1. Elovl6 Deficiency Improves Glycemic Control in Diabetic db / db Mice by Expanding β-Cell Mass and Increasing Insulin Secretory Capacity.
- Author
-
Zhao H, Matsuzaka T, Nakano Y, Motomura K, Tang N, Yokoo T, Okajima Y, Han SI, Takeuchi Y, Aita Y, Iwasaki H, Yatoh S, Suzuki H, Sekiya M, Yahagi N, Nakagawa Y, Sone H, Yamada N, and Shimano H
- Subjects
- Acetyltransferases physiology, Animals, Apoptosis genetics, Blood Glucose metabolism, Diabetes Mellitus, Experimental metabolism, Diabetes Mellitus, Type 2 metabolism, Endoplasmic Reticulum Stress, Fatty Acid Elongases, Fatty Acids, Nonesterified metabolism, Female, Immunohistochemistry, In Vitro Techniques, Inflammation chemically induced, Inflammation genetics, Insulin Secretion, Insulin-Secreting Cells drug effects, Insulin-Secreting Cells pathology, Islets of Langerhans drug effects, Islets of Langerhans metabolism, Islets of Langerhans pathology, Lipid Metabolism genetics, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Oleic Acid pharmacology, Organ Size, Palmitates adverse effects, Real-Time Polymerase Chain Reaction, Receptors, Leptin genetics, Acetyltransferases deficiency, Acetyltransferases genetics, Diabetes Mellitus, Experimental genetics, Diabetes Mellitus, Type 2 genetics, Insulin metabolism, Insulin-Secreting Cells metabolism
- Abstract
Dysfunctional fatty acid (FA) metabolism plays an important role in the pathogenesis of β-cell dysfunction and loss of β-cell mass in type 2 diabetes (T2D). Elovl6 is a microsomal enzyme that is responsible for converting C16 saturated and monounsaturated FAs into C18 species. We previously showed that Elovl6 played a critical role in the development of obesity-induced insulin resistance by modifying FA composition. To further define its role in T2D development, we assessed the effects of Elovl6 deletion in leptin receptor-deficient C57BL/KsJ db / db mice, a model of T2D. The db / db ; Elovl6 mice had a markedly increased β-cell mass with increased proliferation and decreased apoptosis, an adaptive increase in insulin, and improved glycemic control.
-/- mice had a markedly increased β-cell mass with increased proliferation and decreased apoptosis, an adaptive increase in insulin, and improved glycemic control. db / db mice exhibited reduced susceptibility to palmitate-induced inflammation, endoplasmic reticulum stress, and β-cell apoptosis. In contrast, oleate-treated islets resulted in impaired glucose-stimulated insulin secretion with suppressed related genes irrespective of the Elovl6 gene. Taken together, Elovl6 is a fundamental factor linking dysregulated lipid metabolism to β-cell dysfunction, islet inflammation, and β-cell apoptosis in T2D, highlighting oleate as the potential culprit of β-cell lipotoxicity.Elovl6-/- mice exhibited reduced susceptibility to palmitate-induced inflammation, endoplasmic reticulum stress, and β-cell apoptosis. In contrast, oleate-treated islets resulted in impaired glucose-stimulated insulin secretion with suppressed related genes irrespective of the Elovl6 gene. Taken together, Elovl6 is a fundamental factor linking dysregulated lipid metabolism to β-cell dysfunction, islet inflammation, and β-cell apoptosis in T2D, highlighting oleate as the potential culprit of β-cell lipotoxicity., (© 2017 by the American Diabetes Association.)- Published
- 2017
- Full Text
- View/download PDF