Volume 37 • Number 1 March/April 2018 PracticalDiabetology

ResearchCREATING A DIABETES TECHNOLOGY KIOSK IN THE CLINICJennifer Shine Dyer, MD, MPHIt is often said that “the language of millenials is digital.” It’s not surprising that this generation raised by technology would prefer a kiosk type of digital, customizable consumer experience in health care. Therefore, the use of a diabetes kiosk for medical devices within our pediatric endocrinology office has been successful.

ISSUES RELATED TO SHIFT WORK IN PEOPLE WITH DIABETESDaniel Lorber, MD, FACP, CDEExtensive literature shows that shift work increases insulin resistance, the risk of Type 2 diabetes and related metabolic abnormalities. A recent email to the American Diabetes Association Legal Advocacy listserv asked for advice on diabetes management in workers whose jobs require changing shifts. Read the collated and edited replies.

ColumnsCOMMENTARYChronobiology and Type 2 Diabetes MellitusMolecular studies have identified genes that are crucial for maintaining circadian rhythms. Targeted disruption of some of these genes has led to Type 2 diabetes in animal studies. Lifestyle factors such as shift work lead to alterations in circadian rhythms and may disrupt the molecular clock mechanisms, resulting in permanent alterations of pancreatic beta-cell function.

JOURNAL WATCHThis column highlights recent clinical trial data and landmark trials to provide relevant information and links for obtaining trial data and articles to facilitate discussion with patients and other providers. Each trial is identified by its acronym, its ClinicalTrials.gov Identifier and its journal reference.

EDUCATOR’S CORNERYoga in the ClinicThis edition of Educator’s Corner defines and describes yoga and its common components, evaluates the scientific evidence of yoga as an adjunctive treatment modality for diabetes, and provides “practice pearls” for implementing yoga in the clinic and/or in diabetes self-management curricula and programs.

Volume 37 • Number 1March/April 2018

Practical Approaches to Diabetes and Related DiseasesPractical Diabetology

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Practical Diabetology • Vol. 37, No. 1 • March/April 2018Practical Diabetology • Vol. 37, No. 1 • March/April 2018 1

EDITORIALEditor

Kathleen Wyne, MD, PhD, Associate Professor, Division of Endocrinology,

Diabetes and Metabolism, The Ohio State University, Wexner Medical Center Columbus, Ohio

Editor, Educator’s CornerMeghan Jardine, MS, MBA, RDN, LD, CDE, Associate Director of Diabetes Education,

Physicians Committee for Responsible Medicine, Washington, D.C.

Editorial Director, Wellness Maureen McCarthyManaging Editor

Joan EdgettAssociate Editors

Sandra D. Burke, PhD, APRN Urbana, Illinois

Robert J. Chilton, DO San Antonio, Texas

Editorial BoardArnaud Bastien, MD Camden, New Jersey

Jackie Boucher, MS, RD, LD, CDE Minneapolis, MinnesotaStephen Brunton, MD

Charlotte, North CarolinaSteven Edelman, MD San Diego, California

Marion J. Franz, MS, RD, CDE Minneapolis, Minnesota

Martha M. Funnell, MS, RN, CDE Ann Arbor, Michigan

George Grunberger, MD, FACP, FACE Detroit, Michigan

Richard Hellman, MD, FACP, FACE Leawood, Kansas

Robert Ratner, MD Washington, D.C.

Nancy J. Rennert, MD, FACE, FACP Norwalk, ConnecticutJulio Rosenstock, MD

Dallas, TexasJane Jeffrie Seley, MPH, MSN, NP, CDE

New York, New YorkFred Whitehouse, MD

Detroit, MichiganJoel Zonszein, MD

New York, New York

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Practical Diabetology is a supplement to Diabetes Self-Management and is published quarterly by Madavor Media, LLC

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EDITOR’S NOTEI would like to take this opportunity to welcome you to our first issue of Practical Diabetology for 2018 and introduce you to our updated design.

Many of you know that I have recently moved to The Ohio State Uni-versity Wexner Medical Center, where my primary role is to develop an adult Type 1 diabetes program, along with performing clinical research, teaching and seeing patients. However, the goal of Practical Diabetol-ogy remains unchanged: to provide busy health-care professionals with straightforward, practical information to enhance the care and treatment they provide to their diabetes patients. Our articles concern all aspects of diabetes and its complications and are designed to be quickly read, easily understood and readily incorporated into daily practice.

This issue is very exciting as we are addressing some very practical issues in diabetes management, including empowering patients by teaching them to download their devices in the clinic, considering stress and shift work as modifiable factors contributing to hyperglycemia, and utilizing yoga to decrease stress and improve metabolic biomarkers.

As you’ll see, our new design introduces photos of our contributors. We encourage you to approach those you see at conferences and other events. Not only do authors enjoy hearing your feedback on their articles, they also look forward to discussing any questions that you may have.

The “Journal Watch” feature provides the NCT number, references and a brief summary of either landmark trials or emerging therapies. We are expanding the photos and figures with each article to include more material for the reader to use in teaching patients as well as colleagues about the respective topic.

In future issues, we will be featuring the section “2 Minutes with Diabetes.” I encourage all readers to submit topics or questions, which will then be sent to experts for replies to be published in the print issues. Please use “Practical Diabetology” in the subject line and send to [email protected].

EditorKathleen Wyne

P R A C T I C A L A P P R O A C H E S T O D I A B E T E S A N D R E L A T E D D I S E A S E SPractical Diabetology

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PATIENT GUIDEThis Diabetes Self-Management article provides information for your patients on the expanding role of technology in diabetes care: bit.ly/2D47IFX

CREATING A DIABETES TECHNOLOGY KIOSK IN THE CLINICIf there’s one thing you can say about interactive kiosks, it’s that they are impossible to ignore, even in the outpatient endocrinology office. This technology has been front and center at some of the largest and most successful retail, food, hotel and transporta-tion businesses for quite some time. Less known, however, is the reason for their recent proliferation in medicine and diabetes.

Currently, there is a lot of conversation about the rise of the “consumer” as a newly empowered stakeholder in our country’s health-care system. It’s admirable to do whatever we can to make health care more accessible and transparent to the people who need it and to help patients become active partici-pants in their own care. Giving patients a voice—and listening closely to that voice—is the single most important driver to a better health-care system. Compared to a decade ago, we now have a system in which patients feel they have more information and more choice. Health reforms and new technologies are, to some degree, starting to put the patient in the driver’s seat.

As medicine shifts from viewing people as patients to consumers, expect to see changes such as kiosks in offices. While it’s easy for the casual observer to dismiss them as a novelty or cost-cutting measure, major players in this technology space understand that kiosks can play a critical role in the way they engage customers, promote new products and improve operational efficiencies.

The birth of interactive kiosksThe first self-service interactive kiosk was devel-oped in 1977 at the University of Illinois at Urbana-Champaign by premed student Murray Lappe. The content was created on the PLATO computer system and was accessible by plasma touch screen interface. The plasma display panel was also invented at the University of Illinois at Urbana-Champaign, by Donald Bitzer. Lappe’s kiosk, called The Plato Hotline, allowed students and visitors to find movies, maps, directories, bus schedules, extracurricular activities and courses. When it debuted in the University of Illinois stu-dent union in 1977, more than 30,000 students, teachers and visitors stood in line during its first six weeks to try their hand at a “personal computer” for the first time. The first successful network of interactive kiosks used for commercial purposes was developed by the Florsheim Shoe Company in 1985. The network of more than 600 kiosks pro-

vided images and video promotion for customers who wished to purchase shoes that were not avail-able in the retail location. Style, size and color could be selected, and the product paid for on the kiosk itself. The transaction was sent to the Florsheim mainframe in St. Louis, Missouri, via dial-up lines for next-day delivery. This kiosk network operated for six years in Florsheim retail locations.

In 1991, the first commercial kiosk with Internet connection was displayed at the Comdex computer expo to locate missing children.

Kiosks todayKiosks now combine the classic vending machine with high-tech communications and complex robotic and mechanical internals. Such interactive kiosks can include self-checkout lanes, e-ticketing, hospital check-ins, medical device downloads and viewing, and vending. Interactive kiosks have become a larger part of the retail and medical landscape as customers embrace technology in their daily lives.

