Andreas Daiber

The SGLT2 inhibitor empagliflozin improves the primary diabetic complications in ZDF rats

Hyperglycemia associated with inflammation and oxidative stress is a major cause of vascular dysfunction and cardiovascular disease in diabetes. Recent data reports that a selective sodium-glucose co-transporter 2 inhibitor (SGLT2i), empagliflozin (Jardiance®), ameliorates glucotoxicity via excretion of excess glucose in urine (glucosuria) and significantly improves cardiovascular mortality in type 2 diabetes mellitus (T2DM). The overarching hypothesis is that hyperglycemia and glucotoxicity are upstream of all other complications seen in diabetes. The aim of this study was to investigate effects of empagliflozin on glucotoxicity, β-cell function, inflammation, oxidative stress and endothelial dysfunction in Zucker diabetic fatty (ZDF) rats. Male ZDF rats were used as a model of T2DM (35 diabetic ZDF‐Leprfa/fa and 16 ZDF-Lepr+/+ controls). Empagliflozin (10 and 30 mg/kg/d) was administered via drinking water for 6 weeks. Treatment with empagliflozin restored glycemic control. Empagliflozin improved endothelial function (thoracic aorta) and reduced oxidative stress in the aorta and in blood of diabetic rats. Inflammation and glucotoxicity (AGE/RAGE signaling) were epigenetically prevented by SGLT2i treatment (ChIP). Linear regression analysis revealed a significant inverse correlation of endothelial function with HbA1c, whereas leukocyte-dependent oxidative burst and C-reactive protein (CRP) were positively correlated with HbA1c. Viability of hyperglycemic endothelial cells was pleiotropically improved by SGLT2i. Empagliflozin reduces glucotoxicity and thereby prevents the development of endothelial dysfunction, reduces oxidative stress and exhibits anti-inflammatory effects in ZDF rats, despite persisting hyperlipidemia and hyperinsulinemia. Our preclinical observations provide insights into the mechanisms by which empagliflozin reduces cardiovascular mortality in humans (EMPA-REG trial).

Modulation of Vascular Function by AMPK: Assessment of NO Bioavailability and Surrogates of Oxidative Stress

The endothelium plays a pivotal role in the development of vascular disease. Decreased bioavailability of nitric oxide, a condition known as endothelial dysfunction, is considered an early step in this process before atherosclerotic changes of the vessel wall occur. Endothelium-derived nitric oxide (•NO) may be rapidly scavenged by superoxide anions; therefore, the equilibrium between •NO production on one hand and its inactivation by oxidative stress on the other hand is of particular interest. Metabolic enzyme systems such as AMP-activated protein kinase (AMPK) may affect the cellular production of •NO or reactive oxygen species (ROS), while AMPK activity itself can also be modulated by ROS. Therefore, the analysis of •NO as well as ROS levels is essential to understand how metabolism regulating enzymes like AMPK may modulate vascular disease.

Pharmacology of Nitrovasodilators

Organic nitrates such as nitroglycerin, isosorbide mono- and dinitrate, and pentaerythrityl tetranitrate, are potent vasodilators that improve clinical symptoms in patients with acute and chronic congestive heart failure, coronary artery disease, or arterial hypertension. The mechanisms underlying vasodilation include the release of nitric oxide or a related compound in response to intracellular bioactivation (for GTN, the mitochondrial aldehyde dehydrogenase), the activation of the enzyme soluble guanylyl cyclase, and the activation of the cGMP-dependent kinase. Side effects of organic nitrates include nitrate tolerance development and the induction of endothelial dysfunction, phenomena, which are likely being linked to increased production of reactive oxygen and nitrogen species.