Like day 1, day 2 was filled with incredible presentations although when the sun peeked through the clouds I did take advantage of the opportunity to go for a walk and accumulate some vitamin D! Although the learning is great at the meeting, there is a lot of sitting indoors. I was fortunate that my family got me a Fitbit for Fathers’ Day so that I can track my activity and it reminds me to get out and walk a little. McCormick Place is huge and I get a lot of movement in, but taking a nice walk outdoors broke up the day and got me to my step target!
Enough about me, to the sessions:
The morning started with the Edwin B Astwood Award Lecture: Mechanism of Insulin Action & the Pathogenesis of Diabetes with a Focus on Pancreatic Beta Cell Failure. The talk challenged one of the basic notions I had about type 2 diabetes; I, like many people outside the field, thought beta cells underwent apoptosis and were lost at the end stage of type 2 diabetes. Dr. Accili showed that what was happening was not loss of cells, but dedifferentiation of the cells. They were actually becoming alpha cells, contributing to overproduction of glucagon in type 2 diabetes. This dedifferentiation was brought on by what he referred to as “metabolic inflexibility”- the inability to utilize glucose and increased use of fatty acids as an energy source. The cells now were unable to respond to glucose and secrete insulin. This opens up a new therapeutic avenue: restoring the beta cells from their confused state.
The second plenary talk was Dr. David Altshuler who presented the Roy O Greep Award Lecture: Human Genetic Variation & the Inherited Basis of Type 2 Diabetes. This talk touched on a topic that blows my mind: the power of bioinformatics to take massive amounts of data and extract useful information. The challenge of type 2 diabetes is a massive one and as he noted, it is a disease where we are losing ground on prevention and treatment. Many treatments in development fail not because of safety but because of lack of efficacy. They work in model systems, but when they get to humans, the same effects are not seen. His idea is to “front load the pipeline” with drugs based on genetics in humans where there are already human phenotypes that we are hoping to accomplish. I loved Dr. Altshuler’s approach to talking about the genetics of type 2 diabetes. Most people want absolutes- genes where you get a black and white, 2 state response- 1 allele gives you type 2 diabetes, the other is normal, or in Dr. Altshuler’s words a “Tastes great/ Less Filling” mentality. Instead, most alleles showed modest affects on early onset of type 2 diabetes. His approach was to look for alleles where variation leading to inactivation of the gene product results in protection from type 2 diabetes. The precedent for this approach can be found in HIV where mutations in CCR5 leads to decreased infection by HIV or cardiovascular disease where inactivation of psck9 leads to decreased risk of heart attack. In this model, nature selects for the phenotype, guiding researchers towards designing inhibitors that can achieve the same effect. As Dr. Altshuler noted- it is much easier to design inhibitors than activators.
Speaking of “Tastes great/Less Filling” the next session I went to was on the role of GPCRs in taste sensing. Dr. Josephine Egan set the context with a very interesting point: the rise of artificial sweeteners has not stemmed the increase of obesity and type 2 diabetes worldwide. One would have expected sugar substitutes to have a positive effect but instead as portion size has increased people tend to use low calorie products to justify increases in caloric intake in other foods. Instead, Dr. Egan believes, we need to get a better understanding of the molecular foundations of the gut-brain connection to better understand the behavior of eating. I then had my mind blown by the fact that cells in taste buds produce hormones like GLP-1, CCK, and ghrelin as well as the receptors for these hormones. Altering the presence of these hormones and receptors actually alters taste preferences, which suggests that there is both endocrine and paracrine (and maybe even autocrine) regulation of taste. I think this could be really interesting as there is a large body of anecdotal evidence that taste preferences change after bariatric surgery and hormone levels change after bariatric surgery. Could hormone action at the tongue be the connection?
