Invited Review
Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes

https://doi.org/10.1016/j.diabres.2014.04.006Get rights and content

Abstract

It is recognized that a chronic low-grade inflammation and an activation of the immune system are involved in the pathogenesis of obesity-related insulin resistance and type 2 diabetes. Systemic inflammatory markers are risk factors for the development of type 2 diabetes and its macrovascular complications. Adipose tissue, liver, muscle and pancreas are themselves sites of inflammation in presence of obesity. An infiltration of macrophages and other immune cells is observed in these tissues associated with a cell population shift from an anti-inflammatory to a pro-inflammatory profile. These cells are crucial for the production of pro-inflammatory cytokines, which act in an autocrine and paracrine manner to interfere with insulin signaling in peripheral tissues or induce β-cell dysfunction and subsequent insulin deficiency. Particularly, the pro-inflammatory interleukin-1β is implicated in the pathogenesis of type 2 diabetes through the activation of the NLRP3 inflammasome. The objectives of this review are to expose recent data supporting the role of the immune system in the pathogenesis of insulin resistance and type 2 diabetes and to examine various mechanisms underlying this relationship. If type 2 diabetes is an inflammatory disease, anti-inflammatory therapies could have a place in prevention and treatment of type 2 diabetes.

Introduction

Obesity, in particular excess visceral adiposity, is associated with insulin resistance, hyperglycaemia, dyslipidaemia and hypertension, which together are termed “metabolic syndrome” [1]. These metabolic disorders increase the risk of development of type 2 diabetes mellitus (T2DM) and cardiovascular diseases and contribute to high rates of mortality and morbidity [1]. T2DM is the most prevalent metabolic disease in the world and is characterized by defects in insulin secretion and a peripheral insulin resistance in the skeletal muscle, the adipose tissue and the liver. The progression from obesity-related insulin resistance to T2DM remains poorly understood but implicates a failure of pancreatic β-cells to compensate for insulin resistance leading to chronic hyperglycaemia. A chronic low-grade inflammation and an activation of the immune system are observed in abdominal obesity and may have a role in the pathogenesis of obesity-related metabolic disorders [2], [3], [4], [5]. This review summarizes data implicating the immune system in the pathophysiogy of insulin resistance and T2DM. We will also examine the biological, tissular and cellular inflammatory markers associated with obesity-related metabolic disorders that may predict the development of T2DM. Molecular mechanisms underlying this inflammatory activation state will be reviewed and preliminary results obtained with anti-inflammatory therapies in the prevention and treatment of T2DM will be described.

Section snippets

Inflammatory markers in obesity, metabolic syndrome and T2DM

White blood cell counts and plasma levels of coagulation factors (fibrinogen and plasminogen activator inhibitor 1 (PAI-1)), acute-phase proteins such as C-reactive protein (CRP) and serum amyloid A (SAA), pro-inflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6), and chemokines are elevated in obese and T2DM patients and shown to be reduced when these patients are engaged in a more intensive lifestyle causing weight loss [6], [7], [8], [9], [10], [11]. These

Tissue inflammation in obesity and T2DM

A number of experimental and clinical data have clearly established that adipose tissue, liver, muscle and pancreas are sites of inflammation in presence of obesity and T2DM. An infiltration of macrophages into these tissues is seen in animal models of obesity and diabetes as well as in obese human individuals with metabolic syndrome or T2DM. These cells are crucial for the production of pro-inflammatory cytokines [4], including TNFα, IL-6 and IL-1β. They act in an autocrine and paracrine

Sensors and mediators of inflammation in obesity and T2DM

Although subclinical inflammation is important in the pathogenesis of T2DM, the events initiating this inflammatory process remain unclear and could involve different but synergic mechanisms leading to the activation of NF-κB and JNK pathways, cytokines and chemokines release and recruitment of immune cells.

Anti-inflammatory therapeutic perspectives

Given the obvious link between inflammation and pathogenesis of T2DM, anti-inflammatory strategies have been proposed for its prevention and treatment. They are extensively reviewed elsewhere [66].

Conclusions

The concept of T2DM as an inflammatory disease has recently emerged and seems to be confirmed by accumulating evidences. A number of studies have shown that abdominal obesity is associated with systemic low grade inflammation leading to insulin resistance and metabolic disorders. Moreover, systemic inflammatory markers can predict development of T2DM and cardiovascular diseases in the general population, and should be therefore used more widely in clinical practice to detect individuals at

Conflict of interest statement

None declared.

References (79)

  • J.C. Pickup et al.

    NIDDM as a disease of the innate immune system: association of acute-phase reactants and interleukin-6 with metabolic syndrome X

    Diabetologia

    (1997)
  • J.S. Yudkin et al.

