Xenin and Related Peptides: Potential Therapeutic Role in Diabetes and Related Metabolic Disorders.

Xenin bioactivity and its role in normal physiology has been investigated by several research groups since its discovery in 1992. The 25 amino acid peptide hormone is secreted from the same enteroendocrine K-cells as the incretin hormone glucose-dependent insulinotropic polypeptide (GIP), with early studies highlighting the biological significance of xenin in the gastrointestinal tract, along with effects on satiety. Recently there has been more focus directed towards the role of xenin in insulin secretion and potential for diabetes therapies, especially through its ability to potentiate the insulinotropic actions of GIP as well as utilisation in dual/triple acting gut hormone therapeutic approaches. Currently, there is a lack of clinically approved therapies aimed at restoring GIP bioactivity in type 2 diabetes mellitus, thus xenin could hold real promise as a diabetes therapy. The biological actions of xenin, including its ability to augment insulin secretion, induce satiety effects, as well as restoring GIP sensitivity, earmark this peptide as an attractive antidiabetic candidate. This minireview will focus on the multiple biological actions of xenin, together with its proposed mechanism of action and potential benefits for the treatment of metabolic diseases such as diabetes.

A novel neurotensin/xenin fusion peptide enhances ß-cell function and exhibits antidiabetic efficacy in high-fat fed mice.

Neurotensin and xenin possess antidiabetic potential, mediated in part through augmentation of incretin hormone, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), action. In the present study, fragment peptides of neurotensin and xenin, acetyl-neurotensin and xenin-8-Gln, were fused together to create Ac-NT/XN-8-Gln. Following assessment of enzymatic stability, effects of Ac-NT/XN-8-Gln on in vitro ß-cell function were studied. Subchronic antidiabetic efficacy of Ac-NT/XN-8-Gln alone, and in combination with the clinically approved GLP-1 receptor agonist exendin-4, was assessed in high-fat fed (HFF) mice. Ac-NT/XN-8-Gln was highly resistant to plasma enzyme degradation and induced dose-dependent insulin-releasing actions (P<0.05 to P<0.01) in BRIN-BD11 ß-cells and isolated mouse islets. Ac-NT/XN-8-Gln augmented (P<0.001) the insulinotropic actions of GIP, while possessing independent ß-cell proliferative (P<0.001) and anti-apoptotic (P<0.01) actions. Twice daily treatment of HFF mice with Ac-NT/XN-8-Gln for 32 days improved glycaemic control and circulating insulin, with benefits significantly enhanced by combined exendin-4 treatment. This was reflected by reduced body fat mass (P<0.001), improved circulating lipid profile (P<0.01) and reduced HbA1c concentrations (P<0.01) in the combined treatment group. Following an oral glucose challenge, glucose levels were markedly decreased (P<0.05) only in combination treatment group and superior to exendin-4 alone, with similar observations made in response to glucose plus GIP injection. The combined treatment group also presented with improved insulin sensitivity, decreased pancreatic insulin content as well as increased islet and ß-cell areas. These data reveal that Ac-NT/XN-8-Gln is a biologically active neurotensin/xenin fusion peptide that displays prominent antidiabetic efficacy when administered together with exendin-4.

The methionine aminopeptidase 2 inhibitor, TNP-470, enhances the antidiabetic properties of sitagliptin in mice by upregulating xenin.

