Modulation of glucose metabolism by the renin-angiotensin-aldosterone system

Abstract

The renin-angiotensin-aldosterone system (RAAS) is an enzymatic cascade functioning in a paracrine and autocrine fashion. In animals and humans, RAAS intrinsic to tissues modulates food intake, metabolic rate, adiposity, insulin sensitivity, and insulin secretion. A large array of observations shows that dysregulation of RAAS in the metabolic syndrome favors type 2 diabetes. Remarkably, angiotensin-converting enzyme inhibitors, suppressing the synthesis of angiotensin II (ANG II), and angiotensin receptor blockers, targeting the ANG II type 1 receptor, prevent diabetes in patients with hypertensive or ischemic cardiopathy. These drugs interrupt the negative feedback loop of ANG II on the RAAS cascade, which results in increased production of angiotensins. In addition, they change the tissue expression of RAAS components. Therefore, the concept of a dual axis of RAAS regarding glucose homeostasis has emerged. The RAAS deleterious axis increases the production of inflammatory cytokines and raises oxidative stress, exacerbating the insulin resistance and decreasing insulin secretion. The beneficial axis promotes adipogenesis, blocks the production of inflammatory cytokines, and lowers oxidative stress, thereby improving insulin sensitivity and secretion. Currently, drugs targeting RAAS are not given for the purpose of preventing diabetes in humans. However, we anticipate that in the near future the discovery of novel means to modulate the RAAS beneficial axis will result in a decisive therapeutic breakthrough.

Insulin Signaling and Heart Failure

“…Furthermore, increased catecholamine concentrations stimulate hepatic glycogenolysis and gluconeogenesis leading to increased circulating glucose. Heart failure is also associated with hyperactivation of the renin-angiotensin-aldosterone system (RAAS), system, which has been implicated in the pathophysiology of insulin resistance 96 . In addition to increasing circulating concentrations of angiotensinogen (originating from adipose tissue) 97 , chronic hyperinsulinemia may also increase the expression of angiotensin II receptors, which may further exacerbate adverse left ventricular remodeling 98 .…”

Metabolic Effects of Obesity and Its Interaction with Endocrine Diseases

“…In humans, obesity is associated with mildly increased serum thyroid-stimulating hormone and triiodothyronine concentrations, 66 increased serum growth hormone (but not insulinlike growth factor-1) concentrations, 67 increased circulating concentrations of angiotensinogen, renin, angiotensin-converting enzyme, and aldosterone, 68 and low androgen levels. 67 The functional implications of most of these changes are not well-understood, although obesity is known to interfere with reproductive capability, 69 and changes in the components of the renin-angiotensin-aldosterone system are thought to contribute to oxidative stress and altered glucose metabolism.…”

“…67 The functional implications of most of these changes are not well-understood, although obesity is known to interfere with reproductive capability, 69 and changes in the components of the renin-angiotensin-aldosterone system are thought to contribute to oxidative stress and altered glucose metabolism. 68 In dogs and cats, information about the effects of obesity on these variables is limited. No increase in thyroid-stimulating hormone was found with weight gain in cats, although free T4 was increased with obesity, likely because of increased NEFA concentrations.…”

Mineralocorticoid Receptor Blockade Improves Insulin Sensitivity in the Rat Heart and a Possible Molecular Mechanism

“…Recent findings suggest a pivotal role of aldosterone in the pathogeneses of inflammation, insulin resistance and metabolic syndrome [12,13]. Evidence indicates that a high level of aldosterone leads to a greater prevalence of hyperglycemia and induces a high rate of cardiovascular events [14]. Moreover, recent studies have revealed that aldosterone treatment increases the mRNA levels of tumor necrosis factor-α (TNFα) and interleukin-6 (IL-6) and inhibits adiponectin mRNA expression; however, the possible mechanisms remain unclear.…”