Glucagon-like-peptide-1 receptor agonists and the management of type 2 diabetes-backwards and forwards

This editorial is stimulated by the article by Alqifari et al published in the World Journal of Diabetes(2024).Alqifari et al focus on practical advice for the clinical use of glucagon-like-peptide-1(GLP-1)receptor agonists(GLP-1RAs)in the management of type 2 diabetes and this editorial provides complementary information.We initially give a brief historical perspective of the development of GLP-1RAs stimulated by recognition of the‘incretin effect’,the substantially greater insulin increase to enteral when compared to euglycaemic intravenous glucose,and the identification of the incretin hormones,GIP and GLP-1.In addition to stimulating insulin,GLP-1 reduces postprandial glucose levels by slowing gastric emptying.GLP-1RAs were developed because native GLP-1 has a very short plasma half-life.The majority of current GLP-1RAs are administered by subcutaneous injection once a week.They are potent in glucose lowering without leading to hypoglycaemia,stimulate weight loss in obese individuals and lead to cardiovascular and renal protection.The landscape in relation to GLP-1RAs is broadening rapidly,with different formulations and their combination with other peptides to facilitate both glucose lowering and weight loss.There is a need for more information relating to the effects of GLP-1RAs to induce gastrointestinal symptoms and slow gastric emptying which is likely to allow their use to become more effective and personalised.

A Novel Insulinotropic Peptide from the Skin Secretions of Amolops loloensis Frog

Various kinds of biologically active peptides have previously been isolated from the skin secretions of Amolops loloensis frog,such as antimicrobial peptides,bradykinin-like peptides and algesic peptides.A novel insulinotropic peptide named amolopin was identified in A.loloensis frog’s skin secretion.Its primary structure sequence was determined by Edman degradation as:FLPIVGKSLSGLSGKL-NH2.BLAST search indicates that the amino acid sequence of amolopin is quite different from other known insulin secretagogues,including mastoparan,exendins and a-latrotoxin,nor does it like incretins(e.g.glucagons like peptide-1 and glucose-dependent insulinotropic ploypeptide)either.However,amolopin shows certain structural similarity with amphibian antimicrobial temporins and vespid chemotactic peptides isolated from Vespa magnifica.Amolopin can stimulate insulin release in INS-1 cells in a dose-dependent manner.Primary investigation on its action mechanisms reveals that amolopin does not increase the influx of Ca2?.In conclusion,a novel 16-amino acid peptide with insulin-releasing activity is initially discovered from the skin secretion of A.loloensis frog.Further work is necessary to evaluate its potential as novel anti-diabetic candidate.

Pharmacological inhibition of diacylglycerol acyltransferase-1 and insights into postprandial gut peptide secretion

AIM To examine the role that enzyme Acyl-CoA:diacylglycerol acyltransferase-1(DGAT1) plays in postprandial gut peptide secretion and signaling.METHODS The standard experimental paradigm utilized to evaluate the incretin response was a lipid challenge.Following a lipid challenge,plasma was collected via cardiac puncture at each time point from a cohort of 5-8 mice per group from baseline at time zero to 10 h.Incretin hormones [glucagon like peptide-1(GLP-1),peptide tyrosine-tyrosine(PYY) and glucose dependent insulinotropic polypeptide(GIP)] were then quantitated.The impact of pharmacological inhibition of DGAT1 on the incretin effect was evaluated in WT mice.Additionally,a comparison of loss of DGAT1 function either by genetic ablation or pharmacological inhibition.To further elucidate the pathways and mechanisms involved in the incretin response to DGAT1 inhibition,other interventions [inhibitors of dipeptidyl peptidase-IV(sitagliptin),pancreatic lipase(Orlistat),GPR119 knockout mice] were evaluated.RESULTS DGAT1 deficient mice and wildtype C57/BL6J mice werelipid challenged and levels of both active and total GLP-1 in the plasma were increased.This response was further augmented with DGAT1 inhibitor PF-04620110 treated wildtype mice.Furthermore,PF-04620110 was able to dose responsively increase GLP-1 and PYY,but blunt GIP at all doses of PF-04620110 during lipid challenge.Combination treatment of PF-04620110 and Sitagliptin in wildtype mice during a lipid challenge synergistically enhanced postprandial levels of active GLP-1.In contrast,in a combination study with Orlistat,the ability of PF-04620110 to elicit an enhanced incretin response was abrogated.To further explore this observation,GPR119 knockout mice were evaluated.In response to a lipid challenge,GPR119 knockout mice exhibited no increase in active or total GLP-1 and PYY.However,PF-04620110 was able to increase total GLP-1 and PYY in GPR119 knockout mice as compared to vehicle treated wildtype mice.CONCLUSION Collectively,these data provide some insight into the mechanism by which inhibition of DGAT1 enhances intestinal hormone release.