The impact of variations in gastric emptying, which influence the magnitude of GIP and GLP-1 secretion, on glucose-lowering by DPP-4 inhibitors is unclear. We evaluated responses to intraduodenal glucose infusion (60g over 120min, ie. 2kcal/min – a rate that predominantly stimulates GIP, but not GLP-1) after sitagliptin vs. control in 12 healthy lean and 12 obese subjects, and in 12 type 2 patients taking metformin 850mg bd vs. 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 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 subjects, with no additional glucose-lowering when combined with sitagliptin. These observations indicate that in type 2 diabetes (i) the capacity of endogenous GIP to lower blood glucose is impaired, (ii) the effect of DPP-4 inhibition on glycemia is likely to be dependent on adequate endogenous GLP-1 release, requiring gastric emptying above 2kcal/min, and (iii) the action of metformin to lower blood glucose is not predominantly via the incretin-axis.
- Received October 21, 2013.
- Accepted March 11, 2014.
- © 2014 by the American Diabetes Association.
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