SDRC Member Publications Roundup

The SDRC has a superb team of talented investigators committed to developing novel therapeutic strategies for diabetes. The SDRC promotes collaborations among its members and with other institutions through robust enrichment programs, core services and financial support via pilot and feasibility grants. We are proud to list some of the innovative research findings published by our researchers (in bold) that were directly supported by the SDRC.

  1. Nagy N, Gurevich I, Kuipers HF, Ruppert SM, Marshall PL, Xie BJ, Sun W, Malkovskiy AV, Rajadas J, Grandoch M, Fischer JW, Frymoyer AR, Kaber G, Bollyky PL. J Biol Chem. 2019 May 10;294(19):7864-787

  2. Tikkanen E, Gustafsson S, Knowles JW, Perez M, Burgess S, Ingelsson E. Body composition and atrial fibrillation: a Mendelian randomization study. Eur Heart J. 2019 Apr 21;40(16):1277-1282.

  3. Zanetti D, Rao A, Gustafsson S, Assimes TL, Montgomery SB, Ingelsson E. Identification of 22 novel loci associated with urinary biomarkers of albumin, sodium, and potassium excretion. Kidney Int. 2019 May;95(5):1197-1208.

  4. Kahkoska AR, Adair LA, Aiello AE, Burger KS, Buse JB, Crandell J, Maahs DM, Nguyen CT, Kosorok MR, Mayer-Davis EJ. Identification of clinically relevant dysglycemia phenotypes based on continuous glucose monitoring data from youth with type 1 diabetes and elevated hemoglobin A1c. Pediatr Diabetes. 2019 Aug;20(5):556-566. doi: 10.1111/pedi.12856.

  5. Lee WH, Ong SG, Zhou Y, Tian L, Bae HR, Baker N, Whitlatch A, Mohammadi L, Guo H, Nadeau KC, Springer ML, Schick SF, Bhatnagar A, Wu JC. Modeling Cardiovascular Risks of E-Cigarettes With Human-Induced Pluripotent Stem Cell-Derived Endothelial Cells. J Am Coll Cardiol. 2019 Jun 4;73(21):2722-2737.

  6. Kim SH, Abbasi F. Myths about Insulin Resistance: Tribute to Gerald Reaven. Endocrinol Metab (Seoul). 2019 Mar;34(1):47-52.

  7. Harati H, Zanetti D, Rao A, Gustafsson S, Perez M, Ingelsson E, Knowles JW. No evidence of a causal association of type 2 diabetes and glucose metabolism with atrial fibrillation. Diabetologia. 2019 May;62(5):800-804.

By
Harini Chakravarthy
Harini Chakravarthy is a science writer for the Stanford Diabetes Research Center.

Nutritional Guidelines and Diabetes: A conversation with Dr. Christopher Gardner

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Dr. Christopher D. Gardner has a PhD in Nutrition Science and is a Professor at the Stanford School of Medicine and the Director of the Clinical and Translational Research Core in the Stanford Diabetes Research Center. His work focuses on the study of dietary strategies and their impact on participant health outcomes such as weight, insulin and glucose dynamics and related parameters. He recently spoke at the 79th American Diabetes Association (ADA) Meeting in San Francisco on the role of nutrition in diabetes prevention. Dr. Gardner sat down with us to talk about the nutritional guidelines from the Standards of Medical Care in Diabetes 2019 report by the ADA and his recommendations.  

What changes that were made to the American Diabetes Association nutritional guidelines this year stand out to you? What triggered those changes? 

I would say there were three in particular.

The first was the decision to take on dietary patterns by looking beyond “food” and focusing on “food patterns”. By this, I am referring to diets such as Mediterranean, Vegan, Asian, Paleo, Low-Fat or Low-Carb which represent emphases on specific food groups rather than individual foods. The advantage of making suggestions based on food patterns is that they are more generalizable and adaptable. On the other hand, food patterns tend to be less specific and harder to follow for people who are looking for more structure in their diet. The new guidelines reflect consensus across different food patterns in its summary statements and encourages intake of vegetables and whole grains while minimizing processed foods and added sugars. Because of the emphasis on reducing added sugar and refined grains, this approach suggests a much lower overall carbohydrate intake which is corroborated by a growing body of evidence for the benefits of lower carbohydrate diets on glycemic control.

