Bacterial endotoxin activity in human serum is associated with dyslipidemia, insulin resistance, obesity, and chronic inflammation

OBJECTIVE

To investigate whether bacterial lipopolysaccharide (LPS) activity in human serum is associated with the components of the metabolic syndrome (MetS) in type 1 diabetic patients with various degrees of kidney disease and patients with IgA glomerulonephritis (IgAGN).

RESEARCH DESIGN AND METHODS

Serum LPS activity was determined with the Limulus Amoebocyte Lysate chromogenic end point assay in type 1 diabetic patients with a normal albumin excretion rate (n = 587), microalbuminuria (n = 144), macroalbuminuria (n = 173); patients with IgAGN (n = 98); and in nondiabetic control subjects (n = 345). The relationships of the LPS/HDL ratio and MetS-associated variables were evaluated with Pearson correlation.

RESULTS

The MetS was more prevalent in type 1 diabetic patients (48%) than in patients with IgAGN (15%). Diabetic patients with macroalbuminuria had a significantly higher serum LPS/HDL ratio than patients with IgAGN. In the normoalbuminuric type 1 diabetic group, patients in the highest LPS/HDL quartile were diagnosed as having the MetS three times more frequently than patients in the lowest quartile (69 vs. 22%; P < 0.001). High LPS activity was associated with higher serum triglyceride concentration, earlier onset of diabetes, increased diastolic blood pressure, and elevated urinary excretion of monocyte chemoattractant protein-1.

CONCLUSIONS

High serum LPS activity is strongly associated with the components of the MetS. Diabetic patients with kidney disease seem to be more susceptible to metabolic endotoxemia than patients with IgAGN. Bacterial endotoxins may thus play an important role in the development of the metabolic and vascular abnormalities commonly seen in obesity and diabetes-related diseases.In patients with type 1 diabetes, long duration of the disease and poor glycemic control increase the risk for micro- and macrovascular complications. A significant proportion of type 1 diabetic patients who develop these complications exhibit clinical features commonly seen in subjects with the metabolic syndrome (MetS), including dyslipidemia, insulin resistance, obesity, hypertension, and chronic inflammation (1,2). Vascular diseases are also common in patients with IgA glomerulonephritis (IgAGN), and those with a progressive form of the disease run a significantly elevated risk of developing different cardiovascular sequela (3). Whether the MetS is independently associated with the progression of IgAGN is currently unclear, but at least several related factors, including hyperuricemia, hypertriglyceridemia, weight, insulin resistance, and inflammation, seem to associate with the development of kidney dysfunction in IgAGN (4,5).Many of these clinical subphenotypes likely emerge from the complex interactions between a genetic background, lifestyle, and environmental factors. Recent studies have highlighted the role of the innate immune system in the developmental process of these metabolic abnormalities (6). Our living environment is inhabited with commensal and pathogenic bacteria, which have both beneficial and detrimental effects on human health. If the immune defense functions properly, these microorganisms rarely cause any serious infections in healthy individuals. The situation is different in immunocompromised patients—local infections, use of antibiotics, and even diet may lead to the colonization of opportunistic bacteria in various sites of the body. In diabetic patients, long duration of the disease and poor glycemic control increase the risk for urinary tract, pulmonary, oral, and skin infections (6,7).Lipopolysaccharides (LPS) are unique glycolipids in the cell wall of gram-negative bacteria. LPS molecules, also known as bacterial endotoxins, may trigger acute and chronic inflammation, leading to immune cell activation and cytokine release. HDL cholesterol is one of the most important factors involved in the elimination of LPS molecules from circulation. In healthy subjects, LPS is mainly bound to HDL, whereas in patients with sepsis, LPS is redistributed toward LDL and VLDL lipoproteins (8). High LPS activity combined with low HDL levels increases the risk for cardiovascular disease (9).LPS infusion in mammals leads to the appearance of factors known to be associated with the MetS: elevated levels of proinflammatory markers, dyslipidemia, fasting hyperglycemia, insulin resistance, and obesity (10–12). In some research applications, bacterial endotoxins have been used to induce acute kidney injury in animals. Monocyte chemoattractant protein-1 (MCP1) is a potential marker for progressive renal disease because its expression and excretion are also regulated by bacterial endotoxins (13,14).We have recently shown that high serum levels of LPS activity are associated with the development and progression of kidney disease in Finnish type 1 diabetic patients. Most of the patients with high serum LPS activity exhibited features of dyslipidemia and insulin resistance (15). These metabolic abnormalities are frequently observed in diabetic patients with micro- or macrovascular complications (2). To our knowledge, no previous studies have explored the potential links between bacterial endotoxins and the MetS in subjects with impaired kidney function. Therefore, we wanted to investigate whether serum LPS activity is associated with metabolic risk factors in three distinct study populations: type 1 diabetic patients with various degrees of kidney disease, patients with IgAGN, and nondiabetic subjects.