Loss of pancreatic β-cell identity, rather than β-cell death, has been recently demonstrated in both neonatal and type-2 diabetes. However, the underlying mechanisms and temporal progression remains elusive. By using an insulin secretory-deficient KATP-GOF mouse model of human neonatal diabetes, we demonstrate normal insulin content at day 7 despite severe diabetes, but a dramatic decrease (55%) in content at day 15 of diabetes. Loss of content was accompanied by a marked increase in proinsulin protein, a striking increase in oxidative- and ER-stress markers such as ROS, TXNIP, sXBP1 and ATF6, distended ER and decreased number of insulin granules. These changes lead to later loss of β-cell identity and increased α-cell identity (ARX increased 50%), glucagon content and secretion. We hypothesized that lowering blood glucose alone will be sufficient to reverse this process and improve β-cell function. Therefore, diabetic KATP-GOF mice were treated with dapagliflozin (DAPA), a sodium-glucose transporter-2 (SGLT2) inhibitor clinically used to reduce blood glucose by preventing renal glucose reabsorption. As expected, DAPA therapy significantly reduced blood glucose without changing circulating insulin levels. Ten days DAPA therapy markedly improved insulin content, reduced proinsulin/insulin ratio and enhanced β-cell function by reducing oxidative and ER stress and preventing loss of β-cell identity. Together, we clearly demonstrate that loss of insulin content, increased oxidative and ER stress, and changes in calcium dynamics underlie later loss of β-cell identity in diabetes, and that these features can be prevented/reversed by normalization of blood glucose alone with SGLT2 inhibitors. From the therapeutic perspective, these results have important implications indicating that early alleviation of β-cell stress may prevent loss of β-cell mass and preserve islet-cell identity, architecture and function.


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


National Institutes of Health (DK098584 to M.S.R.), (T32DK108742 to Z.A.S.)

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