Deletion of ABCB10 in beta-cells protects from high-fat diet induced insulin resistance

Autor: Linsey Stiles, Maike Sander, Samuel B. Sereda, Zhiqiang Zhou, Ana Viñuela, Siyouneh Baghdasarian, Vincent Gutierrez, Mayuko Segawa, Laura Nocito, Matthew Wortham, Raffi Gharakhanian, Marc Liesa, Michael Shum, Orian S. Shirihai, Dane M. Wolf
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Blood Glucose
Male
Fasting hyperinsulinemia
Physiology
Type 2 diabetes
Mitochondrion
Inbred C57BL
Transcriptome
Mice
Insulin-Secreting Cells
Insulin Secretion
Hyperinsulinemia
Insulin
2.1 Biological and endogenous factors
Aetiology
Internal medicine
Mice
Knockout
geography.geographical_feature_category
Diabetes
ABCB10
Islet
Mitochondria
Original Article
Female
Beta cell
Type 2
medicine.medical_specialty
endocrine system
Knockout
Biology
Diet
High-Fat
Islets of Langerhans
Insulin resistance
medicine
Diabetes Mellitus
Genetics
Animals
Obesity
Molecular Biology
Metabolic and endocrine
Nutrition
geography
Prevention
Beta-cell
nutritional and metabolic diseases
Cell Biology
Glucose Tolerance Test
medicine.disease
RC31-1245
Diet
Mice
Inbred C57BL
High-Fat
Endocrinology
Glucose
Diabetes Mellitus
Type 2
Cardiovascular and Metabolic Diseases
ATP-Binding Cassette Transporters
Biochemistry and Cell Biology
Zdroj: Molecular Metabolism, Vol 55, Iss, Pp 101403-(2022)
Molecular Metabolism
ISSN: 2212-8778
Popis: Objective The contribution of beta-cell dysfunction to type 2 diabetes (T2D) is not restricted to insulinopenia in the late stages of the disease. Elevated fasting insulinemia in normoglycemic humans is a major factor predicting the onset of insulin resistance and T2D, demonstrating an early alteration of beta-cell function in T2D. Moreover, an early and chronic increase in fasting insulinemia contributes to insulin resistance in high-fat diet (HFD)-fed mice. However, whether there are genetic factors that promote beta-cell-initiated insulin resistance remains undefined. Human variants of the mitochondrial transporter ABCB10, which regulates redox by increasing bilirubin synthesis, have been associated with an elevated risk of T2D. The effects of T2D ABCB10 variants on ABCB10 expression and the actions of ABCB10 in beta-cells are unknown. Methods The expression of beta-cell ABCB10 was analyzed in published transcriptome datasets from human beta-cells carrying the T2D-risk ABCB10 variant. Insulin sensitivity, beta-cell proliferation, and secretory function were measured in beta-cell-specific ABCB10 KO mice (Ins1Cre-Abcb10flox/flox). The short-term role of beta-cell ABCB10 activity on glucose-stimulated insulin secretion (GSIS) was determined in isolated islets. Results Carrying the T2Drisk allele G of ABCB10 rs348330 variant was associated with increased ABCB10 expression in human beta-cells. Constitutive deletion of Abcb10 in beta-cells protected mice from hyperinsulinemia and insulin resistance by limiting HFD-induced beta-cell expansion. An early limitation in GSIS and H2O2-mediated signaling caused by elevated ABCB10 activity can initiate an over-compensatory expansion of beta-cell mass in response to HFD. Accordingly, increasing ABCB10 expression was sufficient to limit GSIS capacity. In health, ABCB10 protein was decreased during islet maturation, with maturation restricting beta-cell proliferation and elevating GSIS. Finally, ex-vivo and short-term deletion of ABCB10 in islets isolated from HFD-fed mice increased H2O2 and GSIS, which was reversed by bilirubin treatments. Conclusions Beta-cell ABCB10 is required for HFD to induce insulin resistance in mice by amplifying beta-cell mass expansion to maladaptive levels that cause fasting hyperinsulinemia.
Highlights • ABCB10 deletion in mouse beta-cells protects from HFD-induced insulin resistance. • ABCB10 deletion increases mouse beta-cell function and limits HFD-induced beta cell expansion. • T2D ABCB10 variant rs348330 is associated with increased ABCB0 expression in beta-cells. • ABCB10 gain-of-function decreases glucose stimulated insulin secretion.
Databáze: OpenAIRE
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