title: Glycation of the complement regulatory protein CD59 is a novel biomarker for glucose handling in humans.
abstract: BACKGROUND
  Human CD59, an inhibitor of the membrane attack complex of complement, is inactivated by glycation. Glycation inactivation of CD59 enhances complement-mediated injury in target organs of diabetes complications.
  
  
  OBJECTIVE
  We hypothesized that circulating soluble glycated CD59 (GCD59) represents a novel biomarker of blood glucose handling and aimed to conduct human study protocols to test this hypothesis. DESIGN, SETTING, PARTICIPANTS, AND OUTCOME MEASURES: Using a newly developed ELISA, we measured circulating soluble GCD59 in samples from 3 separate human studies evaluating acute and chronic glucose handling and glucose responses to insulin therapy. Study 1 (normal vs diabetic subjects) evaluated the cross-sectional association between GCD59 and glycated hemoglobin (HbA1c) in 400 subjects with and without type 2 diabetes. Study 2 (oral glucose tolerance test [OGTT] in nondiabetics) evaluated whether fasting GCD59 independently predicted the 2-hour glucose response to an OGTT in 109 subjects without a diagnosis of diabetes. Study 3 (intensified insulin treatment) evaluated the effect of intensification of glycemic control with insulin on GCD59 in 21 poorly controlled individuals with diabetes.
  
  
  RESULTS
  In study 1 (normal vs diabetic subjects), GCD59 was independently and positively associated with HbA1c in individuals with and without diabetes (β = 1.1, P < .0001 and β = 1.1 P < .001, respectively). In study 2 (OGTT in nondiabetics), a single GCD59 measurement independently predicted the results of the 2-hour OGTT (β = 19.8, P < .05) after multivariate modeling. In study 3 (intensified insulin treatment), intensification of glucose control with insulin resulted in a concomitant and parallel reduction of average weekly glucose and GCD59 within 2 weeks.
  
  
  CONCLUSIONS
  We observed robust relationships between a single measurement of blood levels of GCD59 and both acute (2-hour OGTT) and chronic (HbA1c) measures of glucose handling. Lowering of GCD59 levels closely reflected lowering of average weekly glucose within 2 weeks. The role of GCD59 in the diagnosis, management, and vascular risk stratification in diabetes warrants further investigation.
authors.affiliation: Division of Hematology (P.G., R.S., M.C., J.A.H.), Department of Medicine, and Division of Endocrinology, Diabetes, and Hypertension (A.V.), Brigham and Women's Hospital, Harvard Medical School, and Crimson Biospecimen Core (N.H., L.B.), Partners Healthcare System, Boston, Massachusetts 02115; and Joslin Diabetes Center (A.G.), Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Pamela
authors.initials: P
authors.lastname: Ghosh
authors.forename: Anand
authors.initials: A
authors.lastname: Vaidya
authors.forename: Rupam
authors.initials: R
authors.lastname: Sahoo
authors.forename: Allison
authors.initials: A
authors.lastname: Goldfine
authors.forename: Neil
authors.initials: N
authors.lastname: Herring
authors.forename: Lynn
authors.initials: L
authors.lastname: Bry
authors.forename: Michael
authors.initials: M
authors.lastname: Chorev
authors.forename: Jose A
authors.initials: JA
authors.lastname: Halperin
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism*; D018957:CD59 Antigens / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism; D005260:Female; D005951:Glucose Tolerance Test; D006442:Glycated Hemoglobin / Q000032:analysis / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D007328:Insulin / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D018957:CD59 Antigens; D006442:Glycated Hemoglobin; D007328:Insulin; C517652:hemoglobin A1c protein, human; C051590:CD59 protein, human