It is often said that “the language of the millenni-als is digital.” It’s not surprising that this generation raised by technology would prefer a kiosk type of digital, customizable consumer experience in health care. Therefore, the use of a diabetes kiosk for medi-cal devices within our pediatric endocrinology office in Columbus, Ohio, has been successful.

Pediatric endocrinology office kiosk case examplePatients begin their appointment experience by sitting down at a public computer, or kiosk.

They are greeted by a friendly medical assistant and a set of instructions detailing which software programs they will need to open on the kiosk desk-top. The software program is determined by each patient’s glucose meter, insulin pump or continu-ous glucose monitoring device. Current diabetes device software programs used on the kiosk include Diasend, Glooko, Carelink and Dexcom.

The patient then uses the designated device con-nection cord provided by the medical device com-pany to access the kiosk and software. The cords hang next to the kiosk and are a visible reminder of the lack of interoperability between medical devices.

Once the devices are connected to the software programs, the patient’s device data from the past two weeks are downloaded and printed out by a printer at the kiosk station so that the data can be quantified and visualized. Total daily insulin doses, number of daily boluses, average blood

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glucoses, percent time in range, percentage of time below target, and amount of time between infusion set changes are just a few of the sum-mary data points that quantify each patient’s dia-betes experience and are then discussed during the clinic visit. Having patients successfully use the software programs with their devices allows them to confidently communicate with the office between visits if they need assistance with their data interpretation or pattern management.

In our experience, these kiosks in the outpatient endocrinology clinic have provided benefits in patient empowerment, patient engagement, patient support, communication and office visit efficiency.

Patient empowermentPeople want to feel empowered. The elements for empowerment most often requested by our patients are continuity and connectedness. Kiosks allow for data visualization that makes compari-sons of information collected over time easy. This continuity allows the eye to visualize differences within the same landscape. In other words, the continuity turns the numbers into pictures and then stories that clarify the diabetes experience. Once the diabetes experience is clarified, it can be better understood and consumed. This allows for a common shared connectedness among the patient and the care team (providers, caregivers, parents, spouses, babysitters, school nurses), which eventually leads to empowerment. Once these elements exist, the next logical step of empowerment is engagement.

Patient engagementEngagement, non-hurried and enabled by inter-active kiosk software, is the medical experience all people desire. As noted, sharing a complete quantified diabetes experience aided by the kiosk with the patients themselves and their care team allows for empowerment. The empowerment is often directly related to finding actionable data patterns that relate to each patient’s current dia-betes experience. Sometimes the patient or family cannot find that pattern unless the provider points it out during the clinic visit. However, once that pattern is revealed, it is more likely that a patient can understand what behaviors will help to change that pattern. Nonetheless, behavior change can only happen when a patient is ready.

Patient supportEncouraging families to download data from their child’s medical devices on a weekly basis has allowed parents to reduce the burden of diabetes on their children by helping directly with pattern management and problem-solving. This has been especially true for our teenage patients, who often operate their devices inde-pendently of their parents. However, teens can easily become overwhelmed, which leads to compensatory behaviors such as lying about blood sugars to their parents and ignoring their diabetes all together. Weekly downloads allow parents to be more informed about their teen’s diabetes habits and offer support early and often when a problem first develops.

CommunicationKiosk downloads have allowed for streamlined com-munication between visits when families need extra assistance in pattern management, a core principle for successful diabetes management. When the provider is able to review the data within the full picture of total daily insulin dosing as well as past and present continuous glucose trends, a precise dosing recommendation can be made. Furthermore, discussion of the data visualization and the diabetes experience can be used to teach the principles of pat-tern management to better empower each patient and their families between visits. Communication about device settings (which is noted in the kiosk down-loads) has been very helpful for families that have children with multiple caregivers: daycare, school nurses, teachers, coaches, babysitters, grandparents. Families are able to access the data easily from home to share with these caregivers. The consistent data presentation of device settings from the downloads has allowed each of these stakeholders to clearly see how each device should be set, thereby minimizing dosing errors while the child is in their care.

Office visit efficiencyHaving patients download their own data at the office kiosk has also improved operational effi-

ciencies within the office. Prior to the kiosk, the downloading process by the medical assistants was slowed by the need to perform multiple tasks by one person: vitals, urine checks, in-office A1C checks, device downloads. Having a patient and/or their family member download the device’s data allows the medical assistant to measure the patient’s A1C and check vitals while someone else downloads the information. Furthermore, when there is a line to check into the office, a patient can begin the downloading process at the kiosk, thereby better utilizing the wait time. The downloading time was a bit slower while patients and families initially learned the kiosk process, but after only one or two more visits, patients and families were able to quickly access their data and subsequently were escorted into the exam room. This improved efficiency has allowed for more time to be spent with the provider than on administrative tasks during each office visit.

In conclusion, kiosks have become a tool for patient empowerment, engagement, communication and efficiency within the pediatric endocrinology office. Despite the fact that technology can often be imper-sonal, kiosks can aid in personalization for the diabetes consumer…and just make life with diabetes a little bit easier and quicker. PD

KIOSK CHECKLIST

n Computer

n Printer

n Software programs that coordinate with glucose monitoring devices, i.e., Diasend, Glooko, Carelink and Dexcom

n Cords for connecting devices to the kiosk computer and software

Patient kiosk at Central Ohio Pediatric

Endocrinology and Diabetes Services

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ISSUES RELATED TO SHIFT WORK IN PEOPLE WITH DIABETES

Chronobiology and the effects of circadian rhythms have been important foci of endocrinology research for well over 100 years. It is only with the develop-ment of new insulins, sophisticated glucose monitor-ing techniques and hormone immunoassays that it became apparent that circadian rhythms of hGH and cortisol exert a major impact on glucose metabolism, leading to the discovery of the “dawn phenomenon” and its hormonal mechanisms. The concurrent move toward greater glycemic control, culminating in the Diabetes Control and Complications Trial (DCCT) results, led to greater understanding of the dawn phenomenon and development of new pharmaco-logic and technical approaches to improve morn-ing glycemic control without causing significant increased risk of nocturnal hypoglycemia.

Variations in sleep patterns cause significant changes in counter-regulatory hormone rhythms, leading to changes in insulin requirements. These changes are particularly relevant for people who are employed in careers requiring shift work that changes from day to evening or night work. Exten-sive literature shows that shift work increases insulin resistance, the risk of Type 2 diabetes and related metabolic abnormalities of the metabolic syndrome. A British study of 4,000 randomly selected indi-viduals with diabetes found that shift workers with diabetes complained of higher rates of headache and tiredness. As more insulin-treated people (both Type 1 and Type 2) enter the work force, this issue has become a significant concern for occupational medi-cine physicians. A recent email to the ADA Legal Advocacy listserv (HCPLEGALADVOCACY@ LIST.DIABETES.ORG) asked for advice on dia-betes management in workers whose jobs require changing shifts. The replies were collated and edited. Here they are.

GOOD AFTERNOON:I am posting a question on behalf of an occupational medicine physician for your consideration.“Does anyone have guidance or resources on shift work assignments in patients with insulin- dependent diabetes? It has always been my practice to advise against rapidly changing shift work for these patients, but some of our facilities want more guidance than this. Is there a generally recommended period of time between shift changes that anyone would advise, in the interests of the patient adjust-ing eating schedules and insulin doses in order to

maintain control of insulin-dependent diabetes?What has been your practice for such patients?

Is there any guidance out there on this subject (shift work and insulin-dependent diabetes) that I can reference?”

SHIFT WORK: SUMMARY OF RESPONSESPHYSIOLOGY“This issue is complicated by another factor that is gaining more widespread attention among chro-nobiologists—the role of ‘social jetlag.’ Social jetlag represents the mismatch between your own biologi-cal clock’s timing (i.e., whether you are an ‘owl’ or a ‘lark’) and your social clock (i.e., whether you work a night shift, day shift or variable shift). In fact, a very recent Dutch study demonstrated that those with a median age <61 and a circadian misalign-ment of more than two hours had a nearly twofold greater risk of metabolic syndrome, Type 2 diabetes or prediabetes. This study just adds to the body of literature demonstrating the negative effects of circadian misalignment.”

MULTIPLE INJECTION THERAPY• “…with Tresiba + a rapid-acting insulin for meals,

we no longer worry about timing of insulin versus adjustment to changing shift schedules.”

