title: Exenatide Treatment Alone Improves β-Cell Function in a Canine Model of Pre-Diabetes.
abstract: BACKGROUND
  Exenatide's effects on glucose metabolism have been studied extensively in diabetes but not in pre-diabetes.
  
  
  OBJECTIVE
  We examined the chronic effects of exenatide alone on glucose metabolism in pre-diabetic canines.
  
  
  METHODS
  After 10 weeks of high-fat diet (HFD), adult dogs received one injection of streptozotocin (STZ, 18.5 mg/kg). After induction of pre-diabetes, while maintained on HFD, animals were randomized to receive either exenatide (n = 7) or placebo (n = 7) for 12 weeks. β-Cell function was calculated from the intravenous glucose tolerance test (IVGTT, expressed as the acute insulin response, AIRG), the oral glucose tolerance test (OGTT, insulinogenic index) and the graded-hyperglycemic clamp (clamp insulinogenic index). Whole-body insulin sensitivity was assessed by the IVGTT. At the end of the study, pancreatic islets were isolated to assess β-cell function in vitro.
  
  
  RESULTS
  OGTT: STZ caused an increase in glycemia at 120 min by 22.0% (interquartile range, IQR, 31.5%) (P = 0.011). IVGTT: This protocol also showed a reduction in glucose tolerance by 48.8% (IQR, 36.9%) (P = 0.002). AIRG decreased by 54.0% (IQR, 40.7%) (P = 0.010), leading to mild fasting hyperglycemia (P = 0.039). Exenatide, compared with placebo, decreased body weight (P<0.001) without altering food intake, fasting glycemia, insulinemia, glycated hemoglobin A1c, or glucose tolerance. Exenatide, compared with placebo, increased both OGTT- (P = 0.040) and clamp-based insulinogenic indexes (P = 0.016), improved insulin secretion in vitro (P = 0.041), but had no noticeable effect on insulin sensitivity (P = 0.405).
  
  
  CONCLUSIONS
  In pre-diabetic canines, 12-week exenatide treatment improved β-cell function but not glucose tolerance or insulin sensitivity. These findings demonstrate partial beneficial metabolic effects of exenatide alone on an animal model of pre-diabetes.
authors.affiliation: Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors.forename: Viorica
authors.initials: V
authors.lastname: Ionut
authors.affiliation: Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors.forename: Orison O
authors.initials: OO
authors.lastname: Woolcott
authors.affiliation: Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors.forename: Hasmik J
authors.initials: HJ
authors.lastname: Mkrtchyan
authors.affiliation: Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors.forename: Darko
authors.initials: D
authors.lastname: Stefanovski
authors.affiliation: Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors.forename: Morvarid
authors.initials: M
authors.lastname: Kabir
authors.affiliation: Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors.forename: Malini S
authors.initials: MS
authors.lastname: Iyer
authors.affiliation: Department of Physiology and Biophysics, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Huiwen
authors.initials: H
authors.lastname: Liu
authors.affiliation: Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors.forename: Ana V B
authors.initials: AV
authors.lastname: Castro
authors.affiliation: Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors.forename: Josiane L
authors.initials: JL
authors.lastname: Broussard
authors.affiliation: Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors.forename: Cathryn M
authors.initials: CM
authors.lastname: Kolka
authors.affiliation: Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors.forename: Isaac
authors.initials: I
authors.lastname: Asare-Bediako
authors.affiliation: Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors.forename: Richard N
authors.initials: RN
authors.lastname: Bergman
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001823:Body Composition / Q000187:drug effects; D004195:Disease Models, Animal; D004285:Dogs; D004435:Eating / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D000077270:Exenatide; D005215:Fasting / Q000097:blood; D005934:Glucagon / Q000378:metabolism; D005951:Glucose Tolerance Test; D006442:Glycated Hemoglobin / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000473:pathology*; D008099:Liver / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D010455:Peptides / Q000494:pharmacology* / Q000627:therapeutic use; D011236:Prediabetic State / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D014688:Venoms / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D001786:Blood Glucose; D000077270:Exenatide; D005934:Glucagon; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D010455:Peptides; D014688:Venoms