The second related point that stood out to me from the recent update in the guidelines was the shift to taking a stronger positive stance on lowER carbohydrate diets. I emphasize the “ER” portion of the term because there remains little consensus on “how low is low” when it comes to carbohydrates. Although a considerable body of evidence supports the benefits of low-carbohydrate diets for glycemic control, there is a paucity of data on whether low-carbohydrate diets have a significant benefit for long-term morbidity or mortality. All the available data for this outcome comes from “Low-Fat” studies. Unfortunately, diet studies with morbidity and mortality outcomes are challenging to fund and take many years to conduct. This was acknowledged in the newly released Consensus statement.

Thirdly, the panel was tasked with addressing pre-diabetes. This was in contrast to previous reports which restricted their work to Type I and II diabetes. However, current trends suggest that unless an emphasis is placed on preventing people from becoming diabetic, an unprecedented number of humans are likely to have the disease in the near future. The group of people with pre-diabetes is most likely to make that transition soon and is therefore the focus of the effort to prevent diabetes.

One ADA recommendation is to encourage diabetics to reduce their consumption of sugar sweetened beverages. In this context, what is your view of the effectiveness of the so-called 'soda tax' on changing consumer behavior?

Preliminary data from Berkeley and Mexico – two of the first to implement soda taxes – supports a benefit in terms of influencing consumer behaviors. A definitive answer in the area of health benefits will not be available any time soon. That is because the time frame of studying stability or change in human behavior can be very brief, whereas tracking the health impacts of those behavioral changes (e.g., morbidity, mortality) is a very extensive and intensive undertaking.

For people who consume foods sweetened with non-nutritive sweeteners in lieu of sugar-sweetened foods, what are some of the risks of non-nutritive sweeteners?

The major problem with the consumption of beverages sweetened with non-nutritive sweeteners is the issue of “compensation” – psychological and physiological. The psychological compensation may come from choosing a diet soda rather than a regular soda for lunch and feeling so good about that choice that the person might reward themselves with a sweet treat for dessert that they may not have consumed otherwise. In this case, the sugar and calories from the cake likely diminish or even negate the benefit of the diet soda. The physiological compensation may plausibly come from the body sensing that an incoming sensation of sweetness would be linked with a proportional level of caloric intake that in fact isn’t there. This in turn potentially leads to sub optimal food choices in the future. In addition, chronic consumption of artificial sweeteners could be linked to an increased obesity and type 2 diabetes risk. That said, it is important to note that many of these potential risks have not been proven and are currently plausible rather than definitive.

What, in your experience, is the most common problem diabetic patients face with respect to nutrition?

Although I don’t see patients, my sense is that the most common problem stems from focusing on carbohydrate counting without simultaneously developing a full appreciation of the variability in quantity and quality of carbohydrates across a wide range of food groups – vegetables, nuts and seeds, fruits, whole intact grains. In the past the focus has been on what NOT to eat, rather than also providing guidance on what to include.

The guidelines mostly focus on recommendations for Type 2 diabetics, saying 'There is inadequate research in type 1 diabetes to support one eating plan over another at this time'. Given that type 1 diabetes often has an onset in childhood, do you anticipate there being significant differences in nutrition guidelines for type 1 diabetics?

While there may be certain circumstances that lead to a need for separate dietary guidelines for type 1 vs. type 2 diabetes, in general the broad characteristics of a healthy diet for people with type 1 diabetes is are more similar than different for those with type 2 diabetes.

Dr. Gardner has worked tirelessly over the past 20 years to improve our understanding of the role of nutrition and dietary strategies in the management of diabetes and educate the public on good dietary practices. He also studies the impact of social factors such as the climate change movement and animal welfare concerns that could help people make positive dietary changes. He was instrumental in helping draft the nutritional guidelines section of the American Diabetes Association report on Diabetes Care.

By
Harini Chakravarthy
Harini Chakravarthy is a science writer for the Stanford Diabetes Research Center.

SDRC Member Spotlight: Nadine Nagy

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Stanford Diabetes Research Center (SDRC) member Dr. Nadine Nagy has a mission. She wants to stop type 1 diabetes (T1D) before it starts. By the time an individual is diagnosed with T1D, the damage is usually already done. The precious population of insulin producing beta-cells is scattered in tiny clusters, called islets, throughout the pancreas. Islets are tasked with the job of producing the body’s entire supply of insulin. In the setting of T1D which is an autoimmune disease, islets are attacked by the body’s own immune system, leaving the body unable to meet its own insulin demands. But what if there is a way to stop the immune system from launching an attack on the beta-cells in the first place?  

