest that degranulation of mast cells is related to non-specific symptoms in chicks, although the mechanism seems to be different between peripheral and central tissues. In addition, the effect of peripherally-injected compound 48/80 may be partly mediated by histamine.

Mild Physiologic Hyperglycemia Induces Hepatic Insulin Resistance in Healthy Normal Glucose-Tolerant Participants.

Chronic hyperglycemia worsens skeletal muscle insulin resistance and β-cell function. However, the effect of sustained physiologic hyperglycemia on hepatic insulin sensitivity is not clear. To examine the effect of sustained physiologic hyperglycemia (similar to that observed in patients with type 2 diabetes) on endogenous (primarily reflecting hepatic) glucose production (EGP) in healthy individuals. Volunteers participated in a three-step hyperinsulinemic (10, 20, 40 mU/m2 per minute) euglycemic clamp before and after a 48-hour glucose infusion to increase plasma glucose concentration by ∼40 mg/dL above baseline. EGP was measured with 3-3H-glucose before and after chronic glucose infusion. Sixteen persons with normal glucose tolerance [eight with and eight without a family history (FH) of diabetes] participated in the study. EGP. Basal EGP increased following 48 hours of glucose infusion (from a mean ± SEM of 2.04 ± 0.08 to 3.06 ± 0.29 mg/kgffm⋅ min; P < 0.005). The hepatic insulin resistance index (basal EGP × fasting plasma insulin) markedly increased following glucose infusion (20.1 ± 1.8 to 51.7 ± 6.6; P < 0.005) in both FH+ and FH- subjects. Sustained physiologic hyperglycemia for as little as 48 hours increased the rate of basal hepatic glucose production and induced hepatic insulin resistance in health persons with normal glucose tolerance, providing evidence for the role of glucotoxicity in the increase in hepatic glucose production in type 2 diabetes.

Cardiac autonomic modulation in response to a glucose stimulus.

This paper focuses on the effect of a sudden increase of plasma glucose concentration in the cardiac autonomic modulation using time-domain and frequency-domain heart rate variability (HRV) measures. Plasma glucose and insulin levels, measured each 30 min during an oral glucose tolerance test, and [Formula: see text] (mean of the RR interval), SDNN (standard deviation of normal-to-normal heartbeats), rMSSD (root-mean-square of successive differences between normal heartbeats), TP (total spectral power), LF and HF (power of the low- and high-frequency bands), LF norm and HF norm (LF and HF in normalized units), and LF/HF ratio of the HRV signal, obtained from 5-min-long ECG recordings during each phase of the test, were analyzed for subjects with the metabolic syndrome, marathon runners, and a control group. Results show that, after the glucose load, subjects with the metabolic syndrome experienced an increased sympathetic and decreased parasympathetic tone, which suggests an imbalance in cardiac autonomic modulation as a consequence of hyperglycemia and hyperinsulinemia. The significance of this study lies in the use of the ECG to assess the effects of a sudden increase in plasma glucose concentration on the cardiac autonomic modulation in subjects with different cardiovascular and metabolic conditions. Graphical Abstract Time-domain and frequency-domain heart rate variability measures are altered in subjects with different cardiovascular and metabolic conditions during an oral glucose tolerance test.

Mild Physiologic Hyperglycemia Induces Hepatic Insulin Resistance in Healthy Normal Glucose Tolerant Subjects–Role of Glucagon and Gluconeogenic Substrates

