Natural Products as Lead Compounds for Sodium Glucose Cotransporter (SGLT) Inhibitors

Abstract

Glucose homeostasis is maintained by antagonistic hormones such as insulin and glucagon as well as by regulation of glucose absorption, gluconeogenesis, biosynthesis and mobilization of glycogen, glucose consumption in all tissues and glomerular filtration, and reabsorption of glucose in the kidneys. Glucose enters or leaves cells mainly with the help of two membrane integrated transporters belonging either to the family of facilitative glucose transporters (GLUTs) or to the family of sodium glucose cotransporters (SGLTs). The intestinal glucose absorption by endothelial cells is managed by SGLT1, the transfer from them to the blood by GLUT2. In the kidney SGLT2 and SGLT1 are responsible for reabsorption of filtered glucose from the primary urine, and GLUT2 and GLUT1 enable the transport of glucose from epithelial cells back into the blood stream.The flavonoid phlorizin was isolated from the bark of apple trees and shown to cause glucosuria. Phlorizin is an inhibitor of SGLT1 and SGLT2. With phlorizin as lead compound, specific inhibitors of SGLT2 were developed in the last decade and some of them have been approved for treatment mainly of type 2 diabetes. Inhibition of SGLT2 eliminates excess glucose via the urine. In recent times, the dual SGLT1/SGLT2 inhibitory activity of phlorizin has served as a model for the development and testing of new drugs exhibiting both activities.Besides phlorizin, also some other flavonoids and especially flavonoid enriched plant extracts have been investigated for their potency to reduce postprandial blood glucose levels which can be helpful in the prevention and supplementary treatment especially of type 2 diabetes.

(‐)‐Epicatechin and the Colonic 2,3‐Dihydroxybenzoic Acid Metabolite Regulate Glucose Uptake, Glucose Production, and Improve Insulin Signaling in Renal NRK‐52E Cells

“…Similarly, we have recently shown that EC did not modulate the protein levels of GLUT‐2 in hepatic cells . In addition, it should be mentioned that different natural products, including P and flavonoid enriched plant extracts, inhibit SGLT‐2, which contributed to reduce the glycemia . In this line, our results could suggest that EC and DHBA could contribute to decrease the glucose uptake by inhibiting SGLT‐2 without altering the expression of the glucose transporters, as described for dapagliflozin, empaglifozin, P, or other natural products …”

“…[33] In this line, our results could suggest that EC and DHBA could contribute to decrease the glucose uptake by inhibiting SGLT-2 without altering the expression of the glucose transporters, as described for dapagliflozin, empaglifozin, P, or other natural products. [3,28,33,34] Renal gluconeogenesis predominantly occurs in the proximal tubular cells. [2,4] Indeed, renal proximal tubular cells are particularly sensitive to the hyperglycemia because the glucose uptake is insulin-independent.…”

Plant‐derived glucose transport inhibitors with potential antitumor activity

“…Of these, phlorizin, the first naturally occurring sodium glucose cotransport (SGLT) inhibitor, has been used to identify the SGLT mechanism (Vick, Diedrich, & Baumann, ). Following this, many natural product glucose transport inhibitors have been characterized, of which several compounds have been tested in vitro and in vivo, and in some cases have reached clinical trials as potential cancer chemotherapeutic agents (Blaschek, ; Choi, ; Granchi et al, ; Qian et al, ).…”

“…In previous review articles, the overall information included on glucose transport and metabolism in cancer cells and the progress of new therapeutic developments for glucose transport inhibitors focused on small molecules, with only a limit number of natural products, were summarized (Qian et al, ). Natural product sodium glucose cotransporter (SGLT) inhibitors and their potential antidiabetic activity have been reviewed (Blaschek, ; Choi, ). In addition, synthetic and naturally derived glucose transport inhibitors and their potential anticancer activities have been discussed (Granchi et al, ; Granchi et al, ).…”

Natural products with SGLT2 inhibitory activity: Possibilities of application for the treatment of diabetes

“…These compounds not only control blood glucose but also have the potential to improve cardiovascular system function, reduce kidney disorders, and normalize the lipid profile (Fujita & Inagaki, ). Besides phlorizin, other natural product‐derived compounds have been investigated for their ability to reduce renal glucose reabsorption and improve glycemic control (Blaschek, ).…”