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• 16% of Mexico’s population has type-2 diabetes (T2DM) and each year it kills 70,000
• Mexican mothers feed their children sugary beverages from birth and create soda addicts
• In 2014 a national sugar tax on fizzy drinks was introduced, but sales on untaxed sugary beverages increased
• The Carlos Slim Foundation (CSF) takes fundamental action to dent Mexico’s T2DM epidemic
• The CSF collaborates with MIT’s Broad Institute to conduct the largest and most comprehensive genomic study on T2DM in Mexican populations
• Three years later CSF announces the discovery of the first common genetic variant shown to predispose Mexicans to T2DM
• Findings could lead to improved diagnostics and new therapies for T2DM, say experts
• The Broad Institute and the CSF make their genomic studies and other data freely available to scientists worldwide
• Organizations with bureaucratic walls that restrict the free-flow and sharing of knowhow and information significantly impede the advancement of our understanding and management of globally important chronic conditions such as T2DM

Each year, T2DM related complications kill 70,000 Mexicans. In 2015, there were 11m people with diabetes in Mexico - almost 12% of its adult population - projected to rise to some 16m by 2035. Mexico has one of the world’s highest rates of childhood obesity, a significant contributory risk factor of T2DM. The prevalence of overweight or obese children and adolescents between 5 and 19 years is 35%. This is believed to be the result of mother’s feeding their babies sugary drinks: partly because of the lack of clean water, and partly cultural since many Mexicans consider chubby babies to be good. According to Dr. Salvador Villalpando, a childhood obesity specialist at the Federico Gomez Children's Hospital in Mexico City, “about 10% of Mexican children are fed soda from birth to six months, and by the time they reach two it's about 80%." Mexico has become the No. 1 per capita consumer of sugary beverages, with the average person drinking more than 46 gallons per year: nearly 50% more than the average American.
 
Over the last 20 years, the prevalence of T2DM in Mexico, a country with a population of 122 million, has increased rapidly. The Mexican health system is struggling to effectively adapt to the diabetes burden facing the nation. Healthcare spending represents approximately 6% of GDP and is divided near equally between the public and private sectors. The former, supports mostly low-income non-salaried workers, accounting for about 60% of those in work: some 30m. The latter, is an employer-based scheme linked to salaried workers.

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Sugar tax

So acute is the problem of T2DM in Mexico that in January 2014, the government introduced a 10% tax on sugar-sweetened beverages. Research published in the British Medical Journal in 2016 suggests that the tax resulted in a 6% reduction in the purchases of taxed beverages in the first year, increasing to 12% by the end of the second year. The study also reported increases in purchases of untaxed beverages. Findings are disputed by the drinks industry. “Fizzy drinks only account for 5.6% of Mexico's average calorie consumption so can only be a small part of the solution to obesity and diabetes,” says Jorge Terrazas of Anprac; Mexico's bottled drinks industry body.
  

Carlos Slim Foundation and diabetes

The obesity epidemic, aging population and escalating health costs have increasingly strained resources and exacerbated Mexico’s diabetes burden, which the CSF is intent to reduce. In 2010 the Foundation formed an association with MIT’s Broad Institute. With an investment of US$74m it formed the Slim Initiative in Genomic Medicine for the Americas (SIGMA). It was a natural fit because Slim knows just how big data strategies transformed retail businesses and also cancer research and therapies; and the Broad Institute specialises in developing big genomic data sets and making them available to molecular scientists in premier research centres throughout world in order to transform medicine. From its inception SIGMA set out to systematically identify genes underlying diabetes.
 
The development of T2DM depends on complex inheritance-environment interactions along with certain lifestyle behaviors. Previous HealthPad Commentaries have described such complexities. One described the lifetime research endeavors of Professor Sir Steve Bloom, Head of Diabetes, Endocrinology and Metabolism at Imperial College London, on obesity and the gut-brain relationship.
 
SIGMA believed that having access to genomic research undertaken by a network of world class scientists holds out the possibility of discovering fundamental aspects of the biological mechanisms linked to T2DM. And this could form the basis for more effective diagnostics and new and improved therapies for the condition. Until recently, only a select group of specialists had full access to such data. The CSF was also mindful that their relationship with the Broad Institute would help build Mexico’s capacity in genomic medicine.
 

