It seems like everyday there is a new supplement, additive, powdery substance, workout plan or diet regiment that can rival the Hydroxycuts and the "How to Look Sexy in 15 minutes" plans. Apparently there is one product to beat them all though. The product? Dinitrophenol. The only problem is that it is toxic and can kill you. No big deal right?
2, 4-Dinitrophenol (DNP) is a cellular metabolic poison. Commercially it has been used to make dyes, organic synthesis, wood preservatives, photograph development, explosives, and pesticides. It uncouples oxidative phosphorylation by carrying protons across the mitochondrial membrane, leading to the rapid consumption of energy without the generation of ATP. So why would someone put this in their body? DNP acts as a protonophore (a specific type of lipid soluble molecule used to transport ions across the lipid bilayer of a cellular membrane), thereby allowing protons to leak across the inner mitochondrial membrane and thus bypass ATP synthase. So what right? Well as it turns out, these protons that DNP transports are vital for ATP synthesis. A electrochemical gradient is establish through a series of redox reactions in the Electron Transport Chain of cellular respiration. NADH and FADH are oxidized in a series of enzymatic complexes within the mitochondria that transport H+ protons from the mitochrondrial matrix to the inner membrane space. This established gradient later causes the protons to move back into the matrix by way of ATP synthase. This proton movement initiates Oxidative Phosphorylation which generates ATP. Therefore, if a decreased number/no protons are available, no or hardly any ATP will be produced per 1 mol of glucose. This increases the cells metabolic demands as its energy source is being lost as heat instead of being converted to chemical energy and the cell breaks down fat and other energy stores to compensate.
Sounds great right? Well the danger with DNP is that the inefficiency of ATP synthesis is proportional to the dose of DNP taken. Because of this many people (body builders, athletes, those desperate to lose weight quickly and easily)will take too much that leads to an excessive rise in body temperature due to the heat released by the oxidation uncoupling. This is referred to as hyperthermia (body temperature between 99.5-100.9 degree Fahrenheit) and can be life threatening if body temperature increases above 104 degrees. (Note: The difference between fever and hyperthermia is that fever is an increase in temperature that results in a change in the set point of core temperature in the hypothalamus. Hyperthermia occurs without changing this set point.) Reports have been shown that administration of 20-50mg/kg in humans can be lethal (http://www.ncbi.nlm.nih.gov/pubmed/16035205). Yet, DNP, available in diet pills since 1933, still remains on the market, although its sale is mostly regulated and has to be obtained through illegal/underground means. (Please read this, it's hilarious : http://www.steroid.com/DNP.php)
The true controversy is that some evidence exists that DNP elimination from the body appears to be rapid, unless in the case of compromised liver function (Hmmmm, maybe there is a correlation to all this diabetes/obesity stuff we have been discussing). According to Dr. Edsall, DNP can be eliminated from a healthy person in 3-4 days ( http://www.nejm.org/doi/full/10.1056/NEJM193408302110901) with newly emerging ranges from hours to 5-14 days. Obviously there is controversy with the administration and availability of this drug, but as American continues to get larger and weight loss continues to be viewed as a potential quick fix who knows what people will turn to no matter the risks.
Thoughts?
References:
Cutting WC, Mehrtens HG, Tainter ML (1933). "Actions and uses of dinitrophenol: Promising metabolic applications". J Am Med Assoc 101: 193–195.
Tainter ML, Cutting WC, Stockton AB (1934). "Use of dinitrophenol in nutritional disorders: a critical survey of clinical results". Am J Public Health 24 (10): 1045–1053
http://ajph.aphapublications.org/cgi/reprint/24/10/1045
Simkins S. (1937). "Dinitrophenol and desiccated thyroid in the treatment of obesity: a comprehensive clinical and laboratory study". J Am Med Assoc 108: 2110–2117.
