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ADAM17 and Impaired Endothelial Insulin Signaling in Type 2 Diabetes
Author(s) -
Restaino Robert M.,
CastorenaGonzalez Jorge A.,
Marshall Kurt D.,
Padilla Jaume,
MartinezLemus Luis A.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.837.12
Subject(s) - medicine , endocrinology , unfolded protein response , downregulation and upregulation , endothelial dysfunction , enos , insulin , endothelial stem cell , type 2 diabetes , endothelium , glut2 , insulin receptor , endoplasmic reticulum , nitric oxide synthase , chemistry , nitric oxide , diabetes mellitus , insulin resistance , glucose transporter , biochemistry , in vitro , gene
Endothelial dysfunction and impaired insulin signaling are hallmark vascular abnormalities associated with cardiovascular pathogenesis in type 2 diabetes (T2D). Such abnormalities result from impaired insulin‐induced activation of endothelial nitric oxide synthase (eNOS). Hyperglycemia in T2D has been associated with an aggregation of misfolded proteins and resultant endoplasmic reticulum (ER) stress with activation of the unfolded protein response (UPR) in various cell types. Herein, following immunohistochemical examination of mesenteric arteries from T2D patients undergoing bariatric surgery, we show a reduction (P<0.05) in the presence of the insulin receptor alpha subunit (IRα) in all three layers of the vascular wall, notably within the endothelium vs. that in vessels from Non‐T2D individuals. The reduced presence of IRα was associated with an upregulation of ADAM17, an enzyme that is involved in cleavage of outer membrane proteins. We hypothesize that hyperglycemia in T2D induces an upregulation in ADAM17 expression and activity leading to cleavage of IRα from the cell membrane in an ER stress dependent mechanism. To test this hypothesis, serum‐starved human umbilical vein endothelial cells were exposed over night to 5mM glucose (control), 30mM glucose (hyperglycemia) or 0.5μM phorbol 12‐myristate 13‐acetate (PMA, a PKC activator) in 5mM glucose as a positive control of ADAM17 induction. These treatments were administered alone or in combination with the ER stress alleviator tauroursodeoxycholic acid (TUDCA). Cells were harvested for determination of ADAM17 expression and activity. Following treatment with high glucose and PMA, ADAM17 expression was significantly increased (n=7, P<0.05 compared to control) in endothelial cells. Concurrent treatment with TUDCA reduced (n=7, P<0.05) expression of ADAM17 in the hyperglycemic condition. ADAM17 activity was elevated under both hyperglycemic and PMA conditions (fold change from control hyperglycemia=1.97±0.15 A.U., PMA=1.84±0.23 A.U.; n=8, P<0.05) and not affected by TUDCA (p>0.05). Taken together, these results suggest a potential role of ADAM17 in mediating endothelial cell insulin resistance through cleavage of IRα from the cell membrane. This mechanism could be secondary to hyperglycemia‐induced ER stress in T2D. Support or Funding Information National Institutes of Health HL‐125503 and DK‐105368 to J.P., HL‐073101 and HL‐088105 to L.A.M‐L.