title: Relationships between circulating metabolic intermediates and insulin action in overweight to obese, inactive men and women.
abstract: OBJECTIVE
  To determine whether circulating metabolic intermediates are related to insulin resistance and beta-cell dysfunction in individuals at risk for type 2 diabetes.
  
  
  METHODS
  In 73 sedentary, overweight to obese, dyslipidemic individuals, insulin action was derived from a frequently sampled intravenous glucose tolerance test. Plasma concentrations of 75 amino acids, acylcarnitines, free fatty acids, and conventional metabolites were measured with a targeted, mass spectrometry-based platform. Principal components analysis followed by backward stepwise linear regression was used to explore relationships between measures of insulin action and metabolic intermediates.
  
  
  RESULTS
  The 75 metabolic intermediates clustered into 19 factors comprising biologically related intermediates. A factor containing large neutral amino acids was inversely related to insulin sensitivity (S(I)) (R(2) = 0.26). A factor containing fatty acids was inversely related to the acute insulin response to glucose (R(2) = 0.12). Both of these factors, age, and a factor containing medium-chain acylcarnitines and glucose were inversely and independently related to the disposition index (DI) (R(2) = 0.39). Sex differences were found for metabolic predictors of S(I) and DI.
  
  
  CONCLUSIONS
  In addition to the well-recognized risks for insulin resistance, elevated concentrations of large, neutral amino acids were independently associated with insulin resistance. Fatty acids were inversely related to the pancreatic response to glucose. Both large neutral amino acids and fatty acids were related to an appropriate pancreatic response, suggesting that these metabolic intermediates might play a role in the progression to type 2 diabetes, one by contributing to insulin resistance and the other to pancreatic failure. These intermediates might exert sex-specific effects on insulin action.
authors.affiliation: Physical Medicine and Rehabilitation, Veterans Affairs Medical Center, Durham, North Carolina, USA. huffm007@mc.duke.edu
authors.forename: Kim M
authors.initials: KM
authors.lastname: Huffman
authors.forename: Svati H
authors.initials: SH
authors.lastname: Shah
authors.forename: Robert D
authors.initials: RD
authors.lastname: Stevens
authors.forename: James R
authors.initials: JR
authors.lastname: Bain
authors.forename: Michael
authors.initials: M
authors.lastname: Muehlbauer
authors.forename: Cris A
authors.initials: CA
authors.lastname: Slentz
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Tanner
authors.forename: Maragatha
authors.initials: M
authors.lastname: Kuchibhatla
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Houmard
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Newgard
authors.forename: William E
authors.initials: WE
authors.lastname: Kraus
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000596:Amino Acids / Q000097:blood; D001786:Blood Glucose; D002331:Carnitine / Q000031:analogs & derivatives / Q000097:blood; D003430:Cross-Sectional Studies; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000097:blood* / Q000503:physiopathology*; D050177:Overweight / Q000097:blood* / Q000503:physiopathology*; D025341:Principal Component Analysis; D053719:Tandem Mass Spectrometry; D055815:Young Adult
chemical_list: D000596:Amino Acids; D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; C116917:acylcarnitine; D002331:Carnitine