AT1 receptor downregulation: A mechanism for improving glucose homeostasis

Figures

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  Figure 1. Mechanism of insulin resistance induced by chronic activation of the AT1 receptor. The binding of insulin to its receptor induces phosphorylation in tyrosine residues of the receptor; from there insulin can exert its function through two signaling pathways. In the first pathway, tyrosine phosphorylation allows the coupling of the IRS1/2, which serves as a scaffold protein for phosphatidylinositol-3 kinase (PI3K). In this way, PI3K has access to plasmatic membrane lipids and phosphorylates phosphatidylinositol 3,4-bisphosphate (PIP2) and converts them into phosphatidylinositol 3,4,5-triphosphate (PIP3). This serves as a storage site for phosphoinositide-dependent protein kinase 1 (PDK1), which together with PDK2 causes the activation of Akt. When Akt is active, it inhibits AS160, allowing GLUT 4 to be released to the cell membrane. The second pathway is the mitogen-activated kinase (MAPK) kinase. This signaling pathway starts with Shc coupling, which serves as a scaffold protein for Grb and son of sevenless (SOS). Activation of SOS can transform guanosine diphosphate or guanosine triphosphate in small G proteins, inducing the MAPK pathway which results in cellular growth and…

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  Figure 2. AT1 receptor antagonists boost glucose homeostasis and body mass index increase in type 2 diabetes mellitus patients. A and B: Comparison between type 2 diabetes mellitus patients and patients diagnosed with type 2 diabetes mellitus and high blood pressure, whose treatment consisted of metformin or metformin + antihypertensive drugs (AHTD), respectively. Glycated hemoglobin A1c was determined for these two groups (A), as well as body mass index (B). Data are expressed as the mean ± SE using GraphPad 7.0 for Windows. n = 18 patients for the metformin group (white bars) and 43 patients for AHTD + metformin group (black bars). Data was collected from the database of patients who came to the internal medicine clinic at Mexicali General Hospital. The protocols carried out in the present study were previously approved by the Hospital General 5 de Diciembre of ISSSTE Mexicali, Mexico, ethics committee (Circular Letter number 0985/2017). aP < 0.05. AHTD: Antihypertensive drugs; BMI: Body mass index; HbA1c: Hemoglobin A1c.

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  Figure 3. AT1 receptor antagonists promote gluconeogenesis decrease in type 2 diabetes mellitus patients. A-D: Comparison between type 2 diabetes mellitus patients and patients diagnosed with type 2 diabetes mellitus and high blood pressure, whose treatment consisted of metformin or metformin + antihypertensive drugs (AHTD), respectively. The age of the patients was reported (A), and the levels of total cholesterol (B), triglycerides (C), and HDL cholesterol (D) in the blood were determined. Data are expressed as the mean ± SE using GraphPad 7.0 for Windows. n = 18 patients for the metformin group (white bars) and 43 patients for AHTD + metformin group (black bars). Data was collected from the database of patients who came to the internal medicine clinic at Mexicali General Hospital. The protocols carried out in the present study were previously approved by the Hospital General 5 de Diciembre of ISSSTE Mexicali, Mexico, ethics committee (Circular Letter number 0985/2017). AHTD: Antihypertensive drugs.