Fetal lower urinary tract obstruction: international Delphi consensus on management and core outcomes set.

OBJECTIVE: To reach a Delphi-generated international expert consensus on the diagnosis, prognostic, management, and core outcome set (COS) of fetal Lower Urinary Tract Obstruction (LUTO). METHODS: A three-round Delphi procedure was conducted among an international panel of LUTO experts. The panel was provided with a list of literature review-generated parameters for the diagnosis, prognostic, management, and outcomes. A parallel procedure was conducted along with patient groups during the development of COS. RESULTS: A total of 160 experts were approached, of whom 99 completed the first round and 80 (80/99, 80.8%) completed all three rounds. In the first trimester, an objective measurement of longitudinal bladder diameter (with ≥7 mm being abnormal) should be used to suspect LUTO. In the second trimester, imaging parameters of LUTO could include: a) an enlarged bladder, b) a keyhole sign, c) bladder wall thickening, d) bilateral hydro (uretero) nephrosis, and e) male sex. There was a lack of consensus on the current prognostic scoring literature. However, experts agreed on the value of amniotic fluid volume (< 24 weeks) to predict survival and that the value of fetal intervention is to improve neonatal survival. While experts endorsed the role of sonographic parameters of renal dysplasia, at least one vesicocentesis, and urine biochemistry for prognosis and counseling, these items did not reach a consensus for determining fetal intervention candidacy. On the other hand, imaging parameters suggestive of LUTO, absence of life-limiting structural or genetic anomalies, gestational age of ≥16 weeks, and oligohydramnios defined as deepest vertical pocket (DVP) <2 cm should be used as candidacy criteria for fetal intervention based on experts' consensus. If a bladder refill was evaluated, it should be assessed subjectively. Vesicoamniotic shunt should be the first line of fetal intervention. In the presence of suspected fetal renal failure, serial amnioinfusion should only be offered as an experimental procedure under research protocols. The core outcome set for future studies was agreed upon. CONCLUSION: International consensus on the diagnosis, prognosis, and management of fetal LUTO, as well as the Core Outcome Set, should inform clinical care and research to optimize perinatal outcomes. This article is protected by copyright. All rights reserved.

The Effects of Resistance Exercise Training on Skeletal Muscle Metabolism and Insulin Resistance Development in Female Rodents with Type 1 Diabetes.

The etiology of insulin resistance (IR) development in type 1 diabetes mellitus (T1DM) remains unclear; however, impaired skeletal muscle metabolism may play a role. While IR development has been established in male T1DM rodents, female rodents have yet to be examined in this context. Resistance exercise training (RT) has been shown to improve IR and is associated with a lower risk of hypoglycemia onset in T1DM compared to aerobic exercise. The purpose of this study was to investigate the effects of RT on IR development in female T1DM rodents. Forty Sprague Dawley eight-week-old female rats were divided into four groups: control sedentary (CS; n = 10), control trained (CT; n = 10), T1DM sedentary (DS; n = 10), and T1DM trained (DT; n = 10). Multiple low-dose streptozotocin injections were used to induce T1DM. Blood glucose levels were maintained in the 4-9 mmol/l range with intensive insulin therapy. CT and DT underwent weighted ladder climbing 5 days/week for six weeks. Intravenous glucose tolerance tests (IVGTT) were conducted on all animals following the six-week period. Results demonstrate that DS animals exhibited significantly increased weekly blood glucose measures compared to all groups including DT (p < 0.0001), despite similar insulin dosage levels. This was concomitant with a significant increase in insulin-adjusted area under the curve following IVGTT in DS (p < 0.05), indicative of a reduction in insulin sensitivity. Both DT and DS exhibited greater serum insulin concentrations compared to CT and CS (p < 0.05). DS animals also exhibited significantly greater glycogen content in white gastrocnemius muscle compared to CS and DT (p < 0.05), whereas DT and DS animals exhibited greater p-Akt: Akt ratio in the white vastus lateralis muscle and citrate synthase activity in the red vastus lateralis muscle compared to CS and CT (p < 0.05). These results indicate that female rodents with T1DM develop poor glycemic control and IR which can be attenuated with RT, possibly related to differences in intramyocellular glycogen content.

