Angiotensin-Converting Enzyme 2 Deficiency Aggravates Glucose Intolerance via Impairment of Islet Microvascular Density in Mice with High-Fat Diet

The aim of this study was to evaluate the effects of angiotensin-converting enzyme 2 (ACE2) on glucose homeostasis and islet function in mice. Male wildtype (WT) and ACE2 knockout (ACE2 KO) mice were divided into chow diet group and long-term high-fat diet (HFD) group. After 16 weeks of feeding, the islet function of the animals was evaluated by intraperitoneal glucose tolerance test (IPGTT) and intraperitoneal insulin releasing test (IPIRT). The pancreas was immunohistochemically stained to analyze the relative content of insulin (IRC), vascular endothelial growth factor (VEGF), and microvessel density (MVD) in islets. There was no difference of body weight, area under curve of glucose (AUCG), area under curve of insulin from 0 to 5？min (AUGI0–5), MVD, and RVC (relative content of VEGF) between WT and ACE2 KO mice with regular chow diet. Under the condition of long-term HFD, the AUCG of ACE2 KO mice was increased obviously in comparison with the WT mice, with decreased IRC, MVD, AUGI0–5, AUCI0–30, and RVC (all ). In conclusion, these results show that ACE2 deficiency deteriorates islet function of mice with long-term HFD via impairment of islet microvasculature. 1. Introduction The classical renin-angiotensin system (RAS), ACE-Ang II-AT1 receptor axis, is a coordinated hormonal cascade facilitating the dynamic control of perfusion in both health and disease [1]. In 2000, a new member of the RAS, ACE2, was discovered by two independent groups [2, 3]. ACE2 is capable of metabolizing Ang II to generate Ang (1-7) [4]. Ang (1-7) interacting with its receptor Mas elicits numerous actions that counterbalance those of Ang II [5]. Accumulating evidence have indicated that ACE2-Ang (1-7)-Mas axis acts as a negative regulator of the ACE-Ang II-AT1 receptor axis [6]. During the past decades, the existence of a local RAS has been confirmed in both the endocrine and exocrine pancreas [7–9]. In 1991, an intrinsic RAS in the pancreas was firstly described by Chappell et al. [10]. Lau et al. [11] identified the expression of several RAS components in mouse pancreatic islet, such as angiotensinogen, ACE, AT1, and AT2 receptors. The evidence for the existence of these above components were also observed in human pancreas [12]. In addition, ACE2 mRNA and protein have been identified in the pancreatic islets [13]. Canine pancreatic Ang (1-7) [10] and rat pancreatic Mas receptor have also been confirmed [14]. Previous studies [15, 16] have provided additional evidence for the close association of RAS with pancreatic endocrine physiology and its pathophysiology. Islet