bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of a Carbohydrate Mouth Rinse on Plasma Glucose and Plasma Insulin during a 40‐km Cycling Time Trial
Authors: Murray Kevin O 
Published: November 2023

Rinsing the mouth with a carbohydrate solution, without ingesting, improves exercise performance of up to an hour in duration. Performance gains are attributed to the activation of brain regions associated with motivation and motor control. In addition to this neural response, a hormonal cascade may also be present, and include a cephalic‐phase insulin response from oral carbohydrate recognition.PURPOSEThe aim of this study was to examine whether exercise performance gains achieved through a carbohydrate mouth rinse are the partial result of a cephalic‐phase insulin response from oral carbohydrate recognition.METHODSEight trained, competitive cyclists [age (mean ± SEM) = 24 ± 2 y; VO2max = 64.5 ± 2.8 ml/kg/min] completed three simulated, 40‐km time trials comprised of a familiarization trial, carbohydrate mouth rinse trial (CHO) and placebo trial (PLA). Mouth rinse was administered prior to onset of exercise, and every 5‐km throughout exercise. During CHO and PLA trials, plasma glucose and plasma insulin samples were obtained immediately prior to mouth rinsing procedures. Metabolic data and cycling time were collected throughout the exercise session. CHO oxidation rates were calculated based on the equation: g/min = 4.210 VCO2 – 2.962 VO2, while fat oxidation rates were calculated based on: (g/min) = 1.695 VO2 – 1.701 VCO2 (Jeukendrup 2005).RESULTSTime to completion was faster for CHO (67.1 ± 1.1 sec) compared to PLA (67.9 ± 1.0 sec). Plasma glucose did not differ between conditions (p = 0.801) and held steady throughout exercise; additionally, respiratory exchange ratio was not statistically different between conditions (p = 0.081). There was no change in plasma insulin either within trials or between trials (p = 0.638). CHO oxidation rates were not statistically different (p = 0.06) between the CHO (3.43 ± 0.80 g/min) and PLA (2.98 ± 0.18 g/min) groups; fat oxidation rates were not statistically different (p = 0.10) between the CHO (0.59 ± 0.09) and PLA (0.76 ± 0.06) groups.CONCLUSIONSRinsing the mouth with a carbohydrate solution prior to exercise and after each 5‐km interval improved 40‐km time trial performance. This finding shows that improved exercise performance occurs independent of changes in plasma glucose, plasma insulin, RER, or substrate oxidation rates. These findings build on previous research to support the notion of a CHO mouth rinse having primarily a neurological response (Chambers 2009), and not acting via a cephalic‐phase insulin response, in order to improve exercise performance.Support or Funding InformationIndiana University – School of Public Health Student Research Grant Award ‐ March 2016 ($1000)BK Betty Stevens Award (UF funding for trip to Experimental Biology 2017)
Mathematical Modeling of Oxidative Phosphorylation Predicts in vivo Phosphorus Kinetics
Authors: Lewis Matthew T , Kasper Jonathan D , Bazil Jason N , Meyer Ronald A , Wiseman Robert W 
Published: November 2023

Mitochondrial density is a key contributor to exercise capacity. Diseases such as diabetes and age related illnesses lower mitochondrial densities in skeletal muscle and result in a mismatch between energy supply and demand. The precise relationship between mitochondrial energetics and cell metabolism for these conditions is not well described. To address this, a mathematical model of oxidative phosphorylation and in vivo measurements of muscle energetics were used to analyze the role that mitochondrial density has in cellular energy homeostasis during exercise. The mathematical model simulated a broad range of phosphocreatine (PCr) dynamics to mimic exercise at differing intensities in both normal muscle and where mitochondrial densities were reduced through computation. In parallel, experiments were performed on control and chemically‐treated rats using 31Phosphorus Magnetic Resonance Spectroscopy (PMRS). Rat hindlimb muscles were stimulated via electrode implantation of the sciatic nerve with concurrent PMRS and mechanical force acquisition. This setup allows for quantification of contractile ATP costs, mitochondrial ATP synthesis, PCr recovery rates, and intracellular pH. The model accurately simulates the in vivo exercise data in both control and reduced mitochondrial density animals. As the mitochondrial density is decreased, the model correctly predicts a decrease in steady state PCr levels for a given stimulus intensity and an increase in the time to replenish PCr levels after exercise. This result is indicative of decreased mitochondrial ATP production capacity as inferred by model analysis. These results demonstrate the ability of this model to simulate PCr dynamics in Wistar rat skeletal muscle for a range of exercise intensities irrespective of their mitochondrial content. The model serves as a valuable tool to gain insight into future experimental approaches to study the relationship between mitochondrial energetics and various pathological conditions associated with exercise intolerance such as heart failure, COPD and diabetes.Support or Funding InformationSupported by NIH DK 095210, NIH R00HL121160.