Thromboxane-induced cerebral microvascular rarefaction predicts depressive symptom emergence in metabolic disease.

Previous studies have suggested that the loss of microvessel density in the peripheral circulation with evolving metabolic disease severity represents a significant contributor to impaired skeletal muscle oxygenation and fatigue-resistance. Based on this and our recent work, we hypothesized that cerebral microvascular rarefaction was initiated from the increased prooxidant and proinflammatory environment with metabolic disease and is predictive of the severity of the emergence of depressive symptoms in obese Zucker rats (OZRs). In male OZR, cerebrovascular rarefaction followed the emergence of elevated oxidant and inflammatory environments characterized by increased vascular production of thromboxane A2 (TxA2). The subsequent emergence of depressive symptoms in OZR was associated with the timing and severity of the rarefaction. Chronic intervention with antioxidant (TEMPOL) or anti-inflammation (pentoxifylline) therapy blunted the severity of rarefaction and depressive symptoms, although the effectiveness was limited. Blockade of TxA2 production (dazmegrel) or action (SQ-29548) resulted in a stronger therapeutic effect, suggesting that vascular production and action represent a significant contributor to rarefaction and the emergence of depressive symptoms with chronic metabolic disease (although other pathways clearly contribute as well). A de novo biosimulation of cerebrovascular oxygenation in the face of progressive rarefaction demonstrates the increased probability of generating hypoxic regions within the microvascular networks, which could contribute to impaired neuronal metabolism and the emergence of depressive symptoms. The results of the present study also implicate the potential importance of aggressive prodromic intervention in reducing the severity of chronic complications arising from metabolic disease.NEW & NOTEWORTHY With clinical studies linking vascular disease risk to depressive symptom emergence, we used obese Zucker rats, a model of chronic metabolic disease, to identify potential mechanistic links between these two negative outcomes. Depressive symptom severity correlated with the extent of cerebrovascular rarefaction, after increased vascular oxidant stress/inflammation and TxA2 production. Anti-TxA2 interventions prevasculopathy blunted rarefaction and depressive symptoms, while biosimulation indicated that cerebrovascular rarefaction increased hypoxia within capillary networks as a potential contributing mechanism.

Hybrid reduced graphene oxide nanosheets with negative magnetoresistance for the diagnosis of hypoglycemia.

Few glucometers are available to easily and quickly measure low blood glucose levels (≤4 mmol L-1) from a small amount of blood samples. Here, a hybrid reduced graphene oxide (rGO)-based magnetoresistance (MR) sensor has been developed to monitor blood glucose levels to quickly detect hypoglycemia. Hybrid rGO nanosheets, incorporating Fe50Co50 nanoparticles onto rGO nanosheets, with an unusual large negative MR (-5.7%) at room temperature under a small magnetic field (9.5 kOe) have been successfully fabricated through a one-pot reaction. To quickly detect the low concentration of glucose in a small amount of blood (1 µL), a two-step process has been further developed by using the "sandwich" structural MR sensor. The results show that the higher the negative MR value of the sensor, the lower the concentration of glucose that can be detected. A linear relationship between the MR and the concentration of the spiked plasma glucose taken from streptozotocin-induced diabetic rats can be found when the concentration of glucose is in the range of 0-6 mmol L-1. The limit of detection (LOD) of this MR glucose sensor is 0.867 mmol L-1. The accuracy of the rGO-based MR sensor is improved in measuring low concentration of plasma glucose as compared to that of a commercialized glucometer. Furthermore, the selectivity of the rGO-based MR sensor has been studied. The results demonstrate that the rGO-based MR sensor is a flexible and sensitive detection platform and specifically suitable for monitoring low concentrations of plasma glucose to prevent from hypoglycemia.

Assessment of executive function in a rodent model of Type 1 diabetes.