Hsiao AL, Santucci KA, Seo-Mayer P, et al. (2005). "Pediatric fatality following ingestion of dinitrophenol: postmortem identification of a "dietary supplement"". Clin Toxicol (Phila) 43 (4): 281–285.
19 September 2011
Economic Issues in Diabetes
Reading all of the lay articles last week, especially "Candy Not Dandy" and "We're Not Saying Drink Wine to Lose Weight" really made me think about the economic classes of the majority of diabetic patient.
"Low income appears to be associated with a higher prevalence of diabetes and diabetes related complications..."
"... the author finds that high school dropouts are roughly sixty percent more likely to have diagnosed diabetes and twice as likely to have actual diabetes as men who have attended college."
High school drop outs make less money than college graduates generally. If this lower middle class population has a higher rate of diabetes and obesity then I see a link. I would take this to mean that it takes more effort to find healthier meals for people of a lower economic status, and they tend to have high fat diets leading to obesity, and then to diabetes. In "Candy Not Dandy" we discussed in class how they do not take into consideration what is being eaten instead of candy and what can be practical to have in the house at all times for these children as well. "We're Not Saying Drink Wine to Lose Weight," doesn't consider economic status either. If you look at the stereotype for people who usually drink wine, it is associated with a higher economic standing. This means that they can afford to shop at organic markets and buy healthier meals. It also usually means that they are educated which goes along with the above article saying that college graduates are less likely to be diabetic.
I want to talk about how this is highlighted in Jamie Oliver's Food Revolution, a show that sees how class is the root for many issues in obesity. Jamie Oliver has been heading to schools in low income areas to try to shed light on and implement the need for better nutritional meals in order to lower obesity rates, which are high in these low income areas. For example, Huntington, West Virginia was one of his stops. The show did place healthier meals in the cafeteria but the budgets for keeping up these meals skyrocketed, causing children to drop from school food programs and putting the schools in debt. A higher economic standing means easier access to healthier meals, and so to a healthier lifestyle.
I think it is interesting to see how economic standing is really an important factor in obesity rates. If better food was made more readily available then would people eat healthier? I would hope so and I hope that changes like these would be able to have more positive effects on the US markets.
Insulin and Breast Cancer
While obesity and diabetes have been linked to inflammation which is then contributed to cardiovascular disease, the inflammatory effects of obesity and hyperinsulinemia of diabetes can also contribute to the increased mortality rate of obese woman with breast cancer. It has been suggested that TNF-alpha causes hyperinsulinemia and insulin resistance by inhibiting the serine phosphorylation on IRS-1 which inhibits downstream signaling. In the article, “ORIGINAL REPORTS - Breast Cancer: Associations of Insulin Resistance and Adiponectin With Mortality in Women With Breast Cancer,” the researchers measure glucose, insulin and adiponectin in 527 obese women with Type I-IIIa breast cancer and compared their HOMA score with breast cancer survival. They found that an increase in the HOMA score correlated with a decrease in survival. The HOMA score is a determinant of insulin sensitivity and beta cell function. They also suggested that women with increased levels of adiponectin had an increased survival rate of breast cancer. In people who are obese there is a decrease in adiponectin. The authors also discussed that in another study of non-obese diabetic mice, the mice had severe hyperinsulinemia and insulin resistance, there was accelerated mammary gland development and breast cancer development independent of obesity and inflammation. Their findings supported the tumor promoting effect of increased circulation insulin levels and that insulin could stimulate cell proliferation. In people with diabetes and insulin resistance, they could substantially reduce the impact of insulin resistance through simple lifestyle changes. Thus in obese women with breast cancer they could increase their chance of survival by eating healthier and exercising.
Duggan Catherine, Melinda L. Irwin, Liren Xiao, et al. “ORIGINAL REPORTS - Breast Cancer:
Associations of Insulin Resistance and Adiponectin With Mortality in Women With Breast Cancer.” JCO Jan 1, 2011:32-39; published online on November 29, 2010.
