Diabetes and Renin-Angiotensin-Aldosterone System: Pathophysiology and Genetics

Abstract

Diabetes mellitus (DM) is a metabolic disorder and characterized by hyperglycemia. Being a concern of both the developed and developing world, diabetes is a global health burden and is a major cause of mortality world-wide. The most common is the type 2 diabetes mellitus (T2DM), which is mainly caused by resistance to insulin. Long-term complications of diabetes cause microvascular related problems (eg. nephropathy, neuropathy and retinopathy) along with macrovascular complications (eg. cardiovascular diseases, ischemic heart disease, peripheral vascular disease). Renin-angiotensin-aldosterone system (RAAS) regulates homeostasis of body fluid that in turn, maintains blood pressure. Thus, RAAS plays pivotal role in the pathogenesis of long-term DM complications like cardiovascular diseases and chronic kidney diseases. T2DM is a polygenic disease, and the roles of RAAS components in insulin signaling pathway and insulin resistance have been well documented. Hyperglycemia has been found to be associated with the increased plasma renin activity, arterial pressure and renal vascular resistance. Several studies have reported involvement of single variants within particular genes in initiation and development of T2D using different approaches. This chapter aims to investigate and discuss potential genetic polymorphisms underlying T2D identified through candidate gene studies, genetic linkage studies, genome wide association studies.

The Relationship between Renin–Angiotensin–Aldosterone System (RAAS) Activity, Osteoporosis and Estrogen Deficiency in Type 2 Diabetes

“…The renin-angiotensin-aldosterone system is pathologically activated in type II diabetes; this has been noted to result in various detrimental effects, including osteoporosis and estrogen deficiency [22][23][24]. Recent studies have evidenced the presence and activity of the renin-angiotensin system in T2D in various tissues, with observable changes in angiotensinogen, renin, ACE, aldosterone, angiotensin II, AT1R, AT2R, Ang 1-7 and Ang 1-9 in bones [22,25]. Furthermore, patients who suffer from T2D and hypertension usually have osteoporosis, with this phenomenon being highly prevalent in postmenopausal women [26].…”

“…This results in hyperglycinemia due to impaired glucose uptake and insulin resistance [30]. Hyperglycemia induces p53 glycosylation, which has been implicated in angiotensinogen transcription and the subsequent generation of Ang II from the local RAAS [31], thus promoting the upregulation of local RAAS in various organs [25]. Furthermore, the upregulation of RAAS induces insulin resistance in adipose tissue [30].…”

“…Osteoclasts are cells that mediate bone loss by increasing their resorptive activity and causing bone degradation, leading to the initiation of the normal bone remodeling process [93]. In pathological conditions such as T2D, systemic and local RAAS are upregulated, particularly the ACE/Ang II/AT1R axis, which may promote osteoclast over-production leading to bone degradation [25,28,94]. Chronic upregulation of RAAS, as observed in T2D, may result in continued bone breakdown, a decline in bone density, osteoporosis and an increased risk of bone fracture.…”

Insulin resistance and cardiovascular diseases: focus on common in pathogenesis and treatment.

“…Результати останніх мета-аналізів довели, що гіперактивація РААС викликає розвиток ІР і зниження синтезу інсуліну, а фармакологічна блокада РААС покращує секрецію інсуліну та індекс HOMA-IR у пацієнтів з порушенням толерантності до глюкози або ЦД-2 . Наприклад, застосування БРА кандесартану 8 мг на добу протягом 3 місяців посилює першу фазу секреції інсуліну у пацієнтів з АГ та предіабетом, що зменшує постпрандіальну гіперглікемію і HbA1C [1, [40][41][42][43] . Прийом валсартану протягом 6 місяців покращує як першу, так і другу фазу секреції інсуліну, значно зменшує ІР у пацієнтів з АГ та порушенням толерантності до глюкози [34] .…”

Association of rs5051 and rs699 polymorphisms in angiotensinogen with coronary artery disease in Iranian population: A case-control study

“…[4,5] RAAS is involved in many diseases, including atrial fibrillation, congestive heart failure, myocardial fibrosis, cardiomyopathy, hypertension, and type 2 diabetes mellitus. [6][7][8][9][10] Angiotensinogen (AGT) plays a crucial role in RAAS. Angiotensin-converting enzyme converts Angiotensin I to Angiotensin II, which acts as a vasoconstrictor and a growth-promoting factor in the cardiovascular system.…”