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Table 5 List of Major Candidate Genes Involved in the Inflammation Pathway

From: Important genetic checkpoints for insulin resistance in salt-sensitive (S) Dahl rats

Gene Symbol

Gene Name

Chromosomal Location

Transcript information



tumor necrosis factor receptor superfamily


Exons: 9

Transcript length: 1,247 bps

Protein length: 289 residues

TNF-α, a potential mediator of insulin resistance, promotes serine phosphorylation of IRS-1 and -2, impairs the ability of IRS-1 and -2 to associate with the insulin receptor and inhibits insulin-stimulated tyrosine phosphorylation [54–56]. TNF-α is upregulated in Dahl S rats [52].

NF-kappa-B-activating protein

Nuclear factor kappa-B-activating protein

chr X: 7,762,299–7,781,765.

Exons: 9

Transcript length: 1,248 bps

Protein length: 415 residues

Renal NF-{kappa}B is significantly upregulated in high-salt-fed Dahl S rats [58].


Nuclear factor kappa-B kinase subunit beta

chr16: 73,805,082–73,858,088.

Exons: 21

Transcript length: 3,022 bps

Protein length: 757 residues

Inhibition of IKBKB with salicylates or through targeted gene disruption causes a dramatic improvement of insulin sensitivity in animal models of insulin resistance such as ob/ob mice and obese Zucker fatty rats [59,60].


Interleukin-1β receptor accessory protein precursor

chr11: 76,092,840–76,222,495.

Exons: 11

Transcript length: 1,862 bps

Protein length: 570 residues

IL1β activates jnk which is upregulated in high-salt-fed Dahl S rats [57].


interleukin 17D

chr 15: 36,566,307–36,583,168.

Exons: 9

Transcript length: 621 bps

Protein length: 206 residues

IL-17 D, a proinflammatory cytokine that enhances T cell priming and stimulates the production of proinflammatory molecules such as IL-1, IL-6, TNF-alpha, NOS-2, and chemokines resulting in inflammation.


Interleukin-10 precursor (IL-10) (Cytokine synthesis inhibitory factor) (CSIF).

chr 13: 43.95m

Exons: 5

Transcript length: 1,289 bps

Protein length: 178 residues

IL-10, also known as human cytokine synthesis inhibitory factor (CSIF), is an anti-inflammatory cytokine. This cytokine can block NF-kappa B activity, and is involved in the regulation of the JAK-STAT signaling pathway. It is capable of inhibiting synthesis of pro-inflammatory cytokines like Interferon-gamma, IL-2, IL-3, TNFα and GM-CSF made by cells such as macrophages and the Type 1 T helper cells.


C-reactive protein precursor

chr 13: 88,674,743–88,715,585.

Exons: 2

Transcript length: 1,655 bps

Protein length: 230 residues

Insulin resistance and C-reactive protein (CRP) levels are strongly correlated in adults [110].


Selenoprotein S (VCP-interacting membrane protein) (Sg2).

chr 1: 120,509,128–120,518,322.

Exons: 6

Transcript length: 573 bps

Protein length: 190 residues

In humans, polymorphisms in the encoded plama membrane selenoprotein (SEPS1, or SELS gene) correlate to diabetes mellitus and coronary heart diseases. The selenoprotein regulate red-ox balance and clear cells of misfolded proteins. Gene polymorphisms result in accumulation of these proteins even higher under cell stress. Carriers have higher IL1, -6, -10, and TNF [111].


protein tyrosine phosphatase, non-receptor type 22 (lymphoid) (predicted)

chr 2: 199,083,234–199,132,761

Exons: 22

Transcript length: 2,476 bps

Protein length: 803 residues

Tyrosine phosphatase gene (PTPN22) prevents spontaneous T-cell activation. In humans, mutations (C1858T, R620W) was associated with type 1 diabetes [112–114].


Corticotropin-releasing factor receptor 1 precursor (CRF-R) (CRF1) (Corticotropin-releasing hormone receptor 1) (CRH-R 1).

chr 10: 93.31 m

Exons: 12

Transcript length: 1,218 bps

Protein length: 405 residues

Crhr1 is required for a normal chromaffin cell structure and function and deletion of this gene is associated with a significant impairment of epinephrine release.


Interleukin-6 precursor

chr 4: 456,799–461,376.

Exons: 6

Transcript length: 1,042 bps

Protein n length: 210 residues

Impaired glucose tolerance is associated with increased serum concentrations of interleukin 6 [115].


Interleukin-15 precursor.

chr 19: 27,482,376–27,499,255.

Exons: 6

Transcript length: 768 bps

Protein length: 161 residues

IL-15 increases insulin sensitivity therefore increasing glucose transport and utilization in muscles [116].


interleukin 18

chr 9: 39,676,026–39,698,748.

Exons: 10

Transcript length: 1,884 bps

Protein length: 604 residues

Elevated plasma interleukin-18 is a marker of insulin-resistance in type 2 diabetic and non-diabetic humans [117,118].


Dual specificity mitogen-activated protein kinase kinase 7

chr 12: 1,543,467–1,552,353.

Exons: 13

Transcript length: 1,407 bps

Protein length: 468 residues

MAP2K7 selectively activates the JNKs which suppresses insulin signaling [57].


