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

Figures & data

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.^63,64

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.

Table 1 Selected pro-inflammatory cytokine gene polymorphisms positively associated with T2DM and related risk factors and clinical complications^68–72 a

Condition^b	SNP
BMI	IL-6 -174C>G, IL6 CA rep., TNFα -308G>A
IGT	IL-6 -174C>G
Insulin resistance	IL-6 -174C>G, TNFα -308G>A
Obesity	IL-6 -174C>G, IL6R 394T>G, TNFα -308G>A
T2DM	IL-6 -174C>G, IL6R 48867A>G, TNFα -308G>A, TNFα -863C>A
Diabetic nephropathy	IL-6 -634C>G, IL1β–511C>T

a Note: A selected list of SNPs positively linked to T2DM and related conditions was presented.

Abbreviations: BMI, body mass index; IGT, impaired glucose tolerance; IL, interleukin.

Table 2 Effect of attenuating inflammation by anti-inflammatory factors on biochemical measures of predisposition to T2DM¹⁰⁵ a

Characteristic	Effectb	% Changec
Fasting plasma glucose	↓	25
Basel hepatic glucose production	↓	20
Glucose uptake	↑	20
Insulin-stimulated peripheral glucose uptake	↑	20
Insulin clearance	↓	30
Total cholesterol	↓	15
Fatty acid levels	↓	50
Triglycerides	↓	50
CRP	↓	15

a Notes: Subjects with T2DM (n = 9) were treated with high-dose aspirin (~7 g/day divided in 5 equal doses) for two weeks;

b Effect is shown as decrease (↓) or increase (↑);

c Changes represent the difference in biochemical measures (%) before and after treatment.

Abbreviations: CRP, C-reactive protein; T2DM, type 2 diabetes mellitus.

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