Shortening Heat In Cardiac Muscle
Authors: Tran Kenneth 
Published: November 2023

The ‘heat of shortening’ in muscle was first demonstrated by Fenn (1923). Tectanically‐contracting skeletal muscle, released to shorten at a fixed afterload, was shown to produce heat at a rate in excess of the steady‐state isometric heat rate. Subsequent studies in the following decades have provided ample evidence to support the existence of shortening heat in skeletal muscle. The situation is much less clear in cardiac muscle. Using the ‘latency release’ method, Holroyd and Gibbs (1992) showed that no heat was liberated when cardiac muscle was shortened against zero afterload. Adding legitimacy to the latency release protocol, its use showed the existence of shortening heat in both fast‐twitch and slow‐twitch hind‐limb muscles of the rat. (Holroyd et al., 1996). Since that time, the existence of shortening heat in cardiac muscle seems not to have been further investigated, leaving the field in the curious situation that shortening heat is present in skeletal muscle but not in cardiac muscle, despite their micro‐structural similarities. Since it must be imagined that shortening heat is the thermal accompaniment of cross‐bridge cycling, and its attendant thermogenic ATP hydrolysis, we undertake a re‐examination of the issue. We do so using two independent approaches.Firstly, we quantify shortening heat in isolated preparations (right ventricular trabeculae carneae) from rat hearts. Trabeculae were dissected from the left ventricles of 14–16 week old male Sprague‐Dawley rats and mounted in a flow‐through microcalorimeter at 32 °C, as previously described (Taberner et al., 2011). The muscle was subjected to a series of steady‐state trains of isotonic contractions at progressively diminishing afterloads, and isometric contractions at progressively diminishing muscle lengths. Shortening heat is defined as the difference in twitch heat between these two modes of contractions at a given afterload. Secondly, experimental findings are complemented by predictions of cross‐bridge ATP hydrolysis from a thermodynamically‐constrained, mathematical model of cardiac muscle mechano‐energetics (Tran et al., 2010). In both cases we exploit the difference of enthalpy‐load relations between isometric and isotonic contractions, while ensuring that comparisons are performed at the same peak force.Our experimental results confirm the existence of shortening heat in rat trabeculae. The magnitude of shortening heat was inversely related to the afterload and was a monotonically‐increasing function of the ‘extent of shortening’. Computational simulations reveal that the heat of shortening arises from the cycling of cross‐bridges, and that, even at very low afterloads where no external work is done, there is always a component of energy that is dissipated as heat.
