Abstract
Type 2 diabetes (T2DM) is a heterogeneous group of diseases that is progressive and involves multiple tissues. Goto-Kakizaki (GK) rats are a polygenic model with elevated blood glucose, peripheral insulin resistance, a non-obese phenotype, and exhibit many degenerative changes observed in human T2DM. As part of a systems analysis of disease progression in this animal model, this study characterized the contribution of adipose tissue to pathophysiology of the disease. We sacrificed subgroups of GK rats and appropriate controls at 4, 8, 12, 16 and 20 weeks of age and carried out a gene array analysis of white adipose tissue. We expanded our physiological analysis of the animals that accompanied our initial gene array study on the livers from these animals. The expanded analysis included adipose tissue weights, HbA1c, additional hormonal profiles, lipid profiles, differential blood cell counts, and food consumption. HbA1c progressively increased in the GK animals. Altered corticosterone, leptin, and adiponectin profiles were also documented in GK animals. Gene array analysis identified 412 genes that were differentially expressed in adipose tissue of GKs relative to controls. The GK animals exhibited an age-specific failure to accumulate body fat despite their relatively higher calorie consumption which was well supported by the altered expression of genes involved in adipogenesis and lipogenesis in the white adipose tissue of these animals, including Fasn, Acly, Kklf9, and Stat3. Systemic inflammation was reflected by chronically elevated white blood cell counts. Furthermore, chronic inflammation in adipose tissue was evident from the differential expression of genes involved in inflammatory responses and activation of natural immunity, including two interferon regulated genes, Ifit and Iipg, as well as MHC class II genes. This study demonstrates an age specific failure to accumulate adipose tissue in the GK rat and the presence of chronic inflammation in adipose tissue from these animals.
Highlights
Chronic inflammation is the single most common factor associated with the development of type 2 diabetes (T2DM)
In Western societies obesity is a major cause of chronic inflammation, other chronic inflammatory conditions such as periodontal disease, obstructive pulmonary disease (COPD), arthritis, and myotonic dystrophy are associated with the development of T2DM [4,5,6,7,8,9]
There was no difference in body weights between the two groups of animals at 4 weeks of age, WKY were significantly heavier than GK animals by 8 weeks and this difference increased through the experimental period
Summary
Chronic inflammation is the single most common factor associated with the development of type 2 diabetes (T2DM). In the West, more than eighty percent of patients with T2DM have a body mass index greater than 25 kg/m2 and are considered overweight to obese (.30 kg/m2). Macrophages increasingly infiltrate the tissue [2] It is this increased macrophage infiltration that in part suggests a link between obesity, inflammation, and the development of T2DM. In Asia where obesity is not as prevalent, about sixty percent of type 2 diabetics have body mass indexes less than 25 kg/m2 and are classified as ‘‘lean’’ diabetics [3]. Up to a third of patients with chronic hepatitis C infections develop diabetes [10,11] Linking these disparate conditions associated with T2DM is chronic innate immune activation
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