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Excess adiposity is the most important risk in the development of type 2 diabetes mellitus (T2DM). Adipose tissue produces several proteins (adipocytokines) such as leptin, adiponectin, resistin, tumor necrosis factor-a, and IL-6, that modulate sensitivity and appear to play an important role in the pathogenesis, diabetes, dyslipidemia, inflammation, and atherosclerosis. Visfatin, also known as pre-B cell colony-enhancing factor (PBEF), is a cytokine that is highly expressed in visceral fat and was originally isolated as a secreted factor that synergizes with IL-7 and stem cell factors to promote the growth of B cell precursors. Visfatin homologs have been identified in carp, invertebrate mollusks, and bacteria, as well as in vertebrates, including humans and the mouse. It has been postulated to play a role in innate immunity.
Visfatin exerts mimetic effects that are dose-dependent and quantitatively similar to stimulating muscle and adipocyte glucose transport, and in inhibiting hepatocyte glucose production. Intravenous injection of recombinant visfatin in mice decreased plasma glucose in a dose-dependent fashion. In keeping with its mimetic effects, visfatin was as effective in reducing hyperglycemia in deficient diabetic mice. Visfatin was also found to be bound to and activate receptor, causing receptor phosphorylation and the activation of downstream signaling molecules. However, visfatin did not compete for binding to the receptor, indicating that the two proteins were recognized by different regions of the receptor. Thus, visfatin might play a role in glucose homeostasis and dysregulation in biosynthesis or signal transduction, and might contribute to the pathogenesis of diabetes.

Signal-Regulatory Protein Alpha, SIRPA belongs to the signal-regulatory-protein (SIRP) family, as well as theimmunoglobulin super family. The members of the SIRP family are receptor-type transmembrane glycoproteins which areinvolved in the negative regulation of receptor tyrosine kinase-coupled signaling processes. SIRPA can bephosphorylated by tyrosine kinases. The phospho-tyrosine residues of this PTP have been shown to recruit SH2domain containing tyrosine phosphatases (PTP), and perform as substrates of PTPs. SIRPA take part insignal transduction mediated by a variety of growth factor receptors. CD47 has been shown to be a ligand for SIRPA.

TNFR1 belongs to the TNF-receptor superfamily. TNFR1 is a receptor for TNFSF2/TNF-alpha and homotrimeric TNFSF1/lymphotoxin-alpha.
There are 2 types of soluble TNF receptors: sTNFR-I and sTNFR-II, which act to neutralize the biological activities of TNF alpha and TNF beta. The levels of these soluble receptors seem to increase as a result of shedding of the extracellular domains of the membrane bound receptors. TNF-a, TNFR1 and TNFR2 have roles in cellular differentiation. TNFR1 and TNFR2 function in cell type-specific renal injury.
TNFR1 is capable of signaling both cell survival and apoptosis. TNFR1-induced apoptosis requires 2 sequential signaling complexes. TNFR1 is capable of activating NF-kappaB, mediate apoptosis, and function as a regulator of inflammation. Oxidative stress promotes TNFR1 and TNFR2 self-interaction, ligand-independent and enhanced ligand-dependent TNF signaling. TNFR1 contributes to the induction of non-cytocidal TNF effects including anti-viral state and activation of the acid sphingomyelinase. Human TNFR1 has a major region which controls cell surface expression. High levels of soluble TNF receptors are found in the amniotic fluid of pregnant women.
Germline mutations of the extracellular domains of TNFR1 are linked to the autosomal dominant periodic fever syndrome. The impaired receptor clearance is believed to be a mechanism of the disease. Familial hibernian fever (FHF) is caused by defects in TNFRSF1A gene.

Bone Morphogenetic Protein 3 (BMP3) is one of the BMPs, some of which are members of the TGF-beta superfamily (BMP2-7). There are more than 13 BMPs, which are involved in inducing cartilage and bone formation, embryogenesis and morphogenesis of various tissues and organs. In addition, BMPs regulate the growth, differentiation, chemotaxis, and apoptosis of various cell types. Akin to most other TGF-beta family proteins, BMPs are extremely conserved across animal species. At the amino acid sequence level, mature human and rat BMP3 are 98% identical.

