Effects of long‐acting analogues of lamprey GLP‐1 and paddlefish glucagon on alpha‐ to beta‐cell transdifferentiation in an insulin‐deficient transgenic mouse model

Abstract

The abilities of the long-acting, dual-agonist anti-diabetic peptides [D-Ala 2 ]palmitoyllamprey GLP-1 and [D-Ser 2 ]palmitoyl-paddlefish glucagon to induce α-cell to β-cell transdifferentiation were investigated in Glu CreERT2 ;ROSA26-eYFP mice. These animals have been genetically engineered so that yellow fluorescent protein is specifically expressed in glucagon-producing α-cells, thereby allowing cell lineage tracing.Insulin deficiency was produced by treatment of the mice with multiple low doses of streptozotocin. Administration of the peptides (twice daily intraperitoneal injections of 25 nmol/kg body weight over 10 days) to streptozotocin-treated mice produced significant (P < 0.05) increases in pancreatic insulin content and plasma insulin concentrations compared with control mice. Immunohistochemical studies demonstrated a significant (P < 0.05) increase in the % of cells staining for both insulin and fluorescent protein in islets located in the head region of the pancreas (from 10.0 ± 1.3% of total cells in untreated mice to 20.0 ± 3.85% in mice treated with D-Ala 2 ]palmitoyllamprey GLP-1 and to 17.3 ± 1.1% in mice treated with [D-Ser 2 ]palmitoyl-paddlefish glucagon). Corresponding effects upon islets in the tail region were not significant.The data indicate an improvement in β-cell mass and positive effects on transdifferentiation of glucagon-producing to insulin-producing cells. The study provides further evidence that proglucagon-derived peptides from phylogenetical ancient fish show therapeutic potential for treatment of diabetes.