title: Inhibition of AMP deaminase activity does not improve glucose control in rodent models of insulin resistance or diabetes.
abstract: Inhibition of AMP deaminase (AMPD) holds the potential to elevate intracellular adenosine and AMP levels and, therefore, to augment adenosine signaling and activation of AMP-activated protein kinase (AMPK). To test the latter hypothesis, novel AMPD pan inhibitors were synthesized and explored using a panel of in vitro, ex vivo, and in vivo models focusing on confirming AMPD inhibitory potency and the potential of AMPD inhibition to improve glucose control in vivo. Repeated dosing of selected inhibitors did not improve glucose control in insulin-resistant or diabetic rodent disease models. Mice with genetic deletion of the muscle-specific isoform Ampd1 did not showany favorable metabolic phenotype despite being challenged with high-fat diet feeding. Therefore, these results do not support the development of AMPD inhibitors for the treatment of type 2 diabetes.
authors.forename: Therese
authors.initials: T
authors.lastname: Admyre
authors.forename: Lena
authors.initials: L
authors.lastname: Amrot-Fors
authors.forename: Maria
authors.initials: M
authors.lastname: Andersson
authors.forename: Martin
authors.initials: M
authors.lastname: Bauer
authors.forename: Mikael
authors.initials: M
authors.lastname: Bjursell
authors.forename: Tomas
authors.initials: T
authors.lastname: Drmota
authors.forename: Stefan
authors.initials: S
authors.lastname: Hallen
authors.forename: Judith
authors.initials: J
authors.lastname: Hartleib-Geschwindner
authors.forename: Bo
authors.initials: B
authors.lastname: Lindmark
authors.forename: Jianming
authors.initials: J
authors.lastname: Liu
authors.forename: Lars
authors.initials: L
authors.lastname: Löfgren
authors.forename: Mattias
authors.initials: M
authors.lastname: Rohman
authors.forename: Nidhal
authors.initials: N
authors.lastname: Selmi
authors.forename: Kristina
authors.initials: K
authors.lastname: Wallenius
mesh_terms: D000659:AMP Deaminase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D009765:Obesity / Q000188:drug therapy / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D001786:Blood Glucose; D004791:Enzyme Inhibitors; D007328:Insulin; D011994:Recombinant Proteins; D054852:Small Molecule Libraries; D000659:AMP Deaminase; C577245:AMPD1 protein, mouse