The Trefoil Factor peptides (TFF1, TFF2 and TFF3) are stable secretory proteins expressed in the gastrointestinal tract (gastric mucosa), and are involved in intestinal mucosal defense and repair. TFF1 is an essential protein for normal differentiation of the antral and pyloric gastric mucosa and functions as a gastric-specific tumor suppressor gene. TFF1 is a stabilizer of the mucous gel overlying the gastrointestinal mucosa that provides a physical barrier against various noxious agents. TFF1 protects the mucosa from isults, stabilizes the mucus layer, & affects healing of the epithelium. TFF1 is commonly expressed in tumors. TFF1 is related with the cell membrane of MCF-7 cells. High levels of TFF1 and TFF2 are found in serum from inflammatory bowel disease.

The Trefoil Factor peptides (TFF1, TFF2 and TFF3) are stable secretory proteins expressed in the gastrointestinal tract (gastric mucosa), and are involved in intestinal mucosal defense and repair. TFF1 is an essential protein for normal differentiation of the antral and pyloric gastric mucosa and functions as a gastric-specific tumor suppressor gene. TFF1 is a stabilizer of the mucous gel overlying the gastrointestinal mucosa that provides a physical barrier against various noxious agents. TFF1 protects the mucosa from isults, stabilizes the mucus layer, & affects healing of the epithelium. TFF1 is commonly expressed in tumors. TFF1 is related with the cell membrane of MCF-7 cells. High levels of TFF1 and TFF2 are found in serum from inflammatory bowel disease.

GDF15 is part of the TGF-Beta superfamily which is involved in regulating inflammatory and apoptotic pathways in injured tissues and throughout disease processes. GDF15 is most abundant in the liver. Its expression in liver can be considerably up-regulated in during injury of organs such as liver, kidney, heart and lung. GDF-15 promotes proliferation or growth arrest and differentiation due to differences in cellular differentiation. GDF15 prevents apoptosis in cerebellar granule neurons by activating Akt and inhibiting endogenously active ERK. GDF15 is a novel autocrine/endocrine factor that antagonizes the hypertrophic response and loss of ventricular performance.

IL-12 is a heterodimeric cytokine that stimulates the production of IFNgamma from T-cells and natural killer cells, and also induces differentiation of Th1 helper cells. IL-12 is an initiator of cell-mediated immunity.

Lymphotoxin alpha, a member of the tumor necrosis factor family, is a cytokine produced by lymphocytes. LTA is highly inducible, secreted, and exists as homotrimeric molecule. LTA forms heterotrimers with lymphotoxin-beta which anchors lymphotoxin-alpha to the cell surface. LTA mediates a large variety of inflammatory, immunostimulatory, and antiviral responses. LTA is also involved in the formation of secondary lymphoid organs during development and plays a role in apoptosis.

TNFRSF13B (TACI) is a transmembrane receptor protein found predominantly on the surface of B cells (a significant part of the immune system). TACI was at first discovered owing to its ability to interact with calcium-modulator and cyclophilin ligand (CAML). Later on, it was found that TACI plays a key role in humoral immunity by interacting with two members of the TNF family. Also, TACI controls T cell-independent B cell antibody responses, isotype switching, and B cell homeostasis.

Tumor necrosis factor is a cytokine involved in systemic inflammation and is a member of a group of cytokines that all stimulate the acute phase reaction. TNF is mainly secreted by macrophages.
TNF causes apoptotic cell death, cellular proliferation, differentiation, inflammation, tumorigenesis and viral replication, TNF is also involved in lipid metabolism, and coagulation. TNF's primary role is in the regulation of immune cells.
Dysregulation and, in particular, overproduction of TNF have been implicated in a variety of human diseases- autoimmune diseases, insulin resistance, and cancer.

GM-CSF Receptor Beta, also known as CSF2RB is a member of the type I cytokine receptor family. CSF2RB is a high affinity receptor for interleukin-3, interleukin-5 as well as granulocyte-macrophage colony-stimulating factor. CSF2RB unique form of receptor assembly applies also to IL-3 and IL-5 receptors, providing a structural basis for understanding their activation mechanism which is essential for the development of therapeutics.

