Abstract: TH-PO697

Effect of ACE2 Deletion on Glucose Homeostasis, Renin Angiotensin System, and Necrosis

Session Information

Category: Diabetes

  • 501 Diabetes Mellitus and Obesity: Basic - Experimental

Authors

  • Palau, Vanesa, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
  • Riera, Marta, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
  • Roca Ho, Heleia, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
  • Benito, David, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
  • Pascual, Julio, Hospital del Mar, Parc de Salut Mar, Barcelona, Spain
  • Soler, Maria Jose, Hospital del Mar, Parc de Salut Mar, Barcelona, Spain
Background

Angiotensin converting enzyme 2 (ACE2) acts as a negative regulator of renin angiotensin system (RAS). Downregulation of ACE2 either by gene deletion or by pharmacological inhibition worsens renal injury and hypertension. Indiabetes, ACE2 activity is increased in pancreas from non-obese diabetic (NOD) mice. ACE2 deletion on pancreas from NOD mice has not been previously studied. We propose to study the effect of ACE2 deletion in NOD mice in an early pre-diabetic stage on glucose homeostasis, insulin secretion, RAS, oxidative stress and necroptosis.

Methods

Female NOD-ACE2-/- mice were studied at 12 weeks of age and compared to NOD-ACE2+/+ mice. Glucose tolerance tests were performed by intraperitoneal administration of D-glucose bolus. Circulating glucose levels were determined at 0, 15, 30 and 60 minutes after injection. Insulin secretion was determined by ELISA technique from serum samples collected at 0, 2 and 5 minutes after glucose bolus injection. Immunohistochemistry studies for insulin, ACE, angiotensin II receptor 1 (AT1R), nitrotyrosine and RIP-1 were performed in paraffin-embedded pancreas.

Results

NOD-ACE2-/- mice had less tolerance to glucose bolus, lower insulin secretion after glucose administration, less insulin production and smaller islet area. Regarding RAS, NOD-ACE2-/- mice presented higher levels of ACE and AT1R staining as compared to NOD-ACE2+/+ mice. NOD-ACE2-/- mice had higher levels of nitrotyrosine and RIP-1 as markers of oxidative stress and necroptosis, respectively (Table).

Conclusion

NOD mice with ACE2 deletion present altered glucose tolerance, functional and morphological alterations at a pancreatic level due to insulin synthesis and secretion as well as decreased islet area. ACE2 deletion leads to a worsening glucose homeostasis in NOD mice accompanied to higher levels of oxidative stress and necroptosis and RAS stimulation by increasing ACE and AT1R expression.