Development and characterization of a novel rat model of type 2 diabetes mellitus: the UC Davis type 2 diabetes mellitus UCD-T2DM rat.
The prevalence of type 2 diabetes (T2DM) is increasing, creating a need for T2DM animal models for the study of disease pathogenesis, prevention, and treatment. The purpose of this project was to develop a rat model of T2DM that more closely models the pathophysiology of T2DM in humans. The model was created by crossing obese Sprague-Dawley rats with insulin resistance resulting from polygenic adult-onset obesity with Zucker diabetic fatty-lean rats that have a defect in pancreatic beta-cell function but normal leptin signaling. We have characterized the model with respect to diabetes incidence; age of onset; longitudinal measurements of glucose, insulin, and lipids; and glucose tolerance. Longitudinal fasting glucose and insulin data demonstrated progressive hyperglycemia (with fasting and fed glucose concentrations >250 and >450 mg/dl, respectively) after onset along with hyperinsulinemia resulting from insulin resistance at onset followed by a progressive decline in circulating insulin concentrations, indicative of beta-cell decompensation. The incidence of diabetes in male and female rats was 92 and 43%, respectively, with an average age of onset of 6 mo in males and 9.5 mo in females. Results from intravenous glucose tolerance tests, pancreas immunohistochemistry, and islet insulin content further support a role for beta-cell dysfunction in the pathophysiology of T2DM in this model. Diabetic animals also exhibit glycosuria, polyuria, and hyperphagia. Thus diabetes in the UC Davis-T2DM rat is more similar to clinical T2DM in humans than in other existing rat models and provides a useful model for future studies of the pathophysiology, treatment, and prevention of T2DM.
Cummings
Bethany P
BP
Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, One Shields Ave., Davis, CA 95616, USA.
Digitale
Erin K
EK
Stanhope
Kimber L
KL
Graham
James L
JL
Baskin
Denis G
DG
Reed
Benjamin J
BJ
Sweet
Ian R
IR
Griffen
Steven C
SC
Havel
Peter J
PJ
D054392:Adipokines / Q000097:blood; D050154:Adiposity; D000367:Age Factors; D000375:Aging; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003433:Crosses, Genetic; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005298:Fertility; D054439:Ghrelin / Q000097:blood; D005934:Glucagon / Q000097:blood; D018149:Glucose Intolerance / Q000378:metabolism / Q000503:physiopathology; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D050152:Intra-Abdominal Fat / Q000378:metabolism / Q000503:physiopathology; D008055:Lipids / Q000097:blood; D008297:Male; D009765:Obesity / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D014280:Triglycerides / Q000378:metabolism
D054392:Adipokines; D001786:Blood Glucose; D054439:Ghrelin; D007328:Insulin; D008055:Lipids; D014280:Triglycerides; D005934:Glucagon