title: Telmisartan improves insulin resistance of skeletal muscle through peroxisome proliferator-activated receptor-δ activation.
abstract: The mechanisms of the improvement of glucose homeostasis through angiotensin receptor blockers are not fully elucidated in hypertensive patients. We investigated the effects of telmisartan on insulin signaling and glucose uptake in cultured myotubes and skeletal muscle from wild-type and muscle-specific peroxisome proliferator-activated receptor (PPAR) δ knockout (MCK-PPARδ(-/-)) mice. Telmisartan increased PPARδ expression and activated PPARδ transcriptional activity in cultured C2C12 myotubes. In palmitate-induced insulin-resistant C2C12 myotubes, telmisartan enhanced insulin-stimulated Akt and Akt substrate of 160 kDa (AS160) phosphorylation as well as Glut4 translocation to the plasma membrane. These effects were inhibited by antagonizing PPARδ or phosphatidylinositol-3 kinase, but not by PPARγ and PPARα inhibition. Palmitate reducing the insulin-stimulated glucose uptake in C2C12 myotubes could be restored by telmisartan. In vivo experiments showed that telmisartan treatment reversed high-fat diet-induced insulin resistance and glucose intolerance in wild-type mice but not in MCK-PPARδ(-/-) mice. The protein levels of PPARδ, phospho-Akt, phospho-AS160, and Glut4 translocation to the plasma membrane in the skeletal muscle on insulin stimulation were reduced by high-fat diet and were restored by telmisartan administration in wild-type mice. These effects were absent in MCK-PPARδ(-/-) mice. These findings implicate PPARδ as a potential therapeutic target in the treatment of hypertensive subjects with insulin resistance.
authors.affiliation: Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing, China.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Zhidan
authors.initials: Z
authors.lastname: Luo
authors.forename: Hao
authors.initials: H
authors.lastname: Yu
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Feng
authors.forename: Peijian
authors.initials: P
authors.lastname: Wang
authors.forename: Jian
authors.initials: J
authors.lastname: Chen
authors.forename: Yunfei
authors.initials: Y
authors.lastname: Pu
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhao
authors.forename: Hongbo
authors.initials: H
authors.lastname: He
authors.forename: Jian
authors.initials: J
authors.lastname: Zhong
authors.forename: Daoyan
authors.initials: D
authors.lastname: Liu
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Zhu
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D001565:Benzoates / Q000494:pharmacology* / Q000627:therapeutic use; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007333:Insulin Resistance; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D047495:PPAR gamma / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000737:chemistry / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011897:Random Allocation; D015398:Signal Transduction / Q000187:drug effects; D000077333:Telmisartan; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D001565:Benzoates; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D008024:Ligands; D047495:PPAR gamma; D000081082:Phosphoinositide-3 Kinase Inhibitors; D058539:Phosphatidylinositol 3-Kinase; D005947:Glucose; D000077333:Telmisartan