Non-invasive cardiac imaging techniques and vascular tools for the assessment of cardiovascular disease in type 2 diabetes mellitus

Cardiovascular disease is the major cause of mortality in type 2 diabetes mellitus. The criteria for the selection of those asymptomatic patients with type 2 diabetes who should undergo cardiac screening and the therapeutic consequences of screening remain controversial. Non-invasive techniques as markers of atherosclerosis and myocardial ischaemia may aid risk stratification and the implementation of tailored therapy for the patient with type 2 diabetes. In the present article we review the literature on the implementation of non-invasive vascular tools and cardiac imaging techniques in this patient group. The value of these techniques as endpoints in clinical trials and as risk estimators in asymptomatic diabetic patients is discussed. Carotid intima–media thickness, arterial stiffness and flow-mediated dilation are abnormal long before the onset of type 2 diabetes. These vascular tools are therefore most likely to be useful for the identification of ‘at risk’ patients during the early stages of atherosclerotic disease. The additional value of these tools in risk stratification and tailored therapy in type 2 diabetes remains to be proven. Cardiac imaging techniques are more justified in individuals with a strong clinical suspicion of advanced coronary heart disease (CHD). Asymptomatic myocardial ischaemia can be detected by stress echocardiography and myocardial perfusion imaging. The more recently developed non-invasive multi-slice computed tomography angiography is recommended for exclusion of CHD, and can therefore be used to screen asymptomatic patients with type 2 diabetes, but has the associated disadvantages of high radiation exposure and costs. Therefore, we propose an algorithm for the screening of asymptomatic diabetic patients, the first step of which consists of coronary artery calcium score assessment and exercise ECG

Regulated acid-base transport in the collecting duct

The renal collecting system serves the fine-tuning of renal acid-base secretion. Acid-secretory type-A intercalated cells secrete protons via a luminally expressed V-type H(+)-ATPase and generate new bicarbonate released by basolateral chloride/bicarbonate exchangers including the AE1 anion exchanger. Efficient proton secretion depends both on the presence of titratable acids (mainly phosphate) and the concomitant secretion of ammonia being titrated to ammonium. Collecting duct ammonium excretion requires the Rhesus protein RhCG as indicated by recent KO studies. Urinary acid secretion by type-A intercalated cells is strongly regulated by various factors among them acid-base status, angiotensin II and aldosterone, and the Calcium-sensing receptor. Moreover, urinary acidification by H(+)-ATPases is modulated indirectly by the activity of the epithelial sodium channel ENaC. Bicarbonate secretion is achieved by non-type-A intercalated cells characterized by the luminal expression of the chloride/bicarbonate exchanger pendrin. Pendrin activity is driven by H(+)-ATPases and may serve both bicarbonate excretion and chloride reabsorption. The activity and expression of pendrin is regulated by different factors including acid-base status, chloride delivery, and angiotensin II and may play a role in NaCl retention and blood pressure regulation. Finally, the relative abundance of type-A and non-type-A intercalated cells may be tightly regulated. Dysregulation of intercalated cell function or abundance causes various syndromes of distal renal tubular acidosis underlining the importance of these processes for acid-base homeostasis

Atp6ap2 ablation in adult mice impairs viability through multiple organ deficiencies

Abstract ATP6AP2 codes for the (pro)renin receptor and is an essential component of vacuolar H+ ATPase. Activating (pro)renin for conversion of Angiotensinogen to Angiotensin makes ATP6AP2 attractive for drug intervention. Tissue-specific ATP6AP2 inactivation in mouse suggested a strong impact on various organs. Consistent with this, we found that embryonic ablation of Atp6ap2 resulted in both male hemizygous lethality and female haploinsufficiency. Next, we examined the phenotype of an induced inactivation in the adult animal, most akin to detect potential effect of functional interference of ATP6AP2 through drug therapy. Induced ablation of Atp6ap2, even without equal efficiency in all tissues (aorta, brain and kidney), resulted in rapid lethality marked by weight loss, changes in nutritional as well as blood parameters, leukocyte depletion, and bone marrow hypoplasia. Upon Atp6ap2 ablation, the colon demonstrated a rapid disruption of crypt morphology, aberrant proliferation, cell-death activation, as well as generation of microadenomas. Consequently, disruption of ATP6AP2 is extremely poorly tolerated in the adult, and severely affects various organ systems demonstrating that ATP6AP2 is an essential gene implicated in basic cellular mechanisms and necessary for multiple organ function. Accordingly, any potential drug targeting of this gene product must be strictly assessed for safety