T2DM risk gene found in Latin Americans

A major focus of SIGMA’s 2010 research agenda was to identify the genetic risk factors that contribute to the significantly higher incidence rate of T2DM in Mexico compared with the rest of the world. SIGMA conducted the largest and most comprehensive genomic study to date on T2DM in Mexican populations, which involved scientists at 125 institutions in 40 countries, and resulted in the discovery of the first common genetic variant shown to predispose Latin American’s to T2DM.

Findings show that people who carry the higher risk version of the gene are 25% more likely to have diabetes than those who do not. People who inherit copies of the gene from both parents are 50% more likely to have diabetes. The higher risk-form of the gene is present in half of the people with recent Native American ancestry, including Latin Americans. The elevated frequency of this risk gene in Latin Americans could account for, as much as 20% of the populations’ increased prevalence of T2DM. The gene variant also is found in about 20% of East Asians, but is rare in populations from Europe and Africa.
 

Doing science with one eye closed

"Most genomic research has focused on European or European-derived populations, which is like doing science with one eye closed,” says Eric Lander, Professor of Biology at MIT and President and Founding Director of the Broad Institute, who went on to say, “There are many discoveries that can only be made by studying non-European populations." José Florez, a principal investigator of the SIGMA study adds, “By expanding our search to include samples from Mexico and Latin America, we’ve found one of the strongest genetic risk factors discovered to date, which could illuminate new pathways to target with drugs and a deeper understanding of T2DM.”
 

The impact of evolutionary science on healthcare systems

Roger Kornberg, Professor of Medicine at Stanford University who won the 2006 Nobel Prize in chemistry, "for his studies of the molecular basis of eukaryotic transcription", describes how human genome sequencing and genomic research fundamentally changed the way healthcare is organized and delivered. “Genomic sequencing enables us to identify every component of the body responsible for all life processes. In particular, it enables the identification of components, which are either defective or whose activity we may wish to edit in order to improve a medical condition,” says Kornberg.
 

 

Website helps translating genomic discoveries into therapies

Three years following their discoveries; the CSF launched SIGMA 2 with a mandate to complete its genetic analysis of T2DM, improve diagnostics, and develop therapeutic roadmaps to guide the development of new treatments. SIGMA 2 also planned to ramp up scientific capabilities in both the US, and Mexico by developing a unique resource. In 2016 SIGMA 2 created a website of open-access genetic data on T2DM. The site contains data available from all the SIGMA studies, plus information on major international data networks, including more than 100,000 DNA samples, and the complete results of 28 large genome association studies. Scientists throughout the world have free access to these data.
 

The importance of the open exchange of information

The new web portal represents a breakthrough, because it allows scientists throughout the world access to genetic information, and this is expected to accelerate progress of our understanding and treating diabetes. “The open exchange of information is essential for scientific progress, but it is not always easily achievable. This site not only helps us to overcome this barrier – by allowing access to patient data from around the world – but also will allow directing scientists to the most prevalent genetic risk factors among the populations of Latin America and others who have been underrepresented in large-scale genomic studies,” says Lander who believes that, "It is essential that the benefits of the genomic revolution are accessible to people throughout the Americas and the world."

“The SIGMA project has been a story of total success. Our extraordinary partners, both in Mexico and the US, have made it possible to make historic advances in the understanding of the basic causes of T2DM. We hope that through our contributions we will be able to improve the ways in which the disease is detected, prevented and treated,” says Roberto Tapia-Conyer, CEO of the CSF.
 

Takeaways

 
So, for an investment of US$25m a year for three years SIGMA made a significant discovery, which could beneficially affect the diagnostics and treatment of T2DM, and it also enhanced Mexico’s capacity for genomic research. Such success was due, in part, to the leadership of a 77-year-old Mexican businessman intent on solving problems, who thought globally, partnered with world-class institutions, understood and supported the potential of big data strategies and genomic research, and stood shoulder-to-shoulder with Eric Lander against healthcare organizations, which build and defend bureaucratic walls that significantly restrict the open access of knowhow and data.
 

