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2003
   Verona, Italy

Obesity and Insulin Resistance: A Fat Link

Katarina Jelic, Morten Colding-Jørgensen

Dept. of Scientific Computing, Novo Nordisk A/S, DK-2760 Maaloev

Goal: There is a growing need to understand the link between obesity and type 2 diabetes. An important link is between the fat tissue and the fate of the lipids in the body. To gain an insight in this, a mechanism-based mathematical model of lipid homeostasis has been developed. This type of modelling, called Biosimulation, allows a quantative examination of fatty acids (NEFA), ketones, and triglycerides (TG) and their movements. The model can facilitate a more efficient selection of drugs and drug targets in the hunt for new efficient treatments of type 2 diabetes and obesity.

Method: The model is based on a set of differential equations for the metabolites. The physiological and biochemical relations and parameters are determined based on literature data. Delays are modelled as third-order delays.

Results: It is found that the insulin level and the insulin sensitivity in adipose tissue is the main controller of the NEFA levels in plasma. After a meal, there is typically a suppression of NEFA levels in plasma, but the length and the degree of the suppression are highly dependent on the nutrient mixture and the energy content of the meal. The postprandial decrease in NEFA causes a drop in the fat oxidation rate, thus allowing glucose oxidation to occur. Changing the insulin sensitivity in the adipose tissue gives a change in the plasma NEFA level. This affects other tissue (primarily muscle and liver) both in the postabsorptive and the postprandial situation. Decreased insulin sensitivity in adipose tissue and an increased adipose mass, as seen in obese individuals, results in higher postabsorptive NEFA levels and higher NEFA fluxes to muscle and liver. This decreases the glucose oxidation and increases the hepatic NEFA reesterification. The model shows how a mismatch between insulin levels and adipose insulin sensitivity results in higher postprandial NEFA levels. This exposes extra-adipose tissues to excessive NEFA fluxes and leads to impaired postprandial glucose oxidation and lipid accumulation in other tissues. Weight loss in obese subjects causes a lowering of adipocyte insulin resistance together with a lowering of NEFA levels and NEFA oxidation.

Conclusion: The fat link: Adipose tissue insulin resistance, as seen in obesity, leads to development of insulin resistance in muscle via the fatty acids and their fluxes in the blood. Alleviation of adipose tissue insulin sensitivity via weight loss or pharmacological treatment will result in lowered NEFA levels in the blood. This should improve whole-body glucose homeostasis both postabsorptively and postprandially.



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