Using HIV-1and T Cells to fight cancer
The New York Times published an article yesterday that describes a phase 1 study at http://www.nytimes.com/2011/09/13/health/13gene.html?_r=1&pagewanted=all%3Fsrc%3Dtp&smid=fb-share (referring to a study published in the New England Journal of medicine, at http://www.nejm.org/doi/full/10.1056/NEJMoa1103849) that details an attempt to use HIV to transform T cells so they could host target B cells. The host B cells were being targeted because the the three patients had chronic lymphoid leukemia that was no longer responding to chemotherapy nor were they bone marrow candidates.
So, B cells are the problem--now how to get rid of them? These researchers removed billions of T cells from each patient. The best way to transform T cells through gene therapy is to get a really good and specific virus to "infect" it. For T cells, an obvious source is HIV. Researchers made a new version of HIV that lacked the RNA it needed to actually infect a cell but still was able to target T cells and transfer genetic information into them. This new HIV had DNA from mice, humans, cows, and viruses that infect cows and woodchucks in order to disable it. More DNA was added to program the T cells to make a chimeric antigen receptor (CAR) that included three main components: CD19 (for targeting B cells), CD 137 (a costimulatory receptor), and CD3-zeta (for signal transduction). This study is the first time someone has used HIV as a vector for gene therapy in cancer, though it has been done in other studies for different diseases before. Once these new chimeric antigen receptor-modified T cells were made from the original billion or so (and only 15 million for one of the patients) extracted from the patients, they were put back into the subjects. Remarkably, the T cells infused multiplied by 1000 to 10000 times.
After 10 days of relatively nothing happening, one of the patients began to feel an intense fever, shaking, chills, and experienced a sharp decrease in blood pressure. What was happening here? Cytokines, my friend, lots of cytokines. Fighting a tumor that size means tons and tons of cytokines from attacking all the B cells of the body. Luckily, the patient's symptoms resolved within a few weeks, and with that the tumor had also completely disappeared. The doctors estimated that two pounds of cancer cells had been killed off in those few short weeks, and the patient was declared as being in remission.
But, as you can see, a procedure like this one is not without risk. The patient described above survived the barrage of cytokines, but if it was worse the cytokine storm could have killed him. Another possible problem is cross reaction between the chimeric antigen receptor for the target (in this case, B cells) and another antigen on a healthy cell in the body. This happened before to a woman with colon cancer, whose targeted cancer antigen cross-reacted with a protein found on her lungs. She died shortly after. It is also known that many antigens on cancer cells can cross-react with proteins found on basement membranes.
So, overall we have total remission for two patients, partial remission for one, and a host of possibilities and risks. What do you think are other ways we could use this information? What woud you do to reduce the risks associated with this?
So, B cells are the problem--now how to get rid of them? These researchers removed billions of T cells from each patient. The best way to transform T cells through gene therapy is to get a really good and specific virus to "infect" it. For T cells, an obvious source is HIV. Researchers made a new version of HIV that lacked the RNA it needed to actually infect a cell but still was able to target T cells and transfer genetic information into them. This new HIV had DNA from mice, humans, cows, and viruses that infect cows and woodchucks in order to disable it. More DNA was added to program the T cells to make a chimeric antigen receptor (CAR) that included three main components: CD19 (for targeting B cells), CD 137 (a costimulatory receptor), and CD3-zeta (for signal transduction). This study is the first time someone has used HIV as a vector for gene therapy in cancer, though it has been done in other studies for different diseases before. Once these new chimeric antigen receptor-modified T cells were made from the original billion or so (and only 15 million for one of the patients) extracted from the patients, they were put back into the subjects. Remarkably, the T cells infused multiplied by 1000 to 10000 times.