Nitric Oxide Participation in Thermoregulatory Adjustments During Physical Exercise in Spontaneously Hypertensive Rats
Authors: Drummond Lucas Rios , Campos Helton Oliveira , Pires Washington , de Andrade Lima Paulo Marcelo , Horta Nayara Abreu Coelho , Prímola‐Gomes Thales Nicolau , Coimbra Cândido Celso 
Published: November 2023

This study aimed to investigate the nitric oxide participation in thermoregulatory adjustments during physical exercise in spontaneously hypertensive rats. All experimental procedures were approved by the Ethics Committee on Animal Use at Universidade Federal de Minas Gerais (# 21/2015). Eight male Wistar rats (SAP = 119 ± 3 mmHg) and spontaneously hypertensive rats (SHR; SAP = 195 ± 7 mmHg) with 16 weeks of age were used in the experiments. The rats received an implant of a chronic guide cannula in the lateral cerebral ventricle and a temperature sensor into the abdominal cavity. After recovery, the animals were familiarized to run on a treadmill, and then, each animal was subjected to two constant‐speed exercise protocols at 60% of maximal speed attained in the incremental exercise until fatigue. On the day of the experiments, the rats were assigned to receive a 2 μL intracerebroventricular injection of either NaCl (0.15 mol/L) or sodium nitroprusside (SNP; 8.4 mmol) setting four groups, Wistar SAL, Wistar SNP, SHR SAL and SHR SNP. The tail skin temperature (Tskin) and abdominal temperature (Tabd) were recorded every minute throughout the exercise trials. The Tskin and Tabd dynamics were evaluated by the temperature variation (temperature in each minute ‐ the initial temperature). In Wistar groups, the SNP group showed a greater increase in Tskin from the 14th min until the fatigue (3.12 ± 0.33°C vs. 1.60 ± 0.47°C, fatigue; p < 0.05) with the lower increase in Tabd when compared with SAL group from the 18th min until the fatigue (1.28 ± 0.16°C vs. 1.71 ± 0.26°C; fatigue, p < 0.05). In SHR groups, the SNP group showed a greater increase in Tskin from the 8th until the 19th min (1.58 ± 0.83°C vs. −0.40 ± 0.88°C, 15th min; p < 0.05) and lower increase in Tabd when compared with SAL group from the 23th min until the fatigue (1.09 ± 0.13°C vs. 1.70 ± 0.18°C; fatigue, p < 0.05). SHR groups performed a decreased workload during exercise (SAL: 200.1 ± 23.2 J vs. 277.0 ± 27.1 J, p < 0.05; SNP: 206.0 ± 23.2 J vs. 299.0 ± 27.1 J, p < 0.05) when compared with Wistar groups. The SNP injection did not modify the workload performed during the exercise in Wistar and SHR groups (p > 0.05). We conclude that central injection of sodium nitroprusside increased heat dissipation, resulting in a lower increase in abdominal temperature during exercise in Wistar and SHR rats, without modify physical performance.Support or Funding InformationFinancial Support: FAPEMIG, CAPES and CNPq.
Exercise training reduces TGF‐β mediated epithelial mesenchymal transition in diabetic kidney
Authors: Ren Lu , Sen Utpal , Pushpakumar Sathnur 
Published: November 2023

Transforming growth factor‐β (TGF‐β)‐induced activation of Smad2 and Smad3 is implicated in epithelial mesenchymal transition (EMT) and development of glomerular and interstitial fibrosis in diabetic nephropathy. Sirtuin1 (Sirt1), a deacetylase has been shown to reduce TGF‐β induced mesangial cell apoptosis to improve cell survival and also in the attenuation of TGF‐β‐induced renal damage in subtotal nephrectomized rats. Exercise training can affect acetylation of protein residues and counteract systems impairment. Exercise has recently been shown to regulate Sirt1 activity in skeletal muscles. However, it is not known whether Sirt1 regulates TGF‐β signaling in diabetic nephropathy to reduce EMT and thus fibrosis. The purpose of this study was to investigate whether exercise training in type‐II diabetes attenuates TGF‐β‐induced EMT by upregulation of Sirt1 activity. BKS.Cg‐Dock7m +/+ Leprdb/J and Dock7m +/+ Leprdb mice representing type‐II diabetes and non‐diabetic heterozygous control respectively were used in the study. Mice were exercised on a treadmill using an established protocol for 5 weeks. Mice were initially accustomed to exercise at 7m/min and gradually increased to 11m/min for a distance of 300m every day for 5d/week. A 10 min rest period was allowed after every 100m. Sirt1 expression was decreased in diabetic mice compared to non‐diabetic controls. Diabetic mice also exhibited upregulation of TGF‐β and Smad2, 3. mRNA and protein expression of E‐cadherin and claudin‐6 was suppressed and alpha‐smooth muscle actin (α‐SMA) and fibroblast‐specific protein‐1 (FSP1) was upregulated in diabetic mice compared to controls. Moderate intensity exercise reversed the above changes to enhance Sirt1, reduce TGF‐β and Smad2, 3 and α‐SMA and FSP‐1 in diabetic mice. Exercise training was also associated with decreased collagen IV and fibronectin in diabetic kidney. In conclusion, our data suggests that moderate intensity exercise prevents the progression of renal disease by enhancing Sirt1 and regulation of TGF‐β‐induced EMT in type‐II diabetes.Support or Funding Information15SDG25840013 to SP, DK104653 to US, HL104103 to US
Survival and Growth of C57BL/6J Mice Lacking the BK Channel (KCa1.1): Lower Adult Body Weight Occurs together with Higher Body Fat
Authors: Halm Susan T. , Halm Dan R. 