    C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue

    Arterioscler Thromb Vasc Biol

    (1999)
  • J.P. Bastard et al.

    Elevated levels of interleukin 6 are reduced in serum and subcutaneous adipose tissue of obese women after weight loss

    J Clin Endocrinol Metab

    (2000)
  • S. Haffner et al.

    Intensive lifestyle intervention or metformin on inflammation and coagulation in participants with impaired glucose tolerance

    Diabetes

    (2005)
  • J.M. Bruun et al.

    Diet and exercise reduce low-grade inflammation and macrophage infiltration in adipose tissue but not in skeletal muscle in severely obese subjects

    Am J Physiol Endocrinol Metab

    (2006)
  • L.M. Belalcazar et al.

    Lifestyle intervention and/or statins for the reduction of C-reactive protein in type 2 diabetes: from the look AHEAD study

    Obesity

    (2013)
  • B. Vozarova et al.

    High white blood cell count is associated with a worsening of insulin sensitivity and predicts the development of type 2 diabetes

    Diabetes

    (2002)
  • A. Natali et al.

    Clustering of insulin resistance with vascular dysfunction and low-grade inflammation in type 2 diabetes

    Diabetes

    (2006)
  • C.M. Phillips et al.

    Does inflammation determine metabolic health status in obese and nonobese adults

    J Clin Endocrinol Metab

    (2013)
  • B.B. Duncan et al.

    Low-grade systemic inflammation and the development of type 2 diabetes: the atherosclerosis risk in communities study

    Diabetes

    (2003)
  • J. Spranger et al.

    Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study

    Diabetes

    (2003)
  • C. Herder et al.

    Chemokines as risk factors for type 2 diabetes: results from the MONICA/KORA Augsburg study, 1984–2002

    Diabetologia

    (2006)
  • A. Festa et al.

    Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes: the insulin resistance atherosclerosis study

    Diabetes

    (2002)
  • X. Wang et al.

    Inflammatory markers and risk of type 2 diabetes: a systematic review and meta-analysis

    Diabetes Care

    (2013)
  • G.J. Blake et al.

    Inflammatory bio-markers and cardiovascular risk prediction

    J Intern Med

    (2002)
  • P.M. Ridker et al.

    C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14,719 initially healthy American women

    Circulation

    (2003)
  • A. Jager et al.

    von Willebrand factor, C-reactive protein, and 5-year mortality in diabetic and nondiabetic subjects: the Hoorn Study

    Arterioscler Thromb Vasc Biol

    (1999)
  • I. Saito et al.

    Nontraditional risk factors for coronary heart disease incidence among persons with diabetes: the Atherosclerosis Risk in Communities (ARIC) Study

    Ann Intern Med

    (2000)
  • L.G. Best et al.

    C-reactive protein as a predictor of cardiovascular risk in a population with a high prevalence of diabetes: the Strong Heart Study

    Circulation

    (2005)
  • M. Soinio et al.

    High-sensitivity C-reactive protein and coronary heart disease mortality in patients with type 2 diabetes: a 7-year follow-up study

    Diabetes Care

    (2006)
  • A.P. Kengne et al.

    Association of C-reactive protein with cardiovascular disease mortality according to diabetes status: pooled analyses of 25,979 participants from four UK prospective cohort studies

    Diabetes Care

    (2012)
  • G. Lowe et al.

    Circulating inflammatory markers and the risk of vascular complications and mortality in people with type 2 diabetes and cardiovascular disease or risk factors: the ADVANCE Study

    Diabetes

    (2014)
  • G.S. Hotamisligil et al.

    Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance

    J Clin Invest

    (1995)
  • R. Cancello et al.

    Reduction of macrophage infiltration and chemoattractant gene expression changes in white adipose tissue of morbidly obese subjects after surgery-induced weight loss

    Diabetes

    (2005)
  • S.P. Weisberg et al.

    Obesity is associated with macrophage accumulation in adipose tissue

    J Clin Invest

    (2003)
  • R.W. O’Rourke et al.

    Hypoxia-induced inflammatory cytokine secretion in human adipose tissue stromovascular cells

    Diabetologia

    (2011)
  • T. Skurk et al.

    Relationship between adipocyte size and adipokine expression and secretion

    J Clin Endocrinol Metab

    (2007)
  • N. Esser et al.

    Obesity phenotype is related to NLRP3 inflammasome activity and immunological profile of visceral adipose tissue

    Diabetologia

    (2013)
  • C.N. Lumeng et al.

    Obesity induces a phenotypic switch in adipose tissue macrophage polarization

    J Clin Invest

    (2007)
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