The role of renin-angiotensin agents in altering the natural history of type 2 diabetes mellitus

Abstract

Type 2 diabetes mellitus (T2DM) is a major risk factor for cardiovascular disease (CVD) morbidity and mortality worldwide. Renin-angiotensin system (RAS) blockers have been indispensable in diminishing the macrovascular and microvascular complications of diabetes. In addition, cumulative evidence from retrospective studies pointed toward a beneficial effect of RAS agents in preventing the development and progression of T2DM. This disease-modifying potential of RAS blockers has been substantiated by recent prospective trials. Contemporary concepts regarding the natural history of T2DM and the pathophysiologic processes involved have increased our understanding of the mechanisms underlying the therapeutic potential of these agents in diabetes management. In addition to their established roles in the primary prevention of CVD in patients with diabetes, RAS blockers might be considered a suitable therapeutic choice for preventing the development of frank diabetes in high-risk patients.

Fig. 1

The postulated natural progression from normoglycemic state to frank type 2 diabetes is shown. The numbered items indicate the hypothetical sequence of adverse metabolic events that are associated with the development of the disease

Fig. 2

Shows the sites of action of the renin-angiotensin system blockers in relation to the different mediators that are thought to have favorable (bradykinin, nitric oxide) or deleterious (angiotensin II) effects on insulin sensitivity and/or secretion. ACE—angiotensin-converting enzyme

Fig. 3

Shows the cross-talk between the insulin signaling pathway and the angiotensin II type 1 receptor, in which the metabolic effects of insulin are antagonized, but the proliferative effects are not. CoA—coenzyme A; MAPK—mitogen-activated protein kinase; PI3—phosphatidylinositol-3