Published: November 2023

The BK potassium channel contributes to K+ flow and the electrical behavior of many cell types: including pancreatic β‐cells and cells in the hypothalamic‐pituitary‐adrenal axis. Mice made null for the gene (Kcnma1, slo‐1) producing the BK channel exhibit numerous deficits in physiological functions, but also show resistance toward developing obesity on a high fat diet (Illison J, et al, Diabetes 2016 db160245). Initial breeding pairs lacking a single allele of Kcnma1 (BKhet) in a C57BL/6J background strain were obtained from Dr. Andrea Meredith at the University of Maryland. A colony derived by breeding these heterozygous mice had litter sizes of ~8 pups, 53% male. For the period of maternal care (P0 – P21) pup death peaked at P1 with a second less severe interval of pup death peaking near P13. The later deaths (~P13) of pups null for Kcnma1 (BKKO) were greater than Mendelian expectations. Pup death at ~P1 was twice as likely during the 20 month construction of a building adjacent to the animal facility compared with the quiescent period after cessation of construction. Births also were not consistent with Mendelian predictions, indicating a specific prenatal disadvantage for female BKKO mice in the quiescent period and for female BKhet mice during construction, a change likely induced by this environmental stressor. Death of colony mice after weaning was rare (~0.5%). After weaning, weight gain was lower for BKKO mice compared with wild‐type littermates: male BKKO mice were 5 g smaller and female BKKO mice were 4 g smaller. Lower weight gain for BKKO mice compared to wild‐type occurred in part due to an event of weight loss during the early post‐weaning period, between weeks 3 to 9. Interestingly, wild‐type mice as well as male BKKO mice were ~1 g larger during construction compared with mice during quiescence. Body composition determined by quantitative magnetic resonance (QMR) indicated a higher fat proportion for wild‐type female mice compared with males, as well as a higher hydration ratio (total water mass – free water mass/lean mass). Comparison of lean, fat, and water components for female and male mice suggested an interrelationship that governs changes to body composition. Both male and female BKKO mice showed higher fat proportions than wild‐type, with the female BKKO mice exhibiting a larger variation in fat content and male BKKO mice having a higher hydration ratio than wild‐type. Together these results indicate that BKKO mice suffered disadvantages that led to prenatal and perinatal death. A metabolic difference likely related to glucose handling led to the smaller body size and distinct composition with higher fat for BKKO mice, suggesting a diversion of energy supplies from growth to fat storage.Support or Funding Information[NIH DK65845; WSU‐BSoM Seed Grant]
Plasticity of TRPV1‐dependent Neurotransmission in the Paraventricular Nucleus of db/db Mice
Authors: Gao Hong , Miyada Kayoko , Qiao Xin , Molinas Adrien JR , Zsombok Andrea 
Published: November 2023

Transient receptor potential vanilloid type 1 (TRPV1) has been shown to play a role in the modulation of glucose homeostasis. Preautonomic, liver‐related neurons in the paraventricular nucleus (PVN) of the hypothalamus contribute to the regulation of sympathetic and parasympathetic outflow to the liver. Our previous findings demonstrated that liver‐related PVN neurons are controlled by TRPV1‐dependent excitatory neurotransmission. In this study, liver‐related PVN neurons were identified with a retrograde, trans‐neuronal viral tracer and whole‐cell patch‐clamp recordings were conducted. We tested the hypothesis that the TRPV1‐dependent synaptic control of liver‐related PVN neurons is reduced in db/db mice. Application of the