After 10 days of relatively nothing happening, one of the patients began to feel an intense fever, shaking, chills, and experienced a sharp decrease in blood pressure. What was happening here? Cytokines, my friend, lots of cytokines. Fighting a tumor that size means tons and tons of cytokines from attacking all the B cells of the body. Luckily, the patient's symptoms resolved within a few weeks, and with that the tumor had also completely disappeared. The doctors estimated that two pounds of cancer cells had been killed off in those few short weeks, and the patient was declared as being in remission.
But, as you can see, a procedure like this one is not without risk. The patient described above survived the barrage of cytokines, but if it was worse the cytokine storm could have killed him. Another possible problem is cross reaction between the chimeric antigen receptor for the target (in this case, B cells) and another antigen on a healthy cell in the body. This happened before to a woman with colon cancer, whose targeted cancer antigen cross-reacted with a protein found on her lungs. She died shortly after. It is also known that many antigens on cancer cells can cross-react with proteins found on basement membranes.
So, overall we have total remission for two patients, partial remission for one, and a host of possibilities and risks. What do you think are other ways we could use this information? What woud you do to reduce the risks associated with this?
15 September 2011
“Surgery may cure diabetes in overweight”
this is the title of one of the articles discussed in our previous class session, and in my opinion the lay article that received the most comments. With that idea in mind I decided to dive in a little further and take a look at the band procedure.
When I first read this I was pretty disturbed by the claim of the title. As my background in science has taught me there is no cure for diabetes. What’s scary is people that are unaware of the science will see this article or others like it and take the easy way out and have the surgery without looking at the consequences.
Members of the class did mention that the potential surgery patients cant just decide to do it and proceed with the surgery right away….of course there are explanations from specialists and physician but ultimately the decision is up to the patient and if a doctor refuses to proceed with the surgery the patient can find another one to perform the procedure.
There is defiantly a correlation between obesity and diabetes. Obesity is a result of hyper-nutrition, which leads to insulin resistance and dyslipidema and eventually through a series of interwoven pathways, after several decades results in type II diabetes. Weight loss has shown to improve some of the secondary symptoms and bring diabetes into remission, but the diabetes is still present and will “reactivate” if long term modifications to lifestyle are not taken seriously.
So if obesity results in diabetes then we should be able to resolve the diabetes by getting the obesity in check right?
If only it were that easy…. As I mentioned during the discussion in class function follows structure. Our stomachs along with the various enzymes use mechanical breakdown of the food to proceed with digestion. Most of the time when we have to alter the way something in our body works something else malfunctions as a result, this is the case with this type of surgery.
1) Ok first question, how is the band put into our bodies?
The steps are pretty simple and can be found at (http://www.lapband.com/en/learn_about_lapband/the_procedure_safety/)
| Step One: | Your surgeon implants the LAP-BAND® System around the upper part of your stomach, much like a belt. |
| Step Two: | A tube is then connected from the LAP-BAND® System to a small access port, fixed beneath the skin of your abdomen. |
| Step Three: | After the first four to six weeks, adjustments to the LAP-BAND® System are made through the access port. This is done as needed — more frequently in the first year — to maintain optimal weight loss, by adding or removing saline solution. |
2) The hard part comes next
· NOW the patient has to re-develop a relationship with food…
o Eat ridiculously small portions ( we are talking about a couple bites)
o Chew for a long time (30 chews per bite)
· I took this quote from http://www.lapband.com/en/learn_about_lapband/safety_information/
o “Patients can experience complications after surgery. Most complications are not serious but some may require hospitalization and/or re-operation. In the United States clinical study, with 3-year follow-up reported, 88% of the 299 patients had one or more adverse events, ranging from mild, moderate, to severe. Nausea and vomiting (51%), gastroesophageal reflux (regurgitation) (34%), band slippage/pouch dilatation (24%) and stoma obstruction (stomach-band outlet blockage) (14%) were the most common post-operative complications. “
There are a lot more complications besides the aforementioned above. So the question now is…. Is going through something like this to lose weight (since the article states obesity is a major risk factor to diabetes) really worth it?
