Protective Effects of Dipeptidyl Peptidase-4 (DPP-4) Inhibitor against Increased β Cell Apoptosis Induced by Dietary Sucrose and Linoleic Acid in Mice with Diabetes

Chronic exposure to high glucose and fatty acid levels caused by dietary sugar and fat intake induces β cell apoptosis, leading to the exacerbation of type 2 diabetes. Oleic acid and linoleic acid are two major dietary fatty acids, but their effects in diabetes are unclear. We challenged β cell-spec...

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Published in:The Journal of biological chemistry 2011-07, Vol.286 (29), p.25467-25476
Main Authors: Shirakawa, Jun, Amo, Kikuko, Ohminami, Hirokazu, Orime, Kazuki, Togashi, Yu, Ito, Yuzuru, Tajima, Kazuki, Koganei, Megumi, Sasaki, Hajime, Takeda, Eiji, Terauchi, Yasuo
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Apoptosis
Apoptosis - drug effects
Arachidonic Acid - metabolism
Diabetes
Diabetes Mellitus - genetics
Diabetes Mellitus - metabolism
Diabetes Mellitus - pathology
Dietary Carbohydrates - adverse effects
Dipeptidyl Peptidase 4 - metabolism
Dipeptidyl Peptidase-4 (DPP-4)
Dipeptidyl-Peptidase IV Inhibitors - administration & dosage
Dipeptidyl-Peptidase IV Inhibitors - chemistry
Dipeptidyl-Peptidase IV Inhibitors - pharmacology
Dose-Response Relationship, Drug
E-cadherin
Endoplasmic Reticulum (ER)
Endoplasmic Reticulum - drug effects
Endoplasmic Reticulum - metabolism
Fatty Acid
Glucagon-Like Peptide 1 - metabolism
Glucagon-Like Peptide-1 Receptor
Glucokinase
Glucokinase - genetics
Glucose - metabolism
Haploinsufficiency
Insulin-Secreting Cells - drug effects
Insulin-Secreting Cells - metabolism
Insulin-Secreting Cells - pathology
Linoleic Acid - adverse effects
Male
Mice
Molecular Bases of Disease
Pancreatic Islets
Peptide Hormones
Pyrazines - administration & dosage
Pyrazines - chemistry
Pyrazines - pharmacology
Receptors, Glucagon - metabolism
Signal Transduction - drug effects
Sitagliptin Phosphate
Sterol Regulatory Element-binding Protein-1c (SREBP-1c)
Sucrose - adverse effects
Triazoles - administration & dosage
Triazoles - chemistry
Triazoles - pharmacology
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Summary:Chronic exposure to high glucose and fatty acid levels caused by dietary sugar and fat intake induces β cell apoptosis, leading to the exacerbation of type 2 diabetes. Oleic acid and linoleic acid are two major dietary fatty acids, but their effects in diabetes are unclear. We challenged β cell-specific glucokinase haploinsufficient (Gck+/−) mice with a diet containing sucrose and oleic acid (SO) or sucrose and linoleic acid (SL) and analyzed β cell apoptosis. In Gck+/− but not wild-type mice, SL significantly decreased the β cell mass and β cell proportion in islet cells arising from increased apoptosis to a greater degree than did SO. The mRNA expression of SREBP-1c was significantly higher, and that of E-cadherin was significantly lower in the islets of Gck+/− mice fed SL compared with mice fed SO. We next evaluated monotherapy with desfluorositagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, in these mouse groups. DPP-4 inhibitor protected against β cell apoptosis, restored the β cell mass, and normalized islet morphology in Gck+/− mice fed SL. DPP-4 inhibition normalized the changes in the islet expression of SREBP-1c and E-cadherin mRNA induced by the SL diet. Furthermore, linoleic acid induced β cell apoptosis to a greater degree in the presence of high glucose levels than in the presence of low glucose levels in vitro in islets and MIN6 cells, whereas a GLP-1 receptor agonist prevented apoptosis. In conclusion, SL exacerbated β cell apoptosis in diabetic Gck+/− mice but not in euglycemic wild-type mice, and DPP-4 inhibition protected against these effects.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M110.217216