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.
•Insulin-treated Type 1 Diabetic rats do not show a decrease in executive function, or more specifically set-shifting abilities.•This is the first study to examine set-shifting in a relevant rodent model of Type 1 Diabetes using insulin-treatment.
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.
The etiology of insulin resistance (IR) development in type 1 diabetes (T1D) remains unclear; however, impaired glucose metabolism in skeletal muscle may play a role. While IR development has been ...established in male rodents with T1D, 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 T1D compared to aerobic exercise. The purpose of this study was to investigate the effects of RT on IR development in female rodents with T1D. Forty Sprague-Dawley 8-week-old female rats were divided into four groups: control sedentary (CS; n=10), control trained (CT; n=10), T1D sedentary (DS; n=10), T1D trained (DT; n=10). Multiple low-dose Streptozotocin injections (20 mg/kg each day for 7 consecutive days) were used to induce T1D. Blood glucose levels were maintained in normal range (4-9mmol/L) with one implanted insulin pellet (2IU/day). CT and DT underwent weighted ladder climbing 5 days/week for 6 weeks. Intravenous glucose tolerance tests (IVGTT) were conducted on all animals during weeks 4 and 7. Results demonstrate that DS animals exhibited significantly increased weekly blood glucose measures compared to all groups including DT (p<0.05), despite similar insulin dosage levels. This was concomitant with a significant increase in area under the curve following IVGTT from week 4 to week 7 in DS (p<0.05), indicative of a reduction in insulin sensitivity. DS animals also exhibited significantly greater glycogen content in white gastrocnemius muscle compared to all groups (p<0.05). These results indicate that female rodents with T1D develop poor glycemic control and IR which can be attenuated with RT, possibly related to differences in glycogen content within muscle. This data supports the negative role of elevated muscle glycogen on insulin sensitivity in T1D and the potential role of RT in ameliorating these metabolic changes.
Disclosure
M.Sammut: None. D.Mcbey: None. C.Melling: None.
Adjuvant therapy in pancreatic cancer Jones, Owain Peris; Melling, James Daniel; Ghaneh, Paula
World journal of gastroenterology,
10/2014, Letnik:
20, Številka:
40
Journal Article
Odprti dostop
Pancreatic cancer remains one of the leading causesof cancer related death worldwide with an overall fiveyear survival of less than 5%.Potentially curative surgery,which alone can improve 5-year ...survival to 10%,is an option for only 10%-20%of patients at presentation owing to local invasion of the tumour or metastaticdisease.Adjuvant chemotherapy has been shown toimprove 5-year survival to 20%-25%but conflicting evidence remains with regards to chemoradiation.In thisarticle we review the current evidence available frompublished randomised trials and discuss ongoing phaseⅢtrials in relation to adjuvant therapy in pancreaticcancer.
Insulin stimulates nerve arterial vasodilation through a nitric oxide (NO) synthase (NOS) mechanism. Experimental diabetes reduces vasa nervorum NO reactivity. Studies investigating hyperglycemia and ...nerve arterial vasodilation typically omit insulin treatment and use sedentary rats resulting in severe hyperglycemia. We tested the hypotheses that 1) insulin-treated experimental diabetes and inactivity (DS rats) will attenuate insulin-mediated nerve arterial vasodilation, and 2) deficits in vasodilation in DS rats will be overcome by concurrent exercise training (DX rats; 75-85% VO2 max, 1 h/day, 5 days/wk, for 10 wk). The baseline index of vascular conductance values (VCi = nerve blood flow velocity/mean arterial blood pressure) were similar (P ≥ 0.68), but peak VCi and the area under the curve (AUCi) for the VCi during a euglycemic hyperinsulinemic clamp (EHC; 10 mU·kg(-1)·min(-1)) were lower in DS rats versus control sedentary (CS) rats and DX rats (P ≤ 0.01). Motor nerve conduction velocity (MNCV) was lower in DS rats versus CS rats and DX rats (P ≤ 0.01). When compared with DS rats, DX rats expressed greater nerve endothelial NOS (eNOS) protein content (P = 0.04). In a separate analysis, we examined the impact of diabetes in exercise-trained rats alone. When compared with exercise-trained control rats (CX), DX rats had a lower AUCi during the EHC, lower MNCV values, and lower sciatic nerve eNOS protein content (P ≤ 0.03). Therefore, vasa nervorum and motor nerve function are impaired in DS rats. Such deficits in rats with diabetes can be overcome by concurrent exercise training. However, in exercise-trained rats (CX and DX groups), moderate hyperglycemia lowers vasa nervorum and nerve function.
