Diabetes mellitus is a combined metabolic disorder which includes hyperglycemia, dyslipidemia, stroke and several other complications. Various groups all over the world are relentlessly working out the possible role of a vast number of genes associated with type 2 diabetes (T2DM). Inflammation is an important outcome of any kind of imbalance in the body and is therefore an indicator of several diseases, including T2DM. Various ethnic populations around the world show different levels of variations in single nucleotide polymorphisms (SNPs). The present review was undertaken to explore the association of cytokine gene polymorphisms with T2DM in populations of different ethnicities. This will lead to the understanding of the role of cytokine genes in T2DM risk and development. Association studies of genotypes of SNPs present in cytokine genes will help to identify risk haplotype(s) for disease susceptibility by developing prognostic markers and alter treatment strategies for T2DM and related complications. This will enable individuals at risk to take prior precautionary measures and avoid or delay the onset of the disease. Future challenges will be to understand the genotypic interactions between SNPs in one cytokine gene or several genes at different loci and study their association with T2DM.

Type 2 diabetes mellitus (T2DM) is a group of metabolic disorders characterized by high blood sugar levels, which results from defects in insulin secretion or action or both, leading to complications[1]. Diabetes mellitus has now been associated with the development of a long term organ disease. T2DM has changed from a mild disorder of old age to a serious cause of morbidity and mortality in young and middle-aged people. The Diabetes Atlas estimates have shown that 371 million people suffer from diabetes worldwide, with India alone having 63.0 million affected individuals and the number is expected to rise to 101.0 million by 2030[2-4]. This alarming figure has instigated several workers worldwide to undertake genetic studies and contribute to the understanding and early detection of the disease.

A predisposition to T2DM or “Adult Onset Diabetes” is probably inherited as an autosomal recessive trait[5]. T2DM is treated initially by diet control, either alone or in combination with orally administered anti-diabetic drugs. It is described as a syndrome on the basis of clustering of many abnormalities, like resistance to insulin-stimulated glucose uptake, hyperinsulinemia, hyperglycemia, increased very low density lipoprotein (VLDL), increased triglycerides, decreased high density lipoproteins (HDL) cholesterol, high blood pressure, micro albuminuria, hyperuricemia, fibrinolytic and coagulation abnormalities, etc[3].

Evidence has shown that T2DM is associated with chronic inflammation that can be attributed to dysregulation of the innate immune system and this is a potential link between metabolic syndrome, diabetes and atherosclerosis[6]. A large and diverse family of small, low molecular weight cell signaling proteins mediating complex interaction are called “cytokines”, which include interleukins and interferons[7] secreted by white blood cells and various other cells in response to a number of stimuli. The cytokines and their receptors exhibit a very high affinity for each other. Another subgroup of low molecular weight cytokines called chemokines affect leukocyte behavior. Cytokines are of two types, namely pro-inflammatory [e.g., interleukins (IL)-1, -6, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β] and anti-inflammatory (e.g., IL-1Ra, -4, -10, -13), which function opposite to each other. The release of adipocytokines by adipocytes, such as leptin, resistin, adiponectin and visfatin, as well as some of the classical inflammatory cytokines like TNF-α, IL-6, MCP-1 (CCL-2) etc., help to achieve this. Studies have shown that it is the fat tissue that exerts the endocrine and immune functions. Macrophages and T cells are found in abundance in adipose tissue which develops into an organized immune organ[8]. Inflammation resulting from an imbalance between pro- and anti-inflammatory cytokines leads to T2DM and its complications (Figure 1).

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Figure 1 A schematic diagram showing the involvement of various cytokines in diabetes[3]. IL: Interleukin; TNF: Tumor necrosis factor.

Mediators of inflammation, such as IL-1β, -1Ra, -18, -4, -6, -10, TNF-α and adiponectin (ADIPOQ), have been proposed to be involved in causing T2DM. Elevated blood levels of certain acute phase markers such as IL-6 can characterize the immune response[9], while IL-1 regulates the basic metabolic rate, blood glucose levels, blood pressure, iron metabolism and bone remodeling. Adiponectin levels and its gene variants have also been confirmed to be associated with increased risk of T2DM[10]. To date, more than 1240 gene loci are associated with diabetes in humans[3]. The susceptibility to complex forms of T2DM is associated with frequent polymorphisms that influence the expression of genes belonging to the same or different causal pathways[7]. It is important to understand the nature and actions of these adipocytokines in order to find their association with diseases like T2DM, atherosclerosis, other metabolic and vascular diseases (Figure 2). Studies have reported that Asian Indians are a unique population for carrying out genetic studies due to their greater susceptibility to T2DM and increased insulin resistance[11,12]. This review is an attempt to put together certain important cytokine gene polymorphisms and their association with T2DM in different populations around the world.

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Figure 2 A schematic diagram showing the metabolic defects and biochemical effects of cytokines leading to type 2 diabetes. T2DM: Type 2 diabetes; IL: Interleukin; TNF: Tumor necrosis factor.

Certain chemokines/cytokines, like IL-1β, -1Ra, -18, -4, -6, -10, TNF-α, etc., and some members of the adipocytokine family, namely adiponectin, leptin and resistin, are important mediators in inflammation/disease and glucose metabolism and may be involved in the pathogenesis of T2DM. They can be used as biological markers for diabetes and are related to obesity and hypertension. The single nucleotide polymorphisms (SNPs) present in the regulatory regions of cytokine genes often have an impact on their expression levels and can be disease modifiers. The degree of inflammation is controlled, thereby leading to the progression of various immunological diseases, including T2DM[13-20]. The polymorphisms in cytokine genes lead to interindividual differences in their production, leading to variations in immune responses[21].

The greater tendency to diabetes in Indians may result from some genetic factors in addition to environmental and dietary factors. It is reported that the severity of diabetes (T2DM) in patients, from chronic to newly diagnosed, is related to certain biochemical and pathological examinations. The risk factors include lipid metabolism abnormalities (VLDL, HDL, LDL, TGA etc.) and relationship to body mass index, WHR, food habits and family history. Different correlation with lipid profile and response to anti-diabetic drugs are additional indications of a genetic predisposition. SNPs in specific genes which show considerable levels of variation amongst ethnic groups around the world have been implicated in the pathogenesis of diabetes. Therefore, identification of polymorphic variants of cytokine genes in different populations and the genotypic associations between SNPs and gene-gene interactions will have clinical importance as indicators of T2DM susceptibility. Association studies of cytokine genes will help in the development of prognostic markers to identify individuals at risk. The prognostic regimens arising from such genetic studies will alter and ease out treatment strategies for T2DM and related complications. Individuals at risk will be able to take prior precautionary measures and avoid or delay the onset of the disease.