Type 2 diabetes disease progression and gene array analysis in adipose tissue of Goto-Kakizaki rats
Type 2 diabetes is an epidemic disease involving disrupted glucose homeostasis and is characterized by hyperglycemia. The common form of this disease involves both polygenetic components and environmental contributors, including dietary fat intake diet. However, the precise etiology of type 2 diabetes remains elusive. The Goto-Kakizaki (GK) rat is a non-obese, polygenetic, spontaneous diabetic model, widely used in diabetes related studies, while the Wistar-Kyoto (WKY) rat is its inbreed normoglycemic control. To investigate the interaction of genetic background and fat content of diet, a population study of disease progression and high-fat diet effect in GK rats was conducted with an emphasis on gene expression in adipose tissue along with phenotypic indices relevant to diabetes and adipose tissue function. Male GK and WKY rats fed on a rodent normal diet (ND) or a high fat (HF) diet were sacrificed at 4, 8, 12, 16 and 20 weeks of age. Body weights and food consumption were recorded throughout the study period. At the time of sacrifice, plasma and fat pads were harvested. Glucose and hormones (insulin, corticosterone, adiponectin and leptin), lipid profiles and blood cell counts were measured. RNA samples prepared from abdominal fat were used for Affymetrix 230-2 gene array analyses to explore differential gene expression in these animals. The most prominent difference between GK and WKY rats is that GK rats exhibit an age-specific failure to accumulate body fat starting from 8 weeks of age, despite their relatively higher calorie consumption, which indicates a mild lipoatrophy in these animals. Another novel observation is the significantly elevated total white blood cell (WBC) counts in GK rats which occurred throughout the entire experimental period, indicating chronic systemic inflammation. Gene expression analysis reflects the failure of GK rats to accumulate adipose tissue, suggesting that the molecular mechanisms of lipoatrophy involve 3 aspects: a defect in lipogenesis, decreased lipid storage and accumulation, and impaired preadipocyte differentiation. In addition, array results support the presence of chronic inflammation in GK adipose tissue. Moreover, several diabetes biomarkers were differentially expressed only in animals fed a high fat diet, suggesting that exposure to HF diet subclinically exacerbates type 2 diabetes or accelerates the disease progression in GK rats. Increased dietary fat did result in increased fat accumulation and plasma FFAs in these animals. Combined with food consumption data, we conclude that WKY rats are more efficient in energy use than GK animals, and that GK animals may be more efficient in the use of lipid energy sources than carbohydrates. The microarray analysis on the data comparing diet effects within strains supports the conclusion that HF induces an adaptive increase in lipid utilization as well as adipose tissue macrophage infiltration accompanying increased adiposity in both strains. HF diet also induces adaptive responses of decreased fatty acid synthesis and lipogenesis in WKY rats, but increased lipid elimination and suppressed inflammation in GK animals. This study evaluated the influence of genetic background interacting with increased dietary fat as an environmental contributor to diabetes disease progression in the polygenetic spontaneous diabetic inbred GK rat model, providing insights into the underlying molecular mechanisms and aiding in the identification of potential biomarkers useful in development of new anti-diabetic drugs.