Adipose tissue dysregulation and reduced insulin sensitivity in non-obese individuals with enlarged abdominal adipose cells

32 non-obese first-degree relatives of Type 2 diabetic patients were recruited. Glucose tolerance was determined by an oral glucose tolerance test and insulin sensitivity was measured with the hyperinsulinaemic-euglycaemic clamp. Blood samples were collected and subcutaneous abdominal adipose tissue biopsies obtained for gene/protein expression and adipocyte cell size measurements.Our findings show that also in non-obese individuals low insulin sensitivity is associated with signs of adipose tissue metabolic dysfunction characterized by low expression of GLUT4, altered adipokine profile and enlarged adipocyte cell size. In this group, insulin sensitivity is positively correlated to GLUT4 mRNA (R？=？0.49, p？=？0.011) and protein (R？=？0.51, p？=？0.004) expression, as well as with circulating adiponectin levels (R？=？0.46, 0？=？0.009). In addition, insulin sensitivity is inversely correlated to circulating RBP4 (R？=？？0.61, 0？=？0.003) and adipocyte cell size (R？=？？0.40, p？=？0.022). Furthermore, these features are inter-correlated and also associated with other clinical features of the metabolic syndrome in the absence of obesity. No association could be found between the hypertrophy-associated adipocyte dysregulation and HIF-1alpha in this group of non-obese individuals.In conclusion, these findings support the concept that it is not obesity per se, but rather metabolic dysfunction of adipose tissue that is associated with systemic insulin resistance and the metabolic syndrome.There is currently a global epidemic of Type 2 diabetes due to recent changes in lifestyle. Obesity is the major factor promoting the diabetes epidemic and this suggests that the expanded adipose tissue is a major driver through induction of obesity-associated insulin resistance [1]. In agreement with this concept, insulin resistance is observed locally in the adipose tissue long before glucose intolerance develops [2]. Early cellular markers of insulin resistance in adipose tissue are reduced adipose