Beneficial metabolic actions of a stable GIP agonist following pre-treatment with a SGLT2 inhibitor in high fat fed diabetic mice.

The purpose of the present study was to examine if a stable glucose-dependent insulinotropic polypeptide (GIP) agonist could exert beneficial metabolic control in diabetic mice which had been pre-treated with sodium-glucose-cotransporter-2 (SGLT2) inhibitor dapagliflozin (DAPA). High fat fed mice administered low dose streptozotocin (STZ) received vehicle, DAPA once-daily over 28 days, or DAPA once-daily for 14 days followed by (DAla(2))GIP once-daily for 14 days. Energy intake, body weight, glucose and insulin concentrations were measured at regular intervals. Glucose tolerance, insulin tolerance test, dual-energy X-ray absorptiometry (DEXA) and pancreatic histology were examined. Once-daily administration of (DAla(2))GIP for 14 days in high fat fed diabetic mice pre-treated with DAPA demonstrated significant decrease in body weight, blood glucose and increased insulin concentrations which were independent of changes in energy intake. Similarly, glucose tolerance, glucose-stimulated insulin secretion, insulin sensitivity and HOMA-ß were significantly enhanced in (DAla(2))GIP-treated mice. DEXA analysis revealed sustained percentage body fat loss with no changes in lean mass, bone mineral content and density. Pancreatic immunohistochemical analysis revealed decreased islet number and increases in islet area, beta cell area and pancreatic insulin content. The DAPA-induced increase in alpha cell area was also reversed. Additional acute in vitro and in vivo experiments confirmed that the impaired action of (DAla(2))GIP under hyperglycaemic-induced conditions was significantly reversed by DAPA treatment. These data demonstrate that (DAla(2))GIP can exert beneficial metabolic control in high fat fed diabetic mice pre-treated with DAPA. The results highlight possibility of a targeted and personalized approach using a GIP agonist and SGLT2 inhibitor for the treatment of type 2 diabetes.

Non-invasive electrocardiographic assessments of cardiac autonomic modulation in individuals with spinal cord injury.

STUDY DESIGN: Review. OBJECTIVES: The purpose of this review is to discuss the utility of linear and non-linear heart rate variability (HRV) as well as the QT-variability index (QTVI) as indices of cardiac autonomic control in individuals with spinal cord injury (SCI). SETTING: Brock University, Department of Kinesiology, St Catharines, Ontario, Canada. Brock-Niagara Centre for Health and Well-being, St Catharines, Ontario, Canada. METHODS: Literature review. CONCLUSION: Non-invasive markers determined from the electrocardiogram, such as linear and non-linear HRV, and, more recently, the QTVI have all shown some promise as indices of cardiac autonomic regulation in the SCI population. However, there are inconsistencies in the literature that call to question their true validity in this regard. Studies using pharmacological blockade, sympathetic manoeuvres and exercise suggest that both linear and non-linear HRV reflect cardiac parasympathetic activity, whereas their ability to quantify cardiac sympathetic outflow remains uncertain. The QTVI, although a novel method, correlates with both limbs of the autonomic nervous system and therefore may hold value as a measure of both cardiac sympathetic and parasympathetic activity in individuals with SCI; however, more research is required to confirm its utility.

Isometric handgrip training lowers blood pressure and increases heart rate complexity in medicated hypertensive patients.

