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“When my son was diagnosed [with Type 1], I knew nothing about diabetes. I changed my research focus, thinking, as any parent would, ‘What am I going to do about this?’” says Douglas Melton.

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Breakthrough within reach for diabetes scientist and patients nearest to his heart

Harvard Correspondent

100 years after discovery of insulin, replacement therapy represents ‘a new kind of medicine,’ says Stem Cell Institute co-director Douglas Melton, whose children inspired his research

When Vertex Pharmaceuticals announced last month that its investigational stem-cell-derived replacement therapy was, in conjunction with immunosuppressive therapy, helping the first patient in a Phase 1/2 clinical trial robustly reproduce his or her own fully differentiated pancreatic islet cells, the cells that produce insulin, the news was hailed as a potential breakthrough for the treatment of Type 1 diabetes. For Harvard Stem Cell Institute Co-Director and Xander University Professor Douglas Melton, whose lab pioneered the science behind the therapy, the trial marked the most recent turning point in a decades-long effort to understand and treat the disease. In a conversation with the Gazette, Melton discussed the science behind the advance, the challenges ahead, and the personal side of his research. The interview was edited for clarity and length.

Douglas Melton

GAZETTE: What is the significance of the Vertex trial?

MELTON: The first major change in the treatment of Type 1 diabetes was probably the discovery of insulin in 1920. Now it’s 100 years later and if this works, it’s going to change the medical treatment for people with diabetes. Instead of injecting insulin, patients will get cells that will be their own insulin factories. It’s a new kind of medicine.

GAZETTE: Would you walk us through the approach?

MELTON: Nearly two decades ago we had the idea that we could use embryonic stem cells to make functional pancreatic islets for diabetics. When we first started, we had to try to figure out how the islets in a person’s pancreas replenished. Blood, for example, is replenished routinely by a blood stem cell. So, if you go give blood at a blood drive, your body makes more blood. But we showed in mice that that is not true for the pancreatic islets. Once they’re removed or killed, the adult body has no capacity to make new ones.

So the first important “a-ha” moment was to demonstrate that there was no capacity in an adult to make new islets. That moved us to another source of new material: stem cells. The next important thing, after we overcame the political issues surrounding the use of embryonic stem cells, was to ask: Can we direct the differentiation of stem cells and make them become beta cells? That problem took much longer than I expected — I told my wife it would take five years, but it took closer to 15. The project benefited enormously from undergraduates, graduate students, and postdocs. None of them were here for 15 years of course, but they all worked on different steps.

GAZETTE: What role did the Harvard Stem Cell Institute play?

MELTON: This work absolutely could not have been done using conventional support from the National Institutes of Health. First of all, NIH grants came with severe restrictions and secondly, a long-term project like this doesn’t easily map to the initial grant support they give for a one- to three-year project. I am forever grateful and feel fortunate to have been at a private institution where philanthropy, through the HSCI, wasn’t just helpful, it made all the difference.

I am exceptionally grateful as well to former Harvard President Larry Summers and Steve Hyman, director of the Stanley Center for Psychiatric Research at the Broad Institute, who supported the creation of the HSCI, which was formed specifically with the idea to explore the potential of pluripotency stem cells for discovering questions about how development works, how cells are made in our body, and hopefully for finding new treatments or cures for disease. This may be one of the first examples where it’s come to fruition. At the time, the use of embryonic stem cells was quite controversial, and Steve and Larry said that this was precisely the kind of science they wanted to support.

GAZETTE: You were fundamental in starting the Department of Stem Cell and Regenerative Biology. Can you tell us about that?

MELTON: David Scadden and I helped start the department, which lives in two Schools: Harvard Medical School and the Faculty of Arts and Science. This speaks to the unusual formation and intention of the department. I’ve talked a lot about diabetes and islets, but think about all the other tissues and diseases that people suffer from. There are faculty and students in the department working on the heart, nerves, muscle, brain, and other tissues — on all aspects of how the development of a cell and a tissue affects who we are and the course of disease. The department is an exciting one because it’s exploring experimental questions such as: How do you regenerate a limb? The department was founded with the idea that not only should you ask and answer questions about nature, but that one can do so with the intention that the results lead to new treatments for disease. It is a kind of applied biology department.

GAZETTE: This pancreatic islet work was patented by Harvard and then licensed to your biotech company, Semma, which was acquired by Vertex. Can you explain how this reflects your personal connection to the research?

MELTON: Semma is named for my two children, Sam and Emma. Both are now adults, and both have Type 1 diabetes. My son was 6 months old when he was diagnosed. And that’s when I changed my research plan. And my daughter, who’s four years older than my son, became diabetic about 10 years later, when she was 14.

When my son was diagnosed, I knew nothing about diabetes and had been working on how frogs develop. I changed my research focus, thinking, as any parent would, “What am I going to do about this?” Again, I come back to the flexibility of Harvard. Nobody said, “Why are you changing your research plan?”

GAZETTE: What’s next?

MELTON: The stem-cell-derived replacement therapy cells that have been put into this first patient were provided with a class of drugs called immunosuppressants, which depress the patient’s immune system. They have to do this because these cells were not taken from that patient, and so they are not recognized as “self.” Without immunosuppressants, they would be rejected. We want to find a way to make cells by genetic engineering that are not recognized as foreign.

I think this is a solvable problem. Why? When a woman has a baby, that baby has two sets of genes. It has genes from the egg, from the mother, which would be recognized as “self,” but it also has genes from the father, which would be “non-self.” Why does the mother’s body not reject the fetus? If we can figure that out, it will help inform our thinking about what genes to change in our stem cell-derived islets so that they could go into any person. This would be relevant not just to diabetes, but to any cells you wanted to transplant for liver or even heart transplants. It could mean no longer having to worry about immunosuppression.

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• Weill Cornell Medicine

New Study Reveals Promising Findings to Treat Type 2 Diabetes

A new  study   published in the   Journal of Clinical Investigation  has demonstrated that activating a pathway to promote cell division not only expanded the population of insulin-producing cells, but, surprisingly, also enhanced the cells’ function.  The findings hold promise for future therapeutics that will improve the lives of individuals with type 2 diabetes—a condition that affects more than half a billion people worldwide.

Dr. Laura Alonso

“That’s reassuring because there is a long-standing belief in the field that proliferation can lead to ‘de-differentiation’ and a loss of cell function,” said study senior author   Dr. Laura Alonso , chief of the division of endocrinology, diabetes and metabolism, director of the   Weill Center for Metabolic Health , and the E. Hugh Luckey Distinguished Professor in Medicine at Weill Cornell Medicine. “Our result flies in the face of that dogma and suggests if we can find a way to trigger replication of the beta cells in the body, we won’t impair their ability to produce and secrete insulin.”

First author, Rachel Stamateris, also contributed to this work as an MD, PhD student at the University of Massachusetts Medical School and visiting graduate assistant in medicine at Weill Cornell Medicine.

