Specific role of cytokines in the pathogenesis of type 1 and type 2 diabetes.
| Cytokine | Mechanism of action | Effect |
|---|---|---|
| TNF-α [34] | Via promotion of the JNK pathway and phosphorylation of the serine residues on the IRS-1 receptor. | Disruption of insulin signaling pathways, insulin resistance, and disrupted glucose uptake. |
| IL-6 [35] | IL-6 has been shown to reduce GLUT4 and IRS-1 expression, which can have potentially deleterious effects on insulin secretion. | IL-6 can counterintuitively promote glucose uptake in muscle cells and have a beneficial role in decreasing blood glucose. However, IL-6 levels are low in muscle cells in obese patients and those with type 2 diabetes. |
| IL-1 [30] | As previously mentioned, IL-1 cytokine signaling has been shown to impair β-cell proliferation and mass. IL-1 signaling promotes inflammation and amyloidosis. | Inflammation secondarily recruits macrophages, which can potentially damage the β cells within pancreatic islets. IL-1 also leads to amyloidosis of the islets, which is associated with β-cell apoptosis and decreased insulin secretion. |
| IL-18 [36] | IL-18 can act through the activation of the AMPK and STAT3 signaling pathways. | IL-18 normally has a positive role in blood glucose regulation via stimulation of glucose uptake and phosphorylation of STAT3. However, IL-18 levels are significantly increased in patients with type 2 diabetes, nonetheless. |
| Adiponectin [37] | Adiponectin plays a beneficial role in insulin signaling by acting as an insulin-sensitizing hormone, as it leads to the activation of the AMPK pathway. | Activation of the AMPK pathway increases glucose uptake and fatty acid oxidation, which have positive effects in terms of managing blood glucose. Higher levels of Adiponectin are associated with insulin sensitivity, while lower levels are associated with type 2 diabetes. |
| Resistin [38] | Resistin promotes insulin resistance by increasing phosphorylation of the serine residues on the IRS-1 receptor. Resistin also binds to TLR4 and activates the JNK pathway. | IRS-1 inhibition leads to decreased downstream glucose uptake via decreased GLUT4 translocation.Activation of the JNK pathway leads to inflammation and ER stress that can exacerbate insulin resistance. Liver insulin sensitivity is also impaired, which can lead to increased liver gluconeogenesis and insulin resistance. |
| IL-27 [13] | Secreted by APCs like dendritic cells and macrophages, which results in activation of STAT family proteins and the MAPK pathway. | Promotes the infiltration and accumulation of T cells and APCs onto the pancreatic islets, which can potentially cause damage and subsequent insulin resistance. |
| IL-10 [19] | Acts as an anti-inflammatory TH2-type cytokine by inhibiting TNF-α and IL-6 secretion via the STAT3 signaling pathway. | It has been shown to increase β-cell functions and insulin secretion. Decreases macrophages and cytokine infiltration in muscle cells, which helps protect against insulin resistance. |
| IL-4 [17, 18] | Upregulates glucose uptake in adipocytes without activating the IRS-1 pathway and other normal insulin signaling pathways, but has been shown to decrease insulin secretion over the long term. | It has complex effects on insulin resistance, as it has been shown to have positive effects in managing glucose levels via adipocyte glucose intake, but it may also have detrimental effects over time, as long-term IL-4 decreases insulin secretion. |
| IL-5 [15, 16] | Helps promote eosinophilia and inflammation through activation of the JAK-STAT and Ras/Raf ERK signaling pathways. | IL-5 may have a protective role against insulin resistance, as IL-5 deficiency has been shown to decrease oxidative metabolism and increase adipose tissue growth and potential metabolic impairment. |
| IL-13 [14] | Produced by TH2 cells and activates the JAK/STAT signaling cascade and PI3K pathway. It acts as an anti-inflammatory cytokine by suppressing the secretion of pro-inflammatory cytokines IL-6 and TNF-α. | Limits adipose tissue inflammation and promotes the survival of β cells and IRS-2 expression, which have beneficial effects in stopping the development of insulin resistance. |
AMPK: 5’ AMP-activated protein kinase; APCs: antigen-presenting cells; ER: endoplasmic reticulum; ERK: extracellular signal-regulated kinase; GLUT4: glucose transporter 4; IL: interleukin; IRS: insulin receptor substrates; JAK: Janus kinase; JNK: c-Jun N-terminal kinase; MAPK: mitogen-activated protein kinase; STAT: signal transducer and activator of transcription; TNF: tumor necrosis factor.