ACE2 modulates glucose homeostasis through GABA signaling during metabolic stress

Abstract

<jats:p>The angiotensin-converting enzyme 2 (ACE2)/angiotensin 1-7 (A1-7)/MAS axis and glutamate decarboxylase 67 (GAD67)/gamma-aminobutyric acid (GABA) signal both exist in the islet and play important roles in regulating blood glucose metabolism. It has been reported that the activation of ACE2 in the brain increases GABA expression to improve biological effects; however, it is unclear whether there is functional correlation between the ACE2/A1-7/MAS axis and GAD67/GABA signal in the islet. In this study, we showed that the ACE2/A1-7/MAS and GABA signaling systems decreased in the islet of different metabolic stress models. In ACE2-knockout mice, we found that GAD67 and GABA expression decreased significantly, which was reversed by exogenous administration of A1-7. Furthermore, A1-7 mediated PDX1 and AKT activation was inhibited by allylglycine (a specific GAD67 inhibitor) in MIN6 cells. Moreover, giving A1-7 and GABA could significantly reduce beta-cell dedifferentiation and improved glucose metabolism during metabolic stress in vivo and in vitro. In conclusion, our study reveals that the ACE2/A1-7/MAS axis improves beta-cell function through regulating GAD67/GABA signal in beta cells, and up-regulating the ACE2/A1-7/MAS axis and GABA signals delays the development of obesity-induced diabetes.</jats:p>

miR-98 Regulates TMPRSS2 Expression in Human Endothelial Cells: Key Implications for COVID-19

“…Our data are significant in the clinical scenario; indeed, since TMPRSS2 is known to play a crucial role in the pathophysiology of COVID-19, our results could open the field to new research in order to verify the role of miR-98-5p in other tissues and cell types. It is important to note that several potential therapeutic strategies targeting ACE2 have been already proposed to tackle COVID-19; however, mainly owing to the critical metabolic and hemodynamic roles of ACE2, including the regulation of glucose homeostasis [56][57][58][59] as well as the cleavage of Angiotensin I and Angiotensin II [60,61], these approaches could lead to major issues in the clinical scenario [57,62,63]. Therefore, TMPRSS2 could represent a valid alternative target in COVID-19 [64][65][66].…”

ACE2 function in the pancreatic islet: Implications for relationship between SARS‐CoV‐2 and diabetes

“…24 One mechanism by which ACE2/Ang (1-7)/MAS pathway maintains glucose homoeostasis is by modulating the GAD67/ GABA signalling in pancreatic islets. 36 Interestingly, Ang (1-7) enhances insulin secretion in mice through the Ang (1-7)/Ang (1-2)/GPRC6A axis as well, which is mediated through the proteolytic action of another peptidase called Neprilysin that generates the smaller peptide Ang (1-2) from Ang (1-7) (Table 1). 37 Ang II is known for triggering the generation of reactive oxygen species (ROS) such as superoxide and hydrogen peroxide.…”

“…Pancreatic explants treated with the MAS receptor inhibitor decreases numbers of Ins+/Ki67+ cells indicating a decline in beta cell proliferation (Table 1). 24 One mechanism by which ACE2/Ang (1‐7)/MAS pathway maintains glucose homoeostasis is by modulating the GAD67/GABA signalling in pancreatic islets 36 . Interestingly, Ang (1‐7) enhances insulin secretion in mice through the Ang (1‐7)/Ang (1‐2)/GPRC6A axis as well, which is mediated through the proteolytic action of another peptidase called Neprilysin that generates the smaller peptide Ang (1‐2) from Ang (1‐7) (Table 1).…”

Changes of ACE2 in different glucose metabolites and its relationship with COVID-19

“…[ 10 ] ACE2 can improve the endothelial function of islet microvessels to protect islet function, ACE2/Ang1-7 can regulate glucose homeostasis by regulating GAD67/GABA signal transduction in β cells, improving β-cell function, and delaying the induction of diabetes. [ 11 ] ACE2 can reduce oxidative stress and apoptosis in islet cells and improve insulin secretion. [ 12 ]…”