Beneficial impact of Ac3IV, an AVP analogue acting specifically at V1a and V1b receptors, on diabetes islet morphology and transdifferentiation of alpha- and beta-cells

Abstract

Ac3IV (Ac-CYIQNCPRG-NH2) is an enzymatically stable vasopressin analogue that selectively activates Avpr1a (V1a) and Avpr1b (V1b) receptors. In the current study we have employed streptozotocin (STZ) diabetic transgenic Ins1Cre/+;Rosa26-eYFP and GluCreERT2;Rosa26-eYFP mice, to evaluate the impact of sustained Ac3IV treatment on pancreatic islet cell morphology and transdifferentiation. Twice-daily administration of Ac3IV (25 nmol/kg bw) to STZ-diabetic Ins1Cre/+;Rosa26-eYFP mice for 12 days increased pancreatic insulin (p<0.01) and significantly reversed the detrimental effects of STZ on pancreatic islet morphology. Such benefits were coupled with increased (p<0.01) beta-cell proliferation and decreased (p<0.05) beta-cell apoptosis. In terms of islet cell lineage tracing, induction of diabetes increased (p<0.001) beta- to alpha-cell differentiation in Ins1Cre/+;Rosa26-eYFP mice, with Ac3IV partially reversing (p<0.05) such transition events. Comparable benefits of Ac3IV on pancreatic islet architecture were observed in STZ-diabetic GluCreERT2;ROSA26-eYFP transgenic mice. In this model, Ac3IV provoked improvements in islet morphology which were linked to increased (p<0.05-p<0.01) transition of alpha- to beta-cells. Ac3IV also increased (p<0.05-p<0.01) CK-19 co-expression with insulin in pancreatic ductal and islet cells. Blood glucose levels were unchanged by Ac3IV in both models, reflecting the severity of diabetes induced. Taken together these data indicate that activation of islet receptors for V1a and V1b positively modulates alpha- and beta-cell turnover and endocrine cell lineage transition events to preserve beta-cell identity and islet architecture.

Pancreatic islet cell plasticity: Pathogenic or therapeutically exploitable?

“…79,143 Intriguingly, somewhat similar to the effects on β-cell dedifferentiation and restoration of β-cell identity, sub-chronic administration of enzymatically stable GLP-1, GIP and Y1 receptor agonists stimulates αto β-cell transdifferentiation in STZ-induced insulin-deficient mice, 61,73,157 an enteroendocrine K-cellderived hormone co-secreted with GIP following nutrient ingestion 158 has also been shown to exert similar dual benefits on islet cell lineage alterations, 73 with the non-classical islet hormone vasopressin eliciting comparable benefits on both retention of β-cell identity 157 and stimulation of αto β-cell transdifferentiation. 66 Notably, a long-acting oxyntomodulin analogue, (D-Ser 2 )-Oxm[Lys 38 PAL], 159 has a demonstrable capacity to transform mature α-cells towards a β-cell-like phenotype. 73 This finding is even more intriguing given recent observations that specific antagonism of the glucagon receptor promotes the elevation of a functional β-cell mass.…”

The Glucagon Receptor Antagonist desHis1Pro4Glu9-Glucagon(Lys12PAL) Alters Alpha-Cell Turnover and Lineage in Mice, But Does Not Cause Alpha-Cell Hyperplasia

“…The twice-daily 100 nmol/kg dose was then employed as a high dose regimen, with the current study representing the first observations with desHis 1 Pro 4 Glu 9 -glucagon (Lys 12 PAL) at this dosage. A multiple low-dose STZ model was preferred since previous investigations confirm detrimental effects of this approach on islet cell lineage in Glu CreERT2 ; Rosa26-eYFP mice associated with increased alpha-cell population and enhanced alpha-to-beta cell ratio (Mohan et al, 2021;Lafferty et al, 2021b;Sarnobat et al, 2020Sarnobat et al, , 2022). An additional separate group of saline treated Glu CreERT2 ;Rosa26-eYFP female mice (n = 6), that did not receive STZ or desHis 1 Pro 4 Glu 9 -glucagon (Lys 12 PAL) injections, were employed for comparative purposes.…”

“…Throughout the study, body weight, circulating blood glucose, cumulative food and fluid intake were assessed at regular intervals. At termination, pancreatic tissues were excised and immediately fixed in 4% paraformaldehyde for 48 h at 4 • C for histological analysis (Mohan et al, 2021).…”