Xenin-25[Lys13PAL]: a novel long-acting acylated analogue of xenin-25 with promising antidiabetic potential

Abstract

These data indicate that sustained administration of a stable analogue of xenin-25 exerts a spectrum of beneficial metabolic effects in high-fat-fed mice.

An enzymatically stable GIP/xenin hybrid peptide restores GIP sensitivity, enhances beta cell function and improves glucose homeostasis in high-fat-fed mice

“…However, further investigations, including euglycaemic-hyperinsulinaemic clamps, glucose uptake and gene and protein expression studies, are required to fully address the molecular mechanisms underpinning this benefit. Somewhat surprisingly, at the dose tested, (DAla 2 )GIP/xenin-8-Gln had no effect on energy intake, although similar observations have been reported previously with xenin-based drugs [38]. This limited satiety effect presumably reflects the requirement of supraphysiological doses of xenin to impart appetite-suppressive effects [10].…”

“…However, normalisation of blood glucose levels, as clearly demonstrated in both (DAla 2 )GIPand (DAla 2 )GIP/xenin-8-Gln-treated mice, has also been shown to independently restore GIP insulin-secretory function in type 2 diabetes [5,6]. In addition, we have already confirmed that xenin has significant glucose-lowering activity independent of the GIP receptor [38]. Therefore, further studies are required to systematically assess the direct and indirect beneficial effects of (DAla 2 )GIP/xenin-8-Gln in restoring GIP action in type 2 diabetes.…”

“…As expected, the biological action of GIP was severely perturbed in high-fat-fed mice, akin to the situation in patients with type 2 diabetes [4]. It would be more than reasonable to link a major part of the positive therapeutic effects of (DAla 2 )GIP/ xenin-8-Gln directly to augmentation of GIP action, as previously observed with other xenin-related compounds [10,38]. Thus, the main rationale for inclusion of the xenin component of our novel hybrid peptide was essentially to enhance GIPmediated actions [10,38].…”

Sustained high‐fat diet modulates inflammation, insulin signalling and cognition in mice and a modified xenin peptide ameliorates neuropathology in a chronic high‐fat model

“…injection of vehicle alone (0.9% NaCl w/v). The dosage of 25 nmol/kg was chosen based on previous studies of the effects of Xenin‐25[Lys(13)PAL] on metabolic endpoints . Injections were administered daily at 3:00 pm to avoid potentially confounding effects of injection and restraint stress, and acute drug effects, on behavioural testing, which was performed in the morning.…”

Luminal chemosensing in the gastroduodenal mucosa

“…Plasma xenin concentrations are increased by meal ingestion or sham feeding in humans, suggesting that vagal reflexes stimulate xenin release from the duodenal mucosa [68]. The infusion of low concentrations (4–12 pmol/kg) of xenin to humans delays gastric emptying, inhibits GLP-1 release, and causes mild diarrhea [69;70]. Since RYGB obesity surgery diminishes exogenous xenin-associated diarrhea and the inhibition of GLP-1 release in response to liquid meal, duodenal xenin signals may significantly activate unknown neural pathways [71*].…”