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Update on Resistin

Evan David Rosen, M.D., Ph.D. Assistant Professor of Medicine, Harvard Medical School

A few years ago I wrote about an interesting new molecule called resistin. Resistin was isolated independently by three different groups looking for proteins involved in inflammation, fat cell formation, and insulin resistance in mice. For those interested in diabetes, the major reason to know about resistin is that it was shown to be a fat-derived hormone that interfered with the ability of insulin to reduce blood sugar. In the original reports, resistin was shown to be elevated in obese, insulin resistant animals, and to decrease in response to thiazolidinedione (TZD) drugs such as Avandia™.

The initial reports, however, were followed by others from groups stating that some types of insulin resistant, obese animals do not have elevated resistin levels. There were also some papers that demonstrated that TZDs actually increase resistin levels in mice.

These points of contention have never been completely explained away by either side, but neither have they deterred researchers from continuing to investigate resistin and its effects on glucose control. Now, three years after it’s initial discovery, we know more about this interesting molecule than ever. The overall picture, however, is still a bit murky.

Several different investigators have pursued studies in mice and rats, the workhorses of the modern biology lab. In these animals, it appears clear that adding extra resistin compromises insulin action, as predicted by the original reports. Short-term administration of resistin or a related hormone called RELM-beta caused insulin resistance, with the dominant effect seen on the liver. The liver plays an important role in the production of glucose and its release into the bloodstream between meals; insulin suppresses this activity. When resistin is given as a single injection, insulin is less able to exert these repressive effects on the liver. Newer studies have confirmed this with longer periods of resistin treatment, delivered either by injection or by genetic modification of mice so that they produce more resistin than they would normally.

These effects were seen with doses of resistin that were 5-10 times higher than are normally seen in the blood, so one could still question the relevance of these findings. Lots of things will perturb insulin action if added at high enough doses, preventing us from drawing definitive conclusions about what resistin does in normal animals. To get at this issue, two groups used genetic tricks to reduce or eliminate resistin in mice. The results were generally consistent, and showed that reduction of resistin levels reduces fasting blood sugars. This effect is primarily due to, no surprise, the liver’s improved ability to listen to insulin in the absence of resistin.

So, the weight of the evidence so far indicates that resistin is secreted by fat cells whereupon it acts mainly on the liver to antagonize the action of insulin. Adding more resistin makes this worse, and taking it away makes it better. So far so good, as long as we’re talking about rodents. There are still significant questions surrounding the biology of resistin in humans, however. Unlike mice, which have four resistin-like genes, humans have only two. More importantly, human resistin is not made by fat cells, but rather by macrophages. Regular readers of this Viewpoint may recall that I recently wrote about macrophages accumulating in the fat of obese animals and people, so it’s still possible that human resistin can play an important role in regulating glucose homeostasis, even though it’s site of origin differs from the mouse. These and other differences, however, highlight that conclusions about resistin drawn from mouse studies need to be examined critically in humans.

Other important issues remain as well, including the nature of the resistin receptor, and the molecular pathways by which resistin transmits its signal to the liver and other tissues. These are all active areas of investigation, and more answers will be forthcoming.
If (and this is a big if at this point) the actions of resistin translate from the rodent to the human, we will have identified a new target in the fight against insulin resistance and type 2 diabetes.

Viewpoint is an editorial column that expresses the opinion of the specific Medical Director, who is solely responsible for its content. Viewpoint does not represent the views or opinions of Veritas Medicine and does not reflect the opinions of other physicians and researchers.

References
Hiroaki Satoh, M.T. Audrey Nguyen, Philip D.G. Miles, Takeshi Imamura, Isao Usui, and Jerrold M. Olefsky. Adenovirus-mediated chronic “hyper-resistinemia” leads to in vivo insulin resistance in normal rats. Journal of Clinical Investigation 2004 114:224-231.
Evan D. Muse, Silvana Obici, Sanjay Bhanot, Brett P. Monia, Robert A. McKay, Michael W. Rajala, Philipp E. Scherer, and Luciano Rossetti. Role of resistin in diet-induced hepatic insulin resistance. Journal of Clinical Investigation 2004 114:232-239
Michael W. Rajala, Silvana Obici, Philipp E. Scherer, and Luciano Rossetti. Adipose-derived resistin and gut-derived resistin-like molecule–ß selectively impair insulin action on glucose production. Journal of Clinical Investigation 2003 111:225-230
Shamina M. Rangwala, A. Sophie Rich, Ben Rhoades, Jennifer S. Shapiro, Silvana Obici, Luciano Rossetti, and Mitchell A. Lazar. Abnormal Glucose Homeostasis due to Chronic Hyperresistinemia. Diabetes 53: 1937-1941.
Ronadip R. Banerjee, Shamina M. Rangwala, Jennifer S. Shapiro, A. Sophie Rich, Ben Rhoades, Yong Qi, Juan Wang, Michael W. Rajala, Alessandro Pocai, Phillipp E. Scherer, Claire M. Steppan, Rexford S. Ahima, Silvana Obici, Luciano Rossetti, and Mitchell A. Lazar. Regulation of Fasted Blood Glucose by Resistin. Science 2004; 303: 1195-1198.

This information was last reviewed August 4, 2004.