- Author
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K.W. ter Horst
- Title
- Obesity, ectopic lipids, and insulin resistance
- Subtitle
- Tissue-specific defects in nutrient handling
- Supervisors
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J.A. Romijn
- Co-supervisors
- Award date
- 20 September 2017
- Number of pages
- 234
- ISBN
- 978-94-028-0686-1
- Document type
- PhD thesis
- Faculty
- Faculty of Medicine (AMC-UvA)
- Abstract
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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.
- Permalink
- http://hdl.handle.net/11245.1/4cdeccf0-af03-43dc-95d6-07316c12a276
- Downloads
-
Thesis (complete)
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Front matter
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Chapter 1: General introduction
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Chapter 2: Insulin resistance in obesity can be reliably identified from fasting plasma insulin
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Chapter 3: Methods for quantifying adipose tissue insulin resistance in overweight/obese humans
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Chapter 4: Impaired insulin action in the liver, but not in adipose tissue or muscle, is a distinct metabolic feature of impaired fasting glucose in obese humans
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Chapter 5: Sexual dimorphism in hepatic, adipose tissue, and peripheral tissue insulin sensitivity in obese humans
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Chapter 6: Effect of fructose consumption on insulin sensitivity in nondiabetic subjects: a systematic review and meta-analysis of diet-intervention trials
Chapter 7: Fructose acutely regulates hepatic gluconeogenesis and lipogenesis gene programs in obese humans
Chapter 8: The FGF21 response to fructose predicts metabolic health and is conserved after bariatric surgery in obese humans
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Chapter 9: The vitamin D metabolites 25(OH)D and 1,25(OH)2D are not related to either glucose metabolism or insulin action in obese women
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Chapter 10: Hepatic diacylglycerol-associated protein kinase Cε translocation links hepatic steatosis to hepatic insulin resistance in humans
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Chapter 11: Summary, general discussion, and future perspectives
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Appendices
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