• “I have found that switching to Tresiba as the basal insulin works great for shift workers since it does not have to be taken [at the] same time every day. Meal time is not as concerning and no changes usually need to be made.”

INSULIN PUMPS• “As a certified pump trainer for over 17 years, I

find the alternate basal pattern an awesome feature. Takes work and time to decipher needs but has been great. Used with everyone from a nuclear power plant engineer to medical personnel. The person has to be paying attention to flip the pattern but it can work nicely.“

• “As a RD CDE for over 35 years in the South with mill workers, I have had success with setting their rest basal rates and working basal rates to be the focus. So what they would run at night, I have them run when they are asleep. Also agree with the person who had them eat consistent carb and protein every 4-5 hours when they are awake.”

• “My insulin pump basal amount is set specifically for the requirement of my basal needs. So, in other

RESEARCH

PATIENT GUIDEYour patients can learn more about this topic in the March/April Diabetes Self-Management article “Diabetes and the Graveyard Shift.”

Daniel Lorber, MD, FACP, CDE Chair, National Advocacy Committee American Diabetes Association

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words, during the daytime, my insulin needs are quite different than at nighttime, when I am sleep-ing. If I was awake (with nighttime basal amounts) during the time I usually sleep, my blood glucose would be high and, conversely, the opposite would be true as well. If I was asleep with my pump set for daytime insulin, my blood glucose would be too low.

“Furthermore, my prescribing physician and I determine my basal insulin needs on patterns derived over time. Consequently, analyzing pat-terns required for my basal amount on incon-sistent data would be quite difficult with shift work. Certainly if I chose to do this, at least in my case, achieving and maintaining tight con-trol would most likely be near impossible.” • “The biggest change to accommodate shift work is

to lower the basals during active work, when both mother and baby are consuming glucose. Clearly this is easier to do with a pump, but we often have to change Lantus for NPH (shorter action) so we can target the increased insulin resistance times and not push glucose low during active periods.”

• “I care for pregnant women on pumps (and long-acting insulins), many of whom are nurses and physicians who do strings of PMs and nights. Dur-ing pregnancy, the ‘dawn effect’ and progressively

intense insulin resistance from 4 a.m. to 8 a.m. results in a tripling of the basal over the course of gestation, whereas the basals between 9 p.m. and 4 a.m. are very stable. As the baby gets larger, there is an increasing tendency for hypoglycemia at 11 a.m. and 5 p.m. and 3 a.m., requiring either snacking or decreased basal or both. These patterns are largely sustained even on PMs and nights.”

DIET MODIFICATION“The literature is sparse, which perpetuates the problem in regards to finding a best practice. The patients that I have that do the best are the ones that keep their days and nights on the same sched-ule. This is very challenging because of hormone release that affects appetite, stress, etc. Most of my patients struggle but I encourage them to pack the same foods for a night shift as they would for a day shift and attempt to eat at intervals similar to the day shift. As I said, it is quite challenging, but the patients that can do this do very well.”

LEGAL CASE“Many years ago, I represented a USPS worker with Type I. He was assigned to rotating shifts, but was requesting a single daytime shift to control his blood sugars. His treating physician supported his request, but an examining physician did not. Unfor-tunately, there were two other physicians who had examined him as a part of a worker’s compensation claim who also did not support his request. They were never disclosed as experts in his ADA case, but their reports were allowed to cross the treating physician who admitted, when confronted with the two reports, that if my client was really strict and observant in testing and eating, he could prob-ably work rotating shifts. Also undisclosed until days before trial were surveillance films (the U.S. attorney truthfully said he knew of none, but just before trial, the worker’s comp people gave him the films, and the judge let them in). Those films showed him doing yard work and loading cardboard boxes into his pickup truck. Although I got past S/J due to the combination of the two (I believe) evidence errors by the court, the jury found against him. I recall there was an agreement if we did not appeal, the USPS would not seek costs, e.g., expert witness fees, etc.”

SUMMARYAs one can see, there are a number of approaches to this common problem. If you have a different solution, please feel free to send it to the Ameri-can Diabetes Association Legal Advocacy listserv ([email protected]). Even better—join us in fighting for fair employment for people with diabetes by going to www.diabetes.org/patientrights and signing up. PD

COMMENTARY

CHRONOBIOLOGY AND TYPE 2 DIABETES MELLITUS

When patients tell us that they think the stress of their job or lifestyle caused their diabetes, we often talk to them about how they could make their life-styles healthier. We may even discuss the effect stress can exert on cortisol regulation, which could contrib-ute to diabetes but certainly does not cause it. But how often do we consider the causal role circadian rhythms play in the development of hyperglycemia? Examples of environmental influences that alter circadian rhythms include shift work—especially rotating shifts—and inadequate sleep, which are common risk factors for diabetes.

When people think of circadian rhythms, they don’t typically think of the molecular mechanisms that underlie these patterns. Circadian clocks are ancient programming that has been conserved in most organisms. They represent a complex time-keeping mechanism that is controlled both at the level of gene transcription and protein translation to coordinate body processes throughout the ambi-ent 24-hour light/dark cycle. While the circadian pattern of regulation of these genes is set by the Earth’s 24-hour cycle, there is some modulation of these genes by certain environmental cues such as exposure to light, temperature and food intake, thereby allowing adaptation to schedules other than the classic 9-to-5 schedule.

Controlling circadian rhythmsIn mammals, the circadian system is organized as a multilevel oscillator network. The pacemaker (or master clock) is located in the suprachiasmatic nucleus (SCN) of the hypothalamus, where it receives infor-mation from specialized ganglion cells in the retina, synchronizing the body’s clock to the solar day. In fact, exposure to sunlight is the most important stimulus to develop and maintain the body’s clock. The SCN then establishes the circadian rhythms throughout the body using a combination of neural, endocrine and systemic outputs. The pancreatic beta-cell is actually one of the organs in the body that responds to the output from the SCN to develop a circadian pattern to the oscillations of islet cell gene transcrip-tion and insulin secretion. The most detailed studies have been completed in animal models of diabetes in which experimental disruption of circadian rhythms led to a rise in glucose, accelerated loss of beta-cell function, decreased beta-cell mass and increased insulin resistance. In contrast, studies of rats who were not prone to diabetes found no disruption of

circadian rhythms on glucose homeostasis. Human studies are still needed to confirm these findings but they do suggest that if one is prone to diabetes, i.e., has a family history of diabetes, then interruption of circadian rhythms could potentially accelerate the progression to hyperglycemia.

Genetic regulation of the circadian clockAt the molecular level, the mammalian circadian clock is composed of several “clock genes” and proteins involved in hour transcription-translation feedback loops that function on a 24-hour clock. One arm of this loop includes activation of the genes Circadian Loco-motor Output Cycles Kaput (CLOCK) and brain and muscle ARNT-like 1 (BMAL1) that encode the basic helix-loop-helix Per-Arnt-Single-minded (bHLH-PAS) proteins that form the CLOCK-BMAL1 activa-tor complexes and initiate transcription of target genes by binding to specific DNA sequences (E-boxes) in their promoter regions. These target genes include Period (Per1/2/3) and Cryptochrome (Cry1/2), which make up the negative limb of the feedback loop. PER and CRY proteins form heterodimers and inhibit the transcriptional activation by CLOCK-BMAL1, allowing the circadian cycle to repeat itself. Posttrans-lational modifications of clock-regulated proteins such as phosphorylation, ubiquitination and sumoylation control stability of proteins necessary to establish the 24-hour-clock period and maintain the ongoing pro-gression of the circadian cycle. GWAS studies have shown that approximately 3-20 percent of all genes may be under circadian control. In general, these are genes related to vital cellular processes and functions.