exogenous TRPV1 agonist, capsaicin (1μM) increased the average frequency of miniature excitatory post‐synaptic currents (mEPSCs) in liver‐related PVN neurons from lean mice. In contrast, in db/db mice capsaicin application did not change the overall frequency of mEPSCs. Capsaicin did not alter the frequency of miniature inhibitory post‐synaptic currents (mIPSCs) neither in lean or db/db mice. We did not observe significant difference in the basal frequency of mEPSCs and mIPSCs in liver‐related PVN neurons of lean and db/db mice. On the other hand, the amplitude of mIPSCs was smaller in liver‐related PVN neurons of db/db mice compared with lean mice. GABAA‐mediated inhibitory tonic currents as bicuculline‐dependent inward shift of the holding current were also revealed in liver‐related PVN neurons. Our data did not show difference in the magnitude of tonic inhibition between the groups. Together, this study suggests that the TRPV1‐dependent control of liver‐related PVN neurons is diminished in db/db mice. These findings are consistent with our previous data demonstrating synaptic plasticity of hypothalamic autonomic circuits in hyperglycemic conditions, and further suggest dysregulation of neuronal activity at the level of the PVN in obese‐diabetic state.Support or Funding InformationSupported by NIDDK R01DK099598
Neuregulin‐1 Decreases Hepatic Glucose Production in db/db Mice
Authors: Sirvent Pascal , Teixeira Allison , Etienne Monique , Delcros Geoffrey , Lantier Louise , McGuinness Owen P , Otero Yolanda Fernandez 
Published: November 2023

Background and aimsPrevious studies from our laboratory had shown that neuregulin‐1 (NRG1) has a role in glucose homeostasis, improving glucose tolerance in db/db mice. A predominant role of the liver has been suggested, since NRG1 receptors were activated only in the hepatic tissue, but not in skeletal muscle or adipose tissue. Our aim was to study whole body insulin sensitivity and hepatic response to an acute treatment with NRG1.MethodsThree hour fasted 9‐week old db/db mice were injected with NRG1 (50μg/kg) or saline (SAL) as control. After 2h, a hyperinsulinemic‐euglycemic clamp was performed. A different group under the same conditions, was used to study hepatic signalling after the NRG1 or SAL injection.ResultsTwo hours after injection, insulin levels were lower in db/db mice injected with NRG1 (38±9 SAL vs 18±4 NRG1, ng/ml). As consequence, this group of mice showed lower glucose infusion rate (GIR) during the clamp (21±2 SAL vs 13±3 NRG1, mg/kg·min). Despite lower insulin levels, glucose turnover (Rd) and hepatic glucose production (endo‐Ra) were significantly decreased in the presence of NRG1 (Rd: 32±3 SAL vs 24±2 NRG1, mg/kg·min. EndoRa: 10±1 SAL vs 7±1 NRG1, p<0.05; mg/kg·min). Tissue‐specific glucose uptake was not different.Liver Akt phosphorylation (Ser 473) ratio was significantly higher in db/db mice 2h after NRG1 treatment (1±0.4 SAL vs 4.5±0.9 NRG1, p<0.05, arbitrary units). GSK3‐β phosphorylation (Ser9) ratio was not different. Hepatic gene expression of G6pc was lower in db/db mice treated with NRG1 (Rq 1±0.03 SAL vs 0.6±0.1 NRG1). Hepatic glycogen content was not different among groups.ConclusionsAcute (2h) treatment with neuregulin‐1 caused a decrease in insulin levels, glucose turnover, and hepatic glucose production during the hyperinsulinemic‐euglycemic clamp. The stronger inhibition in endo‐Ra with lower insulin levels, may reflect an increase in hepatic insulin sensitivity and/or a direct effect of NRG1 on hepatic glucose production. The increased Akt phosphorylation ratio and decreased G6pc gene expression could be involved in the mechanism used by NRG1.Support or Funding InformationThis work has been supported by a grant from Université Blaise Pascal.
