Dynamic modelling of glucose homeostasis during ageing

Barbara M. Bakker

Laboratory of Paediatrics, University Medical Center Groningen, The Netherlands

 

Abstract:

Glucose is an important fuel for our body, particularly for the brain. In healthy people blood glucose levels are regulated within a narrow range. The hormone insulin plays a key role in this glucose homeostasis. If the liver and the skeletal muscle become less sensitive to insulin, this may lead to type 2 diabetes.

Diet and physical exercise modulate the development of insulin resistance during ageing. This involves organ-specific alterations in insulin signalling and mitochondrial lipid handling, which ultimately affect glucose homeostasis. It has long been debated whether insulin resistance is due to dietary lipid overload or to age-dependent decline of mitochondrial function. Using a multi-omics approach, in combination with computational modelling and metabolic control analysis, we investigated the interplay between diet, exercise and mitochondrial function, as well as the contribution of the liver and the skeletal muscle to the development of insulin resistance.

In this lecture I will illustrate how we used two types of kinetic models to elucidate the  role of mitochondria in insulin-dependent glucose handling. The first type was used to predict, based on detailed knowledge of enzyme kinetics, how metabolic fluxes and concentrations respond to measured alterations in the proteome. The second type of model was used to infer from the dynamics of a deuterium-labelled glucose tracer, how fluxes of glucose production and utilisation in the body respond to insulin.