The therapeutic mechanism of action of methionine aminopeptidase 2 (MetAP2) inhibitors for obesity-diabetes has not yet been fully defined. Xenin, a K-cell derived peptide hormone, possesses an N-terminal Met amino acid residue. Thus, elevated xenin levels could represent a potential pharmacological mechanism of MetAP2 inhibitors, since long-acting xenin analogues have been shown to improve obesity-diabetes. The present study has assessed the ability of the MetAP2 inhibitor, TNP-470, to augment the antidiabetic utility of the incretin-enhancer drug, sitagliptin, in high fat fed (HFF) mice. TNP-470 (1 mg/kg) and sitagliptin (25 mg/kg) were administered once-daily alone, or in combination, to diabetic HFF mice (n = 10) for 18 days. Individual therapy with TNP-470 or sitagliptin resulted in numerous metabolic benefits including reduced blood glucose, increased circulating and pancreatic insulin and improved glucose tolerance, insulin sensitivity, pyruvate tolerance and overall pancreatic islet architecture. Further assessment of metabolic rate revealed that all treatments reduced respiratory exchange ratio and increased locomotor activity. All sitagliptin treated mice also exhibited increased energy expenditure. In addition, treatment with TNP-470 alone, or in combination with sitagliptin, reduced food intake and body weight, as well as elevating plasma and intestinal xenin. Importantly, combined sitagliptin and TNP-470 therapy was associated with further significant benefits beyond that observed by either treatment alone. This included more rapid restoration of normoglycaemia, superior glucose tolerance, increased circulating GIP concentrations and an enhanced pancreatic beta:alpha cell ratio. In conclusion, these data demonstrate that TNP-470 increases plasma and intestinal xenin levels, and augments the antidiabetic advantages of sitagliptin.

Individual and combined effects of GIP and xenin on differentiation, glucose uptake and lipolysis in 3T3-L1 adipocytes.

The incretin hormone glucose-dependent insulinotropic polypeptide (GIP), released postprandially from K-cells, has established actions on adipocytes and lipid metabolism. In addition, xenin, a related peptide hormone also secreted from K-cells after a meal, has postulated effects on energy regulation and lipid turnover. The current study has probed direct individual and combined effects of GIP and xenin on adipocyte function in 3T3-L1 adipocytes, using enzyme-resistant peptide analogues, (d-Ala2)GIP and xenin-25-Gln, and knockdown (KD) of receptors for both peptides. (d-Ala2)GIP stimulated adipocyte differentiation and lipid accumulation in 3T3-L1 adipocytes over 96 h, with xenin-25-Gln evoking similar effects. Combined treatment significantly countered these individual adipogenic effects. Individual receptor KD impaired lipid accumulation and adipocyte differentiation, with combined receptor KD preventing differentiation. (d-Ala2)GIP and xenin-25-Gln increased glycerol release from 3T3-L1 adipocytes, but this lipolytic effect was significantly less apparent with combined treatment. Key adipogenic and lipolytic genes were upregulated by (d-Ala2)GIP or xenin-25-Gln, but not by dual peptide culture. Similarly, both (d-Ala2)GIP and xenin-25-Gln stimulated insulin-induced glucose uptake in 3T3-L1 adipocytes, but this effect was annulled by dual treatment. In conclusion, GIP and xenin possess direct, comparable, lipogenic and lipolytic actions in 3T3-L1 adipocytes. However, effects on lipid metabolism are significantly diminished by combined administration.

Ψ-Xenin-6 enhances sitagliptin effectiveness, but does not improve glucose tolerance.

Recent studies have characterised the biological properties and glucose-dependent insulinotropic polypeptide (GIP) potentiating actions of an enzymatically stable, C-terminal hexapeptide fragment of the gut hormone xenin, namely Ψ-xenin-6. Given the primary therapeutic target of clinically approved dipeptidyl peptidase-4 (DPP-4) inhibitor drugs is augmentation of the incretin effect, the present study has assessed the capacity of Ψ-xenin-6 to enhance the antidiabetic efficacy of sitagliptin in high fat fed (HFF) mice. Individual administration of either sitagliptin or Ψ-xenin-6 alone for 18 days resulted in numerous metabolic benefits and positive effects on pancreatic islet architecture. As expected, sitagliptin therapy was associated with elevated circulating GIP and GLP-1 levels, with concurrent Ψ-xenin-6 not elevating these hormones or enhancing DPP-4 inhibitory activity of the drug. However, combined sitagliptin and Ψ-xenin-6 therapy in HFF mice was associated with further notable benefits, beyond that observed with either treatment alone. This included body weight change similar to lean controls, more pronounced and rapid benefits on circulating glucose and insulin as well as additional improvements in attenuating gluconeogenesis. Favourable effects on pancreatic islet architecture and peripheral insulin sensitivity were more apparent with combined therapy. Expression of hepatic genes involved in gluconeogenesis and insulin action were partially, or fully, restored to normal levels by the treatment regimens, with beneficial effects more prominent in the combination treatment group. These data demonstrate that combined treatment with Ψ-xenin-6 and sitagliptin did not alter glucose tolerance but does offer some metabolic advantages, which merit further consideration as a therapeutic option for type 2 diabetes.

