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Nephrology beyond JASN |
It 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 expression of angiotensinogen, ACE, and AT1 and AT2 receptors with an intensity comparable to that noted in liver and kidney, respectively. It is not unreasonable to assume that concentrations of locally produced AngII considerably exceed AngII concentrations in the circulation. It is also possible that Ang II does interfere with -cell function not only directly, but also indirectly by causing vasoconstriction as well as long-term changes such as fibrosis.
What are the potential implications of this finding? Metabolic syndrome and impaired glucose tolerance are common features in hypertensive patients treated with antihypertensive agents. If one tries to reduce the risk of de novo diabetes, antihypertensive agents that block the RAS appear to be a logical choice, although this has not yet been proven by a randomized, controlled, prospective intervention trial, currently considered the gold standard of proof in medicine (15). A further twist in this issue is introduced by the recent finding that, unrelated to their effect on the AT-receptors, the angiotensin receptor blockers telmisartan and irbesartan act as partial agonists of peroxisome proliferator-activated receptor 
(PPAR), i.e., act as insulin sensitizers (16–18). There is no doubt that diuretics with or without -blockers provoke a metabolic syndrome, as recently shown in a head-on comparison (ALPINE Trial) (19). It is unknown whether and when such adverse metabolic changes provoked by the prediabetic antihypertensive medication will translate into different outcomes with respect to diabetes and renal risk. Concerning cardiovascular risk, this effect took quite some time (20). At least in animal experiments, however, blockade of the RAS in the prediabetic stage even attenuated renal lesions after full-blown diabetes had developed (21). If this can be shown in humans, unexpected opportunities may become available to tackle the problem of diabetic nephropathy at the root. Only time will tell whether this assessment is realistic or too optimistic.
Footnotes
Address correspondence to: Prof. Eberhard Ritz, Department Internal Medicine, Division of Nephrology, Bergheimer Strasse 56a, D-69115 Heidelberg, Germany. Phone: 49-0-6221-601705 or 49-0-6221-189976; Fax: 49-0-6221-603302; E-mail: Prof.E.Ritz{at}t-online.de
References
The metabolic syndrome has become a major health problem. Its central feature is insulin resistance. The metabolic syndrome is associated with hypertension, a high risk of diabetes, and—documented only recently—a high risk of microalbuminuria and chronic kidney disease (1–4). The same relation to renal risk is also found for insulin resistance per se (5).
One feature of the metabolic syndrome is obesity: not a simple excess of depot fat, but maldistribution of fat with deposition of fat in visceral organs (visceral obesity), particularly in the liver and in skeletal muscle (6–9). That it is visceral, rather than subcutaneous, fat which is related to the diminished action of insulin is illustrated by the observation that liposuction, i.e., selective removal of subcutaneous fat, had no impact whatsoever on metabolic indices of insulin action (10).
Against this background, the recent observation of the laboratory of Stoffel and colleagues in the Howard Hughes Institute in New York is of particular interest (11). The investigators showed in normal mice that plasma insulin inhibits the action of the forkhead transcription factor Foxa2 in the liver by retaining it in the cytoplasm and excluding it from the nucleus, thus preventing its action on nuclear transcription. This factor activates transcriptional programs of lipid metabolism and ketogenesis. The authors went one step further and showed that in insulin-resistant hyperinsulinemic mice, Foxa2 is permanently inactivated. However, in these mice adenoviral expression of a constitutively active Foxa2 that is resistant to inhibition by insulin had dramatic effects on the typical features of hepatic-metabolism insulin resistance: The elevated hepatic triglyceride content decreased and the hepatic hyporesponsiveness to insulin was reversed. As a result, hepatic overproduction of glucose was reduced, plasma glucose concentration normalized, and hyperinsulinemia was corrected. This spectrum of changes was associated with increased expression of genes encoding enzymes of fatty acid oxidation, ketogenesis, and glycolysis. To fully understand the implications of "outfoxing insulin resistance" (12), it is useful to discuss the molecular switches that control and adjust the rates of glucose production and fatty acid oxidation in the liver. The type of fuel used depends on whether the organism is fed or fasted. After feeding, glucose is the main source of energy, while in the fasting state the main fuel is fatty acids, but even then the brain’s need for glucose oxidation has to be met by ongoing glucose production (gluconeogenesis) in the liver. As a result, constant adaptation of the hepatic metabolism is required. Insulin is the main, but by no means only, signal to elicit such adjustment of the rates of glucose synthesis and fatty acid oxidation in the liver (13).
In the insulin-resistant state, the insulin response is diminished and the liver is no longer able to adequately shut off gluconeogenesis. Yet the response of fatty acid oxidation is still appropriate: Fatty acid oxidation is turned off and as a result fat accumulates in the liver. Although matters are certainly more complex (14), this sequence provides one explanation for the development of hepatic steatosis (fat deposition in the liver), which is one of the hallmarks of insulin-resistant states and the metabolic syndrome (8,15).
How does this tie in with the Foxa2 story above and can it explain the curious dissociation between the response of gluconeogenesis and of fatty acid oxidation to insulin?