When Beta Cells Fail

In type 2 diabetes, the body’s tissues become resistant to insulin, which means they can’t take in and use blood sugar. At the same time, insulin-producing beta cells in the pancreas fail—diminishing in number and losing their ability to function.

Dr. Alonso and her colleagues reproduced these conditions in a mouse model of diabetes that lacks IRS2, a protein that allows insulin to transmit its signal for cells to absorb blood sugar. These mice displayed insulin resistance, a seminal feature of human type 2 diabetes. “On top of that,” said Dr. Alonso, “the IRS2 protein also turns out to be critical for beta cell function and beta cell number.” So, their pool of beta cells was depleted.

The first order of business to rescue these mice: boost beta cell numbers. But how? She and her team took a closer look at the molecular machinery that controls cell proliferation. The researchers observed that in the IRS-deficient diabetic mice, beta cells failed to elevate production of cyclin D2. This protein, when partnered with a protein called CDK4, drives cell division. Previous studies had shown that mice lacking CDK4 also develop diabetes.

It seemed logical to test if boosting CDK4 activity would help increase beta cell quantity. When Dr. Alonso’s team genetically introduced an active form of CDK4 into the diabetic mice that was more available to attach to cyclin D2, the first thing they noticed was the animals’ blood sugars were restored to normal. Their beta cells were more plentiful than in the untreated, IRS2 mutant mice. But even better: “The beta cells looked amazingly healthy in the treated mice compared with the original diabetic mice, whose beta cells look terrible. Increasing the activity of CDK4 resulted in beta cells packed full of insulin,” said Dr. Alonso, who is also an endocrinologist at NewYork-Presbyterian/Weill Cornell Medical Center.

This supports the concept that beta cell mass can be expanded without compromising function.

While CDK4 is not, itself, a viable therapeutic target because its ability to stimulate proliferation could increase the risk of cancer, Dr. Alonso is confident that probing the molecular pathways that govern beta cell division and function could someday lead to a clinical breakthrough. She pointed to Ozempic, one of the most talked about new treatments for diabetes. “That medication was discovered by a scientist studying toxins in the saliva of the Gila monster,” said Dr. Alonso. “So, it’s clear that understanding how fundamental biology works can lead to real advances in treating or even preventing diabetes.”

Many Weill Cornell Medicine physicians and scientists maintain relationships and collaborate with external organizations to foster scientific innovation and provide expert guidance. The institution makes these disclosures public to ensure transparency. For this information, see the profile for Dr. Laura Alonso .

This study was supported by grants K08DK076562, R01DK095140, R01DK124906, and R01DK114686 from the National Institute of Diabetes and Digestive and Kidney Diseases.

Releated Links: Boosting Beta Cells to Treat Type 2 Diabetes

Back to News

• Endocrinology, Diabetes & Metabolism

Recent Advances

ADA-funded researchers use the money from their awards to conduct critical diabetes research. In time, they publish their findings in order to inform fellow scientists of their results, which ensures that others will build upon their work. Ultimately, this cycle drives advances to prevent diabetes and to help people burdened by it. In 2018 alone, ADA-funded scientists published over 200 articles related to their awards!

Identification of a new player in type 1 diabetes risk

Type 1 diabetes is caused by an autoimmune attack of insulin-producing beta-cells. While genetics and the environment are known to play important roles, the underlying factors explaining why the immune system mistakenly recognize beta-cells as foreign is not known. Now, Dr. Delong has discovered a potential explanation. He found that proteins called Hybrid Insulin Peptides (HIPs) are found on beta-cells of people with type 1 diabetes and are recognized as foreign by their immune cells. Even after diabetes onset, immune cells are still present in the blood that attack these HIPs.

Next, Dr. Delong wants to determine if HIPs can serve as a biomarker or possibly even targeted to prevent or treat type 1 diabetes. Baker, R. L., Rihanek, M., Hohenstein, A. C., Nakayama, M., Michels, A., Gottlieb, P. A., Haskins, K., & Delong, T. (2019). Hybrid Insulin Peptides Are Autoantigens in Type 1 Diabetes. Diabetes , 68 (9), 1830–1840.

Understanding the biology of body-weight regulation in children

Determining the biological mechanisms regulating body-weight is important for preventing type 2 diabetes. The rise in childhood obesity has made this even more urgent. Behavioral studies have demonstrated that responses to food consumption are altered in children with obesity, but the underlying biological mechanisms are unknown. This year, Dr. Schur tested changes in brain and hormonal responses to a meal in normal-weight and obese children. Results from her study show that hormonal responses in obese children are normal following a meal, but responses within the brain are reduced. The lack of response within the brain may predispose them to overconsumption of food or difficulty with weight-loss.

With this information at hand, Dr. Schur wants to investigate how this information can be used to treat obesity in children and reduce diabetes.

Roth, C. L., Melhorn, S. J., Elfers, C. T., Scholz, K., De Leon, M. R. B., Rowland, M., Kearns, S., Aylward, E., Grabowski, T. J., Saelens, B. E., & Schur, E. A. (2019). Central Nervous System and Peripheral Hormone Responses to a Meal in Children. The Journal of Clinical Endocrinology and Metabolism , 104 (5), 1471–1483.

A novel molecule to improve continuous glucose monitoring

To create a fully automated artificial pancreas, it is critical to be able to quantify blood glucose in an accurate and stable manner. Current ways of continuously monitoring glucose are dependent on the activity of an enzyme which can change over time, meaning the potential for inaccurate readings and need for frequent replacement or calibration. Dr. Wang has developed a novel molecule that uses a different, non-enzymatic approach to continuously monitor glucose levels in the blood. This new molecule is stable over long periods of time and can be easily integrated into miniaturized systems.

Now, Dr. Wang is in the process of patenting his invention and intends to continue research on this new molecule so that it can eventually benefit people living with diabetes.

Wang, B. , Chou, K.-H., Queenan, B. N., Pennathur, S., & Bazan, G. C. (2019). Molecular Design of a New Diboronic Acid for the Electrohydrodynamic Monitoring of Glucose. Angewandte Chemie (International Ed. in English) , 58 (31), 10612–10615.

Addressing the legacy effect of diabetes

Several large clinical trials have demonstrated the importance of tight glucose control for reducing diabetes complications. However, few studies to date have tested this in the real-world, outside of a controlled clinical setting. In a study published this year, Dr. Laiteerapong found that indeed in a real-world setting, people with lower hemoglobin A1C levels after diagnosis had significantly lower vascular complications later on, a phenomenon known as the ‘legacy effect’ of glucose control. Her research noted the importance of early intervention for the best outcomes, as those with the low A1C levels just one-year after diagnosis had significantly lower vascular disease risk compared to people with higher A1C levels.

With these findings in hand, physicians and policymakers will have more material to debate and determine the best course of action for improving outcomes in people newly diagnosed with diabetes.

Laiteerapong, N. , Ham, S. A., Gao, Y., Moffet, H. H., Liu, J. Y., Huang, E. S., & Karter, A. J. (2019). The Legacy Effect in Type 2 Diabetes: Impact of Early Glycemic Control on Future Complications (The Diabetes & Aging Study). Diabetes Care , 42 (3), 416–426.

