Medium-chain fatty acids inhibit jejunal SGLT1 activity in vitro and suppress glucose absorption in vivo in mice.

Medium-chain triglycerides (MCT) in diet improves glucose tolerance and insulin sensitivity, compared to long-chain triglycerides (LCT). However, the direct effects of medium-chain fatty acids (MCFA) on glucose transport have not been studied. Luminal glucose is absorbed in the small intestine through the electrogenic sodium-dependent glucose transporter SGLT1 and electroneutral glucose transporter GLUT2. We thus examined the effects of luminal MCFA on electrogenic SGLT1 activity and glucose absorption in mice. SGLT1 activity was assessed in the Ussing chambered, muscle-stripped jejunal mucosa by measuring phlorizin (Phz)-sensitive short-circuit current (I ) evoked by luminal addition of glucose (10 mM). Sodium propionate (C3), caproate (C6), caprylate (C8), caprate (C10), laurate (C12) and myristate (C14) were luminally added before or after glucose application. Furthermore, the effects of C10 on glucose absorption were assessed by oral glucose tolerance test (OGTT, glucose 2g/kg body weight, ig) with or without C10 treatment (1.94g/kg, ig) in conscious mice. Moreover, the portal venous (PV) blood glucose levels were measured though the PV cannulation, followed by intraduodenal bolus injection of glucose solution (100 mM) with or without C10 (10 mM) in the anesthetized mice. Luminal pretreatment of C10 and C12 dose-dependently inhibited the glucose-induced I increase at IC = 1.02 mM and 1.06 mM, respectively. C8 also inhibited the glucose-induced I increase, but less effective (IC 8.4 mM), whereas C3, C6 and C14 had little effect. C10 (10 mM) also inhibited methyl α-D-glucopyranoside (αMG)-induced I increase. Post-treatment of C10 and C12 (10 mM) rapidly reduced the increased I by glucose, mimicking the inhibitory effect of Phz (1 mM). OGTT showed that glucose levels reached the peak at 30 min, while C10 pretreatment remarkably inhibited glucose increase. Furthermore, intraduodenal injection of glucose solution increased the PV glucose levels at 10 - 20 min, while the addition of C10 in the glucose solution abolished the response. These data suggest that C10 and C12 act as the SGLT1 inhibitor. Since MCT releases C10 and C12 via digestion by pancreatic lipase, slower than glucose release by maltase/sucrase, free C10/C12 solution may be more effective therapeutics for the treatment of type 2 diabetes.