Beta-cells and circadian rhythmsNormal pancreatic beta-cell function involves con-tinuous pulsatile insulin release to maintain glucose homeostasis augmented by larger pulses in response to stimuli such as meals. We often are taught that the development of Type 2 diabetes starts with a “loss of first phase and delayed/prolonged second phase insulin release.” We now know that changes in the insulin secretion patterns start prior to the onset of hyperglycemia as even normoglycemic first-degree relatives of patients with Type 2 diabetes demonstrate abnormalities in the secretion of insulin. While the progressive loss of insulin secretory capability clearly plays a role in diabetes development, we do not know how to predict when this will happen or how quickly it will develop. Molecular studies have shown that

Kathleen Wyne, MD, PhD, FACE, FNLA Associate Professor, Division of Endocrinology, Diabetes and Metabolism The Ohio State University, Wexner Medical Center Columbus, OH

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loss of beta-cells through apoptosis can be increased by prolonged exposure to high glucose levels and/or high free fatty acid levels, which activate endoplasmic reticulum, oxidative and inflammatory stress pathways, leading to cell death. Loss of beta-cell insulin secre-tory ability is also multifactorial, including changes in glucose transport, glucose oxidation, increase in reac-tive oxygen species (ROS), leading to mitochondrial dysfunction and impaired exocytosis. Appropriate circadian activation of the feedback loops controlled by the CLOCK and BMAL1 genes could help main-tain the balance of oxidative stress and mitochondrial function in the beta-cell, thereby maintaining beta-cell mass through controlled apoptosis and appropriate insulin secretion. In fact, animal studies of genes identi-fied as playing a role in controlling this feedback loop have shown that targeted disruption of the beta-cell molecular clock, depending on the specific gene, can lead to abnormalities at all levels of glucose sensing, insulin secretion and maintenance of beta-cell mass. These data suggest that any disruption of the circadian clock could lead to hyperglycemia and Type 2 diabetes.

Control of the beta-cell molecular clock is not only internal but also external through stimuli such as cortisol and leptin. These hormones are known to have very specific circadian patterns, including controlling the morning rise in glucose prior to awakening for the day. Studies have shown that disruption of the light-dark cycle, whether in the experimental setting with animal models or through shift work, travel or loss of sleep, causes alteration in levels of cortisol. Similarly, stress can lead to sustained increases in cortisol. Taken together, disruption of the circadian patterns for these hormones could play a role in altered beta-cell func-tion, leading to sustained hyperglycemia.

Alteration of circadian rhythms in Type 2 diabetesEpidemiologic surveys of workers in a variety of professions have shown that rotational shift work is

associated with an increased incidence of Type 2 dia-betes. Rotational shift-work jobs entail shift changes every few days, such as from day shift to afternoon shift to night shift and then several days off before the cycle starts over. Additionally, changes in sleep patterns or decreased sleep have been associated with an increase in Type 2 diabetes. Studies in humans have shown that acute loss of sleep can impact glucose homeostasis in as little as one to three weeks. What is not definitively known is whether this only occurs in those at risk for Type 2 diabetes, as observed in the animal studies, or if the changes in glucose also occur in those with no family history of Type 2 diabetes. Despite large GWAS studies, the gene(s) responsible for Type 2 diabetes remains largely unknown. With regard to the role of the circadian clock in maintenance of beta-cell health, one must consider that subtle mutations in one or more of the clock-regulated genes could lead to a predisposition to Type 2 diabetes that is then exacerbated by a lifestyle with a fluctuating light-dark cycle.

SummaryMolecular studies have identified genes that are crucial for maintaining circadian rhythms. Targeted disruption of some of these genes has led to Type 2 diabetes in animal studies. Lifestyle factors such as shift work and high levels of stress lead to alterations in circadian rhythms and may disrupt the molecular clock mechanisms, resulting in permanent altera-tions of pancreatic beta-cell function. The clinical implication of tying together these pieces of infor-mation is that the patients are probably right when they say that stress caused their diabetes—or at least partially right, because the stress, whether physical or emotional, probably altered the patterns of their circadian clock, thereby bringing on their diabetes at a younger age than would have been expected from their genetic predisposition. PD

SELECTED REFERENCESBoden, G., Ruiz, J., Urbain, J. and Chen, X. (1996). Evidence for a circadian rhythm of insulin secretion. American Journal of Physiology-Endocrinology and Metabolism, 271(2), pp.E246-E252.Coomans, C., van den Berg, S., Lucassen, E., Houben, T., Pronk, A., van der Spek, R., Kalsbeek, A., Biermasz, N., Willems van Dijk, K., Romijn, J. and Meijer, J. (2012). The Su-prachiasmatic Nucleus Controls Circadian Energy Metabolism and Hepatic Insulin Sen-sitivity. Diabetes, 62(4), pp.1102-1108. Gale, J., Cox, H., Qian, J., Block, G., Colwell, C. and Matveyenko, A. (2011). Disruption of Circadian Rhythms Accelerates Devel-opment of Diabetes through Pancreatic Beta-Cell Loss and Dysfunction. Journal of Biological Rhythms, 26(5), pp.423-433. Green, C., Takahashi, J. and Bass, J. (2008). The Meter of Metabolism. Cell, 134(5), pp.728-742.

Marcheva, B., Ramsey, K., Buhr, E., Kobayashi, Y., Su, H., Ko, C., Ivanova, G., Omura, C., Mo, S., Vitaterna, M., Lopez, J., Philipson, L., Bradfield, C., Crosby, S., JeBailey, L., Wang, X., Takahashi, J. and Bass, J. (2010). Disrup-tion of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and dia-betes. Nature, 466(7306), pp.627-631. Mikuni, E., Ohoshi, T., Hayashi, K. and Mi-yamura, K. (1983). Glucose intolerance in an employed population. The Tohoku Jour-nal of Experimental Medicine, 141(Suppl), pp.251-256.Morris, C., Purvis, T., Mistretta, J. and Scheer, F. (2016). Effects of the Internal Circadian System and Circadian Misalignment on Glucose Tolerance in Chronic Shift Work-ers. The Journal of Clinical Endocrinology & Metabolism, 101(3), pp.1066-1074.

Petrenko, V., Saini, C., Giovannoni, L., Gobet, C., Sage, D., Unser, M., Heddad Masson, M., Gu, G., Bosco, D., Gachon, F., Philippe, J. and Dibner, C. (2017). Pancreatic α- and β-cellular clocks have distinct molecular properties and impact on islet hormone secretion and gene expression. Genes & De-velopment, 31(4), pp.383-398.Sadacca, L., Lamia, K., deLemos, A., Blum, B. and Weitz, C. (2010). An intrinsic circadian clock of the pancreas is required for normal insulin release and glucose homeostasis in mice. Diabetologia, 54(1), pp.120-124.Saini, C., Petrenko, V., Pulimeno, P., Giovan-noni, L., Berney, T., Hebrok, M., Howald, C., Dermitzakis, E. and Dibner, C. (2016). A functional circadian clock is required for proper insulin secretion by human pancre-atic islet cells. Diabetes, Obesity and Metab-olism, 18(4), pp.355-365.

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JOURNAL WATCH

A Phase 3 Study to Evaluate the Safety of Sotagliflozin in Patients with Type 1 Diabetes Who Have Inadequate Glycemic Control with Insulin Therapy Alone

Study Title Acronym: inTandem3

ClinicalTrials.gov Identifier: NCT02531035

References (related): 1. Sands, A.T., Zambrowicz, B.P., Rosenstock, J., Lapuerta, P., Bode, B.W., Garg, S.K., Buse, J.B., Banks, P., Heptulla, R., Rendell, M., Cefalu, W.T. and Strumph, P. (2015). Sotagliflozin, a Dual SGLT1 and SGLT2 Inhibitor, as Adjunct Therapy to Insulin in Type 1 Diabetes. Diabetes Care, 38(7), pp.1181-8. PMID: 260495512. Garg, S.K., Henry, R.R., Banks, P., Buse, J.B., Davies, M.J., Fulcher, G.R., Pozzilli, P., Gesty-Palmer, D., Lapuerta, P., Simó, R., Danne, T., McGuire, D.K., Kushner, J.A., Peters, A. and Strumph, P. (2017). Effects of Sotagliflozin Added to Insulin in Patients with Type 1 Diabetes. N Engl J Med,377(24), pp.2337-2348. PMID: 28899222

Sponsor: Lexicon Pharmaceuticals

Study Design: Randomized parallel assignment of sotagliflozin vs. placebo

Primary Outcome Measure: A1c level lower than 7.0% at week 24, with no episodes of severe hypogly-cemia or diabetic ketoacidosis after randomization

Results: The primary endpoint was achieved by 200 of 699 patients [28.6%] in the sotagliflozin group compared with 107 of 703 [15.2%] in the placebo group, P<0.001). The least-squares mean change from baseline was significantly greater in the sotagliflozin group than in the placebo group for A1C (difference, −0.46 percentage points), weight (−2.98 kg), systolic blood pressure (−3.5 mm Hg), and mean daily bolus dose of insulin (−2.8 units per day) (P≤0.002 for all comparisons). The rate of severe hypoglycemia was similar in the two groups, while overall documented hypo-glycemia with a blood glucose level of 55 mg per

deciliter or below was significantly lower in the sotagliflozin group than in the placebo group. The rate of diabetic ketoacidosis was higher (3.0% [21 patients] in the sotagliflozin group compared with the placebo group 0.6% [4 patients).

