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Patients with type 2 diabetes have an elevated risk for dehydration due to high glucose levels, and an increasingly popular class of diabetes drugs may increase this risk even more, researchers said.

Glucagon-like peptide-1 (GLP-1) receptor agonists target the incretin system and increase insulin secretion while inhibiting glucagon release when glucose levels are elevated with a low risk of hypoglycemia. GLP-1 is known to inhibit food intake, and an examination of the role of endogenous GLP-1 in rats revealed that the hormone exhibited a strong inhibitory effect on drinking behavior, reported Naomi McKay, of the State University of New York at Buffalo, and colleagues in the

The first GLP-1 receptor agonist, exenatide (Byetta) was approved for use in the U.S. in 2005, and since then several others, including liraglutide (Victoza), have entered the market. In 2012, FDA approved an extended-release version of exenatide (Bydureon), the first once-weekly treatment for type 2 diabetes.

"Clearly what we are seeing, not just in this paper, but in (our two previous) papers, is that these substances decrease drinking behavior," noted co-author in an accompanying statement. "But we're not saying people shouldn't use these drugs to treat diabetes, and we're not saying they are ineffective tools for the treatment of diabetes. However, for populations already at risk for dehydration it may be something we want to be more concerned about."

Several earlier studies suggested that GLP-1 and possibly in humans, but the precise role of the gastrointestinal hormone on fluid intake has not been previously studied, the researchers wrote.

McKay's group used two strategies to examine the role of endogenous GLP-1 in the control of fluid intake.

"First, we tested the effect of central administration of the GLP-1R antagonist, exendin-9 (Ex-9), on water and saline intake," they wrote. "Second, we examined the effect of water deprivation, with and without subsequent intake, on circulating GLP-1, and on expression of the GLP-1 precursor protein, proglucagon, and GLP-1R in the ileum and [nucleus of the solitary tract] to test the hypothesis that perturbations of fluid intake affect endogenous GLP-1."

The researchers also conducted experiments examining fluid intake in conjunction with food intake in the male Sprague Dawley rats.

In the first experiment, they used rats that had been stimulated to drink by injections of hypertonic saline. When injected with Ex-9, the mice drank more fluid in response to hypertonic saline or water deprivation than did vehicle-treated rats. Another experiment confirmed that injections of Ex-9 increased both water and saline intake in a water deprivation-partial hydration setting.

Analysis of rat lick patterns showed that Ex-9 increased fluid intake by increasing the number of licking bursts, without having an effect on the number of licks per burst. This finding suggests that endogenous GLP-1 suppresses fluid intake by influencing satiety, the researchers wrote.

"Licking patterns can give us hints about why rats drink more or less after an experimental manipulation," Daniels said. "In this study, we found that the rats were probably drinking more because they were feeling less full from the drinking."

Further research suggested that water intake had a selective effect on central GLP-1-related gene expression which, unlike food intake, affected both central and peripheral GLP-1.

"Although water and food intakes both affected central GLP-1-relevant gene expression, there were notable differences in the timing of the effect," the researchers wrote. "These results show a novel role of the endogenous GLP-1 system in fluid intake and indicate that elements of the GLP-1 system can be engaged separately by different forms of ingestive behavior."

The implications of the research for patients with type 2 diabetes taking incretin system-targeting drugs remain to be determined, the researchers noted.

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