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SGLT2 inhibitors therapy protects glucotoxicity-induced ß-cell failure in a mouse model of human KATP-induced diabetes through mitigation of oxidative and ER stress.
Shyr, Zeenat A; Yan, Zihan; Ustione, Alessandro; Egan, Erin M; Remedi, Maria S.
Affiliation
  • Shyr ZA; Division of Endocrinology, Metabolism and Lipid Research, Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, United States of America.
  • Yan Z; Center for the Investigation of Membrane Excitability Diseases, Washington University in St. Louis, St. Louis, Missouri, United States of America.
  • Ustione A; Division of Endocrinology, Metabolism and Lipid Research, Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, United States of America.
  • Egan EM; Center for the Investigation of Membrane Excitability Diseases, Washington University in St. Louis, St. Louis, Missouri, United States of America.
  • Remedi MS; Department of Cell Biology and Physiology, Washington University in St. Louis, St. Louis, Missouri, United States of America.
PLoS One ; 17(2): e0258054, 2022.
Article in En | MEDLINE | ID: mdl-35180212
Progressive loss of pancreatic ß-cell functional mass and anti-diabetic drug responsivity are classic findings in diabetes, frequently attributed to compensatory insulin hypersecretion and ß-cell exhaustion. However, loss of ß-cell mass and identity still occurs in mouse models of human KATP-gain-of-function induced Neonatal Diabetes Mellitus (NDM), in the absence of insulin secretion. Here we studied the temporal progression and mechanisms underlying glucotoxicity-induced loss of functional ß-cell mass in NDM mice, and the effects of sodium-glucose transporter 2 inhibitors (SGLT2i) therapy. Upon tamoxifen induction of transgene expression, NDM mice rapidly developed severe diabetes followed by an unexpected loss of insulin content, decreased proinsulin processing and increased proinsulin at 2-weeks of diabetes. These early events were accompanied by a marked increase in ß-cell oxidative and ER stress, without changes in islet cell identity. Strikingly, treatment with the SGLT2 inhibitor dapagliflozin restored insulin content, decreased proinsulin:insulin ratio and reduced oxidative and ER stress. However, despite reduction of blood glucose, dapagliflozin therapy was ineffective in restoring ß-cell function in NDM mice when it was initiated at >40 days of diabetes, when loss of ß-cell mass and identity had already occurred. Our data from mouse models demonstrate that: i) hyperglycemia per se, and not insulin hypersecretion, drives ß-cell failure in diabetes, ii) recovery of ß-cell function by SGLT2 inhibitors is potentially through reduction of oxidative and ER stress, iii) SGLT2 inhibitors revert/prevent ß-cell failure when used in early stages of diabetes, but not when loss of ß-cell mass/identity already occurred, iv) common execution pathways may underlie loss and recovery of ß-cell function in different forms of diabetes. These results may have important clinical implications for optimal therapeutic interventions in individuals with diabetes, particularly for those with long-standing diabetes.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Benzhydryl Compounds / Oxidative Stress / Protective Agents / Diabetes Mellitus / Insulin-Secreting Cells / KATP Channels / Endoplasmic Reticulum Stress / Gain of Function Mutation / Sodium-Glucose Transporter 2 Inhibitors / Glucosides Type of study: Prognostic_studies Limits: Animals / Female / Humans / Male / Newborn Language: En Journal: PLoS One Journal subject: CIENCIA / MEDICINA Year: 2022 Document type: Article Affiliation country: United States Country of publication: United States

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Benzhydryl Compounds / Oxidative Stress / Protective Agents / Diabetes Mellitus / Insulin-Secreting Cells / KATP Channels / Endoplasmic Reticulum Stress / Gain of Function Mutation / Sodium-Glucose Transporter 2 Inhibitors / Glucosides Type of study: Prognostic_studies Limits: Animals / Female / Humans / Male / Newborn Language: En Journal: PLoS One Journal subject: CIENCIA / MEDICINA Year: 2022 Document type: Article Affiliation country: United States Country of publication: United States