This study examined the impact of Type 1 Diabetes Mellitus (T1DM) on executive function using a series of operant conditioning-based tasks in rats. Sprague Dawley rats were randomized to either non-diabetic (n = 12; 6 male) or diabetic (n = 14; 6 male) groups. Diabetes was induced using multiple low-dose streptozotocin injections. All diabetic rodents were insulin-treated using subcutaneous insulin pellet implants (9-15 mM). At week 14 of the study, rats were placed on a food restricted diet to induce 5-10 % weight loss. Rodents were familiarized and their set-shifting ability was tested on a series of tasks that required continuous adjustments to novel stimulus-reward paradigms in order to receive food rewards. Results showed no differences in the number of trials, nor number and type of errors made to successfully complete each task between groups. Therefore, we report no differences in executive function, or more specifically set-shifting abilities between non-diabetic and diabetic rodents that receive insulin.

The influence of exercise training versus intensive insulin therapy on insulin resistance development in type 1 diabetes.

The etiology of insulin resistance (IR) in Type 1 Diabetes (T1D) is unclear; however, intramyocellular lipids (IMCL) are likely contributors. While exercise lessens IR and IMCL content; T1D patients elevate glycemia to offset exercise-induced hypoglycemic risk. The preferred treatment for T1D patients is tight glucose management through intensive insulin therapy (IIT); however, IIT is accompanied with a sedentary lifestyle. The purpose of this study was to examine IR development and IMCL in combined exercise (DARE; aerobic/resistance) and IIT-treated T1D animals. 76 rats were divided into control sedentary (C), diabetic sedentary (CD), diabetes sedentary intensive insulin therapy (DIT) and DARE groups. Following streptozotocin (STZ), glycemia was maintained at either 9-15 mM (CD, DARE) or 5-9 mM (DIT) using insulin. DARE alternated between running and weighted climbing for 12 weeks. Results demonstrate that DARE exhibited reduced onset of IR compared with C, DIT and CD, indicated by increased glucose infusion rate (hyperinsulinemic-euglycemic-clamp). A shift in lipid metabolism was evident whereby diacylglycerol was elevated in DIT compared to DARE, while triacylglycerol was elevated in DARE. These findings indicate enhanced IMCL metabolism and the sequestration of fat as neutral triacylglycerol leads to reduced IR in DARE. In contrast, IIT and sedentary behavior leads to diacylglycerol accumulation and IR.

Sexual dimorphism in response to repetitive bouts of acute aerobic exercise in rodents with type 1 diabetes mellitus.

The purpose of this study was to examine sex-specific differences in the blood glucose (BG) response to recurrent aerobic exercise in type 1 diabetes rats. Specifically, we examined the role of peak estrogen (E2) concentrations during proestrus on BG response to prolonged repetitive aerobic exercise. To do so, nineteen Sprague-Dawley rats were assigned to four exercised groups: control female (CXF; n = 5), control male (CXM; n = 5), diabetic female (DXF, n = 5) and diabetic male (DXM, n = 4). Diabetes was induced in DX groups via subcutaneous multiple injections of low dose streptozotocin (20mg/day for 7 days). After four days of exercise, muscle and liver glycogen content, liver gluconeogenic enzyme content, muscle Beta oxidation activity and BG responses to exercise were compared. The final bout of exercise took place during proestrus when E2 concentrations were at their highest in the female rats. During days 1-3 DXM had significantly lower BG concentrations during exercise than DXF. While both T1DM and non-T1DM females demonstrated higher hepatic G6Pase expression and muscle beta oxidation activity levels on day 4 exercise, no differences in BG response between the male and female T1DM rats were evident. Further, no differences in liver and muscle glycogen content following day 4 of exercise were seen between the sexes. These results would suggest that heightened E2 levels during proestrus may not be an important factor governing glucose counter regulatory response to exercise in female T1DM rats. Rather, the pre-exercise blood glucose levels are likely to be a large determinant of the blood glucose response to exercise in both male and female rats.

Exploring the relationship between meaningful conditioned pain modulation and stress system reactivity in healthy adults following exposure to the cold pressor task.