Hypertension is characterized by elevated blood pressure (BP) and autonomic dysfunction, both thought to be improved with exercise training. Isometric handgrip (IHG) training may represent a beneficial, time-effective exercise therapy. We investigated the effects of IHG training on BP and traditional and nonlinear measures of heart rate variability (HRV). Pre- and post-measurements of BP and HRV were determined in 23 medicated hypertensive participants (mean ± SEM, 66 ± 2 years) following either 8 weeks of IHG training (n = 13) or control (n = 10). IHG exercise consisted of four unilateral 2-min isometric contractions at 30% of maximal voluntary contraction, each separated by 4 min of rest. IHG training was performed 3 days/week for 8 weeks. IHG training decreased systolic BP (125 ± 3 mmHg to 120 ± 2 mmHg, P < 0.05) and mean BP (90 ± 2 mmHg to 87 ± 2 mmHg, P < 0.05), while sample entropy was increased (1.07 ± 0.1 to 1.35 ± 0.1, P < 0.05) and the fractal scaling distance score was decreased (0.34 ± 0.1 to 0.19 ± 0.1, P < 0.05). No significant changes were observed in traditional spectral or time-domain measures of HRV or control participants. IHG training improves nonlinear HRV, but not traditional HRV, while reducing systolic and mean BP. These results may highlight the benefits of IHG training for patients with primary hypertension.

Autonomic recovery following sprint interval exercise.

The autonomic nervous activity was assessed following supramaximal exercise through heart rate (HR) and blood pressure (BP) variability (HRV and BPV) and baroreflex sensitivity (BRS). The beat-to-beat HR and BP were recorded during the supine and standing states before (PRE) and at 60 (R60) and 120 min (R120) following single (one Wingate, 1W) and multiple sprint intervals (four Wingates interspersed with 4 min of light cycling, 4W). The supine low frequency (LF) component was increased (P<0.001) and the high frequency (HF) was reduced (P<0.01) at R60 (LF, 178.1 ± 11.0; HF, 74.8 ± 10.5) compared with PRE (LF, 140.2 ± 7.4; HF, 110.4 ± 7.2) after both exercises. Supine systolic BPV LF:HF was higher at R60 (4.6 ± 1.4) compared with PRE (6.8 ± 2.4) only after 4W (P=0.035). Supine BRS was lower (P<0.001) at R60 (6.8 ± 1.1) than at PRE (15.3 ± 1.8) and R120 (11.3 ± 1.3). BRS at R120 remained lower after 4W (P=0.02). Standing BRS was less (P<0.001) at R60 (2.3 ± 0.5) than at PRE (5.6 ± 0.8) or R120 (3.7 ± 0.6) and returned to PRE values only after 1W. We concluded that (a) autonomic balance is shifted to a greater sympathetic and less parasympathetic activation following both types of exercise, (b) it takes longer than 1 h to recover following supramaximal exercise and (c) the recovery is longer after 4W than 1W.

Effects of isometric handgrip protocol on blood pressure and neurocardiac modulation.

Isometric handgrip (IHG) remains a well-studied cardiovascular and autonomic stimulus, however the effects of rhythmic IHG protocols remain largely unknown. The purpose of this study was to investigate the acute effects of 4 IHG protocols on blood pressure (BP) and neurocardiac reactivity and recovery responses. 12 healthy older participants (70±5 yrs, ♀=4) each completed 4 bilateral 12-min protocols (sham, IHG1, IHG2, IHG3) on separate visits. IHG1, IHG2, and IHG3 consisted of 4×2-min, 8×1-min, and 16×30-s isometric contractions, respectively, each completed at 30% MVC, while sham consisted of 4×2-min contractions completed at 3% MVC. BP and neurocardiac modulation were assessed during and following each protocol. Systolic BP (SBP) reactivity was increased during IHG1 compared to IHG2 (p<0.05), IHG3 (p<0.05), and sham (p<0.01), although during recovery delta SBP was lower following IHG1 (p<0.01), IHG2 (p<0.01), and IHG3 (p<0.05), compared to sham. Sample entropy, a measure of nonlinear heart rate variability was reduced during IHG1 (p<0.01) and IHG2 (p<0.05), while increased following IHG1 (p<0.05) and IHG3 (p<0.05), compared to sham. In conclusion, recovery responses from rhythmic IHG appear independent of contraction and/or rest period frequency-duration relationships. Investigation of rhythmic IHG protocols warrants further examination.