Pathophysiology of impaired glucose metabolism: the role of the renin-angiotensin system

Diamant, M. [Promotor]Blaak, E.E. [Promotor

Does interference with the renin-angiotensin system protect against diabetes? Evidence and mechanisms

Agents interfering with the renin-angiotensin system (RAS) system were consistently shown to lower the incidence of type 2 diabetes (T2DM), as compared to other antihypertensive drugs, in hypertensive high-risk populations. The mechanisms underlying this protective effect of RAS blockade using angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) on glucose metabolism are not fully understood. In this paper, we will review the evidence from randomized-controlled trials and discuss the proposed mechanisms as to how RAS interference may delay the onset of T2DM. In particular, since T2DM is characterized by beta-cell dysfunction and obesity-related insulin resistance, we address the mechanisms that underlie RAS blockade-induced improvement in beta-cell function and insulin sensitivity

Ectopic Fat Storage in the Pancreas, Liver, and Abdominal Fat Depots: Impact on {beta}-Cell Function in Individuals with Impaired Glucose Metabolism.

Context: Pancreatic fat content (PFC) may have deleterious effects on beta-cell function. Objective: We hypothesized that ectopic fat deposition, in particular pancreatic fat accumulation, is related to beta-cell dysfunction in individuals with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT). Design, Setting and Participants: This was a cross-sectional study in 64 age- and body mass index-matched individuals, with normal glucose tolerance (NGT; n = 16, 60% males), IFG (n = 29, 52% males), or IFG/IGT (n = 19, 63% males) was conducted. Intervention and Main Outcome Measures: Participants underwent the following: 1) a combined hyperinsulinemic-euglycemic and hyperglycemic clamp, with subsequent arginine stimulation to quantify insulin sensitivity and beta-cell function; 2) proton-magnetic resonance spectroscopy to assess PFC and liver fat content (LFC); and 3) magnetic resonance imaging to quantify visceral (VAT) and sc (SAT) adipose tissue. The disposition index (DI; insulin sensitivity adjusted beta-cell function) was assessed. Results: IFG and IFG/IGT were more insulin resistant (P < 0.001) compared with NGT. Individuals with IFG/IGT had the lowest values of glucose- and arginine-stimulated C-peptide secretion (both P < 0.03) and DI (P < 0.001), relative to IFG and NGT. PFC and LFC gradually increased between NGT, IFG, and IFG/IGT (P = 0.02 and P = 0.01, respectively), whereas VAT and SAT were similar between groups. No direct associations were found between PFC, LFC, VAT, and SAT and C-peptide secretion. The DI was inversely correlated with PFC, LFC, and VAT (all P < 0.05). Conclusions: PFC was increased in individuals with IFG and/or IGT, without a direct relation with beta-cell function