• Promising animal study suggests a vaccine for type-1 diabetes
• Harvard’s Dana Faber Cancer Institute endorses the study
• Lab spent years detailing the molecular immune system's response to insulin
• The therapy for type-1 diabetes is insulin, but there’s no cure
• Living with type-1 diabetes is a constant challenge

A molecule that prevents type-1 diabetes in mice has provoked an immune response in human cells, according to scientists from the National Jewish Health and the University of Colorado. The findings, published in the 2015 Proceedings of the National Academy of Sciences, suggest that a mutated insulin fragment could be used to prevent type-1 diabetes in humans.
 

Strategies that work in mice often fail in humans 

Previously, researchers tried administering insulin to people at risk of the disease as a form of immunotherapy similar to allergy injections, but this didn’t provoke an effective response. John Kappler, Professor of Biomedical Research at National Jewish Health says, "Our findings provide an important proof of concept in humans for a promising vaccination strategy." In 2011, researchers from Harvard University’s Dana Farber Cancer Institute reported that Kappler’s strategy prevented type-1 diabetes in mice. However, strategies that work in mice often fail in humans.
 

Promising findings

Kappler’s findings suggest that an insulin fragment with a change to a single amino acid could provoke an immune response. The idea comes from work in Kappler's laboratory detailing the molecular immune system's response to insulin. This suggests that mutating one amino acid in an insulin fragment, and then presenting the insulin to the immune system, might provoke better recognition by the immune system.

Researchers mixed a naturally occurring insulin fragment, and the mutated insulin fragment with separate cultures of human cells. They found that human T-cells responded minimally to the naturally occurring insulin fragment, but relatively strongly to the mutated one. The human T-cells produce both pro-inflammatory and anti-inflammatory chemicals known as cytokines, and scientists believe that healthy immune responses balance pro- and anti-inflammatory factors. Autoimmune disease occurs when the pro-inflammatory response dominates.
                           

Type-1 diabetes

Type-1 diabetes is an autoimmune disease in which a person’s pancreas stops producing insulin, a hormone that enables individuals to get energy from food. It occurs when the body’s immune system attacks and destroys the insulin producing cells in the pancreas, called beta cells. The causes of type-1 diabetes are not fully understood, but scientists believe that both genetic and environmental factors are involved. Dr Sufyan Hussain of Imperial College, London explains:


     

      (click on the image to play the video) 

Type-1 diabetes most typically presents in early age with a peak around the time of puberty. Historically the condition has been most prevalent in populations of European origin, but is becoming more frequent in other ethnic groups. Kuwait, for example, now has an incidence of 22.3/100,000. India and China have relatively low incidence rates, but account for a high proportion of the world’s children with type-1 diabetes because of their large populations. 
 

Living with type1 diabetes

Living with type-1 diabetes is a constant challenge. People with the condition must carefully balance insulin doses (either by multiple injections every day or continuous infusion through a pump) with eating and other activities throughout the day. They must also measure their blood-glucose levels by pricking their fingers for blood six or more times a day. Despite this constant attention, people with type-1 diabetes run the risk of high or low blood-glucose levels, both of which can be life threatening. People with type-1 diabetes overcome these challenges on a daily basis. While insulin injections or infusions allow a person with the condition to stay alive, they don’t cure the disease, nor do they necessarily prevent the possibility of the disease’s complications, which may include kidney failure, blindness, nerve damage, heart attack, stroke, and pregnancy complications. Richard Lane, President of Diabetes UK, and a person living with type-1 diabetes, describes some of the lifestyle changes associated with the condition:

       

        (click on the image to play the video)
 

Takeaways

While Kappler’s results don’t prove that the mutated insulin fragment will work as a vaccine in humans, they do demonstrate a response in humans consistent with the vaccination response in mice. "The new findings confirm that the painstaking work we have done to understand the unconventional interaction of insulin and the immune system has relevance in humans and could lead to a vaccine and a treatment for diabetes," says Kappler.