Effects of long-acting GIP, xenin and oxyntomodulin peptide analogues on alpha-cell transdifferentiation in insulin-deficient diabetic GluCreERT2;ROSA26-eYFP mice
| Autor: | Dipak Sarnobat, Neil Tanday, Charlotte Moffett, Victor A. Gault, Nigel Irwin, Fiona M. Gribble, Frank Reimann, Peter R. Flatt |
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| Přispěvatelé: | Reimann, Frank [0000-0001-9399-6377], Gribble, Fiona [0000-0002-4232-2898], Apollo - University of Cambridge Repository |
| Rok vydání: | 2019 |
| Předmět: |
endocrine system
medicine.medical_specialty Physiology medicine.medical_treatment Xenin Mice Transgenic Gastric Inhibitory Polypeptide Peptide hormone Biochemistry Alpha cell Diabetes Mellitus Experimental Cellular and Molecular Neuroscience chemistry.chemical_compound Islets of Langerhans Mice Endocrinology Bacterial Proteins Gastrointestinal Agents Internal medicine medicine Animals Neurotensin Alpha-cell geography Transdifferentiation geography.geographical_feature_category Chemistry Insulin Glucose-dependent insulinotropic polypeptide (GIP) Streptozotocin Islet Oxyntomodulin Mice Inbred C57BL Luminescent Proteins Oxytomodulin (Oxm) Diabetes Mellitus Type 1 Glucagon-Secreting Cells Cell Transdifferentiation Glu (CreERT2) ROSA26-eYFP mice medicine.drug |
| DOI: | 10.17863/cam.46052 |
| Popis: | Enzyme-resistant long-acting forms of the gut-derived peptide hormones, glucose-dependent insulinotropic polypeptide (GIP), xenin and oxyntomodulin (Oxm) have been generated, and exert beneficial effects on diabetes control and pancreatic islet architecture. The current study has employed alpha-cell lineage tracing in GluCreERT2;ROSA26-eYFP transgenic mice to investigate the extent to which these positive pancreatic effects are associated with alpha- to beta-cell transdifferentiation. Twice-daily administration of (D-Ala2)GIP, xenin-25[Lys13PAL] or (D-Ser2)-Oxm[Lys38PAL] for 10 days to streptozotocin (STZ)-induced diabetic mice did not affect body weight, food intake or blood glucose levels, but (D-Ser2)-Oxm[Lys38PAL] reduced (P < 0.05 to P < 0.001) fluid intake and circulating glucagon. (D-Ala2)GIP and (D-Ser2)-Oxm[Lys38PAL] also augmented (P < 0.05 and P < 0.01, respectively) pancreatic insulin content. Detrimental changes of pancreatic morphology induced by STZ in GluCreERT2;ROSA26-eYFP mice were partially reversed by all treatment interventions. This was associated with reduced (P < 0.05) apoptosis and increased (P < 0.05 to P < 0.01) proliferation of beta-cells, alongside opposing effects on alpha-cells, with (D-Ala2)GIP and (D-Ser2)-Oxm[Lys38PAL] being particularly effective in this regard. Alpha-cell lineage tracing revealed that induction of diabetes was accompanied by increased (P < 0.01) transdifferentiation of glucagon positive alpha-cells to insulin positive beta-cells. This islet cell transitioning process was augmented (P < 0.01 and P < 0.001, respectively) by (D-Ala2)GIP and (D-Ser2)-Oxm[Lys38PAL]. (D-Ser2)-Oxm[Lys38PAL] also significantly (P < 0.05) promoted loss of alpha-cell identity in favour of other endocrine islet cells. These data highlight intra-islet benefits of (D-Ala2)GIP, xenin-25[Lys13PAL] and (D-Ser2)-Oxm[Lys38PAL] in diabetes with beta-cell loss induced by STZ. The effects appear to be independent of glycaemic change, and associated with alpha- to beta-cell transdifferentiation for the GIP and Oxm analogues. |
| Databáze: | OpenAIRE |
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