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HIGHLIGHT |
Department of Pediatrics, University of Erlangen-Nürnberg, Loschgestrasse 15, Erlangen, 91054, Germany
(Correspondence should be addressed to J Dötsch; Email: joerg.doetsch{at}kinder.imed.uni-erlangen.de)
Obesity is associated with an increased risk for the development of type 2 diabetes mellitus (1). Work from the last 15 years has revealed that adipose tissue serves as an endocrine organ, producing a variety of factors that may favour the development of insulin resistance and type 2 diabetes mellitus or protect against its genesis (2). Among these secreted factors are leptin, adiponectin, resistin, tumor necrosis factor and others that have been shown to be involved into the pathogenesis of type 2 diabetes mellitus (3). A brief overview of factors synthesised by adipose tissue, liver and leucocytes is pictured in Figure 1
. However, insulin production is conferred strictly to the pancreas. Hyperinsulinaemia is a physiological attempt by the organism to compensate the ever-increasing state of insulin resistance. Therefore, the production of an insulin-mimetic in human adipose tissue might possibly lengthen the phase until hyperinsulinaemia meets with type 2 diabetes.
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Injecting KKAy mice (obese mice used as a model of type 2 diabetes) with recombinant visfatin exerted a glucose-lowering effect on these animals. The fact that plasma insulin levels were unaffected in these animals implied that visfatin acts independent of insulin. Chronic adenovirus-mediated overexpression of visfatin in mice led to a slight but persistent decrease in glucose and insulin concentrations in these animals. A heterozygous disruption of the visfatin gene in mice resulted in elevated plasma glucose concentrations and defective glucose tolerance (animals that are homozygous for this deletion die in utero). Fukuhara and co-workers (4) demonstrated that visfatin uses a system of tyrosine phosphorylation-dependent signalling comparable to that of the insulin receptor. Visfatin and insulin shared an equal binding affinity for the insulin receptor. However, visfatin did not compete with insulin, leading to the suggestion that the two hormones may use two different binding sites on the insulin receptor.
Despite the exciting discovery of an insulin analogue that is synthesized by visceral fat its exact contribution to the actual lowering of plasma glucose concentrations remains rather uncertain if not disappointing: First, Fukuhara and co-workers (4) demonstrated that plasma visfatin concentration did not change significantly upon fasting or feeding, as is known for insulin. This limits the role of visfatin in regulating glucose concentrations in the acute situation. Second, the absolute concentrations of visfatin in mice were 10–30-fold lower than those of insulin.
Nonetheless, the most interesting description of the visceral fat-derived insulin-mimetic visfatin might become a useful target for future drug therapies of diabetes mellitus. First, in vitro studies in 3T3-L1 adipocytes have already demonstrated a positive regulatory effect of dexamethasone on visfatin mRNA concentration, whereas growth hormone, tumor necrosis factor 
, interleukin-6 and isoproterenol appear to downregulate visfatin expression (8, 9).
In summary, the discovery of visfatin increases the evidence for adipose tissue working as an endocrine organ, by producing a hormone with a direct insulin-mimetic effect.
References
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