Sequential induction of beta cell rest and stimulation using stable GIP inhibitor and GLP-1 mimetic peptides improves metabolic control in C57BL/KsJ db/db mice

Abstract

Aims/hypothesis GIP(6-30)Cex-K 4 0 [Pal] has been characterised as a fatty-acid-derived gastric inhibitory polypeptide (GIP) inhibitor that can induce pancreatic beta cell rest by diminishing the incretin effect. We investigated its therapeutic efficacy with and without the glucagon-like peptide-1 (GLP-1) beta cell cytotropic agent liraglutide. Methods The therapeutic efficacy of GIP(6-30)Cex-K 40 [Pal] alone, and in combination with liraglutide, was determined in C57BL/KsJ db/db mice using a sequential 12 h administration schedule.

Islet distribution of Peptide YY and its regulatory role in primary mouse islets and immortalised rodent and human beta-cell function and survival

“…Streptozotocin and hydrocortisone treatment induced characteristic opposing changes in murine islet morphology, consistent with previous observations (Vasu et al, 2014). As such, streptozotocin reduced islet number and beta-cell area (Vasu et al, 2014), but also induced marked increases in the alpha and PP cell areas with no effect on delta cells, confirming that these cell types are resistant to streptozotocin-induced toxicity (Rombout et al, 1987;Vasu et al, 2015). Co-localisation studies in streptozotocin mice revealed that PP and delta cells had decreased co-expression with PYY, but alpha cell co-localisation was unaltered.…”

“…Furthermore, effects of PYY(1-36) and PYY(3-36) on GLP-1 mediated elevations of intracellular cAMP were assessed in BRIN BD11 cells using a Parameter cAMP assay (R&D Systems, Abingdon, UK), according to the manufacturer's instructions. In a separate series, pancreatic islets were isolated from lean control C57BL/6 mice by collagenase digestion, as described previously (Pathak et al, 2015). Insulin secretion was determined as above, but with a 60 min test incubation period.…”

“…Irrespective of the receptor subtype and mechanism involved, the insulinostatic actions of both forms of PYY could represent a physiologically relevant brake for locally produced islet PYY to limit excessive beta-cell stimulation, potential beta-cell exhaustion and ultimately loss of beta-cell mass. This is potentially therapeutically relevant because beta-cell rest has been shown to preserve long-term beta-cell function and improve overall enduring glycaemic control (Brown and Rother, 2008;Pathak et al, 2015), and is plausible mechanism for PYY-induced beneficial pancreatic actions. Therefore, we next assessed PYY islet expression in both streptozotocin and hydrocortisone treated mice, to evaluate potential impact of locally produced PYY in situations of both islet cell destruction and growth, respectively.…”

Peptide YY (1–36) peptides from phylogenetically ancient fish targeting mammalian neuropeptide Y1 receptors demonstrate potent effects on pancreatic β‐cell function, growth and survival

“…Further important structure/function knowledge relating to the NPY family of peptides concerns the characteristic “PP‐fold” conformation, responsible for bringing the N‐ and C‐terminal ends of the peptide in close contact to be recognized by the NPYR1 . This PP‐fold is characterized by the poly‐proline N‐terminal segment, Pro‐Pro‐Pro, stabilized by a Pro residue situated either at position 13 or 14 and folded back on a long amphipathic α‐helix, interacting with Tyr and Tyr Notably, these residues are all conserved across the four piscine PYY (1–36) sequences. Taken together, the fundamental structural characteristics necessary for specific human NPYR1 binding and activation are present within bowfin, sea lamprey, sturgeon and trout PYY (1–36) peptide sequences.…”

Characterization of 111In-labeled Glucose-Dependent Insulinotropic Polypeptide as a Radiotracer for Neuroendocrine Tumors

“…As shown in our biodistribution studies, [Lys 37 ( 111 In-DTPA)]N-acetyl-GIP 1-42 is cleared from the blood very rapidly, hampering longer tracer circulation and thus higher tumor uptake. Several methods such as PEGylation, multimerization or introduction of free fatty acid tails might increase circulation time 37 and thereby tracer accumulation in the tumor. However, a good balance between tracer retention in blood and tracer targeting dynamics has to be found in order to obtain favorable target-to-background ratios for in vivo imaging.…”