Angiotensin‐II Type 1a Receptor Present in Insulin Producing Cells is Essential for Normal Islet Function
Authors: Chodavarapu Harshita , Xu Jiaxi , Lazartigues Eric 
Published: November 2023

The renin angiotensin system (RAS) has been proposed to regulate glucose homeostasis, notably by modulating insulin secretion. Insulin is produced both by β‐cells in the pancreas and neurons in the brain. However, while Angiotensin‐II type 1a receptors (AT1R) are expressed on both cell types, their specific role in insulin secretion remains unclear. To investigate this nebulous area, we generated specific knockout mice for 1) AT1R on insulin‐producing cells (IC): neurons and β‐cells (IC‐AT1R KO: AT1R floxed bred with Ins2‐cre mice) and 2) AT1R on neurons only (N‐AT1R KO: AT1R floxed bred with synapsin‐cre mice). With respect to the first model, the aim of this study is to elucidate the role of IC‐specific AT1R in the regulation of β‐cell dysfunction in regular diet (RD)‐fed and high fat diet (HFD)‐fed male mice. We used 5–6 weeks old conditional IC‐AT1R KO mice and control littermates (CT), fed them HFD for 3 months and isolated pancreatic islets at the end of the study for further analysis. After 3 months of HFD feeding, CT mice demonstrated increased body weight (HFD: 41±2.1 vs. RD: 28±0.6 g), hyperglycemia (HFD: 154.3±6.2 vs. RD: 108.5±13.23 mg/dl), glucose intolerance (HFD: 48488±5843 vs. RD: 25950±2224 AUC) and β‐cell dysfunction. These changes in glucose homeostasis were associated with a 1.5 fold increase in AT1R mRNA expression, marker of overactive RAS, and 4.3 fold increase in the autophagy marker, LC3II, in the islets of CT HFD‐fed compared to CT RD‐fed mice. On the other hand, both RD‐fed and HFD‐fed IC‐AT1R KO mice displayed β‐cell dysfunction and glucose intolerance (IC‐AT1R KO RD: 39784±4088 vs. CT‐RD: 25950±2224; IC‐AT1R KO HFD: 47502±4782 vs. CT HFD: 48488±5843 AUC) but had normal fasting blood glucose levels (IC‐AT1R KO RD: 97.5±6.4 vs. CT RD: 108.5±13.23; IC‐AT1R KO HFD: 97.4±3.7 vs. CT HFD: 154.3±6.2 mg/dl) and body weights (IC‐AT1R KO RD: 28.6±1.0 vs. CT RD: 28±0.6; IC‐AT1R KO HFD: 34.82±1.6 vs. CT HFD: 41±2.1 g). Furthermore, there was a 5.4 fold increase in islet LC3II protein expression in IC‐AT1R KO‐RD mice compared to CT‐RD mice. In addition, HFD‐fed IC‐AT1R KO mice demonstrated further increase in LC3II expression (1.5 fold vs. IC‐AT1R KO‐RD and 1.9 fold vs. CT‐HFD).Altogether, this is the first study to demonstrate that AT1R present in insulin producing neurons and β‐cells is essential for the maintenance of normal β‐cell function. In addition, our study also sheds light on islet autophagy as a potential mechanistic link between IC specific AT1R and β‐cell dysfunction. However, further studies are required to clarify whether autophagy is upstream/downstream to AT1R and to separate central and peripheral mechanisms.Support or Funding InformationAmerican Heart Association: 12EIA8030004 and 14PRE18830012.