Activation of the aryl hydrocarbon receptor by clozapine induces preadipocyte differentiation and contributes to endothelial dysfunction.

BACKGROUND: The superior therapeutic benefit of clozapine is often associated with metabolic disruptions as obesity, insulin resistance, tachycardia, higher blood pressure, and even hypertension. AIMS: These adverse vascular/ metabolic events under clozapine are similar to those caused by polycyclic aromatic hydrocarbons (PAHs), and clozapine shows structural similarity to well-known ligands of the aryl hydrocarbon receptor (AhR). Therefore, we speculated that the side effects caused by clozapine might rely on AhR signaling. METHODS: We examined clozapine-induced AhR activation by luciferase reporter assays in hepatoma HepG2 cells and we proved upregulation of the prototypical AhR target gene Cyp1A1 by realtime-PCR (RT-PCR) analysis and enzyme activity. Next we studied the physiological role of AhR in clozapine's effects on human preadipocyte differentiation and on vasodilatation by myography in wild-type and AhR-/- mice. RESULTS: In contrast to other antipsychotic drugs (APDs), clozapine triggered AhR activation and Cyp1A1 expression in HepG2 cells and adipocytes. Clozapine induced adipogenesis via AhR signaling. After PGF2α-induced constriction of mouse aortic rings, clozapine strongly reduced the maximal vasorelaxation under acetylcholine in rings from wild-type mice, but only slightly in rings from AhR-/- mice. The reduction was also prevented by pretreatment with the AhR antagonist CH-223191. CONCLUSION: Identification of clozapine as a ligand for the AhR opens new perspectives to explain common clozapine therapy-associated adverse effects at the molecular level.

[Microbiome, diabetes and heart: a novel link?] / Mikrobiom, Diabetes und Herz: neue Zusammenhänge?

Patients with type 2 diabetes suffer from a high cardiovascular risk. The underlying pathomechanisms are not fully understood and treatment options are correspondingly limited. The gut microbiome could be a new important player in cardiometabolic diseases. Dysbiosis of the intestinal flora has been associated with insulin resistance, diabetes mellitus and cardiovascular diseases, such as atherosclerosis and heart failure. The negative cardiovascular effects of type 2 diabetes mellitus could therefore partly be mediated by gut microbiota. This review article discusses specific gut microbiome-associated mechanisms, which are modulated in both type 2 diabetes and cardiovascular diseases. It is presented how intestinal bacteria may contribute to systemic low-grade inflammation. Furthermore, it is shown how the intestinal microbiome as a complex metabolic organ is able to influence the cardiometabolic phenotype via production of bioactive metabolites. Further studies will have to demonstrate whether these mechanisms contribute to the high cardiovascular risk in type 2 diabetes.

Oral hypoglycemic agents and the heart failure conundrum: Lessons from and for outcome trials.

AIM: Type 2 diabetes is not only an independent risk factor for cardiovascular (CV) disease but is also associated with a greater incidence of heart failure (HF). The aim of this review is to examine the effects of oral antidiabetic drugs on CV disease and HF. DATA SYNTHESIS: Trials of anti-diabetic agents are now designed to assess CV safety, but frequently HF is not included as a primary endpoint. However, HF in patients with diabetes is more frequent than other CV events and seems to be underestimated. A burning question is therefore if the most used trial design to monitor CV safety, i.e. non-inferiority, allows clinical translation of trial findings. Available data further suggest that the CV effects of anti-diabetic drugs may be rather class-specific and are only partly due to their glucose-lowering actions. Metformin, recommended as first line in most guidelines, shows positive CV effects while other classes like thiazolidinediones may precipitate HF. Experimental results on the relatively novel dipeptidyl peptidase IV (DPP IV) inhibitors imply CV protective effects, but the non-inferiority trials published to date show an overall neutral CV outcome and a potential increase in HF by saxagliptin. However, results on sitagliptin of the recently released TECOS indicate that HF is not a class-dependent effect of DPP IV inhibitors. CONCLUSION: Further basic research and long-term outcome studies to clarify the effects of antidiabetic agents on CV and HF are required so that we can select the optimal antidiabetic therapy for our patients.