BACKGROUND: The sympathetic nervous system (SNS) and hypothalamic-pituitary-adrenal (HPA) axis have been implicated in conditioned pain modulation (CPM). As there has recently been a push to identify meaningful CPM responses based on ± 2 SEM of the test stimulus, we sought to evaluate if meaningful CPM had relationships with both SNS and HPA axis reactivity. METHODS: 50 university-aged healthy participants (25 males, 25 females) underwent evaluation of pressure pain detection threshold (PPDT), conditioned pain modulation (CPM), galvanic skin response (GSR) and salivary cortisol before and after a cold pressor test (CPT). Meaningful CPM was evaluated based on change ±2 SEM of baseline PPDT to classify participants as experiencing inhibition of pain, facilitation, or non-response. RESULTS: As a group, there were no significant changes in PPDT or salivary cortisol after exposure to noxious cold. GSR was significantly elevated from baseline values during the CPT, and 10 min after (p < 0.001). When meaningful CPM was assessed, only 30% of participants experienced inhibitory CPM. Within this group, there was a large positive correlation ranging from r = 0.63 to 0.69 (p < 0.01) between CPM and the absolute change in GSR from baseline to immersion, and the immediate 5 min after immersion. CONCLUSIONS: This work continues to support the growing body of literature suggesting that CPM is not universally experienced. Inhibitory CPM may be associated with an increase in SNS activity for healthy participants in reaction to noxious cold. Future work is required to ascertain individual characteristics (e.g., age, sex) that relate to CPM responses.

The effects of exercise training versus intensive insulin treatment on skeletal muscle fibre content in type 1 diabetes mellitus rodents.

BACKGROUND: Intensive-insulin treatment (IIT) strategy for patients with type 1 diabetes mellitus (T1DM) has been associated with sedentary behaviour and the development of insulin resistance. Exercising patients with T1DM often utilize a conventional insulin treatment (CIT) strategy leading to increased insulin sensitivity through improved intramyocellular lipid (IMCL) content. It is unclear how these exercise-related metabolic adaptations in response to exercise training relate to individual fibre-type transitions, and whether these alterations are evident between different insulin strategies (CIT vs. IIT). PURPOSE: This study examined glycogen and fat content in skeletal muscle fibres of diabetic rats following exercise-training. METHODS: Male Sprague-Dawley rats were divided into four groups: Control-Sedentary, CIT- and IIT-treated diabetic sedentary, and CIT-exercised trained (aerobic/resistance; DARE). After 12 weeks, muscle-fibre lipids and glycogen were compared through immunohistochemical analysis. RESULTS: The primary findings were that both IIT and DARE led to significant increases in type I fibres when compared to CIT, while DARE led to significantly increased lipid content in type I fibres compared to IIT. CONCLUSIONS: These findings indicate that alterations in lipid content with insulin treatment and DARE are primarily evident in type I fibres, suggesting that muscle lipotoxicity in type 1 diabetes is muscle fibre-type dependant.

Efficacy of electromotive drug administration in delivering botulinum toxin a in children with neuropathic detrusor overactivity-outcomes of a pilot study.

BACKGROUND: Intravesical botulinum toxin A (BtA) injection is well established in managing paediatric neuropathic detrusor overactivity (NDO). Electromotive drug administration (EMDA) is a less invasive method, which can be performed in the clinic, using pulsed electrical current for drug delivery via a urethral catheter. Few small studies report good outcomes following BtA via EMDA (BtA/EMDA) into bladders of children with NDO. OBJECTIVE: The objective of this study is to assess the efficacy of BtA/EMDA in children with NDO, reduced bladder capacity and compliance. METHODS: Twelve children with NDO on baseline urodynamic study were prospectively included. Pre-BtA/EMDA and post-BtA/EMDA results compared the following four parameters: maximal cystometric capacity, bladder compliance, maximal detrusor pressure (pDetmax) during detrusor overactivity and pDetmax at capacity. The Wilcoxon matched-pairs signed-rank test using Graphpad Prism 8 was used for analysis. Secondary outcomes include adverse effects and symptomatic improvement. RESULTS: Fourteen episodes of BtA/EMDA were performed. Five patients received 3.3 IU/kg of Botox®, and five received 10 IU/kg (maximum 300 IU). Four patients received 10 IU/kg of Dysport®. Two patients in the Dysport®/EMDA group also received Botox®/EMDA more than six months previously. Thirteen of 14 post-EMDA results were completed and included in the paired analysis. No statistically significant improvements in any cystometric parameters were demonstrated. Eight patients subsequently had intravesical BtA injections with significant improvements in both cystometric parameters and symptoms. Two patients subsequently transitioned to adult services; one was commenced on mirabegron, and one has undergone ileocystoplasty with Mitrofanoff appendicovesicostomy. DISCUSSION: Despite some evidence to support BtA/EMDA in children with NDO, the authors were unable to replicate previously published positive cystometric and symptomatic outcomes. In addition, BtA/EMDA performed poorly when compared with conventional intravesical BtA injections. This implies failure of EMDA to deliver BtA correctly to the target tissue. The large size of the BtA molecule or the abnormal bladder wall in NDO could account for the negative results. Thorough preparation and consultation was undertaken before this study with BtA/EMDA, and it is discouraging that the authors were unable to reproduce the positive results of other groups. CONCLUSIONS: Although safe and acceptable to most patients, the authors cannot recommend the use of BtA/EMDA for NDO in children at present.