The session Oral Presentations in Reproductive Science was actually an award session supported by Ansh Labs. My favorite talk in this session was Dr. Kim Jonas’ presentation on single molecule tracking of GPCRs (specifically the LH/hCG receptor). Wow. I have always been under the impression that atomic force microscopy was the gold standard in high resolution imaging but the PD-PALM approach described by Dr. Jonas was almost the same. I was not familiar with PD-PALM before this, so I will need to do some homework but she was able to get <10nm resolution of signaling complexes and determine the components of the complex. I ended up sending Dr. Jonas some follow up questions by email, but the fact that she was able to model the numbers and arrangements of GPCRs in her system opens up new understandings of the receptors and the possibility for developing new therapeutics for either enhancing or interfering with fertility by altering the sizes of these complexes.
The afternoon plenary sessions were interesting but I was most intrigued by the late afternoon symposia I attended. The first was on the 11 beta-hydroxysteroid dehydrogenase type I enzyme. My endocrinology (BIO370) students know that I am thoroughly enamored with the idea of peripheral conversion to activate or inactivate hormones as an additional level of regulation and the importance of 11 beta-HSD I as a way to increase local glucocorticoids. This is especially important in the context of visceral adipose and what has been called "Cushing's syndrome of the omentum". Inhibition of 11 beta-HSD type I has been long observed by licorice root, but licorice root also inhibits 11 beta HSD II, which acts in the kidney to inactivate cortisol to protect the kidney from local action of glucocorticoids. The idea behind this, as I explain it to my students, is that the best defense is a good offense. Defects in or inhibiting this enzyme leads to a syndrome known as apparent mineralcorticoid excess. The development of novel inhibitors of 11 beta hsd I has promise in treating metabolic syndrome and obesity, so there has been a push to come up with these drugs, but they do not have the extreme effects that most people are looking for in terms of weight loss. On the other hand, the inhibitors work very well on treating defects in collagen quality seen in Cushing's syndrome and aging. This raises a great point: sometimes the challenge is being able reason by analogy to see similarities between systems. Dr. Lavery was able to see the similarity between skin defects in Cushing's and aging, and applied a topical 11 beta HSD I inhibitor to improve wound healing. Total aside: during the question period I met Dr. Theodore Friedman from UCLA. Students from my BIO370 class will recognize him as the doctor in the Science of Obesity special from National Geographic treating the woman with Cushing's Disease.
A quick hop and jump across McCormick Place got me to the last 2 presentations of the day on the gut microbiome and the interplay between the endocrine system and the intestinal flora. Understanding the microbiome is a problem of similar magnitude to the genetics of the morning plenary sessions. The there are more cells in our microbiota than there are in our body, and the microbiome (the genes of our microbiota) contain 100x more genes than our genome. Cataloging and characterizing the microbiota and microbiome is a massive undertaking.
The first talk focused on the role of the microbiome in protection from autoimmune diseases such as type I diabetes. Many people are familiar with the hygiene hypothesis as it relates to asthma and allergies, but this extended the idea to other autoimmune diseases. However, there were also gender specific alterations in the host microbiome as well as alterations of hormone levels when bacteria were transferred between genders. For example, testosterone levels were higher in females who received transfer of gut microbiota from males. I missed the first speaker in this session, but my student Jordan, who is at the meeting with me, told me that bacterial transfer from ob mice (mice bred to be obese; they actually have a loss of leptin) to lean mice resulted in the ob phenotype in the lean mice. This reinforces the idea that there is feedback between the endocrine system and the microbiome. I don't expect transfer of bacteria between lean and obese humans will ever be a thing (I hope not!) but as Dr. Danska suggested the microbiome could be a target for treatment that is much more achievable than targeting human genetics.
Dr. Rosa Krajmalnik-Brown followed Dr. Danska with a related presentation on alterations in gut microbiota in response to bariatric surgery. Her takeaway point was that "you are what you eat, including your microbiome." What was cool was her perspective: Dr. Krajmalnik-Brown is an environmental engineer. This gives her a very different view of the gut as an environment, not as an organ. Understanding the alterations of the "environment" and its effects on microbiota is a very unique way to look at the gut changes in response to bariatric surgery. Sometimes it is important to get outside of our normal perspective to view problems from a new angle to find unique solutions.
Okay, time to grab some breakfast and head off to the plenary sessions for day 3. I am hoping to get some pictures today to share with you in tomorrow's post!