Competing Effects of Renin Angiotensin System Blockade and Sodium-Glucose Cotransporter-2 Inhibitors on Erythropoietin Secretion in Diabetes.

BACKGROUND: Anaemia is a common finding in diabetes, particularly in those patients with albuminuria or renal dysfunction and is associated with impaired erythropoietin (EPO) secretion. This review focuses on mechanisms involved in the regulation of erythropoiesis in diabetic patients in an effort to elucidate the competing effects of the renin angiotensin system (RAS) blockade and sodium-glucose cotransporter-2 (SGLT2) inhibitors on haemoglobin concentration and hematocrit values. SUMMARY: The RAS shows significant activation in diabetic subjects. Angiotensin II, its active octapeptide, causes renal tubulointerstitial hypoxia, which stimulates hypoxia-inducible factors (HIF) and increases EPO secretion and erythropoiesis. As expected, drugs that inactivate RAS, such as angiotensin converting enzyme inhibitors or angiotensin receptor blockers (ACEi/ARB) are associated with a significant hematocrit-lowering effect and/or anaemia in various clinical conditions, including diabetes. Dual blockade by a combination of ACEi and ARB in diabetic patients achieves a better RAS inhibition, but at the same time a worse drop of haemoglobin concentration. Increased glucose reabsorption by SGLTs in diabetic subjects generates a high-glucose environment in renal tubulointerstitium, which may impair HIF-1, damage renal erythropoietin-producing cells (REPs) and decrease EPO secretion and erythropoiesis. SGLT2 inhibitors, which inhibit glucose reabsorption, may attenuate glucotoxicity in renal tubulointerstitium, allowing REPs to resume their function and increase EPO secretion. Indeed, EPO levels increase within a few weeks after initiation of therapy with all known SGLT2 inhibitors, followed by increased reticulocyte count and a gradual elevation of haemoglobin concentration and hematocrit level, which reach zenith values after 2-3 months. Key Messages: The competing effects of RAS blockade and SGLT2 inhibitors on erythropoiesis may have important clinical implications. The rise of hematocrit values by SGLT2 inhibitors given on top of RAS blockade in recent outcome trials may significantly contribute to the cardiorenal protection attained. The relative contribution of each system to erythropoiesis and outcome remains to be revealed in future studies.

WITHDRAWN: The potential contribution of endocrine disrupting chemicals to acne.

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Effect of aliskiren on circulating endothelial progenitor cells and vascular function in patients with type 2 diabetes and essential hypertension.

BACKGROUND: The aim of this study was to investigate the effects of aliskiren on vascular function and endothelial progenitor cells (EPCs) in patients with type 2 diabetes and essential hypertension. METHODS: The study enrolled type 2 diabetic patients aged >50 years under stable glycemic control and first diagnosed mild essential hypertension. In phase A (n = 20), patients received aliskiren 150-300 mg daily for 3 months. In phase B (n = 12), hydrochlorothiazide (HCTZ) 12.5-25mg daily substituted for aliskiren for 3 more months. At baseline and at the end of each phase, we assessed (i) brachial blood pressure (BBP); (ii) central aortic systolic pressure (CSP), aortic augmentation index (Aix), and pulse wave velocity (PWV) as markers of arterial stiffness; (iii) brachial artery flow-mediated dilatation (FMD) as a marker of endothelial function; (iv) left ventricular (LV) twisting and untwisting as markers of LV function and (v) EPC numbers in culture of peripheral blood mononuclear cells. RESULTS: Aliskiren similarly reduced BBP and CSP, increased FMD (P < 0.001) and EPC numbers (P < 0.001), decreased PWV and Aix (P < 0.05), and improved LV twisting and untwisting (P < 0.05). Although substitution of HCTZ sustained BBP at similar levels, CSP and echocardiographic indices nearly returned at baseline levels, and the improvement of FMD, PWV, Aix, and EPC numbers was abolished. CONCLUSIONS: Aliskiren had a favorable effect on endothelial function and EPCs, reduced arterial stiffness, and improved LV twisting and untwisting. These effects were independent of BBP lowering, as they were not observed after the achievement of similar values of BBP with HCTZ.

What the radiologist needs to know about the diabetic patient.

Diabetes mellitus (DM) is recognised as a major health problem. Ninety-nine percent of diabetics suffer from type 2 DM and 10% from type 1 and other types of DM. The number of diabetic patients worldwide is expected to reach 380 millions over the next 15 years. The duration of diabetes is an important factor in the pathogenesis of complications, but other factors frequently coexisting with type 2 DM, such as hypertension, obesity and dyslipidaemia, also contribute to the development of diabetic angiopathy. Microvascular complications include retinopathy, nephropathy and neuropathy. Macroangiopathy mainly affects coronary arteries, carotid arteries and arteries of the lower extremities. Eighty percent of deaths in the diabetic population result from cardiovascular incidents. DM is considered an equivalent of coronary heart disease (CHD). Stroke and peripheral artery disease (PAD) are other main manifestations of diabetic macroangiopathy. Diabetic cardiomyopathy (DC) represents another chronic complication that occurs independently of CHD and hypertension. The greater susceptibility of diabetic patients to infections completes the spectrum of the main consequences of DM. The serious complications of DM make it essential for physicians to be aware of the screening guidelines, allowing for earlier patient diagnosis and treatment.

Implication of lipoprotein associated phospholipase A2 activity in oxLDL uptake by macrophages.

Recognition and uptake of oxidized LDL (oxLDL) by scavenger receptors of macrophages and foam cell formation are mediated by the oxidatively modified apolipoprotein B (ApoB) and lipid moiety of oxLDL. A great amount of oxidized phosphatidylcholine (oxPC) of oxLDL is hydrolyzed at the sn-2 position by lipoprotein associated phospholipase A(2) (Lp-PLA(2)) to lysophosphatidylcholine and small oxidation products. This study examines the involvement of Lp-PLA(2) in the uptake of oxLDL by mouse peritoneal macrophages. LDL with intact Lp-PLA(2) activity [LDL(+)] and LDL with completely inhibited Lp-PLA(2) activity [LDL(-)] were subjected to oxidation with 5 microM CuSO(4) for 6 h [moderately oxLDL (MoxLDL)], or 24 h [heavily oxLDL (HoxLDL)] and peritoneal macrophages were incubated with these preparations. The uptake of MoxLDL(-) was about 30% increased compared with that of MoxLDL(+), and HoxLDL(-) uptake was about 20% increased compared with that of HoxLDL(+). Inhibition of Lp-PLA(2) activity had no effect on the uptake of ApoB-liposomes conjugates with ApoB isolated from MoxLDL(-), MoxLDL(+), HoxLDL(-), and HoxLDL(+). Liposomes prepared from the lipid extract of MoxLDL(-), MoxLDL(+), HoxLDL(-), and HoxLDL(+) exhibited a similar pattern to that observed in the uptake of the corresponding intact lipoproteins. This study suggests that the progressive inactivation of Lp-PLA(2) during LDL oxidation leads to an increased uptake of oxLDL by macrophages, which could be primarily attributed to the increased uptake of the oxidized phospholipids enriched lipid moiety of oxLDL.