A new way to prevent immune cells from attacking insulin-producing beta-cells

Replacing insulin-producing beta-cells that have been lost in people with type 1 diabetes is a promising strategy to restore control of glucose levels. However, because the autoimmune disease is a continuous process, replacing beta-cells results in another immune attack if immunosorbent drugs are not used, which carry significant side-effects. This year, Dr. Song reported on the potential of an immunotherapy he developed that prevents immune cells from attacking beta-cells and reduces inflammatory processes. This immunotherapy offers several potential benefits, including eliminating the need for immunosuppression, long-lasting effects, and the ability to customize the treatment to each patient.

The ability to suppress autoimmunity has implications for both prevention of type 1 diabetes and improving success rates of islet transplantation.

Haque, M., Lei, F., Xiong, X., Das, J. K., Ren, X., Fang, D., Salek-Ardakani, S., Yang, J.-M., & Song, J . (2019). Stem cell-derived tissue-associated regulatory T cells suppress the activity of pathogenic cells in autoimmune diabetes. JCI Insight , 4 (7).

A new target to improve insulin sensitivity

The hormone insulin normally acts like a ‘key’, traveling through the blood and opening the cellular ‘lock’ to enable the entry of glucose into muscle and fat cells. However, in people with type 2 diabetes, the lock on the cellular door has, in effect, been changed, meaning insulin isn’t as effective. This phenomenon is called insulin resistance. Scientists have long sought to understand what causes insulin resistance and develop therapies to enable insulin to work correctly again. This year, Dr. Summers determined an essential role for a molecule called ceramides as a driver of insulin resistance in mice. He also presented a new therapeutic strategy for lowering ceramides and reversing insulin resistance. His findings were published in one of the most prestigious scientific journals, Science .

Soon, Dr. Summers and his team will attempt to validate these findings in humans, with the ultimate goal of developing a new medication to help improve outcomes in people with diabetes.

Chaurasia, B., Tippetts, T. S., Mayoral Monibas, R., Liu, J., Li, Y., Wang, L., Wilkerson, J. L., Sweeney, C. R., Pereira, R. F., Sumida, D. H., Maschek, J. A., Cox, J. E., Kaddai, V., Lancaster, G. I., Siddique, M. M., Poss, A., Pearson, M., Satapati, S., Zhou, H., … Summers, S. A. (2019). Targeting a ceramide double bond improves insulin resistance and hepatic steatosis. Science (New York, N.Y.) , 365 (6451), 386–392.

Determining the role of BPA in type 2 diabetes risk

Many synthetic chemicals have infiltrated our food system during the period in which rates of diabetes has surged. Data has suggested that one particular synthetic chemical, bisphenol A (BPA), may be associated with increased risk for developing type 2 diabetes. However, no study to date has determined whether consumption of BPA alters the progression to type 2 diabetes in humans. Results reported this year by Dr. Hagobian demonstrated that indeed when BPA is administered to humans in a controlled manner, there is an immediate, direct effect on glucose and insulin levels.

Now, Dr. Hagobian wants to conduct a larger clinical trial including exposure to BPA over a longer period of time to determine precisely how BPA influences glucose and insulin. Such results are important to ensure the removal of chemicals contributing to chronic diseases, including diabetes.

Hagobian, T. A. , Bird, A., Stanelle, S., Williams, D., Schaffner, A., & Phelan, S. (2019). Pilot Study on the Effect of Orally Administered Bisphenol A on Glucose and Insulin Response in Nonobese Adults. Journal of the Endocrine Society , 3 (3), 643–654.

Investigating the loss of postmenopausal protection from cardiovascular disease in women with type 1 diabetes

On average, women have a lower risk of developing heart disease compared to men. However, research has shown that this protection is lost in women with type 1 diabetes. The process of menopause increases rates of heart disease in women, but it is not known how menopause affects women with type 1 diabetes in regard to risk for developing heart disease. In a study published this year, Dr. Snell-Bergeon found that menopause increased risk markers for heart disease in women with type 1 diabetes more than women without diabetes.

Research has led to improved treatments and significant gains in life expectancy for people with diabetes and, as a result, many more women are reaching the age of menopause. Future research is needed to address prevention and treatment options.

Keshawarz, A., Pyle, L., Alman, A., Sassano, C., Westfeldt, E., Sippl, R., & Snell-Bergeon, J. (2019). Type 1 Diabetes Accelerates Progression of Coronary Artery Calcium Over the Menopausal Transition: The CACTI Study. Diabetes Care , 42 (12), 2315–2321.

Identification of a potential therapy for diabetic neuropathy related to type 1 and type 2 diabetes

Diabetic neuropathy is a type of nerve damage that is one of the most common complications affecting people with diabetes. For some, neuropathy can be mild, but for others, it can be painful and debilitating. Additionally, neuropathy can affect the spinal cord and the brain. Effective clinical treatments for neuropathy are currently lacking. Recently, Dr. Calcutt reported results of a new potential therapy that could bring hope to the millions of people living with diabetic neuropathy. His study found that a molecule currently in clinical trials for the treatment of depression may be valuable for diabetic neuropathy, particularly the type affecting the brain.

Because the molecule is already in clinical trials, there is the potential that it can benefit patients sooner than later.

Jolivalt, C. G., Marquez, A., Quach, D., Navarro Diaz, M. C., Anaya, C., Kifle, B., Muttalib, N., Sanchez, G., Guernsey, L., Hefferan, M., Smith, D. R., Fernyhough, P., Johe, K., & Calcutt, N. A. (2019). Amelioration of Both Central and Peripheral Neuropathy in Mouse Models of Type 1 and Type 2 Diabetes by the Neurogenic Molecule NSI-189. Diabetes , 68 (11), 2143–2154.

ADA-funded researcher studying link between ageing and type 2 diabetes

One of the most important risk factors for developing type 2 diabetes is age. As a person gets older, their risk for developing type 2 diabetes increases. Scientists want to better understand the relationship between ageing and diabetes in order to determine out how to best prevent and treat type 2 diabetes. ADA-funded researcher Rafael Arrojo e Drigo, PhD, from the Salk Institute for Biological Studies, is one of those scientists working hard to solve this puzzle.

Recently, Dr. Arrojo e Drigo published results from his research in the journal Cell Metabolism . The goal of this specific study was to use high-powered microscopes and novel cellular imaging tools to determine the ‘age’ of different cells that reside in organs that control glucose levels, including the brain, liver and pancreas. He found that, in mice, the cells that make insulin in the pancreas – called beta-cells – were a mosaic of both old and young cells. Some beta-cells appeared to be as old as the animal itself, and some were determined to be much younger, indicating they recently underwent cell division.

Insufficient insulin production by beta-cells is known to be a cause of type 2 diabetes. One reason for this is thought to be fewer numbers of functional beta-cells. Dr. Arrojo e Drigo believes that people with or at risk for diabetes may have fewer ‘young’ beta-cells, which are likely to function better than old ones. Alternatively, if we can figure out how to induce the production of younger, high-functioning beta-cells in the pancreas, it could be a potential treatment for people with diabetes.

