Background
Diabetes mellitus (DM) is one of the most rapidly increasing diseases worldwide and is associated with severe cardio- and cerebrovascular complications. In type 2 diabetes mellitus (T2DM), peripheral insulin resistance and the loss of pancreatic β-cell function and mass are key pathogenic factors. Our previous studies in a β-cell line suggested that activation of dual leucine zipper kinase (DLK; MAP3K12) by prediabetic signals contributes to the pathogenesis of T2DM.
Aim
This study aims to evaluate the effects of the DLK inhibitor GNE-3511 and β-cell–specific genetic deletion of DLK on β-cell function in isolated islets (ex vivo) of Langerhans and in mice (in vivo).
Methods
Isolated islets from wildtype (WT) mice were exposed to glucolipotoxic conditions (high glucose/high palmitate) to mimic prediabetic stress. JNK phosphorylation was assessed with or without the DLK inhibitor GNE-3511. Islets from β-cell-specific Dlk-knockout (β-DLK⁻/⁻) mice were assessed for their response to TNFα-induced JNK activation and apoptosis. In vivo, β-DLK⁻/⁻ and control mice (RIP-Cre and DLKfl/fl) were fed a Western diet (WD; 21.2% fat, 33.2% sucrose) or normal diet (ND) for 20 weeks. Metabolic and histological analyses included HbA1c, blood glucose, serum insulin, insulin/glucose ratio, islet morphology, and proliferation (Ki67 staining). In addition, islets from db/db mice - an obese, diabetic model of T2DM - were treated with GNE-3511 to evaluate the effects of DLK inhibition on β-cell apoptosis.
Results
Glucolipotoxic conditions induced JNK phosphorylation in isolated islets, which was attenuated by GNE-3511. Similarly, TNFα failed to induce JNK phosphorylation in β-DLK⁻/⁻ islets, which were protected against glucose-induced apoptosis. Under WD feeding, the islets of β-DLK⁻/⁻ and of RIP-Cre mice showed increased cell proliferation and islet area. Only β-DLK⁻/⁻ mice maintained stable HbA1c levels after WD, while RIP-Cre and DLKfl/fl mice showed significant increases. Blood glucose was elevated in control genotypes but not in β-DLK⁻/⁻ mice. Consistently, β-DLK⁻/⁻ mice displayed higher insulin levels and a significantly increased insulin/glucose ratio. Furthermore, DLK inhibition with GNE-3511 reduced β-cell apoptosis in db/db mouse islets.
Conclusion
Both genetic ablation and pharmacological inhibition of DLK preserve β-cell mass and function under prediabetic conditions. These findings identify DLK as a critical mediator of β-cell stress and highlight it as a promising therapeutic target for the prevention and treatment of T2DM.
