Pancreatic Renin-Angiotensin-Aldosterone System in the Cardiometabolic Syndrome and Type 2 Diabetes Mellitus

Composite pancreatic function involves a complex interaction between the endocrine, exocrine, and gut neuroendocrine-incretin hormonal axis (insulino-acinar-ductal-incretin axis). This synchronous and dynamic interplay is required for assembly of nutritional intake into usable energy and proper gut uptake of nutrients. Cellular and extracellular matrix (ECM) remodeling may result in isletopathy and exocrinopathy, which contribute to the pathogenesis of the cardiometabolic syndrome (CMS) and type 2 diabetes mellitus (T2DM). These pancreatic end-organ remolding changes involve oxidative stress, islet amyloid deposition, endocrine and exocrine fibrosis, islet b-cell and exocrine acinar apoptosis, exocrine adipose replacement, and exocrine atrophy and may share dynamic interacting roles in the CMS and T2DM. The endocrine islet, exocrine acinar, and ductal system of the pancreas are intermingled to act as one organ dedicated to the goal of synchronizing oral nutritional intake to digestion, absorption, and energy metabolism. Their harmonious action is coordinated via an interdependent array of neural and endocrine, autocrine, and paracrine hormonal factors in conjunction with an intact neurovascular supply. In addition, there are contributing neuroendocrine cells in the gut, which make for a coordinated and synchronous endocrine-exocrine-gut incretin hormone axis. To date, no specific role for a pancreatic renin-angiotensin-aldosterone system (RAAS) in these complex mechanisms has been established. Its presence in both the endocrine and exocrine pancreas, however, may allow the RAAS to be involved in fine-tuning some of the above nutritional responses or coordinating some of its actions. There is emerging evidence, however, that an overactive tissue RAAS is involved in both islet and exocrine pancreatic cellular ECM remodeling and disease. A local tissue RAAS has now been identified in various organ systems such as the adrenal, pituitary, heart, vasculature, kidney, adipose, retina, nervous, reproductive, digestive, and recently the pancreas systems, including both the endocrine and exocrine pancreas. This local RAAS has many important functions including cell growth, differentiation, proliferation and apoptosis, reactive oxygen species generation via angiotensin II (Ang II) activation of its angiotensin type 1 receptor and activation of vascular nonphagocytic nicotine adenine dinucleotide phosphate (reduced) oxidase enzyme, inflammation, hormonal secretion, and importantly ECM remodeling fibrosis. The endocrine and exocrine pancreas are influenced by both circulating and locally generated Ang II. The endocrine pancreas is quite vascular and its blood supply is approximately 10 times greater than that of the exocrine pancreas. Ang II infusion dose-dependently reduces pancreatic blood flow, and this is especially detrimental in the highly vascularized endocrine islets. Further, RAAS blockade has been shown to enhance islet blood flow, oxygen tension, and insulin synthesis, thus improving b-cell function and glucose tolerance. Ang II (the octapeptide and major effector molecule of the RAAS) is synthesized in a multistep process beginning with angiotensinogen (an a globular protein), which is cleaved by the aspartic peptidase renin produced mainly in the juxtaglomerular cells of the kidney to generate the biologically inactive decapeptide angiotensin I. Angiotensin I is converted to the major effector molecule Ang II of the RAAS primarily by the angiotensin-converting enzyme or non–angiotensin-converting enzyme serine proteases (chymase and cathepsin G). Pathophysiologic conditions known to result in activation of a local pancreatic RAAS include hypoxia, pancreatitis, diabetes mellitus (type 1 and type 2), hyperglycemia, islet transplantation, and pancreatic cancer. Importantly, clinical trials have shown that RAS blockade may delay the onset of overt T2DM in patients with impaired glucose tolerance or prediabetes. Ang II is also known to be a potent activator of the adrenocortical hormone aldosterone, which has both glucocorticoid and mineralocorticoid receptor(s). A recent editorial in Melvin R. Hayden, MD; James R. Sowers, MD From the Department of Internal Medicine, Endocrinology, Diabetes, and Metabolism, Diabetes and Cardiovascular Disease Research Group, University of Missouri School of Medicine; the Diabetes and Cardiovascular Center, University of Missouri-Columbia School of Medicine; and the Department of Medicine and the Department of Physiology and Pharmacology, Harry S. Truman VA Medical Center, Columbia, MO