Visfatin is increased in inflammatory conditions such as acute lung injury, sepsis, and rheumatoid arthritis.14-16 Thus, it is considered to be a proinflammatory adipokine via either a compensatory response or an epiphenomenon. Of note, visfatin was recently reported to be expressed almost exclusively in visceral adipose tissue rather than subcutaneous adipose tissue. Adipokines, which are secreted by adipocyte tissue, have been studied in association with insulin resistance and the metabolic syndrome, including obesity, glucose intolerance, and dyslipidemia.

However, studies of visfatin in human populations have obtained conflicting results. Elevated plasma visfatin levels have been reported in patients with type 2 diabetes mellitus.17-20 On the other hand, other investigative results showed decreased plasma visfatin levels in patients with type 1 diabetes, liver cirrhosis, exercise in type 2 diabetes, and 3rd trimester gestational diabetes.21-25 Elevated visfatin levels were also shown in hemodialysis patients26,27 and a positive correlation of visfatin levels with all stages of chronic kidney disease was observed.28 Yilmaz et al.29 published that visfatin levels were positively associated not only with insulin resistance but also with the degree of albuminuria in type 2 diabetic patients. They suggested that the endothelial dysfunction in early diabetic nephropathy is associated with altered circulating levels of visfatin. However, in another experimental study, visfatin was shown to activate endothelial nitric oxide synthase (eNOS) via Akt and mitogen-activated protein (MAP) kinase and MCP-1 and improve endothelial cell function, angiogenesis, and atherosclerosis.30,31 Thus, controversy exists among clinical studies and experimental data for the role of visfatin in diabetic nephropathy. Whether this phenomenon primarily arises from direct vascular defects or is secondary to the presence of visceral obesity and a deranged metabolic milieu that is characteristic of many patients with diabetes remains unclear.

Consistent with several reports, we observed that plasma visfatin levels were elevated in patients and animals with type 2 diabetic nephropathy.32,33 Interestingly, in our in vitro study,34 visfatin was synthesized in renal glomerular mesangial cells, upregulated by high glucose stimulation. In addition, exogenous visfatin stimulation in renal cells upregulated the synthesis of profibrotic molecules, including transforming growth factor (TGF)-β1, plasminogen activator inhibitor (PAI)-1, and type I collagen. Given these findings, the pathophysiologic relevance of visfatin seems to be as a proinflammatory adipokine regarding type 2 diabetes and other metabolic complications.

Despite the insulin-mimic effect of visfatin, controversy exists over its role insulin resistance. The exciting paper of Fukuhara et al., which had described the insulin-mimetic effect of visfatin and its naming, has been finally retracted. Several studies failed to show an association of circulating visfatin with insulin sensitivity.19,35-37 There has been no report of whether the relation between visfatin and insulin is synergistic. However, it is still interesting whether visfatin binds directly to the insulin receptor at a site distinct from insulin and has hypoglycemic effects by reducing glucose release from hepatocytes and stimulating glucose utilization in peripheral tissue.38 Insulin receptor expression has been ascertained in renal cells such as proximal tubular cells, mesangial cells, and podocytes. However, the affinity of visfatin for the insulin receptor and other receptors such as insulin-like growth factor receptor and insulinreceptor like receptor is unclear. In fact, insulin also binds with low affinity to insulin-like growth factor receptor and insulin-receptor like receptor in kidney. A recent study reported that insulin receptor expression was shown to be reduced in the kidney of an insulin-resistant rat animal model.39 Despite a high plasma insulin level, decreased insulin receptor expression has been explained to correlate with insulin resistance in various tissues such as liver, skeletal muscle, and adipose tissue. However, this finding in the kidney can be different among renal cells and may be distinct depending on the organ type, i.e., whether liver, skeletal muscle, or adipose tissue. On the other hand, another study suggested that visfatin does not have insulinmimetic actions but rather has a regulatory role in glucosestimulated insulin secretion in pancreatic β-cells in vitro and in vivo.40 Those authors demonstrated that mice lacking visfatin synthesis develop impaired glucose tolerance and defective insulin secretion, which are restored by administration of visfatin. Taken together, these results suggest that visfatin may act as a multiplayer in either a cell- or tissue-dependent manner.