In the near future, Dr. Arrojo e Drigo’s wants to figure out how to apply this research to humans. “The next step is to look for molecular or morphological features that would allow us to distinguish a young cell from and old cell,” Dr. Arrojo e Drigo said.

The results from this research are expected to provide a unique insight into the life-cycle of beta-cells and pave the way to novel therapeutic avenues for type 2 diabetes.

Watch a video of Dr. Arrojo e Drigo explaining his research!

Arrojo E Drigo, R. , Lev-Ram, V., Tyagi, S., Ramachandra, R., Deerinck, T., Bushong, E., … Hetzer, M. W. (2019). Age Mosaicism across Multiple Scales in Adult Tissues. Cell Metabolism , 30 (2), 343-351.e3.

Researcher identifies potential underlying cause of type 1 diabetes

Type 1 diabetes occurs when the immune system mistakenly recognizes insulin-producing beta-cells as foreign and attacks them. The result is insulin deficiency due to the destruction of the beta-cells. Thankfully, this previously life-threatening condition can be managed through glucose monitoring and insulin administration. Still, therapies designed to address the underlying immunological cause of type 1 diabetes remain unavailable.

Conventional approaches have focused on suppressing the immune system, which has serious side effects and has been mostly unsuccessful. The American Diabetes Association recently awarded a grant to Dr. Kenneth Brayman, who proposed to take a different approach. What if instead of suppressing the whole immune system, we boost regulatory aspects that already exist in the system, thereby reigning in inappropriate immune cell activation and preventing beta-cell destruction? His idea focused on a molecule called immunoglobulin M (IgM), which is responsible for limiting inflammation and regulating immune cell development.

In a paper published in the journal Diabetes , Dr. Brayman and a team of researchers reported exciting findings related to this approach. They found that supplementing IgM obtained from healthy mice into mice with type 1 diabetes selectively reduced the amount of autoreactive immune cells known to target beta-cells for destruction. Amazingly, this resulted in reversal of new-onset diabetes. Importantly, the authors of the study determined this therapy is translatable to humans. IgM isolated from healthy human donors also prevented the development of type 1 diabetes in a humanized mouse model of type 1 diabetes.

The scientists tweaked the original experiment by isolating IgM from mice prone to developing type 1 diabetes, but before it actually occurred. When mice with newly onset diabetes were supplemented with this IgM, their diabetes was not reversed. This finding suggests that in type 1 diabetes, IgM loses its capacity to serve as a regulator of immune cells, which may be contribute to the underlying cause of the disease.

Future studies will determine exactly how IgM changes its regulatory properties to enable diabetes development. Identification of the most biologically optimal IgM will facilitate transition to clinical applications of IgM as a potential therapeutic for people with type 1 diabetes.    Wilson, C. S., Chhabra, P., Marshall, A. F., Morr, C. V., Stocks, B. T., Hoopes, E. M., Bonami, R.H., Poffenberger, G., Brayman, K.L. , Moore, D. J. (2018). Healthy Donor Polyclonal IgM’s Diminish B Lymphocyte Autoreactivity, Enhance Treg Generation, and Reverse T1D in NOD Mice. Diabetes .

ADA-funded researcher designs community program to help all people tackle diabetes

Diabetes self-management and support programs are important adjuncts to traditional physician directed treatment. These community-based programs aim to give people with diabetes the knowledge and skills necessary to effectively self-manage their condition. While several clinical trials have demonstrated the value of diabetes self-management programs in terms of improving glucose control and reducing health-care costs, whether this also occurs in implemented programs outside a controlled setting is unclear, particularly in socially and economically disadvantaged groups.

Lack of infrastructure and manpower are often cited as barriers to implementation of these programs in socioeconomically disadvantaged communities. ADA-funded researcher Dr. Briana Mezuk addressed this challenge in a study recently published in The Diabetes Educator . Dr. Mezuk partnered with the YMCA to evaluate the impact of the Diabetes Control Program in Richmond, Virginia. This community-academic partnership enabled both implementation and evaluation of the Diabetes Control Program in socially disadvantaged communities, who are at higher risk for developing diabetes and the complications that accompany it.

Dr. Mezuk had two primary research questions: (1) What is the geographic and demographic reach of the program? and (2) Is the program effective at improving diabetes management and health outcomes in participants? Over a 12-week study period, Dr. Mezuk found that there was broad geographic and demographic participation in the program. The program had participants from urban, suburban and rural areas, most of which came from lower-income zip codes. HbA1C, mental health and self-management behaviors all improved in people taking part in the Greater Richmond Diabetes Control Program. Results from this study demonstrate the value of diabetes self-management programs and their potential to broadly improve health outcomes in socioeconomically diverse communities. Potential exists for community-based programs to address the widespread issue of outcome disparities related to diabetes.  Mezuk, B. , Thornton, W., Sealy-Jefferson, S., Montgomery, J., Smith, J., Lexima, E., … Concha, J. B. (2018). Successfully Managing Diabetes in a Community Setting: Evidence from the YMCA of Greater Richmond Diabetes Control Program. The Diabetes Educator , 44 (4), 383–394.

Using incentives to stimulate behavior changes in youth at risk for developing diabetes

Once referred to as ‘adult-onset diabetes’, incidence of type 2 diabetes is now rapidly increasing in America’s youth. Unfortunately, children often do not have the ability to understand how everyday choices impact their health. Could there be a way to change a child’s eating behaviors? Davene Wright, PhD, of Seattle Children’s Hospital was granted an Innovative Clinical or Translational Science award to determine whether using incentives, directed by parents, can improve behaviors related to diabetes risk. A study published this year in Preventive Medicine Reports outlined what incentives were most desirable and feasible to implement. A key finding was that incentives should be tied to behavior changes and not to changes in body-weight.

With this information in hand, Dr. Wright now wants to see if incentives do indeed change a child’s eating habits and risk for developing type 2 diabetes. She is also planning to test whether an incentive program can improve behavior related to diabetes management in youth with type 1 diabetes. Jacob-Files, E., Powell, J., & Wright, D. R. (2018). Exploring parent attitudes around using incentives to promote engagement in family-based weight management programs. Preventive Medicine Reports , 10 , 278–284.

Determining the genetic risk for gestational diabetes

Research has identified more than 100 genetic variants linked to risk for developing type 2 diabetes in humans. However, the extent to which these same genetic variants might affect a woman’s probability for getting gestational diabetes has not been investigated.

Pathway to Stop Diabetes ® Accelerator awardee Marie-France Hivert, MD, of Harvard University set out to answer this critical question. Dr. Hivert found that indeed genetic determinants of type 2 diabetes outside of pregnancy are also strong risk factors for gestational diabetes. This study was published in the journal Diabetes .

