Stella Bernardi1, Christos Tikellis2, Riccardo Candido3, Despina Tsorotes4, Raelene J Pickering5, Fleur Bossi6, Renzo Carretta7, Bruno Fabris8, Mark E Cooper9, Merlin C Thomas10. 1. Baker IDI Heart and Diabetes Institute, 75 Commercial Road 3004 VIC, Melbourne, Australia; Department of Internal Medicine, Cattinara University Hospital, Strada di Fiume 447, Trieste, Italy. Electronic address: stella.bernardi@aots.sanita.fvg.it. 2. Baker IDI Heart and Diabetes Institute, 75 Commercial Road 3004 VIC, Melbourne, Australia. Electronic address: chris.tikellis@bakeridi.edu.au. 3. Diabetes Centre "ASS 1 Triestina", Trieste, Italy. Electronic address: riccardocandido@yahoo.it. 4. Baker IDI Heart and Diabetes Institute, 75 Commercial Road 3004 VIC, Melbourne, Australia. Electronic address: desi.tsorotes@bakeridi.edu.au. 5. Baker IDI Heart and Diabetes Institute, 75 Commercial Road 3004 VIC, Melbourne, Australia. Electronic address: raelene.pickering@bakeridi.edu.au. 6. Department of Medical Surgical and Health Sciences, Cattinara University Hospital, Strada di Fiume 447, Trieste, Italy. Electronic address: fbossi@units.it. 7. Department of Medical Surgical and Health Sciences, Cattinara University Hospital, Strada di Fiume 447, Trieste, Italy. Electronic address: r.carretta@fmc.units.it. 8. Department of Medical Surgical and Health Sciences, Cattinara University Hospital, Strada di Fiume 447, Trieste, Italy. Electronic address: b.fabris@fmc.units.it. 9. Baker IDI Heart and Diabetes Institute, 75 Commercial Road 3004 VIC, Melbourne, Australia. Electronic address: mark.cooper@bakeridi.edu.au. 10. Baker IDI Heart and Diabetes Institute, 75 Commercial Road 3004 VIC, Melbourne, Australia. Electronic address: merlin.thomas@bakeridi.edu.au.
Abstract
BACKGROUND: This study aimed at investigating the effects of genetic angiotensin-converting enzyme (ACE) 2 deficiency on glucose homeostasis in the pancreas and skeletal muscle and their reversibility following ACE inhibition. PROCEDURES: ACE2-knockout and C57bl6J mice were placed on a standard diet (SD) or a high-fat diet (HFD) for 12 weeks. An additional group of ACE2-knockout mice was fed a SD and treated with the ACE inhibitor, perindopril (2 mg kg(-1)day(-1)). Glucose and insulin tolerance tests, indirect calorimetry measurements and EchoMRI were performed. Non-esterfied 'free' fatty acid oxidation rate in skeletal muscle was calculated by measuring the palmitate oxidation rate. β-cell mass was determined by immunostaining. Insulin, collectrin, glucose transporter protein, and peroxisome proliferator-activated receptor-γ expression were analysed by RT-PCR. Markers of mithocondrial biogenesis/content were also evaluated. MAIN FINDINGS: ACE2-knockout mice showed a β-cell defect associated with low insulin and collectrin levels and reduced compensatory hypertrophy in response to a HFD, which were not reversed by perindopril. On the other hand, ACE2 deficiency shifted energy metabolism towards glucose utilization, as it increased the respiratory exchange ratio, reduced palmitate oxidation and PCG-1α expression in the skeletal muscle, where it up-regulated glucose transport proteins. Treatment of ACE2-knockout mice with perindopril reversed the skeletal muscle changes, suggesting that these were dependent on Angiotensin II (Ang II). PRINCIPAL CONCLUSIONS: ACE2-knockout mice display a β-cell defect, which does not seem to be dependent on Ang II but may reflect the collectrin-like action of ACE2. This defect seemed to be compensated by the fact that ACE2-knockout mice shifted their energy consumption towards glucose utilisation via Ang II.
BACKGROUND: This study aimed at investigating the effects of genetic angiotensin-converting enzyme (ACE) 2deficiency on glucose homeostasis in the pancreas and skeletal muscle and their reversibility following ACE inhibition. PROCEDURES: ACE2-knockout and C57bl6J mice were placed on a standard diet (SD) or a high-fat diet (HFD) for 12 weeks. An additional group of ACE2-knockout mice was fed a SD and treated with the ACE inhibitor, perindopril (2 mg kg(-1)day(-1)). Glucose and insulin tolerance tests, indirect calorimetry measurements and EchoMRI were performed. Non-esterfied 'free' fatty acid oxidation rate in skeletal muscle was calculated by measuring the palmitate oxidation rate. β-cell mass was determined by immunostaining. Insulin, collectrin, glucose transporter protein, and peroxisome proliferator-activated receptor-γ expression were analysed by RT-PCR. Markers of mithocondrial biogenesis/content were also evaluated. MAIN FINDINGS:ACE2-knockout mice showed a β-cell defect associated with low insulin and collectrin levels and reduced compensatory hypertrophy in response to a HFD, which were not reversed by perindopril. On the other hand, ACE2deficiency shifted energy metabolism towards glucose utilization, as it increased the respiratory exchange ratio, reduced palmitate oxidation and PCG-1α expression in the skeletal muscle, where it up-regulated glucose transport proteins. Treatment of ACE2-knockout mice with perindopril reversed the skeletal muscle changes, suggesting that these were dependent on Angiotensin II (Ang II). PRINCIPAL CONCLUSIONS:ACE2-knockout mice display a β-cell defect, which does not seem to be dependent on Ang II but may reflect the collectrin-like action of ACE2. This defect seemed to be compensated by the fact that ACE2-knockout mice shifted their energy consumption towards glucose utilisation via Ang II.
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