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.

Glucose tolerance, insulin sensitivity and ß-cell function in patients with rheumatoid arthritis treated with or without low-to-medium dose glucocorticoids.

OBJECTIVES: To compare glucose tolerance and parameters of insulin sensitivity and ß-cell function between chronic glucocorticoid (GC)-using and GC-naive patients with rheumatoid arthritis (RA). METHODS: Frequently sampled 75 g oral glucose tolerance tests were performed in 58 chronic GC-using and 82 GC-naive patients with RA with established disease, with no known type 2 diabetes mellitus (T2DM), and 50 control subjects of comparable age with normal glucose tolerance. The associations between cumulative GC dose and disease characteristics and glucose tolerance state, insulin sensitivity and ß-cell function were tested using multivariate linear and logistic regression models, correcting for patient characteristics. RESULTS: Glucose tolerance state, insulin sensitivity and ß-cell function did not differ between the two RA populations; de novo T2DM was detected in 11% and impaired glucose metabolism in 35% of patients with RA. In patients with RA, cumulative GC dose was associated with T2DM, which seemed mostly driven by the effects of cumulative GC dose on insulin resistance; however, the association decreased when corrected for current disease activity. Patients with RA had decreased insulin sensitivity and impaired ß-cell function compared with controls, and multivariate regression analyses showed a negative association between the presence of RA and insulin sensitivity. CONCLUSIONS: GC-using and GC-naive patients with RA had comparable metabolic parameters, and had decreased insulin sensitivity and ß-cell function as compared with healthy controls. Although cumulative GC dose was shown to have a negative impact on glucose tolerance state and insulin sensitivity, confounding by indication remains the main challenge in this cross-sectional analysis.

Low-dose glucocorticoid treatment affects multiple aspects of intermediary metabolism in healthy humans: a randomised controlled trial.

AIM/HYPOTHESIS: To assess whether low-dose glucocorticoid treatment induces adverse metabolic effects, as is evident for high glucocorticoid doses. METHODS: In a randomised placebo-controlled double-blind (participants and the investigators who performed the studies and assessed the outcomes were blinded) dose-response intervention study, 32 healthy men (age 22 ± 3 years; BMI 22.4 ± 1.7 kg/m(2)) were allocated to prednisolone 7.5 mg once daily (n = 12), prednisolone 30 mg once daily (n = 12), or placebo (n = 8) for 2 weeks using block randomisation. Main outcome measures were glucose, lipid and protein metabolism, measured by stable isotopes, before and at 2 weeks of treatment, in the fasted state and during a two-step hyperinsulinaemic clamp conducted in the Clinical Research Unit of the Academic Medical Centre, Amsterdam, the Netherlands RESULTS: Prednisolone, compared with placebo, dose dependently and significantly increased fasting plasma glucose levels, whereas only prednisolone 30 mg increased fasting insulin levels (29 ± 15 pmol/l). Prednisolone 7.5 mg and prednisolone 30 mg decreased the ability of insulin to suppress endogenous glucose production (by 17 ± 6% and 46 ± 7%, respectively, vs placebo). Peripheral glucose uptake was not reduced by prednisolone 7.5 mg, but was decreased by prednisolone 30 mg by 34 ± 6% (p < 0.0001). Compared with placebo, prednisolone treatment tended to decrease lipolysis in the fasted state (p = 0.062), but both prednisolone 7.5 mg and prednisolone 30 mg decreased insulin-mediated suppression of lipolysis by 11 ± 5% and 34 ± 6%, respectively. Finally, prednisolone treatment increased whole-body proteolysis during hyperinsulinaemia, which tended to be driven by prednisolone 30 mg (5 ± 2%; p = 0.06). No side effects were reported by the study participants. All participants completed the study and were analysed. CONCLUSIONS/INTERPRETATION: Not only at high doses but also at low doses, glucocorticoid therapy impaired intermediary metabolism by interfering with the metabolic actions of insulin on liver and adipose tissue. These data indicate that even low-dose glucocorticoids may impair glucose tolerance when administered chronically. TRIAL REGISTRATION: ISRCTN83991850.

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.