Obesity, ectopic lipids, and insulin resistance: Tissue-specific defects in nutrient handling

This thesis described studies on the clinical, nutritional, and molecular aspects of insulin resistance in human obesity. We investigated methods for the identification of insulin resistance in high-risk patients and studied the nutritional and molecular mechanisms that may contribute to insulin resistance in different target tissues. Firstly, we show that insulin resistance can be identified using simple assessment methods, such as a fasting blood sample, thereby promoting the widespread assessment of muscle and adipose tissue insulin resistance in research and clinical settings. Secondly, we demonstrate that high fructose consumption contributes to the development of hepatic insulin resistance. This adverse metabolic effect is likely mediated, in part, by fructose-induced activation of hepatic gluconeogenesis and lipogenesis. Fructose, but not glucose, ingestion acutely regulated hepatic transcription factors and the expression of gluconeogenesis and lipogenesis genes in obese subjects. In accordance, fructose, but not glucose, ingestion raised plasma triglyceride levels. Finally, the relationship between hepatic lipogenesis, fatty liver, and insulin resistance is complex, but emerging evidence from animal studies points to the accumulation of diacylglycerol as an important cause for lipid-mediated hepatic insulin resistance and type 2 diabetes. We demonstrate the human relevance of this mechanism: obese humans with hepatic insulin resistance have increased intrahepatic diacylglycerol levels and activation of protein kinase Cε, an enzyme that can inhibit insulin receptor downstream signaling. Taken together, our findings support the development of interventions that promote healthy adipose tissue and decrease ectopic lipid accumulation for the prevention and treatment of insulin resistance and type 2 diabetes.