Molecular mechanisms of insulin resistance

Obesity and diabetes are growing health concerns across the world. Type 2 diabetes (T2D), originally called adult-onset diabetes, accounts for >90% of diabetes cases. T2D is a disease of insulin resistance, meaning that blood sugar remains high despite high levels of circulating insulin. The most evident clinical risk factors for human T2D are diet and obesity. Despite being a common health issue and heavily investigated, the molecular links between nutrient overload and insulin resistance remain enigmatic. For example, it is known that obese patients show increased levels of the pro-inflammatory molecule Tumor necrosis factor a (TNF-a) in their adipose tissue and we also know that elevated TNF-a promotes insulin resistance. However, the exact regulation for this adipose TNF-a production is still largely unknown. Another molecule implicated in T2D is extracellular adenosine a danger signal that accumulates in stressed and inflamed tissues. However, the current scientific data as to its function during obesity-induced diabetes is rather contradictory: adenosine signaling has been found to have opposing metabolic effects, depending on specific receptors (there are four different adenosine receptors in mammals) and the types of pharmacological agents and animal models used. In our proposal Molecular mechanisms of insulin resistance: The role of adenosine receptor signaling and genetic screening in a fruit fly model of diet-induced diabetes we aim to determine the exact role of adenosine signaling in obesity-induced insulin resistance by using the power of the fruit fly Drosophila melanogaster as a simple animal model that allows sophisticated tissue-specific genetic manipulation. Sugar-fed Drosophila larvae develop increased glucose and insulin levels leading to insulin resistance the same alterations occur in human diabetes patients. Drosophila has only one adenosine receptor and our preliminary results show that the removal of this single adenosine receptor reduces insulin resistance and TNF-a production in over-fed larvae. This suggests that adenosine signaling promotes obesity-induced diabetes in animals and maybe humans. We propose to further analyze adenosine signaling in over-fed larvae in order to uncover the exact mechanisms by which it regulates TNF-a and insulin resistance. As a second approach to identify novel molecular links between caloric overload and insulin resistance, we will use the same over-fed larvae as before to carry out an unbiased genetic screen for novel modifiers of insulin resistance. We will screen molecularly defined chromosomal deletions (covering 98% of the genome) to identify genes that are required for the development of insulin resistance in sugar-fed larvae. In summary, the results from this proposal will uncover novel molecular mechanisms of obesity-driven diabetes and lead to a better understanding of the complex role for adenosine signaling in metabolic disease in humans.

Overeating and in particular high sugar consumption has been linked to the development of obesity and, eventually, insulin resistance and type 2 diabetes. An unhealthy diet causes metabolic disease by inducing low-grade inflammation throughout the body. This is mediated by macrophages - important cells of the immune system that are responsible for detecting, engulfing and destroying pathogens and damaged or dead cells. Our preliminary data suggests that adenosine signalling can promote this inflammatory response by directly regulating the behaviour of macrophages. Feeding fruit fly larvae a high sugar diet prompts macrophages to release adenosine into the extracellular space. Adenosine, a well-known danger signal, then activates adenosine receptors on macrophages to shift the macrophage population toward a more pro-inflammatory phenotype. When we block adenosine signalling we partially alleviate numerous detrimental effects of high sugar stress, including hyperglycemia, insulin resistance and a suppression of systemic growth, in fruit fly larvae. Therefore, targeting this circuit could potentially provide a novel entry point for the treatment of overnutrition-induced metabolic disease.