Content area
Full Text
To clarify the physiological role of Na+-D-glucose cotransporter SGLT1 in small intestine and kidney, Sglt1^sup -/-^ mice were generated and characterized phenotypically. After gavage of D-glucose, small intestinal glucose absorption across the brush-border membrane (BBM) via SGLT1 and GLUT2 were analyzed. Glucose-induced secretion of insulinotropic hormone (GLP) and glucagon-like peptide 1 (GLP-1) in wild-type and Sglt1^sup -/-^ mice were compared. The impact of SGLT1 on renal glucose handling was investigated by micropuncture studies. It was observed that Sglt1^sup -/-^ mice developed a glucose-galactose malabsorption syndrome but thrive normally when fed a glucose-galactose-free diet. In wild-type mice, passage of D-glucose across the intestinal BBM was predominantly mediated by SGLT1, independent the glucose load. High glucose concentrations increased the amounts of SGLT1 and GLUT2 in the BBM, and SGLT1 was required for upregulation of GLUT2. SGLT1 was located in luminal membranes of cells immunopositive for GIP and GLP-1, and Sglt1^sup -/-^ mice exhibited reduced glucose-triggered GIP and GLP-1 levels. In the kidney, SGLT1 reabsorbed ~3% of the filtered glucose under normoglycemic conditions. The data indicate that SGLT1 is 1) pivotal for intestinal mass absorption of D-glucose, 2) triggers the glucose-induced secretion of GIP and GLP-1, and 3) triggers the upregulation of GLUT2. Diabetes 61:187-196, 2012
Obesity, type 2 diabetes, and the metabolic syndrome are some of the major medical and economical challenges of modern societies. DysregLilation of carbohydrate management, increased consumption of carbohydrates and fat, and reduced insulin receptor sensitivity contribute to the metabolic derangements. Drugs that reduce small intestinal uptake of D-glucose and/or reabsorption of D-glucose from the renai filtrate or that modulate secretion of insulinotropic enterohormones can provide new therapeutic strategies (1,2). To further explore these options a better understanding of the underlying molecular mechanisms is required.
The primary transporters that mediate transcellular movements of r>glucose in small intestine have been identified and include the Na+-D-glucose cotransporter SGLTl and GLUT2 (3,4). It is generally accepted that SGLTl mediates uptake of low concentrations of D-glucose across the brush-border membrane (BBM) of the small intestine and that D-glucose leaves enterocytes across the basolateral membrane (BLM) via GLUT2 (3). However, their relative contributions to D-glucose absorption after a carbohydraterich meal remain controversial (5-7). Kellet and coworkers suggested that under these conditions GLUT2 is incorporated into the BBM...