Determination of Insulin-stimulated Hepatic Glucose Uptake by PET-CT Measurements

In the absence of excessive alcohol consumption, increased levels of fat in the liver (\>5%) are diagnosed as non-alcoholic fatty liver (NAFL). It has been shown that NAFL is strongly associated with impairments in metabolic health such as hepatic and whole-body insulin resistance. Insulin resistance is seen as the earliest hallmark in the development of type 2 diabetes. Insulin has two main effects on the liver: suppressing endogenous glucose production (EGP) and increasing glucose uptake. While the former has been extensively studied and is known to be impaired in NAFL, no studies have yet examined whether insulin-stimulated hepatic glucose uptake is affected by NAFL. Recent methodological developments allow us to visualize and quantify glucose uptake in any given tissue using dynamic Positron Emission Tomography (PET) with 18Fluorinated glucose tracer (FDG) during insulin stimulation. In the present study, we will in a first instance optimize the insulin-stimulated whole-body PET protocol and apply the dose as reported in the literature 4 megabequerels per kg of body weight (MBq/kg) (±8 mSv) in the first three subjects. It will then be evaluated whether the dose can be decreased in the remaining measurements. Another twelve individuals will then undergo the optimized dynamic PET protocol to assess insulin-stimulated hepatic glucose together with whole-body glucose uptake measures. Liver fat content and composition will be assessed by proton magnetic resonance spectroscopy (1H-MRS). Fasted De Novo Lipogenesis (DNL) will also be measured by deuterated water. Additionally, a two-step clamp will be performed to measure whole-body insulin sensitivity and insulin-stimulated suppression of EGP. The identification of the contributing factors to insulin resistance during the development of NAFL is crucial in order to develop more effective strategies for the prevention and treatment of metabolic disorders.