Blockade of the renin???angiotensin system decreases adipocyte size with improvement in insulin sensitivity

Developing diabetes mellitus when being treated for hypertension is associated with a three-fold increase in the long-term risk of suffering a cardiovascular event [1]. Several randomized studies investigating a variety of antihypertensive agents have demonstrated an increased incidence of new-onset diabetes in patients treated with β-blockers compared to those treated with angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB) [2,3]. Similarly, studies have shown that ACEIs [4,5] and ARBs [6] reduce the risk of developing diabetes. How blockade of the renin–angiotensin system (RAS) reduces new onset diabetes is not well understood. In this issue of the journal, Furuhashi et al. [7] provide evidence to suggest that ACEIs and ARBs have beneficial effects on adipose tissue function that are associated with an improvement in insulin sensitivity in a rat model. It is now clear that adipose tissue does not simply act as a store for energy, but that it has a role as an endocrine organ and secretes many systemically acting peptides, including adiponectin and tumour necrosis factor (TNF)-α. Adiponectin is expressed in differentiated adipocytes and is found in high concentrations in the bloodstream of healthy individuals. Adiponectin acts systemically by enhancing endothelial-dependent and independent vasodilatation, stimulating glucose utilization and oxidation of fatty acids in muscle, and increasing insulin sensitivity in the liver. Obese and insulin-resistant subjects have reduced levels of adiponectin [8] and administration of adiponectin improves insulin sensitivity in animal models of insulin resistance [9]. TNF-α expression is increased in obese human and rodent adipose tissue and correlates with insulin resistance. Reducing TNF-α with soluble receptors results in an improvement in insulin sensitivity in obese rodents [10]. Adiponectin appears to be secreted in higher levels by smaller adipocytes and TNF-α is secreted in higher levels by larger adipocytes. A recent study of the effects of liposuction on insulin resistance showed that simply removing adipose tissue does not improve insulin sensitivity [11]. It would appear that it is the morphology and function of adipose tissue that affects insulin sensitivity. By affecting adipocyte morphology and function, the RAS may influence insulin sensitivity. Janke et al. [12] demonstrated that the differentiation of preadipocytes is inhibited by angiotensin II. Furthermore, they showed that coculture with mature human adipocytes similarly results in inhibition of differentiation. When either an angiotensin II type 1 receptor blocker or an ACE inhibitor was added to the culture medium, the effects of angiotensin II and the mature adipocytes were abolished. The authors further suggest that a local RAS in adipose tissue plays a role in regulating adipogenesis in human adipose tissue [12]. Sharma et al. [13] hypothesized that large adipocytes produce increased amounts of angiotensin II, which then inhibits the differentiation of preadipocytes. This causes a failure of adequate expansion of adipose tissue and the resulting deposition of lipids in other tissues. They further suggest that blockade of the RAS should result in a reversal of this ectopic lipid deposition and an improvement in insulin sensitivity [13]. Furuhashi et al. [7] investigated this hypothesis using a rat model of insulin resistance. They induced hypertension and insulin resistance in Sprague–Dawley rats by feeding them a diet high in fructose. It was demonstrated that those rats with insulin resistance had adipocyte hypertrophy and increased levels of triglyceride deposition in skeletal muscle compared to rats fed a normal diet and with normal insulin sensitivity. The authors further demonstrate that either an ACEI or ARB attenuates the adverse effects of a high fructose diet [7]. Although it has previously been suggested that increased levels of bradykinin are responsible for the effects of ACEI on insulin sensitivity [14], in this study, the ACEI and ARB were of similar efficacy in improving insulin sensitivity, suggesting that it is the reduction in angiotensin II receptor activation that is responsible for any improvement rather than a kinin effect. It is unfortunate that adiponectin was not measured, although previous research has shown that RAS blockade results in an increased concentration of adiponectin. Triglyceride levels in muscle were reduced in the drug-treated rats, but not significantly. This may be due to the relatively short period of treatment (only 2 weeks of drug treatment) whereas extension of the treatment duration may have led to a significant result being seen. This study provides further evidence for mechanisms that link adipose tissue to the metabolic syndrome and goes some way towards elucidating the mechanisms by which RAS blockade reduces insulin resistance and the onset of new diabetes. However, some caution is required when translating these findings into humans. This study used a fructose-fed rat as a model of insulin resistance, and there are clearly differences in the response of different species to angiotensin II and in the expression of angiotensin II receptor subtypes in adipose tissue. Reproducing this study in humans with obesity and insulin resistance would be of value. What remains unanswered is how insulin resistance is associated with hypertension, as well as the role that adipose tissue may play. There are clearly many possible contributors, including adiponectin, TNF-α and perhaps locally produced products of the RAS. Further research into this interesting subject is required.