title: Hepatic insulin clearance is the primary determinant of insulin sensitivity in the normal dog.
abstract: OBJECTIVE
  Insulin resistance is a powerful risk factor for Type 2 diabetes and a constellation of chronic diseases, and is most commonly associated with obesity. We examined if factors other than obesity are more substantial predictors of insulin sensitivity under baseline, nonstimulated conditions.
  
  
  METHODS
  Metabolic assessment was performed in healthy dogs (n = 90). Whole-body sensitivity from euglycemic clamps (SICLAMP ) was the primary outcome variable, and was measured independently by IVGTT (n = 36). Adiposity was measured by MRI (n = 90), and glucose-stimulated insulin response was measured from hyperglycemic clamp or IVGTT (n = 86 and 36, respectively).
  
  
  RESULTS
  SICLAMP was highly variable (5.9-75.9 dl/min per kg per μU/ml). Despite narrow range of body weight (mean, 28.7 ± 0.3 kg), adiposity varied approximately eight-fold and was inversely correlated with SICLAMP (P < 0.025). SICLAMP was negatively associated with fasting insulin, but most strongly associated with insulin clearance. Clearance was the dominant factor associated with sensitivity (r = 0.53, P < 0.00001), whether calculated from clamp or IVGTT.
  
  
  CONCLUSIONS
  These data suggest that insulin clearance contributes substantially to insulin sensitivity, and may be pivotal in understanding the pathogenesis of insulin resistance. We propose the hyperinsulinemia due to reduction in insulin clearance is responsible for insulin resistance secondary to changes in body weight.
authors.affiliation: Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Marilyn
authors.initials: M
authors.lastname: Ader
authors.forename: Darko
authors.initials: D
authors.lastname: Stefanovski
authors.forename: Stella P
authors.initials: SP
authors.lastname: Kim
authors.forename: Joyce M
authors.initials: JM
authors.lastname: Richey
authors.forename: Viorica
authors.initials: V
authors.lastname: Ionut
authors.forename: Karyn J
authors.initials: KJ
authors.lastname: Catalano
authors.forename: Katrin
authors.initials: K
authors.lastname: Hucking
authors.forename: Martin
authors.initials: M
authors.lastname: Ellmerer
authors.forename: Gregg
authors.initials: G
authors.lastname: Van Citters
authors.forename: Isabel R
authors.initials: IR
authors.lastname: Hsu
authors.forename: Jenny D
authors.initials: JD
authors.lastname: Chiu
authors.forename: Orison O
authors.initials: OO
authors.lastname: Woolcott
authors.forename: Lisa N
authors.initials: LN
authors.lastname: Harrison
authors.forename: Dan
authors.initials: D
authors.lastname: Zheng
authors.forename: Maya
authors.initials: M
authors.lastname: Lottati
authors.forename: Cathryn M
authors.initials: CM
authors.lastname: Kolka
authors.forename: Vahe
authors.initials: V
authors.lastname: Mooradian
authors.forename: Justin
authors.initials: J
authors.lastname: Dittmann
authors.forename: Sophia
authors.initials: S
authors.lastname: Yae
authors.forename: Huiwen
authors.initials: H
authors.lastname: Liu
authors.forename: Ana Valeria B
authors.initials: AV
authors.lastname: Castro
authors.forename: Morvarid
authors.initials: M
authors.lastname: Kabir
authors.forename: Richard N
authors.initials: RN
authors.lastname: Bergman
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001823:Body Composition; D015992:Body Mass Index; D001835:Body Weight; D003924:Diabetes Mellitus, Type 2 / Q000097:blood; D004285:Dogs; D005215:Fasting; D015309:Glucose Clamp Technique / Q000379:methods; D006946:Hyperinsulinism; D007328:Insulin / Q000097:blood*; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D009765:Obesity / Q000097:blood
chemical_list: D001786:Blood Glucose; D007328:Insulin