title: Early metabolic markers of the development of dysglycemia and type 2 diabetes and their physiological significance.
abstract: Metabolomic screening of fasting plasma from nondiabetic subjects identified α-hydroxybutyrate (α-HB) and linoleoyl-glycerophosphocholine (L-GPC) as joint markers of insulin resistance (IR) and glucose intolerance. To test the predictivity of α-HB and L-GPC for incident dysglycemia, α-HB and L-GPC measurements were obtained in two observational cohorts, comprising 1,261 nondiabetic participants from the Relationship between Insulin Sensitivity and Cardiovascular Disease (RISC) study and 2,580 from the Botnia Prospective Study, with 3-year and 9.5-year follow-up data, respectively. In both cohorts, α-HB was a positive correlate and L-GPC a negative correlate of insulin sensitivity, with α-HB reciprocally related to indices of β-cell function derived from the oral glucose tolerance test (OGTT). In follow-up, α-HB was a positive predictor (adjusted odds ratios 1.25 [95% CI 1.00-1.60] and 1.26 [1.07-1.48], respectively, for each standard deviation of predictor), and L-GPC was a negative predictor (0.64 [0.48-0.85] and 0.67 [0.54-0.84]) of dysglycemia (RISC) or type 2 diabetes (Botnia), independent of familial diabetes, sex, age, BMI, and fasting glucose. Corresponding areas under the receiver operating characteristic curve were 0.791 (RISC) and 0.783 (Botnia), similar in accuracy when substituting α-HB and L-GPC with 2-h OGTT glucose concentrations. When their activity was examined, α-HB inhibited and L-GPC stimulated glucose-induced insulin release in INS-1e cells. α-HB and L-GPC are independent predictors of worsening glucose tolerance, physiologically consistent with a joint signature of IR and β-cell dysfunction.
authors.affiliation: Department of Internal Medicine, University of Pisa School of Medicine, Pisa, Italy.
authors.forename: Ele
authors.initials: E
authors.lastname: Ferrannini
authors.forename: Andrea
authors.initials: A
authors.lastname: Natali
authors.forename: Stefania
authors.initials: S
authors.lastname: Camastra
authors.forename: Monica
authors.initials: M
authors.lastname: Nannipieri
authors.forename: Andrea
authors.initials: A
authors.lastname: Mari
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Adam
authors.forename: Michael V
authors.initials: MV
authors.lastname: Milburn
authors.forename: Gabi
authors.initials: G
authors.lastname: Kastenmüller
authors.forename: Jerzy
authors.initials: J
authors.lastname: Adamski
authors.forename: Tiinamaija
authors.initials: T
authors.lastname: Tuomi
authors.forename: Valeriya
authors.initials: V
authors.lastname: Lyssenko
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
authors.forename: Walter E
authors.initials: WE
authors.lastname: Gall
mesh_terms: D000328:Adult; D000818:Animals; D015415:Biomarkers / Q000097:blood; D002460:Cell Line; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000175:diagnosis* / Q000378:metabolism / Q000503:physiopathology; D042241:Early Diagnosis; D005260:Female; D005500:Follow-Up Studies; D044882:Glucose Metabolism Disorders / Q000097:blood / Q000175:diagnosis* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D006885:Hydroxybutyrates / Q000097:blood* / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010713:Phosphatidylcholines / Q000097:blood* / Q000378:metabolism; D011446:Prospective Studies; D012372:ROC Curve; D051381:Rats
chemical_list: D015415:Biomarkers; D006885:Hydroxybutyrates; D007328:Insulin; D010713:Phosphatidylcholines; C002448:1,2-linoleoylphosphatidylcholine; C031570:2-hydroxybutyric acid