Effects of Angiotensin II Type 1 Receptor Blockade on β-Cell Function in Humans

Evidence indicates that activation of the angiotensin II type 1 receptor (AT1R) acutely decreases insulin secretion in animals and humans (1–3), mediated at least partially by reductions in islet blood flow and proinsulin biosynthesis (1,2). In contrast, AT1R blockade increased insulin secretion by 40–60% in Zucker diabetic fatty (ZDF) rats (4) and in obese db/db mice (5), thereby delaying the otherwise premature onset of diabetes in the latter animal model. If this were the case in humans, it would provide an explanation for the finding that AT1R antagonist treatment reduces the incidence of type 2 diabetes by ∼25% in high-risk individuals in clinical trials despite no improvement in insulin sensitivity in most human studies using the euglycemic clamp technique (6).

We therefore studied the effects of 6 weeks of treatment with the AT1R antagonist valsartan (80 mg b.i.d.) on β-cell function and insulin sensitivity in 16 subjects with impaired glucose tolerance (75% male; age 58 ± 2 years; BMI 33 ± 2 kg/m²), using a double-blind, placebo-controlled, randomized, cross-over design. We ensured that all subjects had a blood pressure <130/80 mmHg with or without antihypertensive medications (other than ACE inhibitors or AT1R antagonists) before the study, so as to minimize any potential influence of blood pressure lowering by AT1R antagonist treatment on metabolic outcomes. Three-hour hyperglycemic clamps (∼10 mmol/l) with [3-³H]glucose infusion and indirect calorimetry, followed by intravenous arginine infusion (5 g over 30 s), were performed at the end of both treatment periods for the measurement of glucose-stimulated first- and second-phase insulin secretion, insulin secretory capacity, as well as different aspects of insulin sensitivity. The study was designed to detect 12.5% increases in first- and second-phase insulin secretion with 90% power.

Contrary to our hypothesis, AT1R blockade had no effect on either glucose-stimulated first- (188 ± 13 vs. 184 ± 15 pmol/l, P > 0.6) and second-phase insulin secretion (362 ± 35 vs. 337 ± 31, P > 0.2) or insulin secretory capacity (1,731 ± 128 vs. 1,714 ± 136 pmol/l, P > 0.8). Moreover, whole-body insulin sensitivity, suppression of endogenous glucose production, and stimulation of glucose disposal and glucose oxidation remained unchanged during the clamp (all P > 0.6); suppression of plasma free fatty acid and glucagon also remained unaltered (both P > 0.4).

The present study provides the novel information that, contrary to the studies in rodents (4,5), short-term AT1R blockade does not improve β-cell function in humans who have impaired glucose tolerance, which may be due to species differences. Interestingly, in ZDF rats the improved β-cell function by AT1R blockade was associated not only with increased islet proinsulin content but also with attenuated islet fibrosis and β-cell apoptosis (4). If attenuated islet fibrosis and β-cell apoptosis were important for improved insulin secretion by AT1R blockade in humans, it would probably be seen only with more prolonged treatment than that tested in the present study.

We conclude that short-term AT1R antagonist treatment improves neither β-cell function nor insulin responsiveness in various insulin-sensitive tissues in humans. Whether more prolonged AT1R antagonist treatment can benefit human β-cell function remains to be determined.