Type 2 diabetes mellitus and inflammation: Prospects for biomarkers of risk and nutritional intervention

Abstract

Obesity is a major risk factor for type 2 diabetes mellitus (T2DM), which is a significant health problem worldwide. Active disease is associated with low-grade chronic inflammation resulting in part from the activation of the innate immune system. In obesity, this activation leads to the release of pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin-1β and interleukin-6 that block major anabolic cascades downstream of insulin signaling and thus disrupt insulin homeostasis and action. Cytokines also trigger the production of acute-phase reactants such as C-reactive protein, plasminogen activator inhibitor-1, serum amyloid-A, and haptoglobin. The elevated synthesis of pro-inflammatory cytokines and acute-phase proteins (inflammatory network) characterizes the early (or pre-clinical) stages of T2DM and exhibits a graded increase with the disease progression. Current evidence suggests that understanding inflammatory networks can point to new biomarkers that may permit capturing the interaction between genetic and environmental risk factors in the pathogenesis of T2DM. Such biomarkers have a significant public health potential in the prediction of disease occurrence beyond risk factors presently monitored, such as family history, lifestyle assessment and standard clinical chemistry profiles. Furthermore, inflammatory markers may assist in the evaluation of novel strategies for prevention, particularly in relation to micronutrients. This review discusses the current knowledge linking T2DM risk to inflammatory signaling pathways interacting with the innate immunity system and the prospect of inflammatory markers serving as molecular targets for prevention and/or biomarkers for early risk prediction of T2DM. The potential of micronutrients replenishment to improve insulin action by attenuating inflammation is also evaluated in the context of the public health relevance of this approach.

Keywords: biomarkers; inflammation; prevention; type 2 diabetes.

Figure 1

The interaction between insulin signaling and fatty acids in the synthesis of pro-inflammatory cytokines and inflammatory markers. Notes: Current information suggests that insulin activates INSR to stimulate the phosphorylation of multiple tyrosine residues in the IRS and promote diverse biological responses. Illustrated here is the response of stimulation of glucose transport into muscle and fat cells. Activation of TLR4 by fatty acids initiates intracytoplasmic signals that activate the JNK–AP-1 and IKK–NFκB axes which in turn increase the expression of cytokine-encoding genes. Cytokines initiate the hepatic production of APPs (eg, CRP, fibrinogen, haptoglobin, etc.) and dysregulate the INSR-IRS-mediated glucose transport into promoting serine phosphorylation of IRS that in turn reduces its tyrosine phosphorylation and, thereby, disrupts the insulin action. Abbreviations: AKT, protein kinases B (PKB); AP-1, activator protein-1; APPs, acute phase proteins; G, glucose; GLUT4, glucose tansporter-4; I, insulin; IKK, inhibitor of NFκB kinase-β; IL-1β and -6, interleukin-1 β and -6; INSR, insulin receptor; IRAK1 and 4, interleukin-1 receptor-associated kinase 1 and 4; IRS, insulin substrate; JNK, c-Jun amino-terminal kinase; MyD88, myeloid differentiation primary response gene-88; NFκB, nuclear factor κ B; PI3K, phosphoinositide-3 kinase. PI(3,4,5)P3, Phosphatidylinositol 3,4,5-trisphosphate. PKC, protein kinase C. TAB, TAK binding protein. TAK1, mitogen-activated protein kinase kinase kinase (MAPKKK). TLR4, toll-like receptor-4; TNFα, tumor necrosis factor-α; TRAF6, TNF receptor-associated factor 6.

Figure 2

The relationship of inflammatory markers and disease factors to specific stages pathologic continuum from overweight to T2DM and cardiovascular diseases., Note: Depicted are the increases or decreases (see text) in relative values of various inflammatory markers and disease factors that take place as overweight progresses towards T2DM. Abbreviations: CRP, C-reactive protein; FFA, free fatty acids; IGT, impaired glucose tolerance; IL, interleukin; HDL, high-density lipoprotein; LDL, low-density lipoprotein; TG, triglycerides; T2DM, type 2 diabetes mellitus.