The somatomedins, or IGFs, comprise a family of peptides that play important roles in mammalian growth and development. IGF1 mediates many of the growth-promoting effects of GH. Early studies showed that GH did not directly stimulate the incorporation of sulfate into cartilage, but rather acted through a serum factor, termed 'sulfation factor,' which later became known as somatomedin. Three main somatomedins have been characterized: somatomedin C (IGF1), somatomedin A (IGF2), and somatomedin B.

Binds to tnfrsf13b/taci and tnfrsf17/bcma. tnfsf13/april binds to the same 2 receptors, together, they form a 2 ligands -2 receptors pathway involved in the stimulation of b- and t-cell function and the regulation of humoral immunity. A third b-cell specific baff-receptor (baffr/br3) promotes the survival of mature b-cells and the b-cell response. B Lymphocyte Stimulator functions as a potent B-cell growth factor in costimulation assays. Administration of BAFF Human recombinant to mice disrupts splenic B-cell and T-cell zones and results in elevated levels of serum immunoglobulin.

TNF-related apoptosis-inducing ligand (TRAIL) is a ligand molecule which induces apoptosis. It is a type II transmembrane protein with homology to other members of the tumor necrosis factor family.
In humans, the gene that encodes for TRAIL is located at chromosome 3q26.
TRAIL binds to the death receptors, DR4 and DR5. The process of apoptosis is caspase-8-dependent. This protein preferentially induces apoptosis in transformed and tumor cells, but does not appear to kill normal cells although it is expressed at a significant level in most normal tissues.

Tumor necrosis factor is a cytokine involved in systemic inflammation and is a member of a group of cytokines that all stimulate the acute phase reaction. TNF is mainly secreted by macrophages.
TNF causes apoptotic cell death, cellular proliferation, differentiation, inflammation, tumorigenesis and viral replication, TNF is also involved in lipid metabolism, and coagulation. TNF's primary role is in the regulation of immune cells.
Dysregulation and, in particular, overproduction of TNF have been implicated in a variety of human diseases- autoimmune diseases, insulin resistance, and cancer.

Coagulation factor VIII participates in the intrinsic pathway of blood coagulation; factor VIII is a cofactor for factor IXa which, in the presence of Ca+2 and phospholipids, converts factor X to the activated form Xa. This gene produces two alternatively spliced transcripts. Transcript variant 1 encodes a large glycoprotein, isoform a, which circulates in plasma and associates with von Willebrand factor in a noncovalent complex. This protein undergoes multiple cleavage events. Transcript variant 2 encodes a putative small protein, isoform b, which consists primarily of the phospholipid binding domain of factor VIIIc. This binding domain is essential for coagulant activity. Defects in this gene results in hemophilia A, a common recessive X-linked coagulation disorder.

CFD is an important component of the alternative pathway of complement activation. CFD cleaves and activates factor B when it binds C3b or a C3b-like protein such as C3 or CVF. CFD is a serine protease that exists as a mature protease, but it exhibits a highly restricted specificity and it appears to be substrate activated. CFD cleaves factor B bound to C3b leading to the release of the Ba fragment and leaving the Bb fragment bound to C3b. The C3b,Bb complex is called a C3 or C5 convertase because it converts these proteins to their active forms by cleaving off the small peptides C3a and C5a, respectively.

Nuclear Apoptosis Inducing Factor 1 (NAIF1) is a part of the NAIF1 family. NAIF1 Interacts with HARBI1 and Induces apoptosis.

