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

Abstract

Background: Obesity contributes to Type 2 diabetes by promoting systemic insulin resistance. Obesity causes features of metabolic dysfunction in the adipose tissue that may contribute to later impairments of insulin action in skeletal muscle and liver; these include reduced insulin-stimulated glucose transport, reduced expression of GLUT4, altered expression of adipokines, and adipocyte hypertrophy. Animal studies have shown that expansion of adipose tissue alone is not sufficient to cause systemic insulin resistance in the absence of adipose tissue metabolic dysfunction. To determine if this holds true for humans, we studied the relationship between insulin resistance and markers of adipose tissue dysfunction in non-obese individuals.

Method: 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.

Results: 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.

Conclusions: 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.

Figure 1

Adipocyte cell size correlations. (A) Adipocyte cell size is positively correlated to circulating triglycerides (R = 0.51, p = 0.003) and circulating insulin levels (R = 0.52, p = 0.002). (B) Adipose cell size (R = −0.54, p = 0.001), WHR (R = −0.63, p < 0.001) and BMI (R = −0.35, p = 0.05) are all significantly and inversely associated with circulating adiponectin levels. (C) Adipose cell size tends to be negatively associated with the expression the glucose transporter GLUT4 protein (R = −0.35, p = 0.051) and is negatively associated with mRNA (R = −0.40, p = 0.023) in the adipose tissue in non-obese subjects.

Figure 2

Circulating factors. (A) Circulating total adiponectin level tends to correlate with GLUT4 mRNA (R = 0.34, p = 0.059) and protein (R = 0.32, p = 0.08) expression in the adipose tissue and is negatively correlated with circulating serum RBP4 levels (R = −0.54, p = 0.009).