A novel chemically modified analogue of xenin-25 exhibits improved glucose-lowering and insulin-releasing properties

Abstract

Glutamine (gln)-modified analogues of xenin may represent an attractive therapeutic approach for type 2 diabetes.

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

“…A follow‐up study employing chronic administration of xenin‐25[Lys 13 PAL] to high fat fed diabetic mice confirmed this suggestion, as treated mice presented with augmented insulin secretion, improved glucose homeostasis, enhanced tissue insulin sensitivity, and partial restoration of normal islet morphology . Moreover, knowledge that serine‐like proteases are primarily responsible for xenin‐25 degradation, led to the generation of a modified xenin‐25 analogue where Lysine (Lys) and Arginine (Arg) amino acid residues were substituted for Glutamine (Gln), to yield xenin‐25‐Gln (Table ) . Xenin‐25‐Gln was enzyme resistant and retained biological activity, with chronic administration in high fat fed and ob/ob mice resulting in enhanced metabolic control, increased GIP sensitivity, and improved circulating lipid profile .…”

“…More recent research has highlighted the potential of xenin‐25 as a direct independent insulinotropic agent, along with an ability to potentiate the insulin‐releasing and glucose‐lowering effects of the incretin hormone, glucose‐dependent insulinotropic peptide (GIP) . Furthermore, related studies have revealed that xenin‐25 enhances pancreatic beta‐cell proliferation in both rodent and human beta‐cells (Figure ) .…”

Beneficial long‐term antidiabetic actions of N‐ and C‐terminally modified analogues of apelin‐13 in diet‐induced obese diabetic mice

“…After the 28‐day treatment period, glucose tolerance (18 mmol/kg body weight; i.p. and oral) and metabolic response to feeding, were examined in overnight (12 hours) fasted lean and DIO mice treated with either peptides or saline as described previously . Whole‐body insulin sensitivity tests (25 U/kg body weight) were carried out as described previously using fed mice …”

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

“…Another gut hormone, Xenin‐25, is secreted by K cells in the small intestine following nutrient ingestion and acts through neurotensin receptor 1 (NTR1) . Building on previous research, generation of a stable xenin‐25 mimetic, Xenin‐25[Lys(13)PAL], with potent anti‐diabetic efficacy has been achieved . NTR1 is expressed throughout the brain, particularly in the hippocampus and entorhinal cortex .…”

“…19 Building on previous research, generation of a stable xenin-25 mimetic, Xenin-25[Lys (13)PAL], with potent anti-diabetic efficacy has been achieved. 20 NTR1 is expressed throughout the brain, 21 particularly in the hippocampus and entorhinal cortex. 22 Mutations in the NTR1 gene are associated with impaired working memory in humans 23 and antagonism of NTR1 impairs spatial learning.…”