Summary: These data show that sotagliflozin could be a valuable adjunct therapy in T1D that would not only lower glucose but also weight and SBP. The challenge will be to determine how to predict, and prevent, DKA such that this com-pound could be used safely in patients with T1D.

Thiazolidinediones or Sulphonylureas and Cardiovas-cular Accidents.Intervention Trial

Study Title Acronym: TOSCA.IT


Reference (related):Vaccaro, O., Masulli, M., Nicolucci, A., Bonora, E., Del Prato, S., Maggioni, A.P., et al., for the Thiazolidinediones Or Sulfonylureas Cardio-vascular Accidents Intervention Trial (TOSCA.IT) study group; Italian Diabetes Society. (2017). Effects on the incidence of cardiovascular events of the addition of pioglitazone versus sulfonyl-ureas in patients with type 2 diabetes inadequately controlled with metformin (TOSCA.IT): a ran-domised, multicentre trial. Lancet Diabetes Endo-crinol, 5(11), pp.887-897. PMID: 28917544

Sponsor: Italian Society of Diabetology

Collaborators: Associazione Medici Diabetologi (AMD) and Associazione Nazionale Medici Car-diologi Ospedalieri

Study Design: Open-label randomized parallel assignment

Primary Outcome Measure: A composite end-point including all-causes mortality, nonfatal MI (including silent MI), nonfatal stroke and unplanned coronary revascularization

This column highlights recent clinical trial data and landmark trials to provide relevant information and links for obtaining trial data and articles to facilitate discussion with patients and other providers. The trial is identified by its acronym, its ClinicalTrials.gov Identifier (NCT Number) and its journal reference. When possible, the reference will include the study design paper and the main outcomes. If the Clinical Trial Study Group has made a slide set available, the link will be included. A summary provides primary outcome results. Selected abstracts also may be highlighted with a summary of the main points.

Results: TOSCA.IT was a multicenter, random-ized, pragmatic clinical trial in which patients ages 50 to 75 years with Type 2 diabetes inad-equately controlled with metformin monotherapy (2-3 g per day) were recruited from 57 diabetes clinics in Italy. Patients were randomly assigned (1:1) by permuted blocks randomization, strati-fied by site and previous CV events, to add on pioglitazone (15-45 mg) or a sulfonylurea (5-15 mg glibenclamide, 2-6 mg glimepiride or 30-120 mg gliclazide, in accordance with local practice). The trial was unblinded, but event adjudicators were unaware of treatment assignment.

In all, 3,028 patients were randomly assigned, with 1,535 assigned to pioglitazone and 1,493 to sulfonylureas (glibenclamide 24 [2%], glimepiride 723 [48%], gliclazide 745 [50%]).

The study was stopped early on the basis of a futility analysis after a median follow-up of 57.3 months. The primary outcome occurred in 105 patients (1.5 per 100 person-years) who were given pioglitazone and 108 (1.5 per 100 person-years) who were given sulfonylureas (hazard ratio 0·96, 95% CI 0·74-1·26, p=0·79).

Fewer patients had hypoglycemias in the piogli-tazone group than in the sulfonylureas group (148 [10%] vs. 508 [34%], p<0·0001). Moderate weight gain (less than 2 kg, on average) occurred in both groups. Rates of heart failure, bladder cancer and fractures were not significantly different between treatment groups.

Summary: Unfortunately, the study was stopped early for futility. Therefore, it is not able to prove CV safety of SUs. The futility may be related to the fact that event rates were very low and lower than what has typically been seen in recent CVOTs. However, it does provide safety data regarding both pioglitazone and SU with respect to CV events, rates of heart failure and TZD-spe-cific events such as fractures and bladder cancer. Although there was no CV benefit, the safety data suggest that both pioglitazone and SUs should still be considered as part of combination therapy for glucose control.

Exenatide Study of Cardiovascular Event Lowering

Study Title Acronym: EXSCEL


References (related): 1. Holman, R.R., Bethel, M.A., George, J., Sourij, H., Doran, Z., Keenan, J., Khurmi, N.S., Mentz, R.J., Oulhaj, A., Buse, J.B., Chan, J.C., Iqbal, N., Kundu, S., Maggioni, A.P., Marso, S.P., Öhman, P., Pencina, M.J., Poulter, N., Porter, L.E., Ram-achandran, A., Zinman, B. and Hernandez, A.F. (2016). Rationale and design of the EXenatide Study of Cardiovascular Event Lowering (EXS-CEL) trial. Am Heart J, 174, pp.103-10. PMID: 269953762. Mentz, R.J., Bethel, M.A., Gustavson, S., Thompson, V.P., Pagidipati, N.J., Buse, J.B., Chan, J.C., Iqbal, N., Maggioni, A.P., Marso, S.P., Ohman, P., Poulter, N., Ramachandran, A., Zinman, B., Hernandez, A.F. and Holman, R.R. (2017). Baseline characteristics of patients enrolled in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL). Am Heart J, 187, pp.1-9. PMID: 284547923. Holman, R.R., Bethel, M.A., Mentz, R.J., Thompson, V.P., Lokhnygina, Y., Buse, J.B., Chan, J.C., Choi, J., Gustavson, S.M., Iqbal, N., Maggioni, A.P., Marso, S.P., Öhman, P., Pagidipati, N.J., Poulter, N., Ramachandran, A., Zinman, B. and Hernandez, A.F.; EXSCEL Study Group. (2017). Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med, 377, pp.1228-1239. PMID: 28910237

Sponsor: Amylin Pharmaceuticals; AstraZeneca

Study Design: Randomized parallel assignment of 14752 participants allocated to exenatide once weekly or placebo

Primary Outcome Measure: Composite of cardio-vascular death, nonfatal MI or nonfatal stroke

Results: After a median of 3.2 years, 839 of 7,356 patients (11.4%; 3.7 events per 100 person-years) in the exenatide group and 905 of 7,396 patients (12.2%; 4.0 events per 100 person-years) in the placebo group developed either CV death, non-fatal MI or nonfatal stroke (hazard ratio, 0.91; 95% confidence interval [CI], 0.83 to 1.00).

Kathleen Wyne, MD, PhD, FACE, FNLA Associate Professor, Division of Endocrinology, Diabetes and Metabolism The Ohio State University, Wexner Medical Center Columbus, OH


Intention-to-treat analysis indicated that once-weekly exenatide was noninferior to placebo with respect to safety (P<0.001 for noninfe-riority) but was not superior to placebo with respect to efficacy (P=0.06 for superiority). The rates of death from CV causes, fatal or nonfatal MI, fatal or nonfatal stroke, hospitalization for heart failure, and hospitalization for ACS, and the incidence of acute pancreatitis, pancreatic cancer, medullary thyroid carcinoma and seri-ous adverse events did not differ significantly between the two groups.

Summary: Unlike the liraglutide CVOT, this trial involving a different GLP-1 RA did not find a CV benefit for weekly exenatide. However, it is reassuring that there was no increase in hospi-talization for heart failure, no increase in serious adverse events and no increase in medullary thy-roid carcinoma. Therefore, this remains a valu-able agent for glucose lowering, but does not have any additional nonglycemic benefits.