Exercise Training Induced Cardioprotection with Moderate Hyperglycemia versus Sedentary Intensive Glycemic Control in Type 1 Diabetic Rats.

Intensive insulin therapy (IIT; 4-7 mmol/L) is the preferred treatment for type 1 diabetes mellitus (T1DM) patients to reduce the risk of cardiovascular disease (CVD). However, this treatment strategy has been questioned as it is accompanied with a sedentary lifestyle leading to weight gain and insulin resistance. T1DM patients who partake in high-intensity aerobic training (AThigh) to reduce CVD often utilize conventional insulin therapy (CIT; 9-15 mmol/L) to offset the risk of hypoglycemia. Moreover, exercise modalities incorporating resistance training (RT) have been shown to further reduce this risk. The purpose of this investigation was twofold: (1) to determine if CIT paired with AThigh results in larger cardioprotection from an ischemia-reperfusion (I-R) injury than IIT and (2) to establish if the integration of RT with AThigh (ART) results in similar cardioprotection as AThigh. Diabetic (D) male Sprague-Dawley rats were divided into D-IIT (n = 12), D-CIT (n = 12), D-AThigh (n = 8), D-RT (n = 8), and D-ART (n = 8). T1DM was induced with streptozotocin, and blood glucose was adjusted with insulin. D-AThigh occurred on a treadmill (27 m/min; 1 hr), D-RT performed weighted ladder climbs, and D-ART alternated daily between AThigh and RT. Exercise occurred 5 days/wk for 12 wks. This investigation demonstrates that cardioprotection following an I-R injury was similar between D-AThigh and D-IIT. This cardioprotection is not exercise-specific, and each provides unique advantages. D-AThigh leads to improved glycemia while insulin sensitivity was enhanced following resistance exercises. Thus, exercise is an effective means to elicit cardioprotection in T1DM. However, in addition to glycemia, other factors should be considered when tailoring an exercise program for T1DM patients.

Effect of Combined Exercise Versus Aerobic-Only Training on Skeletal Muscle Lipid Metabolism in a Rodent Model of Type 1 Diabetes.

OBJECTIVES: Abnormal skeletal muscle lipid metabolism is associated with insulin resistance in people with type 1 diabetes. Although lipid metabolism is restored with aerobic exercise training, the risk for postexercise hypoglycemia is increased with this modality. Integrating resistance and aerobic exercise is associated with reduced hypoglycemic risk; however, the effects of this exercise modality on lipid metabolism and insulin resistance remain unknown. We compared the effects of combined (aerobic + resistance) versus aerobic exercise training on oxidative capacity and muscle lipid metabolism in a rat model of type 1 diabetes. METHODS: Male Sprague-Dawley rats were divided into 4 groups: sedentary control (C), sedentary control + diabetes (CD), diabetes + high-intensity aerobic exercise (DAE) and diabetes + combined aerobic and resistance exercise (DARE). Following diabetes induction (20 mg/kg streptozotocin over five days), DAE rats ran for 12 weeks (5 days/week for 1 hour) on a motorized treadmill (27 m/min at a 6-degree grade), and DARE rats alternated daily between running and incremental weighted ladder climbing. RESULTS: After training, DAE showed reduced muscle CD36 protein content and lipid content compared to CD (p≤0.05). DAE rats also had significantly increased citrate synthase (CS) activity compared to CD (p≤0.05). DARE rats showed reduced CD36 protein content compared to CD and increased CS activity compared to CD and DAE rats (p≤0.05). DARE rats demonstrated increased skeletal muscle lipid staining, elevated lipin-1 protein content and insulin sensitivity (p≤0.05). CONCLUSIONS: Integration of aerobic and resistance exercise may exert a synergistic effect, producing adaptations characteristic of the "athlete's paradox," including increased capacity to store and oxidize lipids.

