Progressive loss of β-cell function and mass are classic findings in diabetes, and are frequently attributed to membrane hyperexcitability, insulin hypersecretion and β-cell death. However, we demonstrated that in an insulin secretory-deficient mouse model of human neonatal diabetes (KATP-GOF), loss of β-cell mass still occurs in the absence of these factors. To study the underlying mechanisms of it, we performed experiments on day 7, 15, 22 and 30 post-disease induction. While KATP-GOF mice are hyperglycemic by day 7, insulin content is maintained at control levels. Surprisingly however, there is a dramatic decrease in insulin content at day 15, accompanied by augmented proinsulin/insulin ratio, altered calcium dynamics and increased oxidative and ER stress. We hypothesized that this is induced by hyperglycemia, and not by lack of insulin; and that lowering blood glucose alone will be sufficient to prevent loss of β-cell mass and improve function. KATP-GOF mice were treated with dapagliflozin, a sodium-glucose transporter-2 (SGLT2) inhibitor clinically used to reduce blood glucose by preventing renal glucose reabsorption. Dapagliflozin significantly reduced blood glucose by increasing urinary glucose excretion without changing circulating insulin levels. Dapagliflozin therapy (10 days) markedly improved insulin content, reduced proinsulin/insulin ratio and enhanced β-cell function by alleviating oxidative and ER stress. Together, we demonstrate that β-cell failure and loss of β-cell mass is induced by increased oxidative and ER stress in a reversible manner, and that normalization of blood glucose alone is sufficient to prevent/revert the progressive β-cell dysfunction and failure, opening the exciting possibility of prevention of diabetes progression.


Z.A. Shyr: None. Z. Yan: None. A. Ustione: None. M.S. Remedi: None.

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