Impact of physical inactivity on adipose tissue low-grade inflammation in first-degree relatives of type 2 diabetic patients

OBJECTIVE

First-degree relatives (FDRs) of patients with type 2 diabetes may exhibit a disproportionately elevated risk of developing insulin resistance, obesity, and type 2 diabetes when exposed to physical inactivity, which to some unknown extent may involve low-grade inflammation. We investigated whether subjects who are nonobese FDRs show signs of low-grade inflammation before or after exposure to short-term physical inactivity.

RESEARCH DESIGN AND METHODS

We studied 13 healthy FDR subjects and 20 control (CON) subjects matched for age, sex, and BMI before and after 10 days of bed rest (BR). Insulin sensitivity was measured by the hyperinsulinemic euglycemic clamp. Key low-grade inflammation mediators were measured in arterial blood and microdialysate from subcutaneous abdominal (SCAAT) and femoral adipose tissue. Adipokine mRNA expression was determined in SCAAT.

RESULTS

Before BR, FDR subjects displayed insulin resistance, elevated plasma C-reactive protein, leptin, and monocyte chemoattractant protein (MCP)-1, high interleukin (IL)-6, and MCP-1 expressions, as well as low adiponectin and leptin expressions. FDR subjects responded to BR by decreasing plasma adiponectin and IL-10 expression and increasing plasma expression of IL-10 and tumor necrosis factor-α. In contrast, CON subjects responded to BR by increasing plasma adiponectin and adiponectin expression and by decreasing SCAAT microdialysate leptin.

CONCLUSIONS

Young and nonobese FDR of patients with type 2 diabetes exhibit low-grade inflammation, which is further and disproportionately aggravated when exposed to physical inactivity. The study provides support for the notion that people at increased risk of type 2 diabetes should avoid even short periods of physical inactivity.Human adipose tissue produces a variety of inflammatory mediators that act locally in the adipose tissue and systemically, leading to obesity-associated low-grade inflammation. Many of the inflammatory mediators can regulate insulin action in skeletal muscle and adipose tissue (1,2) and form putative links between adipose tissue and systemic metabolism (3). Chronic low-grade inflammation is pathophysiologically related to the development of type 2 diabetes and atherosclerosis.Physical inactivity contributes to a positive energy balance and the induction of obesity, but the relation between physical inactivity and low-grade inflammation may be independent of obesity. In a cross-sectional design, a low level of physical activity was associated with elevated plasma levels of interleukin (IL)-6 and C-reactive protein (CRP) independently of obesity (4). A review by Hamer (5) found an inverse association between the level of physical activity and one or more inflammatory markers in 27 of 40 observational studies after adjusting for measures of fatness. Furthermore, physically active individuals consistently demonstrated low concentrations of CRP. Recent intervention studies found that exercise training downregulated markers of chronic inflammation such as IL-6 and alanine aminotransferase (6,7). However, it is not known if physical inactivity per se in a longitudinal design upregulates inflammatory markers and changes molecular mechanisms relevant to the development of type 2 diabetes.First-degree relatives (FDRs) of type 2 diabetic patients bear a high lifetime risk of developing insulin resistance and represent a genetic model for studies into the cause of type 2 diabetes. Individuals who progress to type 2 diabetes display features of low-grade inflammation years before onset of the disease, suggesting that low-grade inflammation is involved in the pathogenetic processes (6,8). The objective of the current study was to investigate adipose tissue and systemic markers of low-grade inflammation in healthy, nonobese FDR and control (CON) subjects and in a longitudinal design to explore the effect of physical inactivity on these markers.