Diabetes mellitus and expression of the enterocyte renin-angiotensin system: implications for control of glucose transport across the brush border membrane

Abstract

Streptozotocin-induced (Type 1) diabetes mellitus (T1DM) in rats promotes jejunal glucose transport, but the trigger for this response remains unclear. Our recent work using euglycemic rats has implicated the enterocyte renin-angiotensin system (RAS) in control of sodium-dependent glucose transporter (SGLT1)-mediated glucose uptake across the jejunal brush border membrane (BBM). The aim of the present study was to examine whether expression of enterocyte RAS components is influenced by T1DM. The effects of mucosal addition of angiotensin II (AII) on [14C]-d-glucose uptake by everted diabetic jejunum was also determined. Two-week diabetes caused a fivefold increase in blood glucose level and reduced mRNA and protein expression of AII type 1 (AT1) and AT2 receptors and angiotensin-converting enzyme in isolated jejunal enterocytes. Angiotensinogen expression was, however, stimulated by diabetes while renin was not detected in either control or diabetic enterocytes. Diabetes stimulated glucose uptake into everted jejunum by 58% and increased the BBM expression of SGLT1 and facilitated glucose transporter 2 (GLUT2) proteins, determined by Western blotting by 25% and 135%, respectively. Immunohistochemistry confirmed an enhanced BBM expression of GLUT2 in diabetes and also showed that this was due to translocation of the transporter from the basolateral membrane to BBM. AII (5 μM) or L-162313 (1 μM), a nonpeptide AII analog, decreased glucose uptake by 18% and 24%, respectively, in diabetic jejunum. This inhibitory action was fully accountable by an action on SGLT1-mediated transport and was abolished by the AT1 receptor antagonist losartan (1 μM). The decreased inhibitory action of AII on in vitro jejunal glucose uptake in diabetes compared with that noted previously in jejunum from normal animals is likely to be due to reduced RAS expression in diabetic enterocytes, together with a disproportionate increase in GLUT2, compared with SGLT1 expression at the BBM.