Bacterial Endotoxin Activity in Human Serum Is Associated With Dyslipidemia, Insulin Resistance, Obesity, and Chronic Inflammation

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Abstract

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.

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Endotoxemia Is Associated With an Increased Risk of Incident Diabetes

Pirkko J Pussinen, Aki Havulinna, Markku Lehto … (2011)

OBJECTIVE Diabetes is accompanied with a chronic low-grade inflammation, which may in part be mediated by endotoxins derived from Gram-negative bacteria. RESEARCH DESIGN AND METHODS We investigated in a population-based cohort whether endotoxemia is associated with clinically incident diabetes. The serum endotoxin activity was measured by limulus assay from the FINRISK97 cohort comprising 7,169 subjects aged 25–74 years and followed up for 10 years. RESULTS Both the subjects with prevalent diabetes (n = 537) and those with incident diabetes (n = 462) had higher endotoxin activity than the nondiabetic individuals (P < 0.001). The endotoxin activity was significantly associated with increased risk for incident diabetes with a hazard ratio 1.004 (95% CI 1.001–1.007; P = 0.019) per unit increase resulting in a 52% increased risk (P = 0.013) in the highest quartile compared with the lowest one. The association was independent of diabetes risk factors: serum lipids, γ-glutamyl transferase, C-reactive protein, BMI, and blood glucose. Furthermore, the association of endotoxemia with an increased risk of incident diabetes was independent of the metabolic syndrome as defined either by the National Cholesterol Educational Program-Adult Treatment Panel III or the International Diabetes Federation. Endotoxin activity was linearly related (P < 0.001) to the number of components of the metabolic syndrome. CONCLUSIONS Both prevalent and incident diabetes were associated with endotoxemia, which may link metabolic disorders to inflammation. The results suggest that microbes play a role in the pathogenesis of diabetes.

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Experimental Endotoxemia Induces Adipose Inflammation and Insulin Resistance in Humans

Nehal N Mehta, Fiona McGillicuddy, Paul Anderson … (2009)

OBJECTIVE An emerging model of metabolic syndrome and type 2 diabetes is of adipose dysfunction with leukocyte recruitment into adipose leading to chronic inflammation and insulin resistance (IR). This study sought to explore potential mechanisms of inflammatory-induced IR in humans with a focus on adipose tissue. RESEARCH DESIGN AND METHODS We performed a 60-h endotoxemia protocol (3 ng/kg intravenous bolus) in healthy adults (n = 20, 50% male, 80% Caucasian, aged 27.3 ± 4.8 years). Before and after endotoxin, whole-blood sampling, subcutaneous adipose biopsies, and frequently sampled intravenous glucose tolerance (FSIGT) testing were performed. The primary outcome was the FSIGT insulin sensitivity index (S i). Secondary measures included inflammatory and metabolic markers and whole-blood and adipose mRNA and protein expression. RESULTS Endotoxemia induced systemic IR as demonstrated by a 35% decrease in S i (3.17 ± 1.66 to 2.06 ± 0.73 × 10−4 [μU · ml−1 · min−1], P < 0.005), while there was no effect on pancreatic β-cell function. In adipose, endotoxemia suppressed insulin receptor substrate-1 and markedly induced suppressor of cytokine signaling proteins (1 and 3) coincident with local activation of innate (interleukin-6, tumor necrosis factor) and adaptive (monocyte chemoattractant protein-1 and CXCL10 chemokines) inflammation. These changes are known to attenuate insulin receptor signaling in model systems. CONCLUSIONS We demonstrate, for the first time in humans, that acute inflammation induces systemic IR following modulation of specific adipose inflammatory and insulin signaling pathways. It also provides a rationale for focused mechanistic studies and a model for human proof-of-concept trials of novel therapeutics targeting adipose inflammation in IR and related consequences in humans.

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Influence of diabetes and hyperglycaemia on infectious disease hospitalisation and outcome.

Jens-Erik B Jensen, Camilla Benfield, Borge Nordestgaard (2007)

Diabetes mellitus is believed to increase susceptibility to infectious diseases. The effects of hyperglycaemia per se on infectious disease risk are unknown and the influence of diabetes on infectious disease outcome is controversial. We studied 10,063 individuals from the Danish general population, who were participants in The Copenhagen City Heart Study, over a follow-up period of 7 years. Risk of hospitalisation caused by any infectious disease, and subsequent risk of disease progression to death were estimated by Cox proportional hazards regression analysis. At baseline, 353 individuals reported having diabetes. During 71,509 person-years of follow-up, a total of 1,194 individuals were hospitalised because of an infection. The risk of pneumonia (adjusted hazard ratio [aHR] 1.75, 95% CI 1.23-2.48), urinary tract infection (aHR 3.03, 95% CI 2.04-4.49) and skin infection (aHR 2.43, 95% CI 1.49-3.95) was increased in subjects with diabetes compared with subjects without. Each 1 mmol/l increase in plasma glucose at baseline was associated with a 6-10% increased relative risk of pneumonia, urinary tract infection and skin infection after adjustment for other possible confounders. Among patients hospitalised for urinary tract infection, diabetic patients were at an increased risk of death at 28 days after admission compared with non-diabetic subjects (HR 3.90, 95% CI 1.20-12.66). In the Danish general population, diabetes and hyperglycaemia are strong and independent risk factors for hospitalisation as a result of pneumonia, urinary tract infection and skin infection. Further, diabetes has a negative impact on the prognosis of urinary tract infection.

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Author and article information

Journal

Journal ID (nlm-ta): Diabetes Care

Journal ID (hwp): diacare

Journal ID (pmc): dcare

Journal ID (publisher-id): Diabetes Care

Title: Diabetes Care

Publisher: American Diabetes Association

ISSN (Print): 0149-5992

ISSN (Electronic): 1935-5548

Publication date (Print): August 2011

Publication date (Electronic): 16 July 2011

Volume: 34

Issue: 8

Pages: 1809-1815

Affiliations

[1] ¹Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland

[2] ²Division of Nephrology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland

[3] ³Obesity Research Unit, Division of Internal Medicine, Department of Medicine and Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland

[4] ⁴Department of Internal Medicine, Tampere University Hospital, and University of Tampere Medical School, Tampere, Finland

[5] ⁵Institute of Dentistry, University of Helsinki, Helsinki, Finland

[6] ⁶Department of Public Health, Hjelt Institute, and Centre of Excellence in Complex Disease Genetics, Institute for Molecular Genetics, University of Helsinki, Helsinki, Finland

[7] ⁷National Institute for Health and Welfare, Helsinki, Finland

[8] ⁸Baker International Diabetes Institute, Heart and Diabetes Institute, Melbourne, Victoria, Australia

Author notes

Corresponding author: Markku Lehto, markku.lehto@ 123456helsinki.fi .

Article

Publisher ID: 2197

DOI: 10.2337/dc10-2197

PMC ID: 3142060

PubMed ID: 21636801

SO-VID: 07427b8c-a27e-40a7-a20d-0f8ef4eff181

License:

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

Bacterial Endotoxin Activity in Human Serum Is Associated With Dyslipidemia, Insulin Resistance, Obesity, and Chronic Inflammation

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Abstract

OBJECTIVE

RESEARCH DESIGN AND METHODS

RESULTS

CONCLUSIONS

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GLUT4 biology

Most cited references 13

Endotoxemia Is Associated With an Increased Risk of Incident Diabetes

Experimental Endotoxemia Induces Adipose Inflammation and Insulin Resistance in Humans

Influence of diabetes and hyperglycaemia on infectious disease hospitalisation and outcome.

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