Addressing this question and developing tools to prevent T1D forms the foundation of Dr. Nagy’s research at Stanford. In 2015, she and her mentor Dr. Paul Bollyky showed that a drug called Hymecromone or 4-methylumbelliferone (4-MU) protects beta-cells from autoimmune destruction by reducing the synthesis of hyaluronan in a mouse model of T1D. Hyaluronan is a major component of the extracellular matrix (ECM), a supportive structure, found in all tissues. Interestingly, hyaluronan is massively upregulated in disease, and it seems to be a supporting factor for rogue immune cells to destroy pancreatic beta-cells in T1D. Thus, an immune-mediated attack on the beta-cells may be averted by inhibiting hyaluronan production.

“I was always fascinated by the diverse structure and function of the ECM and especially hyaluronan, a simple molecule which has a major impact in disease. We realized early on that there are massive changes in the ECM that precede the onset of diabetes and that disease prevention is a real possibility” says Dr. Nagy.

Dr. Nagy and her colleagues observed for the first time a build-up of hyaluronan in the pancreatic tissues of younger T1D donors obtained from the Network of Pancreatic Organ Donors (nPOD), who had the disease for less than 5 years. In the years following this discovery, Dr. Nagy used mouse models that spontaneously developed T1D to prove her hypothesis that the presence of hyaluronan was essential in facilitating the immune system to mount an attack on the pancreatic beta-cells. Her work revealed that hyaluronan impairs the induction of a class of immune cells called regulatory T cells or Tregs which restrain another group of immune cells called cytotoxic T cells from killing healthy pancreatic beta cells. 

Dr. Nagy found that 4-MU treatment spared the beta-cells from destruction by inhibiting hyaluronan synthesis and allowing T-regs to control the aggressive cytotoxic T-cells. As a potential early therapeutic intervention for T1D, 4-MU tips the balance between tolerance and destruction by using the body’s own immune system to control the progression of the disease.  

In 2016, Dr. Nagy was awarded a pilot and feasibility award from the SDRC to develop 4-MU analogs to pursue her goal of preventing T1D. The grant enabled her to publish her findings on hyaluronan’s role in autoimmunity and inflammation, making a strong case for pursuing 4-MU as a potential therapeutic. As a drug, 4-MU has been in clinical use for over 4 decades in European and Asian countries for treating biliary spasms and has an excellent safety profile. However, 4-MU has poor pharmacokinetics, and a low bioavailability, hence low utility as a drug in its current form. Once ingested, 4-MU rapidly breaks down into its metabolites. Dr. Nagy’s recent studies found that 4-MU and its main metabolite 4-MUG exist in equilibrium in the body and that both are capable of inhibiting hyaluronan synthesis.  

Dr. Nagy is optimistic about the potential to repurpose 4-MU as a drug to prevent T1D in newly diagnosed or at-risk populations. However, she acknowledges, there is still a lot of work that needs to be done before we see 4-MU in the clinic. “I would like to see our translational work moving forward into clinical trials. I believe using 4-MU has the potential to prevent T1D”, she says.

By
Harini Chakravarthy
Harini Chakravarthy is a science writer for the Stanford Diabetes Research Center. 

SDRC Trainee Highlight

The SDRC is proud to highlight the research achievements of its trainees by presenting outstanding poster awards during its 4th Annual Frontiers in Diabetes Symposium.

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Dr. Keren Ita Hilgendorf’s work focuses on understanding the function of a sensory organelle called the cilium on fat cell development and its role in metabolic diseases like obesity and diabetes. Explaining her focus on cilia, she says, “I have always been interested in understanding how key disease signaling pathways work on a molecular level. The primary cilium is an ancient and spatially distinct antenna-like protrusion that has emerged as a central sensory organelle of the cell. Patients with dysfunctional ciliary signaling present with a broad spectrum of clinical manifestations, including obesity and diabetes.” Her study provides a molecular framework to explain how the primary cilium regulates the formation of fat cells from fat cell precursors by identifying a novel ciliary receptor which is activated by omega-3 fatty acids, known to have anti-diabetic effects.