Interestingly, in our in vitro study,34 high glucose stimulation upregulated visfatin synthesis and then visfatin stimulated glucose uptake via the glucose transporter (GLUT)-1 in renal mesangial cells. However, angiotensin ll stimulation did not induce visfatin synthesis. We found that exogenous visfatin stimulation in renal mesangial cells upregulated the insulin signaling pathway and induced synthesis of its downstream components of profibrotic molecules.

In contrast, another study published data indicating that life span extension in mice is associated with reduced insulin receptor signaling cascade, which upregulates the expression of SIRT-1 proteins.41 Therefore, there could be possible cross-talk between the visfatin-mediated and insulin signaling pathways via various physiologic mechanisms.42

Recent studies have shown that disturbances in the circadian clock feedback cycle through NAMPT/visfatin-mediated NAD⁺ biosynthesis may cause an imbalance in energy metabolism and homeostasis.13 Other data showed that this optimizing of SIRT1-mediated p53 degradation by visfatin induces the extension of human cell life span, such as smooth muscle cells, and the resistance to oxidative stress.43 If visfatin is impaired in the aging-dependent circadian cycle and this leads to the decline of pancreatic cell function in type 2 diabetes, visfatin could be an effective target for the treatment and prevention of type 2 diabetes.

Furthermore, a recent study suggested that angiotensin ll plays a role in the prolongation of the life span in mice.44 Agtr1a-/- mice developed a longevity phenotype and upregulation of visfatin expression in the kidney. Although high glucose stimulation induces renal cell visfatin synthesis and intracellular glucose transport, which leads to increased pro-fibrotic molecular expression as demonstrated in our previous in vitro study,34 angiotensin ll did not induce visfatin synthesis and mice lacking angiotensin receptor expressed visfatin upregulation. Taken together, these data suggest that visfatin may have multiple actions in the kidney, even in the regulation of NAD-consuming enzymes such as sirtuins. In fact, we examined the effect of intraperitoneal visfatin administration on diabetic nephropathy in mice. In our in vivo study, visfatin had a protective effect on the albuminuria of diabetic nephropathy in mice (data not published). Exogenous visfatin infusion did not show a large glucose-lowering effect through glucose uptake into renal cells. Besides, the plasma visfatin concentration is much lower than the insulin concentration, although the affinity of visfatin for the insulin receptor appears to be similar to that of insulin.45 Although high glucose stimulates intrarenal cellular visfatin synthesis, and then glucose taken up by renal cells activates the intracellular signaling pathway leading to injury in diabetic nephropathy, plasma visfatin elevated by autocrine action may act via a different regulatory pathway. The enzymatic and functional role of visfatin remains unknown in the kidney.42 Therefore, visfatin has a compensatory effect via both autocrine and paracrine pathways to improve insulin resistance and lipid metabolism. Particularly, one study showed that long-term visfatin infusion does not decrease the abundance of insulin receptors in the kidney of insulin-resistant rats, which is different in other tissues, such as liver, skeletal muscle, and adipose tissue.39 It is also possible that a more physiologic route of intraperitoneal visfatin injection may have benefit compared with vascular infusion, which is directly accumulated in the liver and visceral adipose tissue, which are the main organs regulating lipid and glucose metabolism, before sufficient concentration levels are reached in the systemic circulation of plasma, heart, and kidney. In addition, an unknown receptor for visfatin may exist, which could indirectly affect the insulin signaling pathway. For example, the enzymatic regulatory action of NAMPT/visfatin-mediated NAD synthesis might have a major effect on diabetic nephropathy through a different pathway. Nonetheless, it is equally possible that differences in the models of insulin resistance studied may have accounted for this seeming discrepancy.