SDF-1 (stromal cell-derived factor-1) is small cytokine belonging to the chemokine family that is officially designated Chemokine (C-X-C motif) ligand 12 (CXCL12). It is produced in two forms, SDF-1?/CXCL12a and SDF-1?/CXCL12b, by alternate splicing of the same gene. Chemokines are characterized by the presence of four conserved cysteines, which form two disulfide bonds. The CXCL12 proteins belong to the group of CXC chemokines, whose initial pair of cysteines are separated by one intervening amino acid. CXCL12 is strongly chemotactic for lymphocytes and has been implicated as an important cell co-ordinator during development. During embryogenesis it directs the migration of hematopoietic cells from foetal liver to bone marrow. Mice which were knocked-out for CXCL12 gene were lethal before the birth or within just 1 hour of life. As another role, CXCL12a alters also the electrophysiology of neurons. CXCL12 was shown to be expressend in many tissues in mice (including brain, thymus, heart, lung, liver, kidney, spleen and bone marrow).
The receptor for this chemokine is CXCR4, which was previously called fusin. This CXCL12-CXCR4 interaction used to be considered exclusive (unlike for other chemokines and their receptors), but recently it was suggested that CXCL12 is also bound by CXCR7 receptor.
The gene for CXCL12 is located on human chromosome 10. In human and mouse both CXCL12 and CXCR4 show high identity of sequence: 99% and 90%, respectively.

SDF-1 (stromal cell-derived factor-1) is small cytokine belonging to the chemokine family that is officially designated Chemokine (C-X-C motif) ligand 12 (CXCL12). It is produced in two forms, SDF-1?/CXCL12a and SDF-1?/CXCL12b, by alternate splicing of the same gene. Chemokines are characterized by the presence of four conserved cysteines, which form two disulfide bonds. The CXCL12 proteins belong to the group of CXC chemokines, whose initial pair of cysteines are separated by one intervening amino acid. CXCL12 is strongly chemotactic for lymphocytes and has been implicated as an important cell co-ordinator during development. During embryogenesis it directs the migration of hematopoietic cells from foetal liver to bone marrow. Mice which were knocked-out for CXCL12 gene were lethal before the birth or within just 1 hour of life. As another role, CXCL12a alters also the electrophysiology of neurons. CXCL12 was shown to be expressend in many tissues in mice (including brain, thymus, heart, lung, liver, kidney, spleen and bone marrow).
The receptor for this chemokine is CXCR4, which was previously called fusin. This CXCL12-CXCR4 interaction used to be considered exclusive (unlike for other chemokines and their receptors), but recently it was suggested that CXCL12 is also bound by CXCR7 receptor.
The gene for CXCL12 is located on human chromosome 10. In human and mouse both CXCL12 and CXCR4 show high identity of sequence: 99% and 90%, respectively.

TNFRSF13B (TACI) is a transmembrane receptor protein found predominantly on the surface of B cells (a significant part of the immune system). TACI was at first discovered owing to its ability to interact with calcium-modulator and cyclophilin ligand (CAML). Later on, it was found that TACI plays a key role in humoral immunity by interacting with two members of the TNF family. Also, TACI controls T cell-independent B cell antibody responses, isotype switching, and B cell homeostasis.

Tissue factor is well-known as the main cellular initiator of blood coagulation. The Tissue factor gene encodes coagulation factor III which is a cell surface glycoprotein that enables cells to initiate the blood coagulation cascades, and functions as the high-affinity receptor for the coagulation factor VII. Following vessel injury, the Tissue Factor and Factor VIIa complex activates the coagulation protease cascade, which leads to fibrin deposition and activation of platelets. The ensuing complex presents a catalytic event, which is responsible for initiation of the coagulation protease cascades by specific limited proteolysis. Therefore, Tissue factor has a role in normal hemostasis by initiating the cell-surface assembly and propagation of the coagulation protease cascade. Tissue Factor can also be stimulated by the inflammatory mediators interleukin 1 and TNF, as well as by endotoxin, to appear on monocytes and vascular endothelial cells as a component of cellular immune response.
Tissue factor is the only one in the coagulation pathway for which a congenital deficiency has not been described. Certain levels of Tissue Factor are essential for the maintained viability and growth of endothelium and Tissue Factor-expressing tumor cells. Additionally, abnormal Tissue Factor expression inside the vasculature initiates life threatening thrombosis in various diseases, for example sepsis, atherosclerosis, and cancer. Alternative spliced Tissue Factor expression advances tumor growth, and is linked to increased tumor cell proliferation and angiogenesis in pancreatic cancer.