Insulin resistance is present in multiple metabolism-related diseases. It is an almost universal phenomenon in type 2 diabetes, and many times obesity plays an important role in its development. In contrast, insulin resistance is also present in cancer cachexia, a syndrome characterized by severe wasting of adipose tissue and skeletal muscle. The overarching goal of this research was to better understand insulin resistance in these two diverse disease states and to test novel therapeutic agents for improving insulin sensitivity and disease outcomes.
The first objective was to determine whether dietary oil supplementation with conjugated linoleic acid (CLA) or safflower oil (SAF) improved markers of glycemia, insulin sensitivity, blood lipids, and inflammation in obese, post-menopausal women with type 2 diabetes. In humans, CLA induces modest weight loss, which can subsequently improve insulin sensitivity and glycemia. SAF was chosen as a comparison oil. Women were supplemented with 8 grams of CLA and SAF in a 16-week double-masked, crossover study. CLA had no effect on any metabolic measurements despite modestly decreasing body weight and fat mass. Unexpectedly, SAF improved HbA1c, fasting glucose, HDL cholesterol, C-reactive protein, and the insulin sensitivity index QUICKI. These improvements may have been in part due to decreased trunk fat mass. All SAF-induced metabolic changes occurred after an increase in serum linoleic acid was detected, suggesting serum fatty acid composition may have a role in inducing the observed metabolic improvements in women with type 2 diabetes.
The second objective was to understand the development and consequences of insulin resistance in a mouse model of cancer cachexia. Insulin resistance has been observed in patients with cancer cachexia, but its time course was not known. Male CD2F1 mice were inoculated with 1x106 colon-26 adenocarcinoma cells. Insulin resistance, measured by an insulin tolerance test, was observed prior to weight loss in tumor-bearing mice, suggesting insulin resistance may be a cause rather than a consequence of weight loss. Additionally, activation of Akt, a central signaling molecule in the insulin signaling pathway, was decreased, and proteolytic gene expression was increased at the end of the study. Treating mice with the insulin sensitizer rosiglitazone (RGZ) prevented tumor-induced insulin resistance and normalized proteolytic gene expression in early-stage cachexia.
Because of the improvements seen with RGZ treatment in mice with early-stage cachexia, the third objective was to determine whether RGZ could improve outcomes in late-stage cachexia. Tumor-bearing mice treated with intraperitoneal injections of RGZ (10mg/kg body weight daily) had a two-day delay in weight loss compared to tumor-bearing mice without RGZ. Additionally, RGZ increased adipose mass and adipocyte size. No improvements were seen in muscle mass, strength or proteolytic gene expression. Delayed weight loss with RGZ was dependent on increased food intake, was associated with a delay in tumor-induced muscle gene expression related to substrate switching from glucose to fatty acids, and was associated with a modest improvement in insulin-induced Akt activation. These data suggest that improved insulin sensitivity and food intake may contribute to the ability of RGZ to delay the onset of overt cachexia.