Pathophysiology and Risk of Atrial Fibrillation Detected after Ischemic Stroke (PARADISE): A Translational, Integrated, and Transdisciplinary Approach.

BACKGROUND: It has been hypothesized that ischemic stroke can cause atrial fibrillation. By elucidating the mechanisms of neurogenically mediated paroxysmal atrial fibrillation, novel therapeutic strategies could be developed to prevent atrial fibrillation occurrence and perpetuation after stroke. This could result in fewer recurrent strokes and deaths, a reduction or delay in dementia onset, and in the lessening of the functional, structural, and metabolic consequences of atrial fibrillation on the heart. METHODS: The Pathophysiology and Risk of Atrial Fibrillation Detected after Ischemic Stroke (PARADISE) study is an investigator-driven, translational, integrated, and transdisciplinary initiative. It comprises 3 complementary research streams that focus on atrial fibrillation detected after stroke: experimental, clinical, and epidemiological. The experimental stream will assess pre- and poststroke electrocardiographic, autonomic, anatomic (brain and heart pathology), and inflammatory trajectories in an animal model of selective insular cortex ischemic stroke. The clinical stream will prospectively investigate autonomic, inflammatory, and neurocognitive changes among patients diagnosed with atrial fibrillation detected after stroke by employing comprehensive and validated instruments. The epidemiological stream will focus on the demographics, clinical characteristics, and outcomes of atrial fibrillation detected after stroke at the population level by means of the Ontario Stroke Registry, a prospective clinical database that comprises over 23,000 patients with ischemic stroke. CONCLUSIONS: PARADISE is a translational research initiative comprising experimental, clinical, and epidemiological research aimed at characterizing clinical features, the pathophysiology, and outcomes of neurogenic atrial fibrillation detected after stroke.

Nanostructured biosensor using bioluminescence quenching technique for glucose detection.

BACKGROUND: Most methods for monitoring glucose level require an external energy source which may limit their application, particularly in vivo test. Bioluminescence technique offers an alternative way to provide emission light without external energy source by using bioluminescent proteins found from firefly or marine vertebrates and invertebrates. For quick and non-invasive detection of glucose, we herein developed a nanostructured biosensor by applying the bioluminescence technique. RESULTS: Luciferase bioluminescence protein (Rluc) is conjugated with ß-cyclodextrin (ß-CD). The bioluminescence intensity of Rluc can be quenched by 8 ± 3 nm gold nanoparticles (Au NPs) when Au NPs covalently bind to ß-CD. In the presence of glucose, Au NPs are replaced and leave far from Rluc through a competitive reaction, which results in the restored bioluminescence intensity of Rluc. A linear relationship is observed between the restored bioluminescence intensity and the logarithmic glucose concentration in the range of 1-100 µM. In addition, the selectivity of this designed sensor has been evaluated. The performance of the senor for determination of the concentration of glucose in the blood of diabetic rats is studied for comparison with that of the concentration of glucose in aqueous. CONCLUSIONS: This study demonstrates the design of a bioluminescence sensor for quickly detecting the concentration of glucose sensitively.

A chronic physical activity treatment in obese rats normalizes the contributions of ET-1 and NO to insulin-mediated posterior cerebral artery vasodilation.