FOURIER (Further cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk) Prespecified Analysis CV Safety and Efficacy of the PCSK9 Inhibitor Evo-locumab in Patients with and without Diabetes and the Effect of Evolocumab on Glycaemia and Risk of New-Onset Diabetes

Study Title Acronym: FOURIER Diabetes


References (related): 1. Sabatine, M.S., Giugliano, R.P., Keech, A., et al. (2016). Rationale and design of the Further cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk trial. Am Heart J, 173, pp.94-101. PMID: 269206012. Sabatine, M.S., Giugliano, R.P., Keech, A.C., Honarpour, N., Wiviott, S.D., Murphy, S.A., Kuder, J.F., Wang, H., Liu, T., Wasserman, S.M., Sever, P.S. and Pedersen, T.R.; FOURIER Steering Committee and Investigators. (2017). Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med, 376, pp.1713-1722. PMID: 283042243. Sabatine, M.S., Leiter, L.A., Wiviott, S.D., Giugliano, R.P., Deedwania, P., De Ferrari, G.M., Murphy, S.A., Kuder, J.F., Gouni-Berthold, I., Lewis, B.S., Handelsman, Y., Pineda, A.L., Hon-arpour, N., Keech, A.C., Sever, P.S. and Pedersen, T.R. (2017). Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a pre-specified analysis of the FOURIER randomised

controlled trial. Lancet Diabetes Endocrinol, 5, pp.941-950. PMID: 28927706

Sponsor: Amgen

Study Design: Randomized placebo controlled parallel assignment of 27,564 participants

Primary Outcome Measure: FOURIER: The primary endpoint is the time to cardiovascular death, myocardial infarction, hospitalization for unstable angina, stroke or coronary revasculariza-tion, whichever occurs first.

Prespecified Diabetes Analysis: 1. CV efficacy and safety of evolocumab by base-line diabetes status: composite of CV death, MI, stroke, coronary revascularisation or hospital admission for unstable angina2. Risk of new-onset diabetes among patients who did not have diabetes at baseline

Results: In all, 27,564 participants were random-ized, of which 11,031 (40%) had diabetes and 16,533 (60%) did not have diabetes (of whom 10,344 had prediabetes and 6,189 had normoglycemia).

Evolocumab significantly reduced CV outcomes consistently in patients with and without diabetes at baseline. For the primary composite endpoint, the hazard ratios (HRs) were 0.83 (95% CI 0.75–0.93; p=0·0008) for patients with diabetes and 0.87 (0.79–0.96; p=0·0052) for patients without diabetes.

Levels of A1C and FPG were similar between the evolocumab and placebo groups over time in patients with diabetes, prediabetes or normogly-caemia. Evolocumab did not increase the risk of new-onset diabetes in patients without diabetes at baseline (HR 1.05, 0.94–1.17), including in those with prediabetes (HR 1.00, 0.89–1.13).

Summary: The two important points that were learned from this analysis are:1. there is no increase in diabetes in people treated with this PCSK9 inhibitor; and2. the addition of the PCSK9 inhibitor, evo-locumab, to statin therapy for patients with dia-betes whose LDL-C was not below 70 mg/dL is associated with a decrease in MACE with a benefit that starts in the first year then increases dramatically after the first year of therapy.

Based on these data, one needs to consider PCSK9 therapy for anyone with diabetes and a history of ASCVD who has not attained an LDL-C below 70 on statin therapy. However, because the CV event rates was not lowered to that of the participants without diabetes it seems reasonable to conclude that there are more factors that must be consid-ered for CV prevention in people with diabetes.

Continuous Glucose Monitoring in Women with Type 1 Diabetes in Pregnancy Trial

Study Title Acronym: CONCEPTT


References (related): 1. Feig, D.S., Asztalos, E., Corcoy, R., De Leiva, A., Donovan, L., Hod, M., Jovanovic, L., Keely, E., Kollman, C., McManus, R., Murphy, K., Ruedy, K., Sanchez, J.J., Tomlinson, G. and Mur-phy, H.R.; CONCEPTT Collaborative Group. (2016). CONCEPTT: Continuous Glucose Monitoring in Women with Type 1 Diabetes in Pregnancy Trial: A multi-center, multi-national, randomized controlled trial - Study protocol. BMC Pregnancy Childbirth, 16, p.167. Erratum in: BMC Pregnancy Childbirth, 16, p.249. PMID: 274307142. Feig, D.S., Donovan, L.E., Corcoy, R., Mur-phy, K.E., Amiel, S.A., Hunt, K.F., Asztalos, E., Barrett, J.F.R., Sanchez, J.J., de Leiva, A., Hod, M., Jovanovic, L., Keely, E., McManus, R., Hutton, E.K., Meek, C.L., Stewart, Z.A., Wysocki, T., O’Brien, R., Ruedy, K., Kollman, C., Tomlinson, G. and Murphy, H.R.; CON-CEPTT Collaborative Group. (2017). Continuous glucose monitoring in pregnant women with type 1 diabetes (CONCEPTT): a multicentre interna-tional randomised controlled trial. Lancet, 390, pp.2347-2359. Erratum in: Lancet, 390(10110), p.2346. PMID: 28923465

Sponsor: Mount Sinai Hospital, Canada

Collaborators: Sunnybrook Research Institute; Jaeb Center for Health Research; Cambridge University Hospitals NHS Foundation Trust; University of Cambridge

Funding Obtained From: Juvenile Diabetes Research Foundation, Canadian Clinical Trials Net-work and National Institute for Health Research.

Study Design: Multicenter, open-label, ran-domized controlled trial with parallel trials for pregnant participants and participants plan-ning pregnancy. In both trials, participants were randomly assigned to either CGM in addition to capillary glucose monitoring or cap-illary glucose monitoring alone with random-ization stratified by insulin delivery (pump or injections) and baseline A1C.

Primary Outcome Measure: Change in A1C from randomization to 34 weeks’ gestation in pregnant

women and to 24 weeks or conception in women planning pregnancy

Results: In all, 325 women (215 pregnant, 110 planning pregnancy) were randomized as follows:

• capillary glucose monitoring with CGM: 108 pregnant and 53 planning pregnancy; and

• capillary glucose monitoring without CGM: 107 pregnant and 57 planning pregnancy).

There was a small difference in pregnant women using CGM (mean difference -0·19%; 95% CI -0·34 to -0·03; p=0·0207). Pregnant CGM users spent more time in target (68% vs. 61%; p=0·0034) and less time hyperglycemic (27% vs. 32%; p=0·0279) than did pregnant control participants, with com-parable severe hypoglycemia episodes (18 CGM and 21 control) and time spent hypoglycemic (3% vs. 4%; p=0·10). Neonatal health outcomes were significantly improved, with lower incidence of large for gestational age (odds ratio 0·51, 95% CI 0·28 to 0·90; p=0·0210), fewer neonatal intensive care admissions lasting more than 24 hours (0·48; 0·26 to 0·86; p=0·0157), fewer incidences of neonatal hypoglycemia (0·45; 0·22 to 0·89; p=0·0250), and one-day shorter length of hospital stay (p=0·0091). The primary outcome did not demonstrate an appar-ent benefit of CGM in women planning pregnancy.

Summary: This study shows that use of CGM in pregnancy does increase time in range and decreases hyperglycemia. Interestingly, there was no decrease in hypoglycemia, although the time below range was very low at 3-4%. Based on these data, one could argue that use of CGM should now be standard of care for all pregnant women who have Type 1 diabetes.

It is interesting that the group planning for preg-nancy did not show a benefit when using CGM. It would be of interest to compare these women to age-matched controls who are not planning for pregnancy to see if their overall control was better than one would expect for their age. PD


EDUCATOR’S CORNER

YOGA IN THE CLINICThis edition of “Educator’s Corner” defines and describes yoga and its common components, evalu-ates the scientific evidence of yoga as an adjunc-tive treatment modality for diabetes, and provides “practice pearls” for implementing yoga in the clinic and/or in diabetes self-management cur-ricula and programs.

The science of yoga is rooted in traditional Indian medicine. Ancient texts vividly describe clinical features and complications of what modern medicine labels as Type 1 diabetes and Type 2 diabetes.1 In Ayurveda, a component of the traditional Indian medical system, the Sanskrit word for diabetes mel-litus is “madhumeha,” which translates as “sweet urine” disease. In these ancient texts, treatment of madhumeha was based on the associated clinical features (i.e., body anthropometrics—thin ver-sus overweight) and typically included meditation (dhyana) and mantra (dharana), breathing exercises (pranayama), dietary regimens (i.e., herbs and spices, various combinations of dietary protein and fat) and physical movement—yoga postures (asanas).2 This ancient or Eastern approach in many ways parallels current allopathic or Western evidenced-based prac-tice of lifestyle modification to include an individu-alized nutrition prescription, stress management, relaxation response training and positive coping skills, and purposeful movement with a reduction in sedentary behaviors.3 The latter can be accomplished in a ‘two-for-one’: yoga. Is there evidence that yoga, a mindful-coordination of breath with movement, facilitates improvements in biomarkers (glycemic control, hemodynamic response, metabolic indices, and psychosocial parameter) of diabetes health?

