The dual peroxisome proliferator-activated receptor alpha/gamma activator muraglitazar prevents the natural progression of diabetes in db/db mice.
There are two major defects in type 2 diabetes: 1) insulin resistance and 2) insulin deficiency due to loss of beta-cell function. Here we demonstrated that treatment with muraglitazar (a dual peroxisome proliferator-activated receptor alpha/gamma activator), when initiated before or after the onset of diabetes in mice, is effective against both defects. In study 1, prediabetic db/db mice were treated for 12 weeks. The control mice developed diabetes, as evidenced by hyperglycemia, hyperinsulinemia, reduced insulin levels in the pancreas, blunted insulin response to glucose, and impaired glucose tolerance. The muraglitazar-treated mice had normal plasma glucose, and insulin levels, equivalent or higher pancreatic insulin content than normal mice, showed a robust insulin response to glucose and exhibited greater glucose tolerance. In study 2, diabetic db/db mice were treated for 4 weeks. The control mice displayed increased glucose levels, severe loss of islets, and their isolated islets secreted reduced amounts of insulin in response to glucose and exendin-4 compared with baseline. In muraglitazar-treated mice, glucose levels were reduced to normal. These mice showed reduced loss of islets, and their isolated islets secreted insulin at levels comparable to baseline. Thus, muraglitazar treatment decreased both insulin resistance and preserved beta-cell function. As a result, muraglitazar treatment, when initiated before the onset of diabetes, prevented development of diabetes and, when initiated after the onset of diabetes, prevented worsening of diabetes in db/db mice.
Tozzo
Effie
E
Metabolic and Cardiovascular Diseases Discovery Biology, HPW-21-2.02, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543, USA.
Ponticiello
Randolph
R
Swartz
JoAnn
J
Farrelly
Dennis
D
Zebo
Rachel
R
Welzel
Gustav
G
Egan
Donald
D
Kunselman
Lori
L
Peters
Andrew
A
Gu
Liqun
L
French
Michele
M
Chen
Sean
S
Devasthale
Pratik
P
Janovitz
Evan
E
Staal
Ada
A
Harrity
Thomas
T
Belder
Rene
R
Cheng
Peter T
PT
Whaley
Jean
J
Taylor
Simeon
S
Hariharan
Narayanan
N
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002096:C-Peptide / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000235:genetics; D018450:Disease Progression; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D005951:Glucose Tolerance Test; D006442:Glycated Hemoglobin / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D010080:Oxazoles / Q000494:pharmacology*; D047493:PPAR alpha / Q000819:agonists*; D047495:PPAR gamma / Q000819:agonists*; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
D002096:C-Peptide; D005230:Fatty Acids, Nonesterified; D006442:Glycated Hemoglobin; D005998:Glycine; D007004:Hypoglycemic Agents; D007328:Insulin; D010080:Oxazoles; D047493:PPAR alpha; D047495:PPAR gamma; D014280:Triglycerides; C500085:muraglitazar