The implications? Because of this finding, doctors in the clinic may soon be able to identify women at risk for getting gestational diabetes and take proactive steps to prevent it. Powe, C. E., Nodzenski, M., Talbot, O., Allard, C., Briggs, C., Leya, M. V., … Hivert, M.-F. (2018). Genetic Determinants of Glycemic Traits and the Risk of Gestational Diabetes Mellitus. Diabetes , 67 (12), 2703–2709.

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• Ther Adv Endocrinol Metab
• v.3(5); 2012 Oct

Diabetes treatment in 2025: can scientific advances keep pace with prevalence?

Despite the known benefits of a healthy lifestyle, many individuals find it hard to maintain such a lifestyle in our modern world, which facilitates sedentary behavior and overeating. As a consequence, the prevalence of type 2 diabetes mellitus is predicted to increase dramatically over the coming years. Will developments in treatments be able to counteract the resulting impact on morbidity and mortality? The various lines of research can be grouped into three main categories: technological, biological, and pharmacological. Technological solutions are focused on the delivery of insulin and glucagon via an artificial pancreas, and components of the system are already in use, suggesting this option may well be available within the next 10 years. Of the biological solutions, pancreas transplants seem unlikely to be used widely, and islet cell transplants have also been hampered by a lack of appropriate donor tissue and graft survival after transplant. However, significant progress has been made in these areas, and additional research suggests manipulating other cell types to replace beta cells may be a viable option in the longer term. The last category, pharmacological research, appears the most promising for significantly reducing the burden of type 2 diabetes mellitus. In recent years, research has concentrated on reducing blood glucose, and the increasing pace of research has been reflected in a growing number of antidiabetic agents. In the past few years, studies of the complementary approach of protecting cells from the damaging effects of high blood glucose have also been reported, as has research into the control of energy intake and energy expenditure. Evidence from studies of dietary restriction and bariatric surgery suggests it may be possible to reset metabolism to effectively cure diabetes, and research into pharmacological agents that could selectively restore energy balance is currently the most exciting prospect for future treatments for people with type 2 diabetes mellitus.

Introduction

Before the availability of insulin in the 1920s, hailed not only as the cure for diabetes but also as one of the greatest advances in the treatment of any disease, a person diagnosed with diabetes would have faced death within a few years. Today, diabetes is not the devastating diagnosis it would have been 100 years ago; in fact, it is now a common misconception among the public that diabetes is not a serious disease. In reality, the impact of diabetes is so significant that it is affecting overall life expectancy: in the United States (US), life expectancy is falling for the first time since statistics were collected, due to obesity and diabetes [ Olshansky et al. 2005 ], and estimates of diabetes prevalence over the coming years suggest many of us reading this article will develop diabetes during our lives [ Whiting et al. 2011 ]. The predictions of the increased prevalence of diabetes are rarely accompanied by predictions of improvements in the treatment of diabetes; however, given the impact of diabetes, it has been the focus of intensive research, resulting in major advances in our understanding of diabetes as well as in treatment options. As the centenary of the discovery of insulin approaches, it seems timely to consider how treatment options may look in the 2020s, and the likelihood that the elusive cure for diabetes could be found by that time.

Technological solutions

The majority of cases of diabetes are type 2 diabetes mellitus (T2DM), and the predicted rise in diabetes prevalence is expected to be driven by increases in the number of T2DM cases. However, it is likely that significant advances in therapy for T2DM will result from the research in type 1 diabetes mellitus (T1DM), as they are both essentially disorders of glucose management ( Box 1 ).

Pathophysiology of type 1 and type 2 diabetes mellitus.

Type 1 (T1DM) and type 2 diabetes mellitus (T2DM) are both characterized by abnormally high levels of glucose in the bloodstream and until the 1930s, when ‘insulin-sensitive’ and ‘insulin-insensitive’ diabetes were differentiated, all patients with diabetes were thought to have a shortage of insulin production [ Saltiel, 2000 ].

Since then the pathophysiology of the two diseases has been researched extensively, and T1DM is relatively well understood. In short, the patient’s immune system attacks and destroys beta cells in the islets of the pancreas, resulting in insulin deficiency. The factors behind the immune response are still uncertain, but are thought to be both genetic and environmental [ van Belle et al. 2011 ].

Even today, the pathophysiology of T2DM is less well understood. At diagnosis, most patients have insulin resistance: the pancreas is producing insulin, but the body cannot use it effectively. Initially, the pancreas compensates by producing more insulin, and patients have larger beta-cell mass. At some point, typically several years after diagnosis, insulin production will decrease, with a corresponding drop in beta-cell mass, and many people with T2DM eventually need to take insulin. Although the underlying cause is unknown, it is thought that liver, fat, and muscle cells all play a role, in addition to the pancreatic beta cells [ Saltiel, 2000 ].

In T1DM, the complete lack of endogenous insulin has focused research on ever-more sophisticated ways to deliver insulin, with the eventual goal of developing an ‘artificial pancreas’. The elements are already available: a sensor to detect blood glucose readings, a computer to calculate insulin requirements, and a pump to automatically deliver insulin. The feasibility of bringing these elements together has already been demonstrated in clinical trials, with sensor-augmented pump therapy, integrating a sensor and a pump, shown to improve glycemic control compared with a regimen of multiple insulin injections per day [ Bergenstal et al. 2010 ; Hermanides et al. 2011 ]. A true artificial pancreas would also deliver glucagon to raise blood glucose and prevent severe hypoglycemia, a concept that has already been shown to be feasible [ El-Khatib et al. 2010 ].

Several technological challenges need to be overcome to produce a clinically useful artificial pancreas. First, currently available continuous glucose monitors measure glucose levels in interstitial fluid rather than directly in the blood, resulting in a time lag before changes are measured. As a consequence, accuracy is not sufficiently reliable, with reported error rates of between 12% and 17%. Accuracy is likely to be lowest when blood glucose levels are low; hence, continuous glucose monitoring of interstitial fluid is currently recommended only as an adjunct to standard blood glucose monitoring [ Weinzimer and Tamborlane, 2008 ]. Insulin pump technology is more advanced; nevertheless, today’s pumps deliver insulin subcutaneously, and the delay while insulin is absorbed into the bloodstream limits the ability of software to regulate blood glucose accurately [ Renard, 2008 ]. Catheter complications have prevented intravenous delivery of insulin, and surgically implanted pumps are expensive. It is clear that none of these technological challenges are trivial, but given the pace of developments in technology, we can expect more practical options for patients within the next 10 years. For example, so-called ‘smart tattoo’ biosensors are capable of detecting glucose levels continuously using a simple infrared detector and providing results in real time. These biosensors, which are based on single-walled carbon nanotubes wrapped in glucose-sensitive polymers that fluoresce in the presence of glucose, are currently being researched in animal models [ Barone and Strano, 2009 ].

Biological solutions

Even as technological solutions advance closer and closer to an artificial pancreas, it is unlikely that technology could ever regulate insulin as precisely as beta cells in a healthy pancreas. Research therefore continues into replacing damaged beta cells with functioning cells, or replacing the entire pancreas [ Claiborn and Stoffers, 2008 ; Sachdeva and Stoffers, 2009 ]. As with the artificial pancreas, most research to date has been conducted in T1DM, but the results will ultimately translate into therapies for T2DM.

