Antidiabetic Effects of a Tripeptide That Decreases Abundance of Na⁺-d-glucose Cotransporter SGLT1 in the Brush-Border Membrane of the Small Intestine

Abstract

In enterocytes, protein RS1 (RSC1A1) mediates an increase of glucose absorption after ingestion of glucose-rich food via upregulation of Na + -D-glucose cotransporter SGLT1 in the brush-border membrane (BBM). Whereas RS1 decelerates the exocytotic pathway of vesicles containing SGLT1 at low glucose levels between meals, RS1-mediated deceleration is relieved after ingestion of glucose-rich food. Regulation of SGLT1 is mediated by RS1 domain RS1-Reg, in which Gln-Ser-Pro (QSP) is effective. In contrast to QSP and RS1-Reg, Gln-Glu-Pro (QEP) and RS1-Reg with a serine to glutamate exchange in the QSP motif downregulate the abundance of SGLT1 in the BBM at high intracellular glucose concentrations by about 50%. We investigated whether oral application of QEP improves diabetes in db/db mice and affects the induction of diabetes in New Zealand obese (NZO) mice under glucolipotoxic conditions. After 6-day administration of drinking water containing 5 mM QEP to db/db mice, fasting glucose was decreased, increase of blood glucose in the oral glucose tolerance test was blunted, and insulin sensitivity was increased. When QEP was added for several days to a high fat/high carbohydrate diet that induced diabetes in NZO mice, the increase of random plasma glucose was prevented, accompanied by lower plasma insulin levels. QEP is considered a lead compound for development of new antidiabetic drugs with more rapid cellular uptake. In contrast to SGLT1 inhibitors, QEP-based drugs may be applied in combination with insulin for the treatment of type 1 and type 2 diabetes, decreasing the required insulin amount, and thereby may reduce the risk of hypoglycemia.

Increased/Targeted Brain (Pro)Drug Delivery via Utilization of Solute Carriers (SLCs)

“…Therefore, it is not likely that higher brain drug disposition can be achieved by utilizing the SGLT-transporters; however, in the cases where GLUTs are downregulated, like in AD, additional glucose transporters may have a more critical role in the transport of glucoconjugates. Some inhibitors of SGLTs (gluco-conjugates and others) have been reported to maintain stable plasma glucose in type 2 diabetic patients, mainly due to the inhibition in the intestine and renal proximal tubules [284][285][286]. Nevertheless, more structural and functional details overall are required from all the above-mentioned transporters in order to deploy them for rational (pro)drug design in brain-targeted applications.…”

Endometrial Glucose Transporters in Health and Disease

“…SGLT2 and dual SGLT1/SGLT2 inhibitors have already been used in the treatment of diabetes (Vallon, 2015;Ghezzi et al, 2018). An overexpression of both transporters has been detected in diabetes and numerous cancer types (Scafoglio et al, 2015;Vallon, 2015;Koepsell, 2017;Vrhovac Madunic et al, 2018;Otto et al, 2020;Wright, 2020), making them a new target for cancer therapy. Among these SGLTs, SGLT1, and SGLT2 have been frequently investigated, as they play key roles in the transport of glucose and sodium across the brush border membrane of intestinal and renal cells.…”

“…SGLT2 and dual SGLT1/SGLT2 inhibitors have already been used in the treatment of diabetes ( Vallon, 2015 ; Ghezzi et al, 2018 ). An overexpression of both transporters has been detected in diabetes and numerous cancer types ( Scafoglio et al, 2015 ; Vallon, 2015 ; Koepsell, 2017 ; Vrhovac Madunic et al, 2018 ; Otto et al, 2020 ; Wright, 2020 ), making them a new target for cancer therapy.…”