No abstract

In healthy humans, SGLT1 substrates stimulate GLP-1 and GIP and slow gastric emptying, regardless of whether they are metabolized, whereas the artificial sweetener sucralose does not. Poorly absorbed sweet tastants (TIM), which probably expose a greater length of gut to nutrients, result in delayed GLP-1 secretion but not in delayed GIP release. These observations have the potential to optimize the use of preloads for glycemic control. This trial was registered at www.actr.org.au as ACTRN12611000775910.

The impact of variations in gastric emptying, which influence the magnitude of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) secretion, on glucose lowering by dipeptidyl peptidase-4 (DPP-4) inhibitors is unclear. We evaluated responses to intraduodenal glucose infusion (60 g over 120 min [i.e., 2 kcal/min], a rate that predominantly stimulates GIP but not GLP-1) after sitagliptin versus control in 12 healthy lean, 12 obese, and 12 type 2 diabetic subjects taking metformin 850 mg b.i.d. versus placebo. As expected, sitagliptin augmented plasma-intact GIP substantially and intact GLP-1 modestly. Sitagliptin attenuated glycemic excursions in healthy lean and obese but not type 2 diabetic subjects, without affecting glucagon or energy intake. In contrast, metformin reduced fasting and glucose-stimulated glycemia, suppressed energy intake, and augmented total and intact GLP-1, total GIP, and glucagon in type 2 diabetic subjects, with no additional glucose lowering when combined with sitagliptin. These observations indicate that in type 2 diabetes, 1) the capacity of endogenous GIP to lower blood glucose is impaired; 2) the effect of DPP-4 inhibition on glycemia is likely to depend on adequate endogenous GLP-1 release, requiring gastric emptying >2 kcal/min; and 3) the action of metformin to lower blood glucose is not predominantly by way of the incretin axis.Inhibition of dipeptidyl peptidase-4 (DPP-4) lowers glycemia by increasing intact glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) concentrations (1). In type 2 diabetes, the insulinotropic effects of GIP and GLP-1 are diminished, although the effect of GLP-1 is better preserved (2,3). GLP-1 also suppresses glucagon secretion (4), appetite, and energy intake (5) and slows gastric emptying (6,7). Therefore, the glucoselowering effect of DPP-4 inhibitors in this disorder is likely to depend primarily on the actions of GLP-1 rather than of GIP.Postprandial incretin secretion is regulated by the rate of nutrient delivery to the small intestine (8,9); GIP

It has been reported that the artificial sweetener, sucralose, stimulates glucose absorption in rodents by enhancing apical availability of the transporter GLUT2. We evaluated whether exposure of the proximal small intestine to sucralose affects glucose absorption and/or the glycaemic response to an intraduodenal (ID) glucose infusion in healthy human subjects. Ten healthy subjects were studied on two separate occasions in a single-blind, randomised order. Each subject received an ID infusion of sucralose (4 mM in 0·9 % saline) or control (0·9 % saline) at 4 ml/min for 150 min (T ¼ 230 to 120 min). After 30 min (T ¼ 0), glucose (25 %) and its non-metabolised analogue, 3-O-methylglucose (3-OMG; 2·5 %), were co-infused intraduodenally (T ¼ 0 -120 min; 4·2 kJ/min (1 kcal/min)). Blood was sampled at frequent intervals. Blood glucose, plasma glucagonlike peptide-1 (GLP-1) and serum 3-OMG concentrations increased during ID glucose/3-OMG infusion (P,0·005 for each). However, there were no differences in blood glucose, plasma GLP-1 or serum 3-OMG concentrations between sucralose and control infusions. In conclusion, sucralose does not appear to modify the rate of glucose absorption or the glycaemic or incretin response to ID glucose infusion when given acutely in healthy human subjects.3-O-methylglucose: Sodium-dependent GLUT 1: GLUT 2: Glucagon-like peptide-1The mechanisms by which the gut senses nutrients are unclear, and the 'receptor' for detecting luminal carbohydrates has, until recently, been elusive. Recent studies indicate the presence of G-protein-coupled taste receptors, T1R2 and T1R3, and their taste signal transduction partners, the G-protein gustducin and the transient receptor potential ion channel TRPM5, in the mucosa of the mouse and human gastrointestinal tract (1,2) . These receptors, analogous to sweet taste receptors on the tongue, broadly respond to sugars and artificial sweeteners, and among several cell types, they appear to co-localise with glucagon-like peptide-1 (GLP-1)-secreting L cells (3) .It has been reported that the artificial sweetener, sucralose, stimulates the secretion of both GLP-1 and glucose-dependent insulinotrophic polypeptide from the mouse enteroendocrine cell line GLUTag (4) , and it stimulates GLP-1 secretion from the human L cell line NCI-H716 (3) , a response that is blocked by the sweet receptor antagonist, lactisole, and siRNA for a-gustducin (3) . However, we recently demonstrated that sucralose, in two different loads, had no effect on GLP-1, glucose-dependent insulinotrophic polypeptide or insulin secretion, and that it did not elicit any feedback response on gastric emptying in healthy human subjects (5) . While this implies that artificial sweeteners may have no therapeutic benefit in the dietary management of diabetes, other than as a substitute for carbohydrates, it remains possible that sucralose affects small intestinal carbohydrate absorption as a result of its interaction with the sweet taste receptors.Glucose is absorbed from the small intestine through both ...