Dr. Hilgendorf used a mouse model which permitted visualization of cilia in fat tissue after the mice were fed a high-fat diet and showed that the ciliated fat precursor cells position themselves close to blood vessels and are thus able to quickly respond to changes in nutrient cues in the blood through proteins called receptors on the cilia. To identify signaling pathways involved in adipogenesis or the generation of fat cells from their precursors, Dr. Hilgendorf screened candidates in fat precursor cells grown in a dish enabling her to identify Ffar4, a novel free fatty acid ciliary receptor that responds to omega-3 fatty acids. Dr. Hilgendorf notes, “Human mutations in the Ffar4 gene have been linked to childhood obesity. Patients with dysfunctional ciliary signaling are obese and diabetic, and fat precursor cells isolated from obese humans are shortened and signaling-defective”, suggesting that she has identified a central pathway that has gone awry in obese and diabetic individuals. However, acknowledging that other signals likely also factor into the molecular dysfunction underlying obesity and diabetes, she notes “The integration of multiple ciliary signaling pathways may occur at the level of the primary cilium and we are actively pursuing this line of investigation”. Dr. Hilgendorf plans to use the SDRC poster prize money to attend the FASEB Cilia Conference this summer. She is a Research Scientist in SDRC member Dr. Peter Jackson’s group at Baxter Laboratories.

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Research Scientist Dr. Owen Jiang and Postdoctoral scholar Dr. Yunshin Jung explore the mechanisms by which brown fat tissues provide metabolic benefits to the body. Brown fat is classically known for its heat generating capabilities which burns calories and contributes to weight loss. However, recent studies show that brown fat also secretes factors that help with blood sugar homeostasis. Drs. Jiang and Jung’s work identified one such secreted protein called Isthmin-1 (ISM1) which improves the ability of fat cells to take up glucose. “Initially, we were looking for secreted proteins that were both hormone-like and enriched in brown fat cells. This gave us 16 candidates, including Isthmin-1 which is expressed in brown fat”, they explained. Their subsequent analyses demonstrated that ISM1 induced glucose uptake by fat cells via an insulin-independent mechanism.

When mice fed with a high-fat diet are treated with ISM1, they display a long-term improvement in insulin sensitivity and glucose uptake. Interestingly, unlike insulin treatment, ISM1 treatment improves blood glucose levels without a concomitant increase in fat accumulation in peripheral tissues like the liver. Drs. Jiang and Jung found that ISM1 shuts down the molecular pathways that drive fat accumulation in the liver in these mice. The researchers are now developing even more sensitive assays to permit them to detect ISM1 in blood. “We have exciting preliminary data suggesting that our ISM1 assay can detect picogram levels of ISM1”, they note.

In terms of how their work is relevant to current and future therapeutic strategies combating diabetes and obesity, they are optimistic. “This could potentially become a recombinant protein therapy for patients with diabetes and insulin resistance”, they say. The power of ISM1 lies in the fact that although it activates a prominent signaling mechanism called the PI3K/AKT pathway in target cells which promotes glucose uptake, it does so without accumulating fat. The researchers plan to test the function of ISM1 in fat cell development and assess its role in human obesity in the future. Drs. Owen Jiang and Yunshin Jung are in Dr. Katrin Svensson’s group in the Department of Pathology at Stanford. They plan to use their SDRC poster prize money to cover travel expenses to conferences.

 By
Harini Chakravarthy
Harini Chakravarthy is a science writer for the Stanford Diabetes Research Center.

Fire without smoke? E-cigarettes may impair blood vessel health even without nicotine

Dr. Joseph Wu

Dr. Joseph Wu

In 2015, the British Government issued a press release stating that electronic cigarettes or e-cigarettes were around 95% less harmful than smoking based on an independent Public Health England expert report. Recent groundbreaking research published by Stanford Diabetes Research Center (SDRC) member Dr. Joseph Wu and his colleagues, Dr. Won Lee, PhD and Dr. Sang-Ging Ong, PhD in the Journal of the American College of Cardiology (JACC) in June 2019 is the latest in a series of studies to challenge the claim that vaping is safer than smoking.  

