title: Altered Plasma Profile of Antioxidant Proteins as an Early Correlate of Pancreatic β Cell Dysfunction.
abstract: Insulin resistance and β cell dysfunction contribute to the pathogenesis of type 2 diabetes. Unlike insulin resistance, β cell dysfunction remains difficult to predict and monitor, because of the inaccessibility of the endocrine pancreas, the integrated relationship with insulin sensitivity, and the paracrine effects of incretins. The goal of our study was to survey the plasma response to a metabolic challenge in order to identify factors predictive of β cell dysfunction. To this end, we combined (i) the power of unbiased iTRAQ (isobaric tag for relative and absolute quantification) mass spectrometry with (ii) direct sampling of the portal vein following an intravenous glucose/arginine challenge (IVGATT) in (iii) mice with a genetic β cell defect. By so doing, we excluded the effects of peripheral insulin sensitivity as well as those of incretins on β cells, and focused on the first phase of insulin secretion to capture the early pathophysiology of β cell dysfunction. We compared plasma protein profiles with ex vivo islet secretome and transcriptome analyses. We detected changes to 418 plasma proteins in vivo, and detected changes to 262 proteins ex vivo The impairment of insulin secretion was associated with greater overall changes in the plasma response to IVGATT, possibly reflecting metabolic instability. Reduced levels of proteins regulating redox state and neuronal stress markers, as well as increased levels of coagulation factors, antedated the loss of insulin secretion in diabetic mice. These results suggest that a reduced complement of antioxidants in response to a mixed secretagogue challenge is an early correlate of future β cell failure.
authors.affiliation: From the Department of Medicine and Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, New York, New York 10032 and.
authors.forename: Taiyi
authors.initials: T
authors.lastname: Kuo
authors.affiliation: From the Department of Medicine and Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, New York, New York 10032 and.
authors.forename: Ja Young
authors.initials: JY
authors.lastname: Kim-Muller
authors.affiliation: the Department of Biochemistry, Weill Cornell Medical College, New York, New York 10065.
authors.forename: Timothy E
authors.initials: TE
authors.lastname: McGraw
authors.affiliation: From the Department of Medicine and Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, New York, New York 10032 and da230@columbia.edu.
authors.forename: Domenico
authors.initials: D
authors.lastname: Accili
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001798:Blood Proteins / Q000235:genetics / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000097:blood* / Q000235:genetics / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000235:genetics / Q000473:pathology; D054795:Incretins / Q000097:blood / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout
chemical_list: D000975:Antioxidants; D001798:Blood Proteins; D054795:Incretins
keywords: FOXO; beta cell (B-cell); biomarker; diabetes; neurodegeneration; oxidative stress