Effects of polymorphisms in nucleotide-binding oligomerization domains 1 and 2 on biomarkers of the metabolic syndrome and type II diabetes

Abstract

The innate immune receptor toll-like receptor 4 (TLR4) has been implicated in mediating some of the effects of dietary lipids on inflammation and type 2 diabetes (T2D). Similar to TLR4, the nucleotide-binding oligomerization domains (Nods) 1 and 2 are also proteins of innate immunity, which can respond to lipids and initiate pro-inflammatory signalling that plays a role in the aetiology of T2D. The objective was to determine the effect of Nod1 (Glu266Lys) and Nod2 (Ser268Pro) genotypes on factors associated with the metabolic syndrome (MetS), and whether they modify the association between dietary lipids and biomarkers of the MetS. Men and women (n = 998) between the ages of 20-29 years were genotyped for both polymorphisms, completed a one-month, semiquantitative food frequency questionnaire and provided a fasting blood sample. The Glu266Lys polymorphism in Nod1 was not associated with any of the biomarkers of the MetS, but modified the association between dietary saturated fat (SFA) and insulin sensitivity, as measured by HOMA-IR (p for interaction = 0.04). Individuals with the Glu/Glu or Glu/Lys genotype showed no significant relationship between dietary SFA and HOMA-IR (b = -0.002 ± 0.006, p = 0.77; and b = -0.003 ± 0.006, p = 0.61), while those with the Lys/Lys genotype showed a positive association (b = 0.033 ± 0.02, p = 0.03). The Nod2 Ser268Pro polymorphism was not associated with components of the MetS and did not modify the relationship between dietary lipid intake and the biomarkers of MetS. In summary, the Nod1 Glu266Lys polymorphism modifies the relationship between dietary SFA intake and HOMA-IR, suggesting that Nod1 may act as an intracellular lipid sensor affecting insulin sensitivity.

NOD1 receptor is up-regulated in diabetic human and murine myocardium

“…Supporting these findings, other studies have described that NOD1 activation promotes insulin resistance in adipocytes and hepatocytes [7,24,27,28]. Supporting these findings, other studies have described that NOD1 activation promotes insulin resistance in adipocytes and hepatocytes [7,24,27,28].…”

“…As previous evidence suggests that NOD1 can participate in diabetes [7,[27][28][29], we have evaluated the expression of NOD1 in the myocardium of a transgenic db mouse model. db mice manifest several indicators common to patients with Type 2 diabetes, including obesity, hyperglycaemia, hyperinsulinaemia and depressed cardiac function [30][31][32][33].…”

Increased NOD1, but not NOD2, activity in subcutaneous adipose tissue from patients with metabolic syndrome

“…In addition to invading pathogens, both NOD1 and NOD2 are also similarly activated by fatty acids and induce non‐infectious chronic inflammation, which is referred to as sterile inflammation. NOD1 may act as an intracellular lipid sensor affecting insulin sensitivity . Bremer et al previously demonstrated significantly increased levels of circulating markers of inflammation in nascent MetS subjects compared to controls, even after adjustment for adiposity.…”

Therapeutic targeting of NOD1 receptors

“…Further supporting a role for NOD genes in dietary fat‐induced inflammatory responses and insulin resistance, a recent study has linked the Glu266Lys polymorphism in the NOD1 gene between dietary saturated fatty acid intake and insulin sensitivity, despite a lack of correlation with other classical biomarkers of the metabolic syndrome (including waist circumference, triglycerides, high density lipoproteins, glucose, systolic and diastolic blood pressure; Cuda et al ., ). In summary, recent evidence illustrate the complex relationship between systems of immune defence and metabolic regulation but may also offer exciting new therapeutic avenues in type 2 diabetes.…”