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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.

SUBMITTER: Otto C 

PROVIDER: S-EPMC7675577 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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

Otto Christoph C   Friedrich Alexandra A   Vrhovac Madunić Ivana I   Baumeier Christian C   Schwenk Robert W RW   Karaica Dean D   Germer Christoph-Thomas CT   Schürmann Annette A   Sabolić Ivan I   Koepsell Hermann H  

ACS omega 20201104 45


In enterocytes, protein RS1 (<i>RSC1A1</i>) mediates an increase of glucose absorption after ingestion of glucose-rich food <i>via</i> upregulation of Na<sup>+</sup>-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 (QS  ...[more]

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