Abstract Individuals with Type 1 Diabetes Mellitus (T1DM) can develop insulin resistance. Regular exercise may improve insulin resistance partially through increased expression of skeletal muscle ...GLUT4 content. Objective To examine if different exercise training modalities can alter glucose tolerance through changes in skeletal muscle GLUT4 content in T1DM rats. Methods Fifty rats were divided into 5 groups; control, diabetic control, diabetic resistance exercised, and diabetic high and low intensity treadmill exercised. Diabetes was induced using multiple low dose Streptozotocin (20 mg/kg/day) injections and blood glucose concentrations were maintained moderately hyperglycemic through subcutaneous insulin pellets. Resistance trained rats climbed a ladder with incremental loads, while treadmill trained rats ran on a treadmill at 27 or 15 m/min, respectively, all for 6 weeks. Results At weeks 3 and 6, area under the curve measurements following an intravenous glucose tolerance test (AUC-IVGTT) in all diabetic groups were higher than control rats (p < 0.05). At 6 weeks, all exercise groups had significantly lower AUC-IVGTT values than diabetic control animals (p < 0.05). Treadmill trained rats had the lowest insulin dose requirement of the T1DM rats and the greatest reduction in insulin dosage was evident in high intensity treadmill exercise. Concomitant with improvements in glucose handling improvements, tissue-specific elevations in GLUT4 content were demonstrated in both red and white portions of vastus lateralis and gastrocnemius muscles, suggesting that glucose handling capacity was altered in the skeletal muscle of exercised T1DM rats. Conclusions These results suggest that, while all exercise modalities can improve glucose tolerance, each mode leads to differential improvements in insulin requirements and protein content alterations.
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.
Celotno besedilo
Dostopno za:
DOBA, FSPLJ, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
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.
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.
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.
•Conditioned pain modulation is potentially an important biomarker in chronic pain.•Identification of what constitutes true change requires investigation.•± 2 SEM of the test stimulus may help to identify pain modulation responders.•Only 30% of healthy subjects exhibited inhibitory pain modulation to noxious cold.•Inhibitory pain modulation may be associated with the sympathetic nervous system.
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.
The dynamic adjustment and amplitude of the endothelium-dependent vasorelaxation of the carotid, aorta, iliac, and femoral vessels were measured in response to acute low- (LI) or high-intensity (HI) ...endurance exercise. Vasorelaxation to 10(-4) M ACh was evaluated in 10 control, 10 LI, and 10 HI rats. Two-millimeter sections of carotid, aorta, iliac, and femoral arteries were mounted onto a myography system. Vasorelaxation responses were modeled as a monoexponential function. The overall τ (control, 10.5 ± 6.0 s; LI, 10.4 ± 5.7 s; HI, 11.0 ± 6.9 s) and time-to-steady-state (control, 47.6 ± 24.0 s; LI, 46.2 ± 22.8 s; HI, 49.1 ± 28.3 s) was similar in LI, HI, and control (P > 0.05). The overall (average of four vessel-type) % vasorelaxation was larger in LI (73 ± 16%) and HI (73 ± 16%) than in control (66 ± 19%) (P < 0.05). The overall rate of vasorelaxation was greater in LI (1.9 ± 0.9%·s(-1)) and HI (1.9 ± 1.1%·s(-1)) compared with control (1.6 ± 0.7%·s(-1)) (P < 0.05). The vessel-specific responses (average response for the three conditions) showed that carotid displayed a slower adjustment (τ, 18.9 ± 4.4 s; time-to-steady-state, 80.4 ± 18.4 s) compared with the aorta (τ, 10.3 ± 3.8 s; time-to-steady-state, 46.3 ± 15.2 s), the iliac (τ, 6.3 ± 2.1 s; time-to-steady-state, 30.3 ± 9.0 s), and the femoral (τ, 6.0 ± 1.9 s; time-to-steady-state, 29.3 ± 8.4 s). The % vasorelaxation was larger in the carotid (82 ± 14%) than in the aorta (67 ± 16%), iliac (61 ± 13%), and femoral (71 ± 19%) (P > 0.05). The rate of vasorelaxation was carotid (1.1 ± 0.2%·s(-1)), aorta (1.5 ± 0.4%·s(-1)), iliac (2.2 ± 0.8%·s(-1)), and femoral (2.6 ± 1.0%·s(-1)). In conclusion, an acute bout of endurance exercise increased vascular responsiveness. The dynamic and percent adjustments were vessel-specific with vessel function likely determining the response.
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