title: Phenotyping of adipose, liver, and skeletal muscle insulin resistance and response to pioglitazone in spontaneously obese rhesus monkeys.
abstract: Insulin resistance and diabetes can develop spontaneously with obesity and aging in rhesus monkeys, highly similar to the natural history of obesity, insulin resistance, and progression to type 2 diabetes in humans. The current studies in obese rhesus were undertaken to assess hepatic and adipose contributions to systemic insulin resistance-currently, a gap in our knowledge-and to benchmark the responses to pioglitazone (PIO). A two-step hyperinsulinemic-euglycemic clamp, with tracer-based glucose flux estimates, was used to measure insulin resistance, and in an intervention study was repeated following 6 wk of PIO treatment (3 mg/kg). Compared with lean healthy rhesus, obese rhesus has a 60% reduction of glucose utilization during a high insulin infusion and markedly impaired suppression of lipolysis, which was evident at both low and high insulin infusion. However, obese dysmetabolic rhesus manifests only mild hepatic insulin resistance. Six-week PIO treatment significantly improved skeletal muscle and adipose insulin resistance (by ~50%). These studies strengthen the concept that insulin resistance in obese rhesus closely resembles human insulin resistance and indicate the value of obese rhesus for appraising new insulin-sensitizing therapeutics.
authors.affiliation: Merck & Company, Incorporated, Kenilworth, New Jersey; and shangjin63@gmail.com.
authors.forename: Jin
authors.initials: J
authors.lastname: Shang
authors.affiliation: Merck & Company, Incorporated, Kenilworth, New Jersey; and.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Previs
authors.affiliation: Merck & Company, Incorporated, Kenilworth, New Jersey; and.
authors.forename: Stacey
authors.initials: S
authors.lastname: Conarello
authors.affiliation: Crown Bioscience, Incorporated, Kannapolis, North Carolina.
authors.forename: Keefe
authors.initials: K
authors.lastname: Chng
authors.affiliation: Merck & Company, Incorporated, Kenilworth, New Jersey; and.
authors.forename: Yonghua
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Merck & Company, Incorporated, Kenilworth, New Jersey; and.
authors.forename: Sandra C
authors.initials: SC
authors.lastname: Souza
authors.affiliation: Crown Bioscience, Incorporated, Kannapolis, North Carolina.
authors.forename: Michael
authors.initials: M
authors.lastname: Staup
authors.affiliation: Merck & Company, Incorporated, Kenilworth, New Jersey; and.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Merck & Company, Incorporated, Kenilworth, New Jersey; and.
authors.forename: Dan
authors.initials: D
authors.lastname: Xie
authors.affiliation: Merck & Company, Incorporated, Kenilworth, New Jersey; and.
authors.forename: Emanuel
authors.initials: E
authors.lastname: Zycband
authors.affiliation: Merck & Company, Incorporated, Kenilworth, New Jersey; and.
authors.forename: Karni
authors.initials: K
authors.lastname: Schlessinger
authors.affiliation: Merck & Company, Incorporated, Kenilworth, New Jersey; and.
authors.forename: Victoria Plamadeala
authors.initials: VP
authors.lastname: Johnson
authors.affiliation: Merck & Company, Incorporated, Kenilworth, New Jersey; and.
authors.forename: Gladys
authors.initials: G
authors.lastname: Arreaza
authors.affiliation: Merck & Company, Incorporated, Kenilworth, New Jersey; and.
authors.forename: Franklin
authors.initials: F
authors.lastname: Liu
authors.affiliation: Merck & Company, Incorporated, Kenilworth, New Jersey; and.
authors.forename: Diane
authors.initials: D
authors.lastname: Levitan
authors.affiliation: Merck & Company, Incorporated, Kenilworth, New Jersey; and.
authors.forename: Liangsu
authors.initials: L
authors.lastname: Wang
authors.affiliation: Merck & Company, Incorporated, Kenilworth, New Jersey; and.
authors.forename: Margaret
authors.initials: M
authors.lastname: van Heek
authors.affiliation: Merck & Company, Incorporated, Kenilworth, New Jersey; and.
authors.forename: Mark
authors.initials: M
authors.lastname: Erion
authors.affiliation: Crown Bioscience, Incorporated, Kannapolis, North Carolina.
authors.forename: Yixin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Merck & Company, Incorporated, Kenilworth, New Jersey; and.
authors.forename: David E
authors.initials: DE
authors.lastname: Kelley
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism; D015309:Glucose Clamp Technique; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007333:Insulin Resistance / Q000502:physiology*; D008066:Lipolysis / Q000502:physiology; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008253:Macaca mulatta; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism*; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D000077205:Pioglitazone
keywords: hyperinsulinemic-euglycemic clamp; insulin resistance; rhesus monkey