A tailored therapy for the metabolic syndrome: the dual peroxisome proliferator-activated receptor-alpha/gamma agonist LY465608 ameliorates insulin resistance and diabetic hyperglycemia while improving cardiovascular risk factors in preclinical models.
A novel nonthiazolidinedione dual peroxisome proliferator- activated receptor (PPAR)-alpha/gamma agonist, LY465608, was designed to address the major metabolic disturbances of type 2 diabetes. LY465608 altered PPAR-responsive genes in liver and fat of db/db mice and dose-dependently lowered plasma glucose in hyperglycemic male Zucker diabetic fatty (ZDF) rats, with an ED(50) for glucose normalization of 3.8 mg small middle dot kg(-1) small middle dot day(-1). Metabolic improvements were associated with enhanced insulin sensitivity, as demonstrated in female obese Zucker (fa/fa) rats using both oral glucose tolerance tests and hyperinsulinemic-euglycemic clamps. Further characterization of LY465608 revealed metabolic changes distinct from a selective PPAR-gamma agonist, which were presumably due to the concomitant PPAR-alpha agonism, lower respiratory quotient, and less fat accumulation, despite a similar impact on glycemia in male ZDF rats. In addition to these alterations in diabetic and insulin-resistant animals, LY465608 dose-dependently elevated HDL cholesterol and lowered plasma triglycerides in human apolipoprotein A-I transgenic mice, demonstrating that this compound significantly improves primary cardiovascular risk factors. Overall, these studies demonstrate that LY465608 beneficially impacts multiple facets of type 2 diabetes and associated cardiovascular risk, including those facets involved in the development of micro- and macrovascular complications, which are the major sources for morbidity and mortality in these patients.
Etgen
Garret J
GJ
Division of Endocrine Research, Lilly Research Laboratories, Eli Lilly, Indianapolis, Indiana 46285, USA. etgen_garret_j@lilly.com
Oldham
Brian A
BA
Johnson
William T
WT
Broderick
Carol L
CL
Montrose
Chahrzad R
CR
Brozinick
Joseph T
JT
Misener
Elizabeth A
EA
Bean
James S
JS
Bensch
William R
WR
Brooks
Dawn A
DA
Shuker
Anthony J
AJ
Rito
Christopher J
CJ
McCarthy
James R
JR
Ardecky
Robert J
RJ
Tyhonas
John S
JS
Dana
Sharon L
SL
Bilakovics
James M
JM
Paterniti
James R
JR
Ogilvie
Kathleen M
KM
Liu
Sha
S
Kauffman
Raymond F
RF
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000819:agonists; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D002149:Energy Intake / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D005951:Glucose Tolerance Test; D006943:Hyperglycemia / Q000188:drug therapy*; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007333:Insulin Resistance; D008297:Male; D024821:Metabolic Syndrome / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D009930:Organic Chemicals; D051381:Rats; D011924:Rats, Zucker; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D000077154:Rosiglitazone; D013844:Thiazoles / Q000627:therapeutic use; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists*
D001786:Blood Glucose; D004268:DNA-Binding Proteins; D007004:Hypoglycemic Agents; C453901:LY 465608; D009930:Organic Chemicals; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone