Characterising a Novel Peptide That Inhibits and Reverses Type 1 Diabetes

Aims: Interventions that regenerate functional pancreatic β-cells are a potential treatment option for type 1 diabetes. D6PV is a small peptide that lowers plasma triglyceride levels. We have found that it also enhances expression of the β-cell survival gene Pdx1 and stimulates insulin production in INS-1E insulinoma cells. This study asks whether D6PV delays diabetes onset and preserves β-cell mass in mice with autoimmune β-cell loss. Methods: Female 8-week-old NOD/ShiLtJ (NOD) mice (n=10-20/group) were treated twice/week for 16 weeks with D6PV (40 mg/kg i.p) or PBS. Diabetes onset was evaluated by measuring blood glucose levels. A separate cohort of female NOD mice were treated with D6PV or PBS twice/week for 4 weeks after they developed diabetes. Glycaemic control was evaluated by glucose tolerance test (1 g/kg i.p). Islet insulin content was quantified by immunostaining of paraffin-embedded, formalin-fixed pancreatic tissue. Expansion of CD8+ T-cells was analysed ex vivo from OTI-TCR transgenic mouse splenocytes and healthy human donors following stimulation via IL-7/15 and incubation ± D6PV. Results: D6PV treatment for 16 weeks decreased fed and fasted blood glucose levels (p<0.05 for both) and delayed diabetes onset in NOD mice (p<0.01). This was accompanied by increased insulin +ve islet area in the D6PV treated, but not the PBS treated animals (p<0.05). D6PV treatment also reduced lymphocyte infiltration into islets but increased lymphocytic migration to the basement membrane (0.2 ± 0.1% vs 1.8 ± 1.7%, p<0.05). When NOD mice with diabetes were treated with D6PV, glucose tolerance improved (AUC 1167±341 vs 543±328, p<0.01). Treatment of both mouse and human cytokine-activated isolated CD8+ T-cells with D6PV suppressed T-cell expansion (p<0.001). Conclusions: D6PV treatment delays diabetes onset, improves glycaemic control in mice with established disease, increases pancreatic insulin expression and inhibits T-cell expansion in NOD mice. D6PV is a potential treatment option for type 1 diabetes. Disclosure T.W.King: None. S.S.Tay: None. F.Colakoglu: None. M.Devalaraja: None. A.Remaley: None. M.Biro: None. B.Cochran: None. K.Rye: None. Funding National Health and Medical Research Council of Australia (RG201951)