High Fat Intake leads to Acute Post-Prandial Exposure to Circulating Endotoxin in Type 2 diabetes mellitus Subjects

Journal Article
, Harte AL, Varma MC, Tripathi G, McGee KC, Al-Daghri NM, Al-Attas OS, Sabico S, O’Hare JP, Ceriello A, Ponnusamy S, Kumar S, McTernan PG. . 2012
Publication Work Type: 
PHD
Magazine \ Newspaper: 
Diabetes Care
Publication Abstract: 

OBJECTIVE To evaluate the changes in circulating endotoxin after a high–saturated fat meal to determine whether these effects depend on metabolic disease state.

RESEARCH DESIGN AND METHODS Subjects (n = 54) were given a high-fat meal (75 g fat, 5 g carbohydrate, 6 g protein) after an overnight fast (nonobese control [NOC]: age 39.9 ± 11.8 years [mean ± SD], BMI 24.9 ± 3.2 kg/m2, n = 9; obese: age 43.8 ± 9.5 years, BMI 33.3 ± 2.5 kg/m2, n = 15; impaired glucose tolerance [IGT]: age 41.7 ± 11.3 years, BMI 32.0 ± 4.5 kg/m2, n = 12; type 2 diabetic: age 45.4 ± 10.1 years, BMI 30.3 ± 4.5 kg/m2, n = 18). Blood was collected before (0 h) and after the meal (1–4 h) for analysis.

RESULTS Baseline endotoxin was significantly higher in the type 2 diabetic and IGT subjects than in NOC subjects, with baseline circulating endotoxin levels 60.6% higher in type 2 diabetic subjects than in NOC subjects (P < 0.05). Ingestion of a high-fat meal led to a significant rise in endotoxin levels in type 2 diabetic, IGT, and obese subjects over the 4-h time period (P < 0.05). These findings also showed that, at 4 h after a meal, type 2 diabetic subjects had higher circulating endotoxin levels (125.4%↑) than NOC subjects (P < 0.05).

CONCLUSIONS These studies have highlighted that exposure to a high-fat meal elevates circulating endotoxin irrespective of metabolic state, as early as 1 h after a meal. However, this increase is substantial in IGT and type 2 diabetic subjects, suggesting that metabolic endotoxinemia is exacerbated after high fat intake. In conclusion, our data suggest that, in a compromised metabolic state such as type 2 diabetes, a continual snacking routine will cumulatively promote their condition more rapidly than in other individuals because of the greater exposure to endotoxin.

Studies examining the interrelationships between adipose tissue, inflammation, and insulin resistance appear key to understanding type 2 diabetes risk (1,2). It is known that low-grade chronic systemic inflammation contributes to this risk, which appears altered by several factors such as increasing age, sex, ethnicity, genetics, and dietary influences. However, systemic inflammation appears to persist in type 2 diabetic subjects, despite medication, while the mechanisms and mediators of this continual inflammation appear less clear. Evidently, adipose tissue accumulation has a significant impact on disease risk and inflammation in type 2 diabetes but may merely act in response to systemic primary insults (39).

One potential cellular mechanism for increased inflammation may arise through activation of the innate immune system in human adipose tissue (1013). Previous studies have shown that increased activation of the innate immune pathway may arise through excess circulating gut-derived bacteria, known as lipopolysaccharide (LPS) or endotoxin, which represents the outer cell wall membrane of gram-negative bacteria (10,11,1417). Our previous work has shown that endotoxin has an immediate impact on the innate immune pathway in human adipose tissue, acting via key receptors known as the Toll-like receptors, which recognize antigens, such as the LPS component, to initiate an acute-phase response to infection (8,10). Stimulation of the Toll-like receptors leads to intracellular activation of nuclear factor-κB (NF-κB), a key transcription factor in the inflammatory cascade that regulates the transcription of numerous proinflammatory adipokines (9,10). Therefore, in vitro endotoxin may act as a mediator of inflammation through activation of NF-κB, leading to a rapid response within adipose tissue that may be exacerbated by increased adipose tissue mass (18–22).

However, clinical studies have also implicated gut-derived endotoxin as a “primary insult” to activate the inflammatory state, contributing to metabolic disease, with current cross-sectional data showing elevated systemic endotoxin levels in conditions of obesity, type 2 diabetes, coronary artery disease, and fatty liver disease (8,10,11,1417). Within these studies, circulating endotoxin is observed to be positively associated with waist circumference, waist-to-hip ratio, insulin levels, inflammatory cytokines and lipids, including total cholesterol, triglycerides (TGs), and LDL cholesterol, and negatively associated with HDL cholesterol (8,10,11,1417). The combined importance of dietary lipids and LPS in determining inflammatory risk may arise, since endotoxin has a strong affinity for chylomicrons (lipoproteins that transport dietary long-chain saturated fatty acids [SFAs] through the gut wall) as endotoxin crosses the gastrointestinal mucosa (2325). As such, atherogenic and inflammatory risk may arise through a combination of dietary lipoprotein patterns and an increase in circulating endotoxin, exacerbated by feeding patterns (26,27). Therefore, altering the lipid profile through dietary intervention may reduce endotoxin and the arising inflammatory response. Recent human studies have explored dietary effects of a high-SFA, high-carbohydrate meal on circulating endotoxin levels in healthy individuals. The findings showed a substantial increase in circulating endotoxin, in subjects given a high-fat meal, in conjunction with markers of inflammation (as noted from mononuclear blood cells) (13,28). Murine studies have also identified an association between endotoxin and insulin resistance, through infusion of endotoxin, with the same effect also noted by a high-fat diet (12), with insulin resistance and weight gain both affecting gut permeability (11,17,28). In studies to date, using either infused endotoxin as a bolus or derived from the gut because of dietary changes, both methods suggest endotoxin has the capacity to affect the inflammatory pathways (28,29). However, it remains to be established whether diets in different metabolic states affect absorption of endotoxin. Also, do such postprandial circulating endotoxin levels correlate with systemic lipid changes postprandially, being compounded in more insulin-resistant states? Therefore, these studies sought to establish whether a high-fat meal increased circulating endotoxin and whether this is altered in different metabolic disease states.