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

Agents interfering with the renin-angiotensin system (RAS) were consistently shown to lower the incidence of type 2 diabetes mellitus (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 or angiotensin-receptor blockers on glucose metabolism are not fully understood. In this article, 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, as T2DM is characterized by ß-cell dysfunction and obesity-related insulin resistance, we address the mechanisms that underlie RAS blockade-induced improvement in ß-cell function and insulin sensitivity.

Impaired insulin sensitivity is accompanied by disturbances in skeletal muscle fatty acid handling in subjects with impaired glucose metabolism.

OBJECTIVE: To determine insulin sensitivity and skeletal muscle fatty acid (FA) handling at baseline and after a high-fat mixed meal in impaired fasting glucose (IFG), impaired glucose tolerance (IGT), IFG/IGT and normal glucose tolerance (NGT) subjects. DESIGN: In this multi-center study, insulin sensitivity and ß-cell function were assessed (n=102), using a euglycemic-hyperinsulinemic and hyperglycemic clamp with additional arginine stimulation and a 75 g oral glucose tolerance test. Fasting and postprandial skeletal muscle FA handling was examined in a substudy using the forearm balance technique (n=35). SUBJECTS: A total of 102 subjects with IFG (n=48), IGT (n=12), IFG/IGT (n=26) and NGT (n=16). RESULTS: IFG, IGT and IFG/IGT subjects had lower insulin sensitivity with no differences between groups, and lower impaired ß-cell function compared with NGT controls. The early postprandial increase in triacylglycerol (TAG) concentration was higher (iAUC(0-2 h) IFG: 238.4±26.5, IGT: 234.0±41.0 and NGT: 82.6±13.8 µmol l(-1) min(-1), both P<0.05) and early TAG extraction was increased (AUC(0-2 h) IFG: 56.8±9.0, IGT: 52.2±12.0 and NGT: 3.8±15.4 nmol·100 ml(-1) min(-1), P<0.05 and P=0.057, respectively) in both IFG and IGT subjects. CONCLUSION: IFG, IGT and IFG/IGT subjects have lower insulin sensitivity and impaired ß-cell function compared with age- and BMI-matched NGT controls. The increased postprandial TAG response and higher muscle TAG extraction in both IFG and IGT compared with NGT may lead to ectopic fat accumulation in the skeletal muscle, thereby contributing to insulin resistance.

Ectopic fat storage in the pancreas, liver, and abdominal fat depots: impact on ß-cell function in individuals with impaired glucose metabolism.

CONTEXT: Pancreatic fat content (PFC) may have deleterious effects on ß-cell function. OBJECTIVE: We hypothesized that ectopic fat deposition, in particular pancreatic fat accumulation, is related to ß-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 ß-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 ß-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 ß-cell function.