Exendin-4(Lys27 PAL)/gastrin/xenin-8-Gln: A novel acylated GLP-1/gastrin/xenin hybrid peptide that improves metabolic status in obese-diabetic (ob/ob) mice.

BACKGROUND: Therapeutic benefits of peptide-based drugs is limited by rapid renal elimination. METHODS: Therefore, to prolong the biological action profile of the recently characterized triple-acting hybrid peptide, exendin-4/gastrin/xenin-8-Gln, a fatty acid (C-16) has been covalently attached, creating exendin-4(Lys27 PAL)/gastrin/xenin-8-Gln. Exendin-4/gastrin and liraglutide/gastrin/xenin-8-Gln were also synthesized as direct comparator peptides. RESULTS: All hybrid peptides evoked significant concentration-dependent increases of insulin secretion from isolated murine islets and BRIN-BD11 cells. Following administration of peptides with glucose to mice, all hybrids significantly reduced the overall glycaemic excursion and increased insulin concentrations. In contrast to other treatments, exendin-4(Lys27 PAL)/gastrin/xenin-8-Gln displayed impressive antihyperglycaemic actions even 12 hours after administration, highlighting protracted duration of effects. Exendin-4/gastrin/xenin-8-Gln, exendin-4/gastrin, and exendin-4(Lys27 PAL)/gastrin/xenin-8-Gln were then progressed to a 31-day twice-daily treatment regimen in obese-diabetic ob/ob mice. All treatments decreased nonfasting glucose and HbA1c concentrations, as well as enhancing circulating and pancreatic insulin levels. Exendin-4/gastrin and exendin-4/gastrin/xenin-8-Gln also decreased food intake. Glucose tolerance was improved by all treatments, but only exendin-4(Lys27 PAL)/gastrin/xenin-8-Gln augmented glucose-induced insulin secretion. Interestingly, treatment regimens that included a xenin component induced clear advantages on the metabolic response to glucose-dependent insulinotropic polypeptide (GIP) and the glucose-lowering actions of insulin. CONCLUSION: This study emphasizes the therapeutic promise of long-acting, multi-targeting hybrid gut peptides for type 2 diabetes.

Emerging therapeutic potential for xenin and related peptides in obesity and diabetes.

Xenin-25 is a 25-amino acid peptide hormone co-secreted from the same enteroendocrine K-cell as the incretin peptide glucose-dependent insulinotropic polypeptide. There is no known specific receptor for xenin-25, but studies suggest that at least some biological actions may be mediated through interaction with the neurotensin receptor. Original investigation into the physiological significance of xenin-25 focussed on effects related to gastrointestinal transit and satiety. However, xenin-25 has been demonstrated in pancreatic islets and recently shown to possess actions in relation to the regulation of insulin and glucagon secretion, as well as promoting beta-cell survival. Accordingly, the beneficial impact of xenin-25, and related analogues, has been assessed in animal models of diabetes-obesity. In addition, studies have demonstrated that metabolically active fragment peptides of xenin-25, particularly xenin-8, possess independent therapeutic promise for diabetes, as well as serving as bioactive components for the generation of multi-acting hybrid peptides with antidiabetic potential. This review focuses on continuing developments with xenin compounds in relation to new therapeutic approaches for diabetes-obesity.