Over the last decade or so, there has been an increase in the number of scientific publications 1,5,6,8,9 as well as lay articles11 on the behavioral and biomedical benefits of yoga on various chronic-lifestyle diseases such as cardiovascular disease,5,9,12 anxiety,5,8,9,10 depression,5,8,9,10 post-traumatic stress disorder,5,8,9 disordered eating and eating disor-ders,13-15 obesity,16 chronic pain,17-20 cancer21, 22 and diabetes.1,6,12,12, 23, 25-28

Despite methodological issues (i.e., limited sample size, lack of blinding and randomization in some studies, sparse analytics in others, hetero-geneity, clinical versus statistical significance, and lack of comparators), the preponderance of data nonetheless indicates improved physiological and psychological benefits of yoga in those with diabetes, most notably those with Type 2 diabetes.

Evidence of yoga’s benefitsA pilot study comparing a yoga intervention with a walking control group reported a significant decrease in weight, BMI and waist circumference compared to the walking group. Reductions in fasting blood sugar (FBS), postprandial blood glucose (PPBG), serum insulin, insulin resistance, blood pressure or cholesterol were not observed. The researchers also noted statistically significant improvements in measures of psychological well-being in both groups.23 Interestingly, noted improvements in mood and positive affect, which were greater in the yoga group, are of clinical and empirical interest. One large randomized controlled trial found that increas-ing positive affect significantly improved physical activity maintenance at one year.24 This suggests a potential positive behavior change advantage for the yoga group versus the walking group.

In a randomized parallel study of a three-month yoga intervention in individuals with Type 2 dia-betes, researchers observed significant (p<0.05) reductions in total cholesterol (TC), LDL cholesterol (LDL-c) and triglycerides (TG) with a nonsignifi-cant elevation in HDL cholesterol (HDL-c) in the

YOGA DICTIONARYAsana: Sanskrit word meaning “physical posture or pose”4

Dharana: Sanskrit word meaning “focused or intentional concentration”4

Dhyana: Sanskrit word for “meditation”4

Hatha yoga: specific branch or style of yoga that predominantly focuses on the asanas or activity with a secondary focus on dharana and dhyana. In Western cultures, hatha yoga itself encompasses such styles as Ashtanga, Bikram, Iyengar, Kundalini, Viniyoga and Vinyasa. In the U.S., hatha yoga is characteristically but inaccurately considered a gentler or less vigorous style of yoga.4-6

Mantra: syllable, sound (i.e., “OM”), word phrase or affirmation repeated aloud or in one’s conscious thought intended to provide dharana (focus) in preparation for or as part of dhyana (meditation)4

Mindfulness: moment-by-moment nonjudgmental (observational) awareness7

Mudra: hand placement or hand gesture typically used in meditation4

Pranayama: focused breath work such as diaphragmatic (belly breathing) or ujjayi (ocean) breathing or alternate nostril breathing4

yoga group versus the control group. The yoga group also had a nonsignificant reduction in BMI and a significant reduction in both weight and waist-to-hip ratio. Interestingly and unfortunately, the con-trol group did not fare so well, showing significant increases in body weight, nonsignificant increases in BMI, TC, LDL-c and TG, and a corresponding decrease in HDL-c.12

Though yoga itself is considered a type of mind-fulness in many circles, a recent study compared standard care plus yoga asana combined with mind-

fulness eating on glycemic parameters in women with gestational diabetes. The results revealed statistically significant (p<0.05) improvements in FBS, PPBG and HbA1c in the intervention group (standard care plus yoga asana and mindfulness eating) versus the control group (standard care alone).25

Mixed resultsA more recent paper also evaluated a dual interven-tion of yoga and peer support on glycemic control, pharmacological adherence and anthropometric Katherine Stephens-

Bogard, MS, RDN, CDE Registered yoga teacher Program coordinator, St. Mary’s Life Center, Diabetes Education & Nutrition Grand Junction, Colorado

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measures. This open-label, parallel three-armed ran-domized controlled trial compared a yoga interven-tion plus continuation of current pharmacotherapy and nutrition prescription, peer support with con-tinuation of medications and diet, and standard care (oral meds plus basic lifestyle education). Results were mixed: FBS improved in all three groups but did not reach statistical significance, with the yoga group experiencing the greatest improvement. The yoga cohort also experienced a decrease in HbA1c, while the other two cohorts experienced an increase in HbA1c. Again, these differences did not reach statistical significance. Relative to pharmacothera-peutic adherence, all three groups benefitted from their respective interventions, but again, the results did not reach statistical significance. Other meta-bolic biomarkers (blood pressure, lipidemia and anthropometric measures) were similarly mixed: improvements in diastolic blood pressure and hip circumference in the yoga intervention compared to the other groups were statistically significant, but other markers were variable (i.e., null change or slight change not reaching statistical significance in the direction of yoga and peer support). The researchers concluded that the interventions showed incremental improvements without significant adverse effects, and that longer duration studies with larger sample sizes are needed to ascertain the absolute benefits of the interventions.26

Two recent systematic reviews and meta-analyses of yoga for adults with Type 2 diabetes were likewise inconclusive about the absolute benefits of yoga for improving diabetes outcomes. However, yoga

may yield benefits as an adjunct to standard care. Of interest, a review of 17 randomized controlled trials documented beneficial effects of yoga as an adjunctive treatment to standard care (medication, lifestyle education and support) that reached statis-tical significance (p<0.00001) for FBS, PPBG and HbA1c.27 Furthermore, an incredibly comprehensive review article noted the additive benefits of yoga to standard care on glycemic control (FBS, PPBG, HbA1c, serum insulin), lipids (decreased TC, LDL-c, TG and increased HDL-c) and anthropometric measures (body weight, BMI and waist-to-hip ratio). Although the data were more limited for other health indices, yoga interventions showed potential to lower oxidative stress and blood pressure, enhance pulmonary and autonomic nervous system func-tion, mood, sleep and quality of life, while possibly reducing medication usage.6

SummaryDespite methodological issues, quantitative studies have demonstrated physiological improvements with a yoga intervention. Concurrently, these papers and others have proposed the mechanisms by which yoga improves said indices. And although the risk-to-benefit ratio is favorable, one question remains: on a qualitative patient experience level, does it matter? While participants of a yoga study stated, “I could move mountains,” Alexander et al. concluded that maintaining a yoga practice presents challenges simi-lar to adopting other lifestyle changes. Furthermore, they emphasized the necessity of diabetes educators and related clinicians to support the adoption and

BRING YOGA TO LIFE1. Write a yoga (a.k.a. movement or exercise) pre-scription for your patients. Studies show that when “exercise” is written on a prescription pad, patients are more likely to follow through.29-31 Since most yoga classes last 60 to 75 minutes, write “attend 2 yoga classes weekly.” Thus, patients would achieve at least 120 minutes to quite possibly the recom-mended 150 minutes weekly of movement.29-31 2. Create a list of yoga studios or classes in your service area. Rural communities often offer classes at a YMCA, Jewish community centers, community recreation centers and/or senior living programs/fa-cilities. Patients in suburban and metropolitan areas are likely to have these same locations as well as yoga studios. Many large teaching hospitals often have classes on site. 3. If teaching diabetes self-management training (DSMT) classes, invite a qualified registered yoga teacher (RYT) through Yoga Alliance (yogaalliance.org) to teach pranayama, a guided meditation, or gentle asana sequence as part of the curricula. De-pending on the curriculum’s written language, this

kinesthetic learning module could fall under either exercise or coping/stress management. 4. Alternatively, if inclusion as part of the DSMT cur-ricula is not feasible, offer yoga and guided medita-tion as a topic for a support group meeting.5. Create yoga asana, pranayama and meditation stress management handouts. Be sure to include a list of apps or DVDs.6. If your lobby or waiting area has closed circuit TV or other educational audio or video, include a module or loop of gentle yoga asana or guided meditation. 7. Take a class or two yourself. Better yet, buy a pass to your local yoga studio. Commit to 150 minutes of classes weekly—the minimum amount of time recommended for health benefits—for the duration of the pass. Not only will you personally reap the benefits of yoga, you may also develop a greater ap-preciation of the challenge of implementing lifestyle changes.32 Although I believe we as educators and clinicians are a passionate and compassionate group, it is equally humbling and rewarding to walk in an-other’s shoes, even if only for a moment.

maintenance of all lifestyle changes.28

So, the next question is, how to bring yoga to the clinic? The sidebar provides seven ideas—one for each day of the week—to bring “Yoga to Life!”