This study tested the hypotheses that obesity-induced decrements in insulin-stimulated cerebrovascular vasodilation would be normalized with acute endothelin-1a receptor antagonism and that treatment with a physical activity intervention restores vasoreactivity to insulin through augmented nitric oxide synthase (NOS)-dependent dilation. Otsuka Long-Evans Tokushima Fatty rats were divided into the following groups: 20 wk old food controlled (CON-20); 20 wk old free food access (model of obesity, OB-20); 40 wk old food controlled (CON-40); 40 wk old free food access (OB-40); and 40 wk old free food access+RUN (RUN-40; wheel-running access from 20 to 40 wk). Rats underwent Barnes maze testing and a euglycemic hyperinsulinemic clamp (EHC). In the 40-wk cohort, cerebellum and hippocampus blood flow (BF) were examined (microsphere infusion). Vasomotor responses (pressurized myography) to insulin were assessed in untreated, endothelin-1a receptor antagonism, and NOS inhibition conditions in posterior cerebral arteries. Insulin-stimulated vasodilation was attenuated in the OB vs. CON and RUN groups (P ≤ 0.04). Dilation to insulin was normalized with endothelin-1a receptor antagonism in the OB groups (between groups, P ≥ 0.56), and insulin-stimulated NOS-mediated dilation was greater in the RUN-40 vs. OB-40 group (P < 0.01). At 40 wk of age, cerebellum BF decreased during EHC in the OB-40 group (P = 0.02) but not CON or RUN groups (P ≥ 0.36). Barnes maze testing revealed increased entry errors and latencies in the RUN-40 vs. CON and OB groups (P < 0.01). These findings indicate that obesity-induced impairments in vasoreactivity to insulin involve increased endothelin-1 and decreased nitric oxide signaling. Chronic spontaneous physical activity, initiated after disease onset, reversed impaired vasodilation to insulin and decreased Barnes maze performance, possibly because of increased exploratory behavior.NEW & NOTEWORTHY The new and noteworthy findings are that 1) in rodents, obesity-related deficits in insulin-mediated vasodilation are associated with increased influence of insulin-stimulated ET-1 and depressed influence of insulin-stimulated NOS and 2) a physical activity intervention, initiated after the onset of disease, restores insulin-mediated vasodilation, likely by normalizing insulin-stimulated ET-1 and NOS balance. These data demonstrate that the treatment effects of chronic exercise on insulin-mediated vasodilation extend beyond active skeletal muscle vasculature and include the cerebrovasculature.

Aerobic Endurance Training Does Not Protect Bone Against Poorly Controlled Type 1 Diabetes in Young Adult Rats.

Streptozotocin (STZ)-induced type 1 diabetes mellitus (T1DM) decreases trabecular bone volume and bone strength in rodents. The current study investigated the potential protective effects of aerobic endurance training (AET) on bone in STZ-induced T1DM young adult rats. Sixty-four 8-week-old male Sprague-Dawley rats were randomly divided into 4 groups of 16: control non-T1DM sedentary (CS) and exercised (CX), T1DM sedentary (DS) and exercised (DX). Blood glucose was maintained at 9-15 mmol/L using subcutaneously implanted insulin pellets (Linplant, Linshin Canada, Inc.). AET was performed at ~75-85% VO2max for 1 h/day, 5 day/week for 10 weeks. Areal and volumetric bone mineral density (aBMD and vBMD; excised femur) were measured using dual-energy X-ray absorptiometry (DXA; QDR 4500A) and micro computed tomography (µCT; Aloka). Bone strength was tested using a 3-point bending test (Instron 5544 Load Frame). Two-way ANOVA was used to test for T1DM and exercise differences followed by Tukey's HSD tests for interaction effects; significance was set at P < 0.05. T1DM had lower body weight (18.0%), aBMD (8.6%), cortical vBMD (1.6%), trabecular vBMD (2.1%), maximum load at break (22.2%), and increased elastic modulus (11.3%) vs. control (P < 0.001). Exercise in T1DM further decreased body weight (4.7%) vs. sedentary (P = 0.043) and maximum extension during the bending test that demonstrated DX was increased (7.3%) vs. CX (P = 0.033). There were no other beneficial effects of exercise on bone. These results suggest that 10 weeks of AET in rats do not have protective effects on bone in the short term and that T1DM rats have compromised bone health.

Metabolomic Response of Skeletal Muscle to Aerobic Exercise Training in Insulin Resistant Type 1 Diabetic Rats.