Pancreas transplants have been performed since the late 1980s, with more than 30,000 pancreas transplants recorded in the past 25 years [ Gruessner, 2011 ]. In principle, pancreas transplants offer the promise of excellent outcomes for patients with diabetes. Indeed, stricter donor criteria, as well as improvements in surgical techniques and immunosuppression, have led to improved success rates, with the majority of patients no longer needing insulin therapy after the transplant [ Gruessner, 2011 ]. In practice, the vast majority of pancreas transplants are done in patients who have end-stage renal disease and also need a kidney transplant; this is partly due to the shortage of donor organs, but also because the risks of the necessary post-transplant immunosuppressant therapy usually outweigh the health risks of diabetes itself.

A less invasive option that has already been shown to be viable, at least for some patients, is replacing pancreatic beta cells via islet cell transplants [ Truong and Shapiro, 2006 ]. Isolating these cells from a donor pancreas and infusing them into the patient’s portal vein has been researched since the 1960s, and a successful protocol using islets from multiple donors, improved cell culture techniques, and reduced toxicity was optimized during the 1990s at the University of Alberta in Edmonton, Canada. Using the Edmonton protocol, initial studies reported success; however, over time transplanted islets lose function and patients still require immunosuppressive drugs, which are known to increase the risk of infections and the incidence of malignancy, as well as being toxic to the islet cells themselves [ Alejandro et al. 2008 ; Shapiro et al. 2000 ].

The treatment is still considered experimental and is only available to patients with very poor glycemic control and severe hypoglycemic events but, given the benefits of a successful therapy, there is significant drive to overcome the challenges of limited availability of donor tissue and graft survival after transplant. As well as optimizing the yield of islets from donor pancreata, basic science research into cell differentiation has identified possible alternative sources of beta cells, including differentiating stem cells and reprogramming somatic cells [ Baiu et al. 2011 ; Kelly et al. 2011 ]. Various strategies are also being researched to improve graft survival after transplantation, by developing immunosuppression regimens that are less toxic to islets and inducing revascularization/reinnervation of the islets [ Plesner and Verchere, 2011 ].

In the longer term, other biological solutions using nonislet cells from the patient themselves are possible options, such as transdifferentiation (mediated by growth factor treatments or gene transfer) of nonislet pancreatic cells or liver cells [ Claiborn and Stoffers, 2008 ; Kojima et al. 2003 ], and regenerating beta cells and/or expanding beta-cell mass using mediators of beta-cell differentiation and maintenance of adult beta cells [ Sachdeva and Stoffers, 2009 ].

Pharmacological solutions

For patients with T1DM, who make no insulin, the only pharmacologic option is replacement insulin. Astonishing progress has been made since replacement insulin first became available, when insulin batches were of variable quality and large, twice-daily injections were needed. Today, it is hard to imagine how difficult it must have been to manage T1DM without disposable needles or patients self-testing glucose. The possibilities for improvement in pharmacological care for these patients should not be underestimated, although most likely they will be essentially improvements in the convenience of insulin delivery.

In patients with T2DM, a range of pharmacologic treatments have been developed, and continue to be developed ( Figure 1 ). For many years, treatment was dominated by two drug classes, sulfonylureas and biguanides. These two drug classes demonstrate not only the advances in clinical research, but also the role that luck, both good and bad, plays in the progress of treatment. Sulfonylureas were discovered serendipitously in France during the Second World War after hypoglycemia was induced in soldiers in whom the drug was being tested as an antimicrobial agent for typhoid fever [ Vaisrub, 1972 ]. In the US, sulfonylureas first became available in 1955 and for many years were the first-line option for treating T2DM. These drugs were no miracle cure: as is well known, the first-generation sulfonylureas were associated with a high risk of hypoglycemia; the second-generation sulfonylureas, which are still used today, were introduced in 1984.

US Food and Drug Administration approval of pharmacological options for type 2 diabetes mellitus.

Like sulfonylureas, drugs of the biguanide class were observed to have antihyperglycemic properties before their mechanism of action was understood. In fact, the class had been studied in the 1920s but, perhaps because of the excitement over insulin, was largely ignored and it was not until the 1950s that phenformin, buformin, and metformin were researched in clinical trials. Unfortunately, the only biguanide marketed in the US, phenformin, was associated with lactic acidosis, leading not only to withdrawal of phenformin but, understandably, to mistrust of other medications in the same class [ Witters, 2001 ]. It was not until the 1990s, when the large United Kingdom Prospective Diabetes Study (UKPDS) showed the benefits of metformin, especially in terms of weight-neutrality, that it became available and more widely used in the US [ United Kingdom Prospective Diabetes Study Group, 1995 ]. More recently, metformin has been associated with reduced risk of cancer in observational studies, although this potential additional benefit needs to be confirmed in long-term randomized controlled trials [ Noto et al. 2012 ].

The last 20 years have seen an astonishing pace in research into the molecular pathology of diabetes. Our improved understanding of diabetes has facilitated the development of drug classes that target specific metabolic pathways such as the thiazolidinediones, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and sodium–glucose cotransporter type 2 (SGLT2) inhibitors ( Figure 1 ) [ Tahrani et al. 2011 ]. In the next 10 years, based on current research, we can expect more purposely targeted drugs for T2DM, and better combinations of drugs with simpler treatment regimens [ Fakhrudin et al. 2010 ].

Beyond the drugs already in the pipeline, where might research take us? Can we begin to think about therapies that would cure or even prevent T2DM?

For some time, researchers have known that the brain plays an important role in eating behavior and satiety, and ‘gut–brain’ connections may be the next therapeutic targets, with newer drugs targeting the central nervous system [ Pagotto, 2009 ]. With the currently available GLP-1 receptor agonists, for example, the brain is likely to mediate at least some of the important effects, such as improved satiety and weight loss, regulation of gastric emptying, and possibly suppression of glucose [ De Silva et al. 2011 ; Knauf et al. 2008 ]. Indeed, the relatively new use of the centrally acting therapy, quick-release bromocriptine, illustrates the potential of the brain as a treatment target for T2DM. Bromocriptine, a D2 dopamine receptor agonist, has been available for many years as a treatment for acromegaly and hyperprolactinemia, and was approved by the US Food and Drug Administration in May 2009 as a treatment for T2DM [ Gaziano et al. 2010 ]. Similar to when metformin was first used, the mechanism by which bromocriptine improves glycemic control is as-yet unknown, although it is clear that improvements in glycemic control are seen without increases in insulin concentration [ Cincotta et al. 1999 ; Vero Science, 2010 ]. Investigators believe the drug acts at a central target in the hypothalamus and may affect circadian rhythms to favor improvements in metabolism. This concept was apparently suggested by the metabolism of migrating birds that develop seasonal insulin resistance before migrating, and then return to a lean state after migration [ Scranton and Cincotta, 2010 ].

