Both
obesity and chronic
inflammation are often associated with
insulin resistance and
type 2 diabetes. The Zucker diabetic fatty (ZDF) rat (fa/fa) is an obese animal model frequently used in
type 2 diabetes research. The current study determines whether chronic administration (from 5 weeks of age through 24 weeks of age) of
salsalate, a
salicylate with anti-inflammatory properties, would be effective in mitigating diabetes
disease progression in ZDF rats. Although a trend existed for lower
blood glucose in the
salsalate-treated group, significant differences were obscured by high animal-level variability. However, even in the non-
drug-treated group, not all ZDF rats became diabetic as expected. Therefore, animals were parsed into two groups, regardless of
drug treatment: normoglycemic ZDF rats, which maintained
blood glucose profiles identical to nondiabetic Zucker lean rats (ZLRs), and hyperglycemic ZDF rats, which exhibited progressive elevation in
blood glucose. To ascertain the differences between ZDF rats that became hyperglycemic and those that did not, relevant physiological indices and expression levels of
adiponectin,
tumor necrosis factor-α,
interleukin-6, and
glucocorticoid-induced leucine zipper messenger RNAs in adipose tissue were measured at sacrifice. Plasma
C-reactive protein concentrations and expression levels of
cytokine and
glucocorticoid-induced leucine zipper messenger RNAs suggested more prevalent chronic
inflammation in hyperglycemic animals. Early elevation of the
insulin-sensitizing
adipokine,
adiponectin, was present in both ZDF groups, with the rate of its age-related decline faster in hyperglycemic animals. The most marked difference between the two groups of ZDF animals was in
insulin output. Although the two ZDF populations had very similar elevated plasma
insulin concentrations for the first 10 weeks, after that time, plasma
insulin decreased markedly in the animals that became hyperglycemic, whereas it remained high in the normoglycemic ZDF rats. Thus, hyperglycemic ZDF animals exhibit both
insulin resistance and progressive beta cell failure, whereas normoglycemic ZDF rats exhibit a lesser degree of
insulin resistance that does not progress to beta cell failure. In these respects, the normoglycemic ZDF rats appear to revert back to a phenotype that strongly resembles that of nondiabetic Zucker fatty rats from which they were derived.