Sodium-glucose cotransporter-2 inhibitors: updated evidence on their efficacy and safety in patients with type-2 diabetes

Management of type-2 diabetes mellitus (T2DM) is challenging. The scope of existing therapies toward T2DM has transformed remarkably. These large assortments of therapies have produced evidence-based data. Sodium-glucose cotransporter-2 inhibitor (SGLT-2i) is the most recent class of oral anti-hyperglycemic agents. They are approved by Food and Drug Administration for the treatment of diabetes mellitus. SGLT-2i has a unique mechanism of action and that lower glucose independent of insulin. They reduce renal tubular glucose reabsorption, thereby lowering blood glucose without stimulating the release of insulin. Additional advantages involve suitable effects on blood pressure and weight. According to guidelines of the American Association of Clinical Endocrinologists/ the American College of Endocrinology 2016, SGLT-2i (in the form of canagliflozin, dapagliflozin, and empagliflozin) is one of the acceptable alternatives to metformin as initial therapy towards T2DM. Canagliflozin, dapagliflozin, and empagliflozin reduce the cardiovascular risk in comparison to placebo as the part of standard care. This review article focuses on the clinical trials published over the past year and specifically the metabolic aspect of SGLT-2i and the adverse effects related to SGLT-2 inhibitors.

Adipose tissue as an endocrine organ

The concept of adipose tissue as an inactive organ, which serves only for the accumulation and storage of energy substrates and triglycerides, has finally remained in the past. Studies of recent decades have shown that adipose tissue is very active in the metabolic aspect, and also produces many hormone-like substances, mediators, cytokines, chemokines that act at the local and systemic level, i.e., para- and endocrine. Regulatory substances produced in adipose tissue have received the general name adipokines or adipocytokines. Their study is the most actively developing area of ​​modern endocrinology. Adipokines made it possible to explain the pathophysiology of the long-known clinical phenomena of the close relationship between obesity, diabetes mellitus (DM), arteriosclerosis and insulin resistance. The list of adipokines produced in adipose tissue is very impressive and will undoubtedly be supplemented. By the beginning of 2008, the following adipokines were described: leptin, adiponectin, resistin, tumor necrosis factor a (TNF-a), interleukin-6 (IL-6), visfatin, apelin, omentine, vaspin, retinol-binding protein-4 (RBP-4) and other factors, including lipoprotein lipase, apolipoprotein E, complement factors, tissue factor, plasminogen activation inhibitor-1 (IAP-1), proteins of the renin angiotensin system (RAS). In addition, adipocytes express chemokines such as MCP-1 and RANTES.This review schematically presents the basic physiological and pathophysiological actions of known adipokines.

Porphyrin-Mediated Binding to Hemoglobin by the HA2 Domain of Cysteine Proteinases (Gingipains) and Hemagglutinins from the Periodontal Pathogen Porphyromonas gingivalis

ABSTRACT Heme binding and uptake are considered fundamental to the growth and virulence of the gram-negative periodontal pathogenPorphyromonas gingivalis. We therefore examined the potential role of the dominant P. gingivalis cysteine proteinases (gingipains) in the acquisition of heme from the environment. A recombinant hemoglobin-binding domain that is conserved between two predominant gingipains (domain HA2) demonstrated tight binding to hemin (Kd = 16 nM), and binding was inhibited by iron-free protoporphyrin IX (Ki = 2.5 μM). Hemoglobin binding to the gingipains and the recombinant HA2 (rHA2) domain (Kd = 2.1 nM) was also inhibited by protoporphyrin IX (Ki = 10 μM), demonstrating an essential interaction between the HA2 domain and the heme moiety in hemoglobin binding. Binding of rHA2 with either hemin, protoporphyrin IX, or hematoporphyrin was abolished by establishing covalent linkage of the protoporphyrin propionic acid side chains to fixed amines, demonstrating specific and directed binding of rHA2 to these protoporphyrins. A monoclonal antibody which recognizes a peptide epitope within the HA2 domain was employed to demonstrate that HA2-associated hemoglobin-binding activity was expressed and released by P. gingivalis cells in a batch culture, in parallel with proteinase activity. Cysteine proteinases from P. gingivalis appear to be multidomain proteins with functions for hemagglutination, erythrocyte lysis, proteolysis, and heme binding, as demonstrated here. Detailed understanding of the biochemical pathways for heme acquisition in P. gingivalis may allow precise targeting of this critical metabolic aspect for periodontal disease prevention.