Serum IgG2 levels are specifically associated with whole-body insulin-mediated glucose disposal in non-diabetic offspring of type 2 diabetic individuals: a cross-sectional study

Elena Succurro,Francesco Andreozzi,Angela Quirino,Teresa Vanessa Fiorentino,Marta Letizia Hribal,Aida Giancotti,Cinzia Peronace,Franco Arturi,Francesco Perticone,Giorgio Sesti,Alfredo Focà,Franz Sesti

doi:10.1038/s41598-018-32108-8

Elena Succurro, Francesco Andreozzi + Show 10 more

Open Access

https://doi.org/10.1038/s41598-018-32108-8

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Abstract

Preclinical studies suggested that IgG2c isotype may specifically impair skeletal muscle insulin sensitivity in mice. In this study we investigated the association between serum levels of the four IgG subclasses and insulin sensitivity in non-diabetic individuals. Total IgG, IgG1, IgG2, IgG3 and IgG4 levels were measured in 262 subjects. Whole-body insulin sensitivity was assessed by euglycemic hyperinsulinemic clamp. IgG2 levels were positively correlated with BMI, waist circumference, 2-h post-load glucose levels and complement C3. Serum IgG2, but not IgG1, IgG3 and IgG4 levels were negatively correlated with whole-body insulin sensitivity (r = −0.17; P = 0.003) and muscle insulin sensitivity index (r = −0.16; P = 0.03) after adjustment for age and gender. No significant correlation was found between IgG2 levels and hepatic insulin resistance assessed by HOMA-IR and liver IR index. In a multivariable regression analysis including variables known to affect insulin sensitivity such as age, gender, BMI, smoking, lipids, inflammatory markers, fasting and 2-h post-load glucose levels, IgG2 levels were independently associated with insulin-stimulated glucose disposal (β = −0.115, 95% CI: −0.541 to −0.024; P = 0.03). These data demonstrate the independent association between higher levels of IgG2 and decreased whole-body insulin sensitivity, thus confirming in humans the animal-based evidence indicating the pathogenic role of IgG2 in insulin resistance.

Highlights

Observational studies have solidified the concept that low-grade inflammation plays a pathophysiological role in insulin resistance associated with type 2 diabetes mellitus[1,2,3,4,5,6,7]
No gender-specific differences were observed in the other indexes of insulin sensitivity either based on fasting measurements such as QUICKI, and homeostasis model assessment insulin resistance (HOMA-IR) or derived by oral glucose tolerance test (OGTT) including liver insulin resistance index, glucose[0–30] (AUC) × insulin[0–30] (AUC) index, Stumvoll Insulin Sensitivity Index (ISI), Gutt’s ISI0,120, and Matsuda index
Serum IgG2, but not IgG1, IgG3, and IgG4 levels were negatively correlated with insulin-stimulated glucose disposal, and with the OGTT-derived insulin sensitivity indexes Stumvoll ISI, Matsuda, Gutt’s ISI0,120, and muscle insulin sensitivity index (Table 2)

Summary

Introduction

Observational studies have solidified the concept that low-grade inflammation plays a pathophysiological role in insulin resistance associated with type 2 diabetes mellitus[1,2,3,4,5,6,7]. Markers of inflammation have been extensively studied in these metabolic conditions, with convincing evidence showing that elevated concentrations of C reactive protein, fibrinogen, complement C3, and white blood cells count are predictors of type 2 diabetes. Prompted by the need to better understand the pathophysiological role of human IgG isotypes in glucose homeostasis disorders, we sought to determine their potential role in insulin resistance. To address this issue, we assessed human serum IgG isotypes (IgG1, IgG2, IgG3, and IgG4) in non-diabetic offspring of type 2 diabetic individuals and correlated their concentration with insulin sensitivity assessed using the euglycemic hyperinsulinemic clamp

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