title: Impaired cardiometabolic responses to glucagon-like peptide 1 in obesity and type 2 diabetes mellitus.
abstract: Glucagon-like peptide 1 (GLP-1) has insulin-like effects on myocardial glucose uptake which may contribute to its beneficial effects in the setting of myocardial ischemia. Whether these effects are different in the setting of obesity or type 2 diabetes (T2DM) requires investigation. We examined the cardiometabolic actions of GLP-1 (7-36) in lean and obese/T2DM humans, and in lean and obese Ossabaw swine. GLP-1 significantly augmented myocardial glucose uptake under resting conditions in lean humans, but this effect was impaired in T2DM. This observation was confirmed and extended in swine, where GLP-1 effects to augment myocardial glucose uptake during exercise were seen in lean but not in obese swine. GLP-1 did not increase myocardial oxygen consumption or blood flow in humans or in swine. Impaired myocardial responsiveness to GLP-1 in obesity was not associated with any apparent alterations in myocardial or coronary GLP1-R expression. No evidence for GLP-1-mediated activation of cAMP/PKA or AMPK signaling in lean or obese hearts was observed. GLP-1 treatment augmented p38-MAPK activity in lean, but not obese cardiac tissue. Taken together, these data provide novel evidence indicating that the cardiometabolic effects of GLP-1 are attenuated in obesity and T2DM, via mechanisms that may involve impaired p38-MAPK signaling.
authors.affiliation: Department of Cellular and Integrative Physiology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202, USA.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Moberly
authors.forename: Kieren J
authors.initials: KJ
authors.lastname: Mather
authors.forename: Zachary C
authors.initials: ZC
authors.lastname: Berwick
authors.forename: Meredith K
authors.initials: MK
authors.lastname: Owen
authors.forename: Adam G
authors.initials: AG
authors.lastname: Goodwill
authors.forename: Eli D
authors.initials: ED
authors.lastname: Casalini
authors.forename: Gary D
authors.initials: GD
authors.lastname: Hutchins
authors.forename: Mark A
authors.initials: MA
authors.lastname: Green
authors.forename: Yen
authors.initials: Y
authors.lastname: Ng
authors.forename: Robert V
authors.initials: RV
authors.lastname: Considine
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Perry
authors.forename: Robin L
authors.initials: RL
authors.lastname: Chisholm
authors.forename: Johnathan D
authors.initials: JD
authors.lastname: Tune
mesh_terms: D000328:Adult; D000818:Animals; D015897:Comorbidity; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000453:epidemiology / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology* / Q000627:therapeutic use*; D005947:Glucose / Q000378:metabolism*; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D006801:Humans; D054795:Incretins / Q000494:pharmacology* / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism*; D009765:Obesity / Q000453:epidemiology / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D010805:Physical Conditioning, Animal / Q000502:physiology; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D012146:Rest / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013552:Swine; D016896:Treatment Outcome; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D054795:Incretins; D052216:Glucagon-Like Peptide 1; D048051:p38 Mitogen-Activated Protein Kinases; D005947:Glucose