I believe it is not worth it…the main goal of our group was to present the point that ultimately the best method for controlling the symptoms of diabetes is through lifestyle changes and physical activity. If a healthy lifestyle is put into play and taken seriously the weight will evenly come off and the diabetes symptoms will go into remission
(if your interested there is much more to read about the lapband @ http://www.lapband.com/en/learn_about_lapband/ )
14 September 2011
Citing Papers on Inflammablog5
Already a number of interesting papers have been referred to, and sometimes it's not clear how to access them. So let me suggest a good way.
Find the paper on PubMed, the National Library of Medicine's huge archive: It's at http://www.ncbi.nlm.nih.gov/pubmed or click here. The easiest way to locate it is by entering one author's name in the search box, thus: fujisaki j
If you get several hits, look through them for the one you wanted and click on it to go to the abstract.
When you find the abstract, copy the URL that shows in the search line, like this: http://www.ncbi.nlm.nih.gov/pubmed/21654805 or click here.
All of us can access the abstract that way. The screen will show you whether there is a link to the actual manuscript (look for a logo in the upper right corner).
You can click to that, and then you will find out if you can access it free; that depends on where your computer is and what your library has negotiated with the publishers.
If you are told you'll have to pay, try asking JJ or Zoë Cohen if they can get a copy for you.
I don't know if you can put a hyperlink in a Comment (has anyone figured that out?), but you can always insert the full URL which we can then cut and paste into our browser.
Find the paper on PubMed, the National Library of Medicine's huge archive: It's at http://www.ncbi.nlm.nih.gov/pubmed or click here. The easiest way to locate it is by entering one author's name in the search box, thus: fujisaki j
If you get several hits, look through them for the one you wanted and click on it to go to the abstract.
When you find the abstract, copy the URL that shows in the search line, like this: http://www.ncbi.nlm.nih.gov/pubmed/21654805 or click here.
All of us can access the abstract that way. The screen will show you whether there is a link to the actual manuscript (look for a logo in the upper right corner).
You can click to that, and then you will find out if you can access it free; that depends on where your computer is and what your library has negotiated with the publishers.
If you are told you'll have to pay, try asking JJ or Zoë Cohen if they can get a copy for you.
13 September 2011
EXTRA, EXTRA! HOT OFF THE PRESS!
This just in. According to the International Diabetes Federation and the European Association for the Study of Diabetes (EASD), an estimated 366 million people are living with diabetes (Type 1 and 2). Think that number is staggering, how about 4.6 million people die every year (about 1 person every 7 mins) and health care spending for diabetes treatment has rose to almost half a trillion dollars a year. This epidemic (as the two aforementioned institutions are calling it) has spurred the United Nations to hold the Summit on Non-Communicable Diseases. This is only the second time this summit has been held on a health-related issue, the first being the HIV/AIDS crisis in 2001.
As we discussed the other day in class, Type 2 diabetes can often times be avoided or "treated" through lifestyle reformation that consists of a healthy diet, proper and constant exercise, and weight loss. With our country and the world in a state of economic turmoil (and poverty levels reaching an recent 18 year high of 15.1% or 46.2 million people), healthy food, gym memberships, and the time to exercise and lose weight is becoming an expense that people cant afford to make. My question is what is it about fast-food that is so bad or more specifically, as one of our recent review article eludes to, what is it in fast food that leads to leptin resistance? As you may or may not recall, leptin is an adipokine that plays a key role in regulating energy intake (aka appetite) and metabolism. If there is a connection between the composition of fast food and increased leptin resistance perhaps we could be one step closer to certainty that obesity and Type 2 diabetes truly go hand in hand. I'm sure the 46.2 million people in poverty (more than 10% of the world population with diabetes) would love to know! Here is a good site to check out: http://atvb.ahajournals.org/content/25/12/2451.full. Enjoy!!
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