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)

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.