Studies of the adipose tissue in insulin resistance with microdialysis

Abstract

Type 2 diabetes is characterized by a combination of insulin resistance and an impaired insulin secretion. Theprevalence of the disease has taken epidemic proportions, and it is therefore of great concern to characterize itspathophysiology, as well as to identify individuals with increased risk for the disease, enabling to take measuresfor prevention and cure. In the present thesis early perturbations in the abdominal adipose tissue metabolism inthe development of type 2 diabetes are characterized. Furthermore, a possible link between adipose tissuedysfunction and a risk marker for cardiovascular disease is studied.To identify early metabolic perturbations, healthy volunteers with known increased risk of developing type 2diabetes, as subjects with heredity for the disease, subjects with increased fat cell size, or subjects with a defectin the adipocyte insulin signalling system (low IRS-1 protein expression) are studied. The microdialysistechnique allows measurements of substances in the subcutaneous interstitial fluid in vivo. 133Xenon-clearancetechnique is applied for adipose tissue blood flow measurements. Subcutaneous needle biopsy is performed toallow measurement of IRS-1 protein expression by immunoblotting and measurement of fat cell size. Arterialstiffness is measured by pulse wave analysis. The euglycemic hyperinsulinemic clamp method is applied formeasurement of insulin sensitivity.In paper I the lactate release per fat cell is shown to be increased during hyperinsulinemia in subjects prone todevelop type 2 diabetes, indicating a disturbance in glucose metabolism in their subcutaneous adipocytes. Anincreased fat cell size is shown to be associated with an increased interstitial lactate concentration. In paper II anincreased fat cell size is shown to be associated with increased subcutaneous interstitial interleukin-6 (IL-6)levels in vivo, as well as increased IL-6 mRNA expression and IL-6 secretion in vitro. Increased IL-6 levels areshown to down regulate adipocyte differentiation markers in vitro, which may result in an increased fat cell size.In paper III the kinetics of transendothelial insulin transport to the adipose tissue is studied in subjects withheredity for type 2 diabetes and a decreased insulin sensitivity. The proportion of insulin passing the capillaryendothelium to the interstitium is similar at two different concentrations of physiological hyperinsulinemia,indicating that insulin action in vivo is primarily dependent on the cellular insulin sensitivity. In paper IVsubjects with a low IRS-1 protein expression in the adipocytes are shown to have an increased arterial stiffness,indicating low IRS-1 protein expression as a potential risk marker for cardiovascular disease.In conclusion, subjects prone to develop type 2 diabetes exhibit increased lactate and IL-6 levels in thesubcutaneous adipose tissue. However, the transcapillary insulin transport in the adipose tissue does not seem tobe a cause of insulin resistance in these subjects. Furthermore, an impairment in the insulin signalling cascade inthe adipocytes is identified as a risk marker for arterial stiffness.