The molecular basis of enhanced glucose transporter, SGLT1, expression in the diabetic intestine

Alshali, Rasha The molecular basis of enhanced glucose transporter, SGLT1, expression in the diabetic intestine. Doctor of Philosophy thesis, University of Liverpool, Institute of Integrative Biology.

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Abstract

Dietary carbohydrates are hydrolyzed in the small intestine ultimately, by the brush-border membrane disaccharidases (sucrase, maltase and lactase) into monosaccharides: D-glucose, D-galactose and D-fructose. D-glucose and D-galactose are transported across the brush border membrane (BBM) from the intestinal lumen into enterocytes by the Na+- dependent glucose transporter 1, SGLT1, while D-fructose is transported by GLUT5. These monosaccharides, exit the cell across the baso-lateral membrane (BLM) into the systemic circulation via the facilitated monosaccharide transporter, GLUT2. SGLT1 regulation is vital for the provision of glucose to the body and for maintaining glucose homoeostasis. The expression and activity of SGLT1 are adaptively regulated by dietary sugars in most species studied. The intestinal capacity to absorb glucose is maintained via basal level of SGLT1 expression. However, this capacity becomes limited when the luminal carbohydrates exceed a threshold level, leading to up-regulation of SGLT1. Previous work in our laboratory has shown that luminal sugar concentration, when above a threshold, is detected by the intestinal glucose sensor, consisting of two subunits, Taste 1 receptor 2 (T1R2) and 3 (T1R3) expressed in enteroendocrine L-cells. This activates a pathway, in endocrine cells, leading to secretion of the gut hormone glucagon like peptide 2 (GLP-2), known to up-regulate SGLT1 expression. Binding of GLP-2 to its receptor on the enteric neurons induces a neuronal response evoking secretion of vasoactive intestinal peptide (VIP) and/or Pituitary adenylate cyclase-activating polypeptide (PACAP) by sub-mucosal plexus. Binding of VIP/PACAP to their receptor VPAC1 (VIP and PACAP receptor type 1) on the basolateral membrane of absorptive enterocytes leads to increased concentration of intracellular cAMP which in turn enhances the half-life of SGLT1 mRNA, increasing the number of SGLT1 proteins per enterocytes. In diabetes, the intestinal capacity for glucose absorption is enhanced complicating the aetiology of the disease. This enhanced expression is independent of either luminal sugar and blood glucose concentrations or insulin levels. The work in this thesis was aimed at identify molecular basis of enhanced SGLT1 expression in the diabetic intestine using intestinal tissues from rats with experimentally induced diabetes and biopsies from the intestine of human diabetics. The data indicate that increased SGLT1 expression is due to dysregulation of pathway controlling SGLT1 expression.

Item Type:	Thesis (Doctor of Philosophy)
Additional Information:	Date: 2014-01 (completed)
Depositing User:	Symplectic Admin
Date Deposited:	07 Aug 2014 11:01
Last Modified:	17 Dec 2022 01:41
DOI:	10.17638/00018411
Supervisors:	Shirazi-Beechey, Soraya Ellis, Anthony
URI:	https://livrepository.liverpool.ac.uk/id/eprint/18411