Bromocriptine is likely to be used in only a minority of patients due to its fairly modest glucose-lowering effects, although it could spark new avenues of research for diabetes treatments, as is always the case when new drug classes are identified. Intriguingly, the theory of seasonal insulin resistance in migrating birds is consistent with studies of insulin resistance in hibernating animals, suggesting the brain is involved via regulation of dopamine and prolactin, and plays a role in accumulation of fat and development of insulin resistance in winter [ Martin, 2008 ]. Humans have no seasonal variations in dopamine, but this neurotransmitter may still play a role in insulin resistance, with people who develop diabetes essentially trapped in a constant state of ‘winter’, characterized by chronic insulin resistance and fat accumulation. Because there is no seasonal food shortage, there is no loss of adipocytes, and the body never returns to ‘summer’ [ Martin, 2008 ]. This pathway, which bromocriptine appears to reset, could open up entirely new approaches to preventing or even curing T2DM.

Could an imposed food shortage help reset metabolism? Studies of bariatric surgery (gastric bypass, sleeve gastrectomy, biliopancreatic diversion or duodenal switch procedure) in obese patients with T2DM seem to suggest that it does, with patients receiving bariatric surgery significantly more likely to eliminate the need for antidiabetic therapies compared with patients receiving only medical therapy for T2DM [ Mingrone et al. 2012 ; Schauer et al. 2012 ; Sovik et al. 2011 ]. These surgical procedures improve diabetes not only by causing weight loss, but also by affecting hormones such as GLP-1 and ghrelin, which help signal satiety and hunger, respectively, to the human brain [ Peterli et al. 2012 ]. Increasing satiety signals and reducing hunger signals to the brain can help patients tolerate extreme caloric restrictions.

Dietary restriction is known to increase lifespan in rodents, and can delay or prevent diseases such as cancer, heart disease, and diabetes; however, studies in nonhuman primates have reported conflicting findings, indicating the effects of dietary restriction are likely to be complex [ Mattison et al. 2012 ]. Such studies are hard to replicate in people, but trials showing a severely restricted diet can improve beta-cell function and insulin sensitivity in patients with a relatively short duration of T2DM suggest that humans, like hibernating mammals, have the capacity for recovering from insulin resistance [ Lim et al. 2011 ]. The problem, the study investigators believe, is that few people could maintain such a limited calorie intake, and any successful nonsurgical solution may therefore rely on drugs mimicking the effects of dietary restriction. Given the current and predicted prevalence of obesity, there is already intensive research into agents that decrease appetite or increase satiety. The endocannabinoid system is known to have a role in the regulation of appetite, but cannabinoid receptor antagonists such as rimonabant have been associated with unacceptable side effects [ Eckel et al. 2011 ], although more selective agonists may be an avenue targeted in the future. To date, other therapies developed for the treatment of obesity have also been plagued by safety issues, but there are now several promising molecules in the early stages of development [ Eckel et al. 2011 ].

Among the currently available therapies for T2DM, various classes also promote weight loss. For example, the subcutaneous agent pramlintide is associated with reduced food intake and body weight in obese people with and without diabetes, although it is associated with only modest hemoglobin A1c (HbA1c) reductions and the amount of weight loss induced is also relatively small [ Lee et al. 2012 ]. Pramlintide is a synthetic form of amylin, which is secreted after meals and signals short-term satiety, and may therefore be more useful in combination with other agents. Therapies combining pramlintide with long-term signaling molecules are in the early stages of development, along with other therapies targeting appetite [ Powell et al. 2011 ].

Metformin is also associated with weight loss, although the amount of weight shed is insufficient to meet FDA criteria for a weight loss drug (at least 5% of body weight). Guidelines now recommend physicians consider metformin for preventing or delaying diabetes in individuals with elevated glucose measurements and a body mass index >35 kg/m 2 [ American Diabetes Association, 2012 ]. Intriguingly, research has shown that metformin-induced alterations mimic many of the same transcriptional changes in the liver that occur with dietary restriction [ Dhahbi et al. 2005 ]. The effects of metformin are still incompletely understood, but activation of AMP-activated protein kinase (AMPK) appears to play a central role [ Zhou et al. 2001 ]. AMPK is a sensor of energy shortage within cells, acting as a metabolic switch ( Box 2 ). The role of AMPK, and possible activators, are being intensively investigated and, at present, this route appears the most exciting line of enquiry into a possible cure for T2DM.

AMP-activated protein kinase: master switch in metabolism.

We often think of glucose as the fuel for cells, but glucose is just one of the fuels used to produce the actual energy source in every cell: adenosine triphosphate (ATP). The energy balance within individual cells is maintained by the enzyme AMP-activated protein kinase (AMPK), which is activated when the ratio of ATP to adenosine monophosphate (AMP) falls [ Viollet et al. 2009 ]. Because AMPK is the ‘master switch’ of energy intake and energy expenditure, this enzyme is a theoretical key target for therapeutic intervention in patients with T2DM. If it is possible to activate AMPK, the resulting signaling pathways could be manipulated to restore energy balance, making people more fit and less likely to develop insulin resistance, without the need to decrease energy intake or lose weight [ Gruzman et al. 2009 ].

Investigations of AMPK activators are already confirming some of these theoretical effects. For example, giving an oral AMPK agonist AICAR to sedentary mice was shown to improve treadmill performance [ Narkar et al. 2008 ]. The polyphenol resveratrol, an AMPK modulator present in red wine, appears to protect mice against diet-induced obesity and insulin resistance [ Lagouge et al. 2006 ], and has also been shown to mimic the effects of calorie restriction in people with obesity [ Timmers et al. 2011 ]. These studies are at early stages, although a phase II/III trial of the effect of resveratrol on inflammatory mediators and insulin resistance in patients with T2DM or obesity is underway [ClinicalTrials.gov identifier: NCT01158417].

The current antidiabetes drug metformin reportedly increases AMPK activity; however, the mechanism of action is incompletely understood and metformin may also act via AMPK-independent pathways [ Foretz et al. 2010 ; Fryer et al. 2002 ]. The antihyperglycemic effect of metformin was discovered by chance, but the subsequent discovery that this drug activates AMPK raises the intriguing possibility of developing drugs to extend the benefits of metformin with fewer side effects. This is certainly possible: although AMPK is found in all cells, different complexes localize to the liver, adipocytes, or skeletal muscles, and a drug targeting these complexes with high specificity could selectively restore energy balance without harming other tissues [ Gruzman et al. 2009 ].

Prevention of diabetes-related complications

Using the World Health Organization cut-offs for diagnosing diabetes may seem rather arbitrary to patients and we often need to explain that an HbA1c level of 6.5% was chosen because people with blood glucose over this level are at much higher risk of diabetic retinopathy. In clinical practice today, patients rarely die from the immediate effects of high blood sugar; instead, we screen for and treat diabetes primarily to prevent complications. It is clear that good control of glucose levels is associated with reduced risk of complications [ Diabetes Control and Complications Trial Research Group, 1993 ; United Kingdom Prospective Diabetes Study Group, 1998 ], but what exactly is it about high glucose that causes complications? Could identifying and targeting those pathways bring the residual rate of complications down to that seen in people without diabetes?

