Kidney in Diabetes: from Organ Damage Target to Therapeutic Target

Abstract

Despite the growing of pharmacological options for the treatment of diabetes, epidemiological studies suggest that a substantial proportion of patients does not achieve glycemic goals and so suffers from the risk of chronic complications. This review explores the inhibition of renal glucose reabsorption as a novel approach to treat hyperglycemia. Sodium-glucose cotransporter 2 (SGLT2), a low-affinity high-capacity transporter located in the brush-border membrane of the early segment (S1) of the proximal renal tubule, accounts for about 90% of the reabsorption of glucose from tubular fluid. Competitive inhibitors of SGLT2 that are responsible for renal excretion of glucose provide a unique mechanism to potentially lower the elevated blood glucose levels in patients with diabetes. They act independently of insulin secretion, thereby minimizing the risk of hypoglycemia and weight gain, to control energy balance in a negative direction, a distinctive advantage of this class of drugs over existing oral hypoglycemic agents. Although this group of medications is still under investigation, it appears to be safe and generally well tolerated and it would be expected to improve the treatment of type 2 diabetes as monotherapy or in combination with other oral or parenteral agents. Dapagliflozin is the first agent within this class, which induces clinically meaningful reductions in FPG, PPG, HbA1c, and body weight in type 2 diabetes.

Empagliflozin, a novel potent and selective SGLT‐2 inhibitor, improves glycaemic control alone and in combination with insulin in streptozotocin‐induced diabetic rats, a model of type 1 diabetes mellitus

“…As SGLT‐2 inhibitors have a unique insulin‐independent mechanism, low risk of hypoglycaemia, as well as weight loss effects [30], this class has the potential as an adjunct to insulin for T1DM treatment. Hypoglycaemic events with SGLT‐2 inhibitors in patients with T2DM are rare because of the protective barrier represented by the renal threshold of glycaemia, below which SGLT‐2 inhibitors are not expected to cause further urinary glucose excretion [31]. Insulin is the major therapy for insulin‐deficient diabetes mellitus, therefore, we first assessed whether empagliflozin has the potential to reduce the insulin dose needed for glucose‐lowering in STZ‐treated rats in an acute setting.…”

Vulvovaginitis and balanitis in patients with diabetes treated with dapagliflozin

“…SGLT2 mediates the body's reabsorption of the majority of glomerular-filtered glucose. Inhibitors of this protein reduce renal glucose reabsorption via an insulin-independent mechanism, thereby reducing blood glucose levels while increasing urinary glucose excretion (Ghosh, Ghosh, Chawla, & Jasdanwala, 2011;Rahmoune et al, 2005;Salvatore et al, 2011;Zhang, Feng, List, Kasichayanula, & Pfister, 2010). In light of the potential association between glucosuria and VV/B, medical treatments such as SGLT2 inhibitors that induce glucosuria should be evaluated to determine their level of risk for genital infection.…”

Sodium-glucose cotransporter 2 inhibitors (SGLT2i): renal implications

“…Catecholamines normally have a direct effect on renal glucose release only; however, they may indirectly affect both hepatic and renal glucose release by increasing the gluconeogenic substrate availability, glucagon secretion, and suppressing insulin release [5]. On the other hand, a group of counter-regulatory hormones: growth hormone, thyroid hormone and cortisol, as well as catecholamines, have long-term stimulatory influences on hepatic glucose release, by modifying the hepatic, renal, adipose tissue and muscular sensitivity to insulin, glucagon, and catecholamines, and by altering the glycogen stores and gluconeogenesis [5,6] After prolong overnight fast, glucose, which comes from hepatic glycogenolysis and hepatic-renal gluconeogenesis, is released into the IVC [5]. The release of endogenous glucose decreases by 61% after meal ingestion to inhibit the development of postprandial hyperglycemia.…”