In the liver, two members of the forkhead family of transcription factors are present: the above-mentioned Foxa2 as well as Foxo1. Foxa2 reduces fatty acid oxidation. Foxo1, however, stimulates gluconeogenesis (13). The results of the study of Wolfrum et al. (11) suggest that fatty acid oxidation (which is mediated via Foxa2) responds more sensitively to insulin than does gluconeogenesis (which is mediated via Foxo1). Consequently, in the hyperinsulinemic insulin-resistant state the organism is confronted with the twin problems of both hyperglycemia and hepatic steatosis. There is an element of self-perpetuation because persisting hyperglycemia drives insulin secretion, causing persisting hyperinsulinemia. Thus, fatty acid oxidation is kept switched off constantly, even in the fasting state, and the tendency to develop hepatic steatosis is aggravated.
The above results have strikingly advanced the understanding of metabolic dysregulation and of hepatic steatosis in insulin-resistant states and in metabolic syndrome. The challenge in the future will be to break the vicious circle and to unblock the Foxa2 switch, which blocks fatty acid oxidation and disrupts the balance between gluconeogenesis and fatty acid oxidation. To nephrologists, it will specifically be of interest to examine whether the state of insulin-resistance unique to renal failure shares these molecular abnormalities with common metabolic syndrome (16).
References
Decades ago, following the work of Ambard and Beaujard (1), dietary sodium restriction became a mainstay of the treatment of patients with renal disease on both sides of the Atlantic, although admittedly based on very limited evidence (2,3). Subsequently, the adverse effect of salt was ascribed to hypervolemia and hypertension. After diuretics and effective antihypertensive agents had become available, dietary restriction of salt had fallen out of fashion in the perhaps premature belief that any adverse effect of salt can be prevented by augmenting natriuresis using diuretics, although at least in experimental studies this was by no means the case (4).
With respect to BP and cardiovascular risk, salt has recently seen a renaissance. In the Dietary Approaches to Stop Hypertension (DASH) Study, lowering of dietary salt from usual to low intake with simultaneous further modifications of the diet decreased systolic BP by 7.1 mmHg overall and by 11.5 mmHg in hypertensive individuals (5). A meta-analysis concluded that the BP difference between intake of 12 g and 3 g of salt, i.e., sodium chloride, was 5.6/3.2 mmHg in hypertensive and 3.5/1.8 mmHg in normotensive subjects (6). In a prospective Finnish study, a 100 mmol/d difference in sodium intake was associated with a relative risk of coronary heart disease of 1.5 and of all cause mortality of 1.2, independent of BP and classic cardiovascular risk factors (7).
In contrast to impressive experimental studies, for instance in intact rats and in antithymocyte serum nephritis as well as postangiotensin infusion (8–10), very little clinical information has been presented. It is therefore of considerable interest that in a cross-sectional cohort study of 7850 subjects aged 28 to 75 yr in the city of Groningen (The Netherlands), a significant positive relationship was demonstrated between dietary sodium intake and urinary albumin excretion. The association was independent of gender, age, BP, body mass index (BMI), waist-to-hip ratio, serum cholesterol, or glucose concentration. The difference between the lowest quintile of sodium excretion (mean, 70.5 mmol/d) and the highest (mean, 220 mmol/d) was 7.5 mg albumin/d (5.3 to 13.3) versus 11.1 mg albumin/d (7.3 to 21.7). It must be admitted that other indicators of food intake were also positively associated with albuminuria, but the effect of sodium intake on urinary albumin excretion was independent of such other food constituents. Of interest with respect to potential pathogenetic mechanisms is the observation that a significant interaction was noted between urinary sodium and BMI. At any given sodium intake, subjects with a higher BMI had higher urinary albumin excretion than subjects with a lower BMI. In a large cohort, this observation amplifies and extends previous observations of the Montpellier group (11). It also confirms with more reliable assessment of sodium intake the previous observations in the National Health and Nutrition Examination Survey (NHANES I) study (12).
The study has the merit of putting squarely back onto the map a hotly debated issue that has caused considerable controversy in the past, i.e., sodium chloride intake in hypertensive and particularly in renal patients. It does not answer, however, which mechanism(s) account(s) for the link. One can only speculate on the basis of animal experiments. High salt has been shown to increase left ventricular mass, AT1 receptor expression, and aldosterone synthase activity in Wistar Kyoto rats despite unchanged BP and suppression of the renin system (13). In addition, salt was also shown to induce myocardial as well as renal fibrosis (14). In the aortic endothelium (15) and in glomeruli (16), high salt increases the activities of the p38 mitogen-activated protein (MAP) kinase. In the kidney, high salt intake also increases oxidative stress (8). Of particular interest is the activation of TGF- induced by high salt (17,18). An interesting interrelation exists between nitric oxide (NO) and TGF-: NO inhibits TGF- (19). The high salt sensitivity of BP in patients with renal failure may be explained by the finding that the BP response to high salt is dependent on NO production (20). In humans, the increase in renal plasma flow in response to salt loading was reduced by inhibition of NO production (21), of considerable interest because the endogenous NO synthase inhibitor L-NMMA is increased very early on in renal failure (22).
In summary, there is no lack of potential pathomechanisms in the kidney (18) to speculate about the interpretation of the above findings; what is lacking is strong human evidence. In a small, retrospective series, a relation between progression and salt intake was noted (23). Certainly this issue deserves more attention. In this respect, the paper by Verhave et al. (24) will hopefully serve to wake up the renal community: There may be a chance out there to improve renal outcomes (25).
References
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