A vitamin B12 conjugate of exendin‐4 improves glucose tolerance without associated nausea or hypophagia in rodents

Abstract

These novel findings highlight the potential clinical utility of B12-Ex4 conjugates as possible future T2DM therapeutics with reduced incidence of adverse effects.

A second‐generation glucagon‐like peptide‐1 receptor agonist mitigates vomiting and anorexia while retaining glucoregulatory potency in lean diabetic and emetic mammalian models

“…In line with previous reports in lean, non-diabetic rats and shrews, 9,14,30,31 both native Ex4 doses (5 and 50 nmol/kg) tested here induced anorexia and body weight loss over 24 hours in shrews. By contrast, no such effects occurred after B12-Ex4 treatments, even at supra-pharmacological doses (i.e.…”

“…The protocol for performing an intraperitoneal glucose tolerance test (IPGTT) in shrews was similar to that previously used in mice. 9 One hour before dark onset, shrews (n = 13) were food-and water- To evaluate the effects of Ex4 and B12-Ex4 on baseline BG without subsequent glucose administration, Ex4, B12-Ex4 or vehicle was administered in a separate cohort of animals (n = 5). Shrews were food-and water-deprived as described above.…”

“…Thirty micrometre-thick frozen sagittal sections were processed via immunohistochemistry for insulin and coverslipped with 4 0 ,6-diamidino-2-phenylindole mounting medium as previously described. 9 Sections were visualized with confocal microscopy (Leica SP5 X) using the 488 and 594 laser lines with 10x and 20x objectives. All images were collected sequentially to avoid contamination of signals from other fluorophores.…”

“…1 Glucagon-like peptide-1 receptor (GLP-1R)-based therapies for the treatment of type 2 diabetes (T2D), such as Exendin-4 (Ex4) and liraglutide, are no exception, 2 causing nausea and vomiting in 25% to 50% of patients prescribed these drugs. [3][4][5][6][7] We have recently reported that a vitamin B12 conjugate of Ex4 (hereafter called 'B12-Ex4') 8,9 shows retention of glucoregulation comparable with native Ex4 without producing Ex4-associated anorexia and conditioned taste avoidance in lean, healthy rats. Furthermore, B12-Ex4 co-localized with insulin-containing β-cells within the pancreas, while brain penetrance of fluorescently tagged B12-Ex4 was not detected within the hypothalamus, nor the area postrema (AP), nor the nucleus tractus solitarius (NTS) of the hindbrain.…”

Liraglutide pharmacotherapy reduces body weight and improves glycaemic control in juvenile obese/hyperglycaemic male and female rats

“…A small drop of blood was collected from the tail tip and analysed for blood glucose (BG) concentrations using a standard handheld glucometer (AccuCheck; TheraSense, Alameda, California) as previously reported. 32 For the oral glucose tolerance test (OGTT) performed prior to the liraglutide treatment and after the baseline BG reading, the rats received an oral gavage of glucose (2 g/kg of 25% glucose solution). Subsequent BG readings were taken at 20, 40, 60 and 120 minutes after glucose gavage.…”