As teachers—be it certified diabetes educa-tors, mid-level practitioners or physicians—we are called upon to teach, inspire and motivate patients to follow our individualized but evi-denced-based recommendations. You can be

certain that recommending movement in the form of yoga asana will, at least, decrease sedentary behavior and quite possibly improve glycemia, lipidemia, anthropometry, sleep hygiene, mood and positive affect.

Traditionally yoga classes end with the saluta-tion “Namaste.” In Sanskrit, this loosely translates as “the teacher in me salutes the teacher in you.”4

Namaste! PD

REFERENCES 1. Sahay, B.K. (2007). The role of yoga in diabetes. JAPI, 55, pp.121-126.2. Patel, S. A mind body approach to diabetes. Available at http://www.cho-pra.com/articles/mind-body-approach-diabetes#sm accessed 7/1/2017.3. Powers, M.A, Bardsley J., Cypress, M., Duker, P., Funnell, M.M., Fischl, A.H., Marynuik, M.D., Siminerio, L. and Vivian, E. (2015). Diabetes self-management edu-cation and support in Type 2 diabetes. Diabetes Care, 38, pp.1372-1382.4. Feuerstein, G. 200 Key Sanskrit yoga terms available at https://www.yogajour-nal.com/yoga-101/200-key-sanskrit-yoga-term accessed 8/19/2017.5. Parasuraman, S., Wen, L.E., Zhen, K.M., Hean, C.K. and Sam, A.T. (2016). Explor-ing the pharmacological and pharmaco-therapeutic effects of yoga. PTB Reports, 6, pp.6-10.6. Innes, K.E., Selfe, T.K. (2016). Yoga for adults with Type 2 diabetes: a systematic review of controlled trials. J Diabetes Re-search, 10, pp.1-23.7. Kabat-Zinn, J. On Defining Mindfulness. Available at https://www.mindful.org/jon-kabat-zinn-defining-mindfulness accessed 8/20/2017. 8. Yoga in depth. Available at https://nccih.nih.gov/health/yoga accessed 6/30/2017.9. Suri, M., Saini, N. and Gupta, S. (2016). Exploring the physiological effects of yoga: a state of the art review. Int J Phys Educ, Sports and Health, 3, pp.316-320. 10. Harvard Medical School. Harvard Mental Health Letter. Yoga for anxiety and depression, 2009.11. Hanley, A. J. (2017). Yoga your way. Diabetic Living, 10, pp.96-100.12. Shantakumari, N., Sequiera, S. and El deeb, R. (2013). Effects of a yoga interven-tion on lipid profiles of diabetes patients with dyslipidemia. Indian Heart Journal, 65, pp.127-131. 13. Vogel, H., Cramer, H. and Oster-man, T. (2015). Effects of yoga on eating disorders-A systematic review and meta-analysis. European J of Integrative Medi-cine, 7, p.26.14. Klein, J., Cook-Cottone, C. (2013). The effects of yoga on eating disorder symptoms and correlates: a review. Inter-national J of Yoga Therapy, 23, pp.41-50.

15. Hall, A., Ofei-Tenkorang, N.A., Machan, J.T. and Gordon, C.M. (2016). Use of yoga in outpatient eating disorder treatment: A pilot study. J Eat Disord, 4, pp.38-44. 16. Kristeller, J., Wolever, R.Q. and Sheets, V. (2014). Mindfulness-Based Eating Awareness Training (MB-EAT) for binge eating: a randomized controlled trial. Mindfulness, 5(3), pp.282-297.17. Tul, Y., Unruh, A. and Dick, B.D. (2011). Yoga for chronic pain management: a qualitative exploration. Scand J Caring Sci-ence, 25, pp.435-443.18. Saper, R.B., Lemaster, C., Delitto, A.,and Weinberg, J. (2017). Yoga, physi-cal therapy or education for chronic low back pain: a randomized noninferiority trial. Annals of Internal Medicine, 167, pp.84-94.19. Telles, S., Bhardwaj, A.K., Gupta, R.K., Sharma, S.K., Montro, R. and Balkrishna, A. (2016). A randomized controlled trial to assess pain and magnetic resonance imaging-based (MRI-Based) structural spine changes in low back pain patients after yoga practice. Med Sci Mont, 22, pp.3228-3247.20. Cheung, C.I., Park, J. and Wyman, J.F. (2016). Effects of yoga on symptoms, physical function, and psychosocial out-comes in adults with osteoarthritis: a fo-cused review. Am J Phys Med Rehabil, 95, pp.139-151.21. Ben-Josef, A.M., Wileyto, E.P., Chen, J. and Vapiwaia, N. (2016). Yoga inter-vention for patients with prostate can-cer undergoing external beam radiation therapy: a pilot feasibility study. J Integr Cancer Ther, 15, pp.272-278.22. Rao, R.M., Raghuram, N., Nagendra, H.R. and Rao, N. (2017). Effects of a yoga program on mood states, quality of life, and toxicity in breast cancer patients receiving conventional treatment: a ran-domized controlled trial. Indian J Palliative Care, 23, pp.237-246. 23. McDermott, K.A., Rao, M.R., Nagaran-tha, R., Murphy, E.J., Burke, A., Nagendra, R.H. and Hecht F.M. (2014). A yoga inter-vention for type 2 diabetes risk reduction: a pilot study. BCM Complementary and Alternative Medicine, 212 pp.1-14.24. Peterson, J.C., Charlson, M.E., Hoff-

man, Z., Wells, M.T., Wong, S.C., Hollen-ber, J.P., Jobe, J.B., Boschert, K.A., Isen, A.M. and Allegrante, J.P. (2012). A ran-domized controlled trial of positive-affect induction to promote physical activity af-ter percutaneous coronary intervention. Arch Intern Med, 172, pp.329-336.25. Youngwanichsetha, S., Phumdoung, S. and Ingkathawornwong, T. (2014). The effects of mindfulness eating and yoga ex-ercise on blood sugar levels in pregnant women with gestational diabetes mellitus. Applied Nursing Research, 27, pp.227-230.26. Sreedevi, A., Gopalakrishnan, U.A., Karimassery Ramaiyer S. and Kamalamma, L. (2017). A randomized controlled trial of the effect of yoga and peer support on glycaemic outcomes in women with type 2 diabetes mellitus: a feasibility study. BMC Complementary and Alternative Medicine, 17, p.100.27. Kumar, V., Jagannathan, A., Philip, M., Thulasi, A. and Raghuram, N. (2016). The role of yoga for patients with type 11 diabetes mellitus: a systematic review and meta-analaysis. Complementary Therapies in Medicine, 25, pp.104-112. 28. Alexander, G.K., Innes, K.E., Selfe, T.K. and Brown, C. J. (2010). “I could move mountains”: adults with or at risk for type 2 diabetes reflect on their experiences with yoga practice. Diabetes Educ, 36, pp. 965-975.29. www.exerciseismedicine.org30. Writing Group for the Activity Coun-seling Trial Research Group. Effects of a physical activity counseling in primary care: the Activity Counseling Trial: a ran-domized controlled trial. (2001). J Am Med Assoc, 286,pp.677-687.31. National Institute for Clinical Excel-lence (NICE). Four commonly used meth-ods to increase physical activity: brief interventions in primary care, exercise referral schemes, pedometers, and com-munity-based walking and cycling. Public Health Guidance No. 2. London: NICE, 2006.32. Lobelo, F., Duperly, J. and Frank, E. (2009). Physical activity habits of doc-tors and medical students influence their counseling practices. Br J Sports Med, 43, pp.98-92.

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Volume 37 • Number 1 March/April 2018 PracticalDiabetology

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