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1.
Am J Physiol Regul Integr Comp Physiol ; 295(6): R1782-93, 2008 Dec.
Article in English | MEDLINE | ID: mdl-18832086

ABSTRACT

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.


Subject(s)
Diabetes Mellitus, Type 2/etiology , Disease Models, Animal , Insulin Resistance , Insulin-Secreting Cells/metabolism , Obesity/complications , Adipokines/blood , Adiposity , Age Factors , Aging , Animals , Blood Glucose/metabolism , Crosses, Genetic , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/pathology , Diabetes Mellitus, Type 2/physiopathology , Disease Progression , Female , Fertility , Ghrelin/blood , Glucagon/blood , Glucose Intolerance/metabolism , Glucose Intolerance/physiopathology , Insulin/blood , Insulin-Secreting Cells/pathology , Intra-Abdominal Fat/metabolism , Intra-Abdominal Fat/physiopathology , Lipids/blood , Male , Obesity/metabolism , Obesity/physiopathology , Rats , Rats, Sprague-Dawley , Rats, Zucker , Triglycerides/metabolism
2.
J Biol Chem ; 279(6): 4051-7, 2004 Feb 06.
Article in English | MEDLINE | ID: mdl-14615480

ABSTRACT

Acylation-stimulating protein (ASP) acts as a paracrine signal to increase triglyceride synthesis in adipocytes. In mice, C3 (the precursor to ASP) knock-out (KO) results in ASP deficiency and leads to reduced body fat and leptin levels yet they are hyperphagic. In the present study, we investigated the mechanism for this energy repartitioning. Compared with wild-type (WT) mice, male and female C3(-/-) ASP-deficient mice had elevated oxygen consumption (VO2) in both the active (dark) and resting (light) phases of the diurnal cycle: +8.9% males (p < 0.05) +9.4% females (p < 0.05). Increased physical activity (movement) was observed during the dark phase in female but not in male KO animals. Female WT mice moved 16.9 +/- 2.4 m whereas KO mice moved 30.1 +/- 5.4 m, over 12 h, +78.4%, p < 0.05). In contrast, there was no difference in physical activity in male mice, but a repartitioning of dietary fat following intragastric fat administration was noted. This was reflected by increased fatty acid oxidation in liver and muscle in KO mice, with increased UCP2 (inguinal fat) and UCP3 (muscle) mRNA expression (p = 0.005 and 0.036, respectively). Fatty acid uptake into brown adipose tissue (BAT) and white adipose tissue (WAT) was reduced as reflected by a decrease in the fatty acid incorporation into lipids (BAT -68%, WAT -29%. The decrease of FA incorporation was normalized by intraperitoneal administration of ASP at the time of oral fat administration. These results suggest that ASP deficiency results in energy repartitioning through different mechanisms in male and female mice.


Subject(s)
Blood Proteins/deficiency , Complement C3a/analogs & derivatives , Complement C3a/deficiency , Energy Metabolism , Adipose Tissue/metabolism , Adipose Tissue, Brown/metabolism , Animals , Blood Proteins/genetics , Carrier Proteins/genetics , Complement C3a/genetics , Dietary Fats/administration & dosage , Fatty Acids/metabolism , Female , Ion Channels , Liver/metabolism , Male , Membrane Transport Proteins/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , Mitochondrial Proteins/genetics , Motor Activity , Muscle, Skeletal/metabolism , Oxygen Consumption , RNA, Messenger/genetics , RNA, Messenger/metabolism , Sex Characteristics , Uncoupling Protein 2 , Uncoupling Protein 3
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