Acetyl-CoA carboxylase 2 inhibition reduces skeletal muscle bioactive lipid content and attenuates progression of type 2 diabetes in Zucker diabetic fatty rats

Insulin resistance occurs early in the disease process, preceding the development of type 2 diabetes. Therefore, the identification of molecules that contribute to insulin resistance and leading up to type 2 diabetes is important to elucidate the molecular pathogenesis of the disease. To this end, we characterized gene expression profiles from insulin-sensitive tissues, including adipose tissue, skeletal muscle, and liver tissue of Zucker diabetic fatty (ZDF) rats, a well characterized type 2 diabetes animal model. Gene expression profiles from ZDF rats at 6 weeks (pre-diabetes), 12 weeks (diabetes), and 20 weeks (late-stage diabetes) were compared with age- and sex-matched Zucker lean control (ZLC) rats using 5000 cDNA chips. Differentially regulated genes demonstrating > 1.3-fold change at age were identified and categorized through hierarchical clustering analysis. Our results showed that while expression of lipolytic genes was elevated in adipose tissue of diabetic ZDF rats at 12 weeks of age, expression of lipogenic genes was decreased in liver but increased in skeletal muscle of 12 week old diabetic ZDF rats. These results suggest that impairment of hepatic lipogenesis accompanied with the reduced lipogenesis of adipose tissue may contribute to development of diabetes in ZDF rats by increasing lipogenesis in skeletal muscle. Moreover, expression of antioxidant defense genes was decreased in the liver of 12-week old diabetic ZDF rats as well as in the adipose tissue of ZDF rats both at 6 and 12 weeks of age. Cytochrome P450 (CYP) genes were also significantly reduced in 12 week old diabetic liver of ZDF rats. Genes involved in glucose utilization were downregulated in skeletal muscle of diabetic ZDF rats, and the hepatic gluconeogenic gene was upregulated in diabetic ZDF rats. Genes commonly expressed in all three tissue types were also observed. These profilings might provide better fundamental understanding of insulin resistance and development of type 2 diabetes.

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Increased intramyocellular lipid content but normal skeletal muscle mitochondrial oxidative capacity throughout the pathogenesis of type 2 diabetes

The FASEB Journal ◽

10.1096/fj.08-112318 ◽

2008 ◽

Vol 22 (11) ◽

pp. 3947-3955 ◽

Cited By ~ 61

Author(s):

Henk M. De Feyter ◽

Ellen Lenaers ◽

Sander M. Houten ◽

Patrick Schrauwen ◽

Matthijs K. Hesselink ◽

...

Keyword(s):

Type 2 Diabetes ◽

Skeletal Muscle ◽

Lipid Content ◽

Oxidative Capacity ◽

Intramyocellular Lipid ◽

Mitochondrial Oxidative Capacity ◽

Intramyocellular Lipid Content

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Hyperglycemia, maturity-onset obesity, and insulin resistance in NONcNZO10/LtJ males, a new mouse model of type 2 diabetes

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00376.2006 ◽

2007 ◽

Vol 293 (1) ◽

pp. E327-E336 ◽

Cited By ~ 37

Author(s):

You-Ree Cho ◽

Hyo-Jeong Kim ◽

So-Young Park ◽

Hwi Jin Ko ◽

Eun-Gyoung Hong ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Skeletal Muscle ◽

Mouse Model ◽

Lipid Content ◽

Insulin Action ◽

Plasma Insulin ◽

Glut4 Expression ◽

Organ Specific

As a new mouse model of obesity-induced diabetes generated by combining quantitative trait loci from New Zealand Obese (NZO/HlLt) and Nonobese Nondiabetic (NON/LtJ) mice, NONcNZO10/LtJ (RCS10) male mice developed type 2 diabetes characterized by maturity onset obesity, hyperglycemia, and insulin resistance. To metabolically profile the progression to diabetes in preobese and obese states, a 2-h hyperinsulinemic euglycemic clamp was performed and organ-specific changes in insulin action were assessed in awake RCS10 and NON/LtJ (control) males at 8 and 13 wk of age. Prior to development of obesity and attendant increases in hepatic lipid content, 8-wk-old RCS10 mice developed insulin resistance in liver and skeletal muscle due to significant decreases in insulin-stimulated glucose uptake and GLUT4 expression in muscle. Transition to an obese and hyperglycemic state by 13 wk of age exacerbated insulin resistance in skeletal muscle, liver, and heart associated with organ-specific increases in lipid content. Thus, this polygenic mouse model of type 2 diabetes, wherein plasma insulin is only modestly elevated and obesity develops with maturity yet insulin action and glucose metabolism in skeletal muscle and liver are reduced at an early prediabetic age, should provide new insights into the etiology of type 2 diabetes.

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