The aim of the present study was to evaluate the effect of a physiologic increase in plasma glucose concentration on endogenous glucose production (EGP) in healthy NGT individuals. 16 NGT subjects [8 with and 8 without family history of T2DM (9M/7F, age = 44± 3 years, BMI = 26 ± 1 kg/m2)] participated in a 3-step hyperinsulinemic (10, 20, 40 mU/m2 min) euglycemic clamp before and after a 48 hour glucose infusion to increase plasma glucose conc by ∼45 mg/dl above baseline (89±4 to 136±4.9 mg/dl). EGP was measured with [3-3H] glucose and gluconeogenic rate was measured following administration of deuterated water. Plasma FFA, glucagon, lactate, glycerol and alanine concentrations also were measured. Following 48 hours of glucose infusion basal EGP increased from 2.05±0.09 to 3.06±0. mg/kg min (p=0.003) and hepatic insulin resistance index (EGP X Fasting Plasma Insulin) increased markedly and similarly (25.1±1.0 vs. 48.3± 3.2, p&amp;lt;0.005). The baseline plasma glucagon concentration tended to be higher following 48 hours of glucose infusion (64±3 vs. 77± 8 pg/ml, p=0.2) while the product of the plasma glucagon and insulin concentrations was markedly increased (540 ± 56 vs. 1336 ± 262, p=0.004). Although the baseline plasma FFA concentration was markedly reduced following 48 hours of glucose infusion (0.482 ±0.to 0.055± 0.01mM), there was no difference in plasma glycerol concentration (13.4±1.2 vs. 13.3 ± 2.2 mg/L p=ns). There were small increases in both the plasma lactate and alanine concentrations. Total body insulin sensitivity declined from 8.75±2.1 to 6.92± 6 mg.kg/min (p&amp;lt;0.05). Conclusion: Chronic (48 hr) physiologic hyperglycemia to levels seen in T2DM increases basal hepatic glucose production and induces hepatic and skeletal muscle insulin resistance in healthy NGT subjects. These results demonstrate, for the first time that glucotoxicity causes resistance to the suppressive effect of insulin on hepatic glucose production. Disclosure D. Tripathy: None. A. Merovci: None. E.R. Maldonado Corchado: None. R. Basu: Research Support; Self; AstraZeneca. R.A. DeFronzo: Speaker-s Bureau; Self; AstraZeneca, Novo Nordisk Inc.. Advisory Panel; Self; AstraZeneca, Novo Nordisk Inc., Janssen Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc.. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Takeda Pharmaceuticals U.S.A., Inc..

Decline in the acute insulin response in relationship to plasma glucose concentrations.

To investigate (1) whether the decline in acute insulin response (AIR) precedes or coincides with defined glucose regulation categories and whether acute insulin response decline varies by race and adiposity, (2) linearity of the relationship between acute insulin response and increasing plasma glucose concentrations, (3) longitudinal changes in acute insulin response accounting for changes in insulin action across categories of glucose tolerance. Clinical cross-sectional and longitudinal study of nondiabetic subjects. Inpatient assessment of oral glucose tolerance (2-h PG, fasting PG), and acute insulin response (intravenous glucose tolerance test) in 326 and 84 Native Americans of full and ≤6/8th Southwestern heritage, respectively, and 115 Whites. Linearity of acute insulin response vs plasma glucose concentrations investigated using spline analyses. Follow-up (average=2.07years) glucose tolerance, acute insulin response, and insulin action (hyperinsulinemic-euglycemic clamp) assessed in 230 full Native Americans. In certain groups, the relationship between acute insulin response and increasing plasma glucose levels was non-linear. In all groups, acute insulin response decline preceded the cut-offs for traditional glucose regulation categories, although the timing with respect to increasing plasma glucose varied by race and adiposity. Longitudinal data indicated that improvement in insulin action is the key factor to preserve insulin secretion, underlying the reversion of glucose tolerance in prediabetic individuals. With worsening insulin action, the decline in insulin secretion occurred prior to current diagnostic guidelines for impaired glucose regulation. However, the relationship between acute insulin response and increasing plasma glucose varies and was not always non-linear. Understanding the dynamics of this relationship may determine when to initiate preventive pharmacotherapy directed at the preservation of β-cell failure.

Contaminants of emerging concern in tributaries to the Laurentian Great Lakes: II. Biological consequences of exposure.

The Laurentian Great Lakes contain one fifth of the world’s surface freshwater and have been impacted by human activity since the Industrial Revolution. In addition to legacy contaminants, nitrification and invasive species, this aquatic ecosystem is also the recipient of Contaminants of Emerging Concern (CECs) with poorly understood biological consequences. In the current study, we documented the presence, concentrations, and biological effects of CECs across 27 field sites in six Great Lakes tributaries by examining over 2250 resident and caged sunfish (Lepomis ssp.) for a variety of morphological and physiological endpoints and related these results to CEC occurrence. CEC were ubiquitous across studies sites and their presence and concentrations in water and sediment were highest in effluent dominated rivers and downstream of municipal wastewater treatment plant discharges. However, even putative upstream reference sites were not free of CEC presence and fish at these sites exhibited biological effects consistent with CEC exposure. Only the Fox River exhibited consistent adverse biological effects, including increased relative liver size, greater prominence of hepatocyte vacuoles and increased plasma glucose concentrations. Canonical Redundancy Analysis revealed consistent patterns of biological consequences of CEC exposure across all six tributaries. Increasing plasma glucose concentrations, likely as a result of pollutant-induced metabolic stress, were associated with increased relative liver size and greater prominence of hepatocyte vacuoles. These indicators of pollutant exposure were inversely correlated with indicators of reproductive potential including smaller gonad size and less mature gametes. The current study highlights the need for greater integration of chemical and biological studies and suggests that CECs in the Laurentian Great Lakes Basin may adversely affect the reproductive potential of exposed fish populations.