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

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

Left Main Coronary Artery Revascularization in Patients with Impaired Renal Function: Percutaneous Coronary Intervention versus Coronary Artery Bypass Grafting

Introduction: The evidence about the optimal revascularization strategy in patients with left main coronary artery (LMCA) disease and impaired renal function is limited. Thus, we aimed to compare the outcomes of LMCA disease revascularization (percutaneous coronary intervention [PCI] vs. coronary artery bypass grafting [CABG]) in patients with and without impaired renal function. Methods: This retrospective cohort study included 2,138 patients recruited from 14 centers between 2015 and 2,019. We compared patients with impaired renal function who had PCI (n= 316) to those who had CABG (n = 121) and compared patients with normal renal function who had PCI (n = 906) to those who had CABG (n = 795). The study outcomes were in-hospital and follow-up major adverse cardiovascular and cerebrovascular events (MACCE). Results: Multivariable logistic regression analysis showed that the risk of in-hospital MACCE was significantly higher in CABG compared to PCI in patients with impaired renal function (odds ratio [OR]: 8.13 [95% CI: 4.19–15.76], p < 0.001) and normal renal function (OR: 2.59 [95% CI: 1.79–3.73]; p < 0.001). There were no differences in follow-up MACCE between CABG and PCI in patients with impaired renal function (HR: 1.14 [95% CI: 0.71–1.81], p = 0.585) and normal renal function (HR: 1.12 [0.90–1.39], p = 0.312). Conclusions: PCI could have an advantage over CABG in revascularization of LMCA disease in patients with impaired renal function regarding in-hospital MACCE. The follow-up MACCE was comparable between PCI and CABG in patients with impaired and normal renal function