The etiology of insulin resistance in Type 1 Diabetes (T1D) is unknown, however it affects approximately 20% of T1D patients. Intramyocellular lipids (IMCL) have been identified as a mechanism of insulin resistance. We examined skeletal muscle of T1D rats to determine if alterations in lipid metabolism were evident and whether aerobic exercise training improves IMCL and insulin resistance. To do so, 48 male Sprague-Dawley rats were divided into control (C), sedentary diabetes (D) and diabetes exercise (DX) groups. Following multiple low-dose Streptozotocin (STZ) injections (20 mg/kg), glycemia (9-15 mM) was maintained using insulin treatment. DX were treadmill trained at high intensity (~75% V02max; 5days/week) for 10 weeks. The results demonstrate that D exhibited insulin resistance compared with C and DX, indicated by decreased glucose infusion rate during a hyperinsulinemic-euglycemic clamp (p < 0.05). There were no differences between C and DX, suggesting that exercise improved insulin resistance (p < 0.05). Metabolomics analysis revealed a significant shift in lipid metabolism whereby notable fatty acid metabolites (arachidonic acid, palmitic acid and several polyunsaturated fatty acids) were significantly elevated in D compared to C and DX. Based on the intermediates observed, insulin resistance in T1D is characterized by an insulin-desensitizing intramyocellular fatty acid metabolite profile that is ameliorated with exercise training.

The glucoregulatory response to high-intensity aerobic exercise following training in rats with insulin-treated type 1 diabetes mellitus.

An acute bout of exercise elicits a rapid, potentially deleterious, reduction in blood glucose in patients with type 1 diabetes mellitus (T1DM). In the current study, we examined whether a 10-week aerobic training program could alleviate the rapid exercise-associated reduction in blood glucose through changes in the glucoregulatory hormonal response or increased hepatic glycogen storage in an insulin-treated rat model of T1DM. Thirty-two male Sprague-Dawley rats were divided evenly into 4 groups: non-T1DM sedentary (C) (n = 8), non-T1DM exercised (CX) (n = 8), T1DM sedentary (D) (n = 8), and T1DM exercised (DX) (n = 8). Exercise training consisted of treadmill running for 5 days/week (1 h, 27 m/min, 6% grade) for 10 weeks. T1DM was induced by multiple streptozotocin injections (20 mg/kg) followed by implantation of subcutaneous insulin pellets. At week 1, an acute exercise bout led to a significant reduction in blood glucose in DX (p < 0.05), whereas CX exhibited an increase in blood glucose (p < 0.05). During acute exercise, serum epinephrine was increased in both DX and CX (p < 0.05), whereas serum glucagon was increased during recovery only in CX (p < 0.01). Following aerobic training in DX, the exercise-mediated reduction in blood glucose remained; however, serum glucagon increased to the same extent as in CX (p < 0.05). DX exhibited significantly less hepatic glycogen (p < 0.001) despite elevations in glycogenic proteins in the liver (p < 0.05). Elevated serum epinephrine and decreased hepatic adrenergic receptor expression were also evident in DX (p < 0.05). In summary, despite aerobic training in DX, abrupt blood glucose reductions and hepatic glycogen deficiencies were evident. These data suggest that sympathetic overactivity may contribute to deficiencies in hepatic glycogen storage.

High Intensity Aerobic Exercise Training Improves Deficits of Cardiovascular Autonomic Function in a Rat Model of Type 1 Diabetes Mellitus with Moderate Hyperglycemia.

Indices of cardiovascular autonomic neuropathy (CAN) in experimental models of Type 1 diabetes mellitus (T1DM) are often contrary to clinical data. Here, we investigated whether a relatable insulin-treated model of T1DM would induce deficits in cardiovascular (CV) autonomic function more reflective of clinical results and if exercise training could prevent those deficits. Sixty-four rats were divided into four groups: sedentary control (C), sedentary T1DM (D), control exercise (CX), or T1DM exercise (DX). Diabetes was induced via multiple low-dose injections of streptozotocin and blood glucose was maintained at moderate hyperglycemia (9-17 mM) through insulin supplementation. Exercise training consisted of daily treadmill running for 10 weeks. Compared to C, D had blunted baroreflex sensitivity, increased vascular sympathetic tone, increased serum neuropeptide Y (NPY), and decreased intrinsic heart rate. In contrast, DX differed from D in all measures of CAN (except NPY), including heart rate variability. These findings demonstrate that this T1DM model elicits deficits and exercise-mediated improvements to CV autonomic function which are reflective of clinical T1DM.