Renin-angiotensin system and diabetes

Diabetes is a chronic disease that occurs when the pancreas produces insufficient insulin, or when the body cannot effectively respond to the insulin that it produces. Hyperglycemia is a characteristic of uncontrolled diabetes that, over time, leads to serious damage to many of the body's systems, especially nerves and blood vessels. According to the World Health Organization (W.H.O.), diabetes causes about 5% of all deaths globally each year. Without effective interventions, diabetes deaths are likely to increase by more than 50% in the next 10 years. To contain the epidemic of diabetes it is imperative to determine the causes of this deadly disease. While many consequences of diabetes are known, there is uncertainty about the exact pathophysiological pathways leading to the disease and its complications. One of the proposed hypotheses includes dysfunctional β-cells in the islets of Langerhans in the pancreas and inefficient utilization of secreted insulin. The focus of this chapter is the participation of a major hormonal system - the renin-angiotensin system (RAS) - in diabetes. Over-activation of this system has been reported to play a key role in diabetes. Major components of the RAS such as Angiotensin Converting Enzyme (ACE), Angiotensin II (Ang-II) type 1 and type 2 receptors (AT1R and AT2R) have been identified in human and rodent pancreatic islet cells. While most studies have addressed RAS over-activation as a consequence of diabetes, there is also research supporting a hypothesis implicating RAS over-activation as a cause of the disease. Abnormal increases in Ang-II levels, resulting from RAS over-activation, can thus impair glucose tolerance and insulin sensitivity in experimental models. These effects can be attributed to several known actions of the peptide such as vasoconstriction reducing β-cells perfusion, and/or oxidative stress decreasing insulinsecretion from the pancreas. Moreover in db/db mice, an established model of type 2 diabetes, RAS over-activation has been reported to worsen diabetic complications. With the recent discovery of a new RAS component, Angiotensin Converting Enzyme 2 (ACE2), capable of regulating Ang-II levels, comes a potential new therapeutic target for Ang-II-mediated insulin resistance and impaired glucose tolerance. Not only can ACE2 hydrolyze Ang-II but by doing so, it generates a new physiologically important peptide, Ang-(1-7). Ang-(1-7) acts on Mas receptors causing vasodilation and potentially reducing oxidative stress; i.e. Ang-(1-7) tends to oppose the actions of Ang-II. In this chapter, we are looking at the evidence for RAS over-activation as a cause and consequence of β-cell dysfunction and diabetes. We will further review the ACE2/Ang-(1-7)/Mas axis of the RAS as a potential therapeutic target to ameliorate symptoms of diabetes.