Microvascular complications such as neuropathy, retinopathy, and nephropathy are highly correlated with glucose levels. Various pathways leading to the damage that high glucose levels cause have been proposed, including osmotic stress from sorbitol accumulation [ Lorenzi, 2007 ]; oxidative damage to cells, with free radical production and reactive oxygen species formation [ Ceriello and Motz, 2004 ]; and toxicity from advanced glycation end-products (AGE). As proof of principle, animal studies have shown that inhibition of AGE accumulation might represent an effective strategy to reduce the rate of diabetes progression and/or prevent diabetes-related complications [ Schmidt and Stern, 2000 ; Watson et al. 2011 ].

Macrovascular complications of T2DM, such as myocardial infarction and ischemic stroke, may not just be related to hyperglycemia; inflammation mediated by macrophages appears to contribute to, or even be responsible for, insulin resistance [ Olefsky and Glass, 2010 ]. Atherosclerosis is also thought to result from chronic inflammation leading to injury to the arterial wall [ Ross, 1999 ]. Anti-inflammatory drugs could therefore provide a direct method to reduce the risk of macrovascular complications. In fact, aspirin, one of the oldest anti-inflammatory medications, is recommended in certain groups of patients with diabetes, but use is limited by the high risk of bleeding [ American Diabetes Association, 2012 ]. Development of compounds to inhibit mediators of inflammation, such as tumor necrosis factor (TNF)-α and interleukin (IL)-6, as well as other cytokines from fat and immune cells, could reduce inflammation-associated insulin resistance if the proteins could be selected to act in a highly tissue-specific manner without affecting other functions of the immune system [ Olefsky and Glass, 2010 ]. Research in this field is still in the early stages. A trial of etanercept (a TNF-α blocker) failed to improve insulin sensitivity in patients with the metabolic syndrome [ Bernstein et al. 2006 ]. However, the IL-1 receptor antagonist drug used to treat rheumatoid arthritis, anakinra, improved beta-cell function in patients with T2DM [ Larsen et al. 2007 , 2009 ], suggesting anti-inflammatory compounds may be part of the future treatment of diabetes.

How might treatment evolve?

The current standard of care for T2DM consists of screening for elevated HbA1c levels or, in some cases, fasting plasma glucose, with diagnosis followed by management with lifestyle modifications and metformin except where contraindicated [ American Diabetes Association, 2012 ]. For patients who do not achieve HbA1c targets, antidiabetes medications are added to metformin; subsequently, patients are monitored and further oral antidiabetes drugs or insulin are added if needed.

Clearly, the care of patients with T2DM is currently suboptimal, largely because our healthcare system has traditionally been based on an acute-care model. In contrast, chronic disease management emphasizes a team approach, medication management and patient adherence, prevention of complications, lifestyle modifications as well as coordination of care among subspecialists. Guidelines for the prevention of T2DM emphasize moving beyond the healthcare system towards integration with other areas, such as government and the media [ Lindstrom et al. 2010 ; Paulweber et al. 2010 ]. There is already evidence that intervention at the public health level could significantly impact rates of T2DM [ Elbel et al. 2012 ; Schwartz et al. 2012 ]. In the future, coordination of care using case managers, technology that helps patients between medical visits, such as mobile health and telemedicine, and restructuring care using patient-centered medical homes and accountable care organizations may be better suited for T2DM management [ Quinn et al. 2011 ].

How might treatment options look in the year 2025? We can certainly expect that genetic testing will be used to determine whether the patient will develop diabetes and, if so, which of the predisposing genes are involved. Genetic testing is already used to diagnose subtypes of maturity-onset diabetes of the young (MODY), for which six different subtypes resulting from mutations in different genes have been identified. Diagnosing the exact subtype can help the physician select the most appropriate treatment, as well as screening family members who may benefit from support with lifestyle changes [ Gardner and Tai, 2012 ]. In the future, analogous genetic tests for T1DM and T2DM will enable us to offer the patient the appropriate solution, either genetic therapy to ‘repair’ the defective gene or pharmacotherapy to compensate for it. Because there will likely be 50 or more drugs to choose from, the choice of pharmacotherapy will be personalized based on the patient’s genetic profile, which will also indicate predisposition to complications such as kidney disease or retinopathy that can then be treated with a ‘complication-prevention’ drug. An artificial pancreas will be an option for severe cases, or in patients who cannot tolerate other options.

To allow us to cope with periods of famine and feast, humans are adapted to make the most of the energy available to them. What ensured our survival then has become our weakness now, and all predictions indicate the prevalence of T2DM will get worse before it improves. Modern lifestyles allow continual access to food and encourage sedentary behavior, leading to a progressive cycle of overeating and weight gain. Despite efforts at education, lifestyles will likely become yet more sedentary over the next 20 years, facilitated by advances in technology. For example, concepts for controlling the world around us with only our thoughts would have been science fiction 20 years ago, but are now actively researched [ Hochberg et al. 2006 ]. There seems little doubt that, without interventions, the prevalence of T2DM will increase.

For those who prefer simplistic views, it is easy to blame individuals for having diabetes. Indeed, despite the clear benefits of a healthy lifestyle, changes in long-term behavior and lifestyle are rare. However, as we understand more about our biology, we can appreciate that our environment naturally puts us all at high risk of diabetes. Nowhere is this seen more clearly than in populations that have been exposed to sudden changes in lifestyles as a result of urbanization, such as the Pima Indians in the US, who have far higher rates of T2DM than Pima Indian populations in Mexico [ Esparza-Romero et al. 2010 ].

Is it realistic to ask people to change their lifestyles? The advances in therapy over the past 50 years have provided a remarkable array of options so that treatment can be tailored for each patient, but, even with expert teams of dieticians and diabetes educators, most patients need drug therapy, probably multiple-drug therapy, to achieve recommended HbA1c targets. However, in spite of achieving HbA1c targets, they still retain a residual risk for complications compared with people without diabetes. In the future, we may accept that drugs are needed to allow us to lead modern lifestyles without increasing our risk of diabetes. The scientific community should be applauded for taking the pragmatic approach of searching for interventions that could help individuals, probably the majority, who are unable to maintain healthy lifestyles in the long term. Because our lifestyle means that diabetes will become a normal aspect of life, the research ongoing today is vital to provide tools to counteract the diabetes epidemic.

Acknowledgments

Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Geraldine Thompson of Envision Scientific Solutions during the preparation of this review. Boehringer Ingelheim was given the opportunity to check the data used in the manuscript for factual accuracy only. The author was fully responsible for all content and editorial decisions, was involved at all stages of manuscript development, and has approved the final version of the review that reflects the authors’ interpretation and conclusions.

Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement: The authors declare no conflicts of interest in preparing this article.

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