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‘Viral endocrinology’ an emerging field in insulin research
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BOSTON — Nearly 100 years after its discovery, insulin and its role in human disease, particularly diseases that negatively affect cognitive function, is a still evolving area of research, according to a keynote lecture given at the 2018 Cardiometabolic Health Congress.
In his presentation, C. Ronald Kahn, MD, the Mary K. Iacocca Professor of Medicine at Harvard Medical School and chief academic officer of the Joslin Diabetes Center, discussed what he called a new and evolving field, “viral endocrinology.” This field is based on research into viral insulin-like proteins or molecules.
“What I wanted people to realize is that there are new dimensions to endocrinology, and in this case, I used insulin as an example,” Kahn told Healio.com. “Insulin is the first hormone we’ve studied, but there are other hormones in the viral sequence. What could be the implications of those in humans?”
Microbial insulins
To date, Kahn said, four such molecules have been found via bioinformatic analysis, with each of the viral molecules a part of the Iridoviridae family. These proteins have similar makeups and structures as insulin and insulin-like growth factor I and can bind with insulin and IGF-1 receptors. Most notably, he said, two of the proteins have been shown to be more effective in binding to IGF-1 receptors than insulin itself.
Once bound, these viral insulin-like proteins can also activate insulin and IGF-1 receptors, even stimulating some of the same pathways as insulin and IGF-1, producing similar responses in the cell, in blood glucose uptake and in DNA synthesis.
These molecules can be found in humans because the iridoviral DNA has been detected in the human fecal virome, according to Kahn. Explanations for their presence can be traced to their origins in some fish, particularly grouper, which have historically been consumed by humans.
Kahn describes this emerging field of research as just the tip of the iceberg, especially as it pertains to the role of these proteins in human disease. He said of the 300,000 viruses that can infect mammals, only 2% have been analyzed to reveal the four viral insulin-like proteins that have already been discovered. These proteins can impair insulin signaling and potentially lead to type 2 diabetes, tumor formation and type 1 diabetes when these viruses interact with immune cells and create insulin immunity.
“One thing I want people to keep in mind is the box, as full as it seems with information, it’s still only partly full, and we’re really learning a lot about new molecules, which while initially we can’t link them to a specific disease, we have to keep an open mind,” Kahn told Healio.com. “By learning more we will have the right diagnostic approaches when looking for insulin-like molecules coming from viruses that we haven’t even sequenced.”
Potential role in human disease
Kahn said the potential exists for about 200 of these proteins, and their discovery could lead to better understanding of diseases related to insulin resistance.
“We would like to raise the possibility that people that develop autoantibodies might either do so because they are triggered by these viral insulin-like proteins, or perhaps alternatively, they are predisposed or somehow protected because they’re desensitized to insulin autoimmunity,” Kahn said in his address. “This is something that we’re now looking at in more detail and looking at the fecal virome in children and the prediabetic and early diabetic stage.”
The role of insulin in human disease also should be examined as it pertains to cognitive complications, such as Alzheimer’s disease, cognitive dysfunction, depression and abnormal brain imaging, according to Kahn, who said a trial is currently underway attempting to use intranasal insulin to slow the progression of Alzheimer’s disease. Further, insulin action in the brain alone can lead to increased appetite, overeating, the development of insulin resistance and other features of human metabolic syndrome. In addition, it can influence hypothalamic function, neural function and hepatic glucose output as well as alter white fat distribution.
Kahn, citing research from investigators at the University of Massachusetts, explained how insulin causes the brain to turn on more genes than muscle and the liver combined. From there, insulin also plays an important role in cholesterol synthesis in the brain, which has a major effect on cognitive performance and mood behavior.
“Cholesterol in the brain is good for you. Cholesterol in the brain is important for forming synapses ... and if you block cholesterol synthesis in the neuron ... you get fewer synapses,” Kahn said in his address. “You need cholesterol in the brain, and the cholesterol that’s made in the liver doesn’t get to the brain. The brain has to make its own cholesterol.”
Ultimately, despite nearly a century of research pertaining to insulin and its effect on the human body and disease, avenues for further research exist.
“There are many things left to still be discovered, and it will be in the future: the presence of insulin-like hormones in viruses in other species, which we are exposed to and could modulate our system; the actions of insulin and insulin-like growth factors in other parts of our body like the brain could impact health and disease,” Kahn said in his address. “It’s only through continuing this kind of basic look at insulin that we’ll truly get better at all there is to know about the role of insulin [in disease].” – by Phil Neuffer
Reference:
Kahn CR. New dimensions in insulin action and why they are important to know. Presented at: Cardiometabolic Health Congress; Oct. 24-27, 2018; Boston.
Disclosure: Kahn reports he has served as a speaker or consultant for AntriaBio, CohBar, ERX Therapeutics, Flagship Pioneering, Kaleido Biosciences, MedImmune and Merck. The research presented in his address was supported by the NIDDK.