Mitogen-activated protein kinase 6 or (Extracellular signal-regulated kinase 3) (ERK-3) (p55-MAPK).

chr 8: 80,212,726–80,236,362

Exons: 6

Transcript length: 4,180 bps

Protein length: 720 residues

ERK3 associates with MAP2 and is involved in glucose-induced insulin secretion [119].


Mitogen-activated protein kinase 4-isoform4

chr 9: 39,070,845–39,211,446.

Exons: 34

Transcript length: 4,401 bps Translation length: 1,232 residues

Map4k4 gene silencing in human skeletal muscle prevents tumor necrosis factor-alpha-induced insulin resistance [120].


Dual specificity mitogen-activated protein kinase kinase 1 or (MAP kinase kinase 1) (MAPKK 1) (ERK activator kinase 1) (MAPK/ERK kinase 1) (MEK1).

chr 8: 68,379,077–68,451,583.

Exons: 11

Transcript length: 2,120 bps

Protein length: 393 residues

MAP2K1 restored insulin action on glucose uptake by cells [120,121].


C-Jun amino terminal kinase

chr 3: 76.78 m

Exons: 12

Transcript length: 2,992 bps

Protein length: 699 residues

JnK is activated by TNF-α and IL-β. Jnk forms a stable complex with IRS-1 and phosphorylates Ser307 that inhibits insulin stimulated tyrosine phosphorylation of IRS-1 [57].


CX3C chemokine receptor 1

chr 8: 125.03 m

Exons: 2

Transcript length: 1,326 bps

Protein length: 354 residues

Modulators of CX3CR1 can be used to treat diabetes, as well as diagnose diabetes by measuring the levels of CX3CR1 in a patient (US patents 2006).


C-C chemokine receptor type 3

chr 8: 128.76 m

Exons: 2

Transcript length: 1,315 bps

Protein length: 359 residues

CCL3was reported to be increased in obese mice and to contribute to insulin resistance and macrophage recruitment [122].


C-C chemokine receptor type 2

chr 8: 128.89 m

Exons: 1

Transcript length: 1,122 bps

Protein length: 373 residues

CCR2 influences the development of obesity and associated adipose tissue inflammation and systemic insulin resistance [123].


C-C chemokine receptor type 5

chr 8: 128.91 m

Exons: 2

Transcript length: 2,495 bps

Protein length: 354 residues

CCR5 polymorphisms in children with insulin-dependent diabetes mellitus [124].


NADPH oxidase 3

chr 1: 38.64 m

Exons: 14

Transcript length: 1,761 bps

Protein length: 586 residues

NOX3, a ROS generating NADPH oxidase, plays an integral role in insulin-induced signal transmission [125].


NADPH oxidase 4

chr 1: 143.42 m

Exons: 18

Transcript length: 2,176 bps

Protein length: 578 residues

The NAD(P)H Oxidase Homolog Nox4 Modulates Insulin-Stimulated Generation of H2O2 and Plays an Integral Role in Insulin Signal Transduction [126].


Prostaglandin G/H synthase 2 precursor (Cyclooxygenase-2) (COX-2) (Prostaglandin H2 synthase 2) (PGH synthase 2) (PGHS-2) (PHS II).

chr 13: 64,427,282–64,432,982.

Exons: 10

Transcript length: 1,825 bps

Protein length: 604 residues

PTGS2 generates prostaglandins, which negatively modulate glucose-stimulated insulin secretion, and functions as a mediator of the inflammatory response [127].


Arachidonate 5-lipoxygenase (5-lipoxygenase) (5-LO)

chr 4: 152.61 m

Exons: 14

Transcript length: 2,450 bps

Protein length: 674 residues

The epidemiologic data suggest that subjects with two variant alleles will have greater ALOX5 gene expression, greater production of arachidonic acid-derived leukotrienes and a more "proinflammatory phenotype than subjects with two common alleles.


Arachidonate 5-lipoxygenase-activating protein (FLAP) (MK-886-binding protein).

chr 12: 6.25 m

Exons: 5

Transcript length: 937 bps

Protein length: 161 residues

ALOX5AP expression, but not gene haplotypes, is associated with obesity and insulin resistance [128].


Nitric-oxide synthase, endothelial (NOSIII) (Endothelial NOS) (eNOS)

chr 4: 6.16 m

Exons: 26

Transcript length: 3,953 bps

Protein length: 1,202 residues

The (-)786T-C mutation of the eNOS gene is associated with insulin resistance in both Japanese non-diabetic subjects and Type II diabetic patients [129]


Nitric oxide synthase, inducible (NOS type II) (Inducible NO synthase) (Inducible NOS) (iNOS)

chr 10: 65.04 m

Exons: 27

Transcript length: 4,106 bps

Protein length: 1,147 residues

obese Nos2 -/- mice exhibited improved glucose tolerance, normal insulin sensitivity in vivo and normal insulin-stimulated glucose uptake in muscles [130].


NADPH-cytochrome P450 reductase (CPR) (P450R).

chr 12: 22.08 m

Exons: 16

Transcript length: 2,438 bps

Protein length: 678 residues

NADPH-cytochrome P450 reductase (CPR) plays a role in type II diabetes [131]


Phospholipase A2 precursor

chr 12: 42.41 m

Exons: 4

Transcript length: 543 bps

Protein length: 146 residues

Mice with targeted inactivation of the group 1B phospholipase A [2] (Pla2glb) gene displayed lower postprandial glycemia than that observed in wild-type mice after being fed a glucose-rich meal [132].