Nephrology beyond JASN

I t requires little persuasion to convince nephrologists that diabetes type 2 and diabetic nephropathy have become major challenges to nephrology. Although the twin culprits of genetic predisposition (1) and modern lifestyle (2) are undoubtedly the major cause of the rising tide of type 2 diabetes, its incidence can be modified by the selection of the type of antihypertensive agents. The idea that blockade of the renin-angiotensin system (RAS) attenuates the risk of type 2 diabetes in hypertensive agents was initially raised by post hoc analysis of small studies (3). Some large studies solidly documented that both angiotensin-converting enzyme (ACE) inhibitors (4,5) and angiotensin receptor blockers (6–8) lowered the risk of de novo type 2 diabetes compared with -blockers or diuretics, respectively. The lingering doubt remained, however, that the difference in incidence of diabetes might reflect an increase of risk conferred by -blockers and diuretics rather than a benefit conferred by RAS blockade. These concerns can today be laid to rest after the Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) Trial (9) unequivocally showed that the rate of de novo diabetes was significantly lower in hypertensive patients treated with valsartan compared with amlodipin, i.e., an agent that is definitely metabolically neutral. The implications for efforts to reduce the frequency of diabetes are obvious. The issue remains, however, to identify the mechanisms accounting for the antidiabetogenic effect of RAS blockade. Against this background, the demonstration of a fully operative renin-angiotensin-system (RAS) in isolated pancreatic islets is of considerable interest. Theoretically, the RAS could augment the risk of diabetes by either increasing peripheral insulin resistance or interfering with insulin secretion (or a combination of both). Indeed, there are reports that angiotensin II (AngII) reduces insulin sensitivity by reducing blood flow in insulin-sensitive tissues and by nonhemodynamic mechanisms, and that, conversely, angiotensin receptor blockers enhance insulin sensitivity (9). Interestingly, however, we had seen paradoxically increased insulin sensitivity during AngII infusion in healthy volunteers (10). On the other hand, in the past a number of studies had documented that AngII reduced insulin secretion by pancreatic islets (11), but the initial observations failed to exclude artifacts resulting from AngII induced vasoconstriction (12). Good arguments were later provided that in the pancreatic islets AngII acted not (only) as a blood-borne agent, but also as a paracrine or autocrine agent generated by a local RAS. Furthermore, early studies showed by immunohistochemistry that some, but not all, components of the RAS were present in the human pancreas. Specifically, renin mRNA could be detected only in the blood vessels surrounding the islets (13). To fully understand this system, however, it was necessary (1) to characterize all of its components (angiotensinogen, ACE, angiotensin type 1 and type 2 [AT1 and AT2] receptors), (2) to verify that the system was expressed within the -cells, and (3) to clarify the mode of action of AngII and to document that the AngII-induced change in insulin secretion was abrogated by blockade of the system at the final step, i.e., the receptor level. The report highlighted here by Lau et al. (14) fulfilled, so to speak, Koch’s postulates and proved the existence of a functional local RAS in the -cells of the islets. In isolated pancreatic islets of male C57BL/6J mice, Lau et al. found dose-dependent inhibition of glucose-stimulated insulin release by AngII; at the highest AngII concentration (100 nmol/L), glucose-induced insulin release was completely suppressed. This suppression was entirely abrogated by pretreatment with the AT1 receptor antagonist losartan, but not by the AT2 receptor–specific antagonist PD123319. AngII did not affect glucose oxidation or global protein synthesis, but it did selectively inhibit (pro)insulin synthesis. Real-time quantitative reverse transcription–PCR documented expres-