Regulation of Innate Immunity by Brain Insulin | American Diabetes Association

Christoph Buettner, MD, PhD

Institution: Icahn School of Medicine at Mount Sinai, New York, New York
Project Title: Regulation of Innate Immunity by Brain Insulin
Type of Grant: Career Development
Therapeutic Goal: -
Diabetes Type: Both Type 1 and Type 2 Diabetes
Project Start Date: January 1, 2012
Project End Date: December 31, 2016
Focus: Signal Transduction (Non-Insulin Action)\Cytokines and Apoptosis, Clinical Therapeutics/New Technology\Treatment of Insulin Resistance, Integrated Physiology\Fatty Acid Metabolism, Signal Transduction (Non-Insulin Action), Clinical Therapeutics/New Technology, Integrated Physiology
Status: Completed

Research Description

Critically ill patients develop what is commonly referred to as "stress diabetes" which is characterized by hyperglycemia and insulin resistance. Intensive insulin treatment (IIT) corrects hyperglycemia, decreases mortality and prevents the incidence of infection and sepsis in critically ill patients. Here we propose that the anti-inflammatory effects of insulin are exerted in part via the brain and would like to provide a rational for modifications to IIT and thus improve the care of critically ill patients.

Research Profile

What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?

Obesity and type 2 diabetes are associated with a pro-inflammatory state. This chronic low grade inflammation is believed to worsen insulin resistance and accelerate diabetes and heart disease. Overeating, nutritional overload is clearly at the heart of this problem at a time when portions are still supersized. Overeating also causes impaired metabolic control. But what causes this link between impaired metabolic control and low grade inflammation? A common pathyphysiological mechanism is still elusive and I hope that the research funded by this award from the ADA will shed light on this important aspect of diabetes and obesity. We have found that hormones that play a key role in metabolic control such as insulin and leptin to regulate lipid and carbohydrate metabolism through signaling in the brain. Further, overeating impairs this ability of insulin for example to regulate metabolism which in turn leads to unrestrained release of fatty acids from adipose tissue. While it has been known for decades that the brain can regulate inflammation via the autonomic nervous system throughout the body, the idea that impaired brain signaling of insulin could be a cause of uncontrolled inflammation is unexplored. Our preliminary data suggest that brain or hypothalamic insulin resistance can be a cause of both impaired metabolic control and of inflammation and thereby could be a common link between inflammation and impaired metabolic control. Indeed, when one stimulates insulin signaling only in the brain, mice that suffer from critical illness comparable to patients that are in the ICU survive at a higher rate.

If a person with diabetes were to ask you how your project will help them in the future, how would you respond?

As clinicians treating individuals with type 2 diabetes we know well that up to 90% of critically ill patients develop what is commonly referred to as "stress diabetes," which is characterized by hyperglycemia and insulin resistance. Intensive insulin treatment (IIT) corrects hyperglycemia, decreases mortality and prevents the incidence of infection and sepsis in critically ill patients. Notably, IIT can lead to hypoglycemic events that worsen clinical outcomes and are likely a chief reason for why several follow up studies of IIT have failed to show a beneficial effect on morbidity and survival. So an improved understanding of the mechanism(s) by which IIT improves survival could lead to therapeutic strategies that provide the anti-inflammatory effects of insulin without causing hypoglycemia. With our research we like to explore the hypothesis that the beneficial effects of IIT are in part mediated through CNS insulin signaling. To establish the clinical relevance of these observations we will test if brain insulin improves survival in rodent models of sepsis. Since brain insulin does not cause hypoglycemia it may be beneficial to increase insulin signaling in the brain, without increasing it in the periphery for example in particular the liver as this may prevent hypoglycemia while still benefitting from the anti-inflammatory effects of insulin. Thus, our studies should advance our understanding of the mechanisms through which IIT affects outcome during sepsis which may provide a rational for novel treatments in patients that are critically ill and suffer from diabetes. They also could provide a novel framework that could explain the close relationship between metabolism and inflammation.

Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?

My father has just recently been diagnosed with type 2 diabetes. He also has been morbidly obese for more than two decades. Besides having a predisposition for type 2 diabetes and a love of good food, I have been fascinated by the quality of the research in the field of diabetes. The progress in our field has been astounding. A particular interesting area I find the connection of neurobiology and metabolism that has become more appreciated after the discovery of the hormone leptin in 1994. I am amazed on a daily basis by all the publications that highlight the potent role that the brain plays in controlling metabolism. To me this interconnection between the brain and the periphery is the modern version of the ancient theme of body and mind interplay. We live in a point of time where sophisticated methods allow us to probe old questions on an unprecedented level of analysis and it is a privilege to participate in this undertaking. The career development award will allow me to extend my studies into the control of innate immunity by the brain. It also is critically important to support my lab and the people that work with me. I also cannot stress enough how important the support is that the ADA provides to scientists that have dedicated their work to metabolism and diabetes. In times of shrinking NIH budgets this support is essential and therefore I am happy to support the ADA in any way I can, whether it is by reviewing grants for the ADA, papers for the scientific journals such as Diabetes, organizing meetings or educating colleagues and the public.

In what direction do you see the future of diabetes research going?

I believe a very important concept in diabetes research is that of organ crosstalk. It refers to the fact that organs communicate with each other not only via hormones and energy substrates, but also via neural connections. This concept is crucial for understanding the complexities of diseases like diabetes where it is not only a single organ that is affected. We have come to think of the brain as the conductor of this organ crosstalk. Well accepted is the role of the brain in controlling food intake, yet other important biological functions like the regulation of liver glucose fluxes, the metabolism of adipocytes but also of other biological functions such as blood pressure and inflammation are emerging. Overeating, a major sin of our time, leads to the loss of adequate control of metabolism and inflammation by the brain. The overabundance of nutrients leaves the brain in a state of paralysis where hormones like insulin and leptin lose their regulatory function in the brain. I believe that in the coming years we will elucidate the defects that make the brain unresponsive to the regulatory action of hormones and nutrients. It is also likely that we will be able to link other biological functions, like the inflammatory state of an organism that is known to be modulated by the autonomic nervous system, to the impaired autonomic function as seen in individuals with diabetes. Thus, I expect that system biology will provide valuable tools to dissect this complex communication between organs including the brain will be of particular importance for diabetes research.