Metabolic dysfunction regarding the insulin system is thought to lead to insulin resistance, metabolic syndrome, obesity, type 2 diabetes and hyperglycaemia. The insulin system is complex and not fully understood, but recent advances have uncovered further details of its mode of action, including evidence of the involvement of the incretin hormones that stimulate insulin release following a meal. Both glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotrophic hormone are now thought to play a major role in the secretion of insulin, and some evidence suggests that GLP-1 secretion is defective in type 2 diabetes. It is at present unclear however, whether the GLP-1 deficiency in type 2 diabetes is a cause or result of the hypoglycaemic state. Glutamine is of interest in this regard, because some evidence suggests that it can enhance GLP-1 secretion and may therefore have hypoglycaemic benefits to diabetic patients.
To investigate the glycaemic benefits of oral glutamine, researchers1 used a randomised, crossover study where they administered oral glutamine, with or without the hypoglycaemic drug sitagliptin, to 15 subjects with type 2 diabetes. The treatment was administered as 30g glutamine, 15g glutamine, 100 mg sitagliptin, 100mg sitagliptin and 15g glutamine, or a control (water), immediately followed by a low fat (5%) meal. Plasma was sampled from the subjects for up to 180 min following the meal, and treatments were separated by 1 to 2 weeks to ensure an adequate washout period. The results showed that all of the glutamine treatments improved the late (60-180 min) postprandial insulin response and postprandial glucagon response, such that the ratio of the two remained the same, albeit elevated. In addition, the glutamine treatments decreased the early postprandial glucose response from the meal, compared to the control.
When sitagliptin was given alone, active GLP-1 increased relative to the control. This is inline with the mechanism of action of DPP-IV (dipeptidyl peptidase-4) inhibitors (also called gliptins). Dipeptidyl peptidase-4 is an enzyme responsible for the degradation of incretins (including GLP-1), and inhibition therefore can increase levels of GLP-1, which is lowered in type 2 diabetes. Although active GLP-1 increased with the use of sitagliptin, total GLP-1 levels declined. This is likely be due to negative feedback from the active GLP-1. However, sitagliptin had no effect on either glycaemia or insulin levels, which was surprising given its use as an oral hypoglycaemic drug. But when glutamine was given in combination with sitagliptin, postprandial glycaemia was reduced. The combination also caused the total GLP-1 concentration to decreased (compared to an increase in active and total GLP-1 with glutamine only treatments), and this was likely a result of the sitagliptin.
By increasing GLP-1 levels, glutamine showed similar potential to the DPP-IV inhibitors. However, the authors considered that the hypoglycaemic effect of glutamine may have been caused by an increase in duration of gastric emptying, as a direct result of GLP-1 release, rather than via an insulin secretory effect. Glucagon-like peptide-1 is a known inhibitor of gastric emptying, and glutamine has previously been reported to increase gastric transit time when given with carbohydrates, compared to carbohydrates given alone. Because levels of C-peptide did not rise with the increased levels of insulin following glutamine administration, it is likely that the insulinaemic effect of the glutamine was due to a reduction in the clearance of insulin (rather than increased secretion). Glutamine therefore shows promise as an effective oral hypoglycaemic agent and could be useful given the poor compliance with hypoglycaemic drugs amongst patients.
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