Vaping refers to the inhalation and exhalation of vapors produced by heating a flavored liquid containing nicotine in a device called an e-cigarette. Often, smokers who want to kick the habit take up vaping as it has been marketed as a safer alternative that has fewer toxic chemicals than regular cigarettes. Conventional cigarette sales and consumption have been on a steady decline in the US, whereas, e-cigarette use has been on the rise, especially among youth. While e-cigarettes do have a lower content of many of the chemicals found in traditional cigarettes, the current study suggests that certain flavoring liquids in e-cigarettes may severely damage the inner lining of blood vessels and increase cardiovascular disease risk even in the absence of nicotine

Dr. Wu’s team studied the effect of 6 popular flavors of e-liquids on the health and integrity of endothelial cells which form the inner lining of blood vessels. Endothelial cells are vital for cardiovascular health and their degradation is associated with increased cardiovascular disease risk. Using a novel approach, the researchers generated endothelial cells for this first-of-its-kind study from induced pluripotent stem cells or iPS cells. Under the right laboratory conditions, iPS cells can be coaxed to become any cell type in the body including endothelial cells. This enabled the researchers to have a ready pool of endothelial cells on which to test e-liquids.  

Dr. Wu found that all 6 flavors of e-liquids had detrimental effects to varying degrees on the endothelial cells, however, exposing the cells to menthol and cinnamon flavored e-liquids had the most dramatic effects in terms of decreasing their ability to survive, form vascular tubes and migrate. Surprisingly, these effects did not appear to be correlated with the presence or absence of nicotine in the e-liquids, suggesting that the flavoring chemicals themselves were toxic. In addition, the researchers found that exposing endothelial cells to blood taken from smokers or vapers after consuming a single e-cigarette or cigarette was sufficient to impair their function and increase the production of free radicals and molecules associated with cell death and inflammation.  

The endothelial cells displayed other signs of damage as well, some of which were dependent on nicotine levels. The scientists noted that exposure of endothelial cells to nicotine containing e-liquids increased their uptake of inflammation-associated lipids and low-density lipoproteins and activated inflammatory immune cells called macrophages. Moreover, the team observed similar levels of nicotine in the blood of participants immediately after vaping or smoking.  

 “It is important for e-cigarette users to realize that these chemicals are circulating within their bodies and affecting their vascular health”, says Dr. Wu in a Stanford News Press Release. Dr. Wu and his colleagues acknowledge caveats in their study including the fact that they tested unheated e-liquids as opposed to the aerosols and their analyses being limited to just six of the hundreds of e-cigarette flavorings available in the market, precluding the universal extrapolation of their results to all e-cigarettes.  

Describing the relevance of the study in an audio summary, JACC Editor-in-Chief Dr. Valentin Fuster said, “Although it has been portrayed that e-cigarettes can be beneficial in smoking cessation, there is growing alarm at the rate of use among teens and adults and increasing concerns that e-cigarette products are in fact a gateway to future tobacco use”. Moreover, he added, advertising promotes e-cigarette flavors targeting children and young adults – flavors that could be toxic as shown by Dr. Wu’s team.  

Dr. Fuster concluded his remarks by citing an editorial comment on the study in the same issue of JACC by Drs. Freedman and Trivedi from the University of Massachusetts Medical School, Division of Cardiovascular Medicine, Worcester, Massachusetts in which they write “The results by Lee et al clearly demonstrate that e-liquid flavorings had stronger effects on cytotoxicity, vascular dysfunction and angiogenesis than nicotine. Thus, in addition to harm from the nicotine, the additives are a potential source of adverse vascular health and one that is being disproportionately placed on the young”. It appears, he said, that even without the smoke of combustible cigarette products, there may be a smoldering fire of adverse health effects.  

Dr. Won Lee, now an assistant professor at the University of Arizona, was the recipient of a Pilot award from the SDRC from a grant sponsored by the National Institutes of Health. Dr. Sang-Ging Ong is an assistant professor at the University of Illinois-Chicago. Other Stanford coauthors include research assistant Yang Zhou, postdoctoral scholars Dr. Lei Tian, Dr. Hongchao Guo, graduate student Hye Ryeong Bae, undergraduate student Natalie Baker and Professor Kari Nadeau, MD, PhD, Department of Pediatrics, Stanford.

 
Dr. Won Lee

Dr. Won Lee

Dr. Sang-Ging Ong

Dr. Sang-Ging Ong

 

By
Harini Chakravarthy
Harini Chakravarthy is a science writer for the Stanford Diabetes Research Center.