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Do Diabetic Athlete Survey by May 15

DiabeticAthleteHandbookWebcover

Are you physically active and do you have diabetes (of any type)? Now is your chance to share how you manage your diabetes regimen while doing a variety of activities!

A new edition of Dr. Sheri Colberg’s book, Diabetic Athlete’s Handbook, is coming out in Spring 2019. Please complete the diabetic athlete survey at the link below no later than May 15 for possible inclusion.

https://www.diabetesmotion.com/athlete-survey

Please pass the survey on to everyone else you know who is active with diabetes. Thanks for your time and input!

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Get Motivated to Get and Stay Fit

Colberg ADA Workplace Photo 2You may have started the new year out with the best of intentions to increase your fitness and better manage your diabetes by exercising regularly. If you have diabetes or are at risk for developing the disease, deciding to commit to fitness could be a real lifesaver. That’s why it’s more important than ever that you make sure this decision sticks. Here are some motivational tips for getting started being more active.
Check Your Blood Glucose: When you start a new exercise, checking your blood glucose before, sometimes during, and after your workout pays off. A reading that changes — especially in the direction that you want it to — can be very rewarding and motivating. If you don’t check, you may never realize what a positive impact you can have on your diabetes simply by being active. For example, if your blood glucose is too high after you eat a meal, and you want it to go lower without taking (or releasing) any more insulin. You can exercise after your meal and bring your blood glucose down within two hours after eating and taking insulin, or you can avoid or lower post-meal spikes.
Start with Easier Activities: Start slowly with easier activities and progress cautiously to harder ones. Exercising too hard right out of the gate is likely to make you end up discouraged or injured, especially if you haven’t exercised in a while. If you often complain about being too tired to exercise, your lack of physical activity is likely what’s making you feel sluggish. After you begin doing even light or moderate activities, your energy levels rise along with your fitness, physical condition, and mental health.
Pick Activities You Enjoy: Most adults need exercise to be fun, or they lose their motivation. It’s human nature to avoid doing the things you really don’t like to do, so try to pick activities you truly enjoy, such as salsa dancing or golfing (as long as you walk and carry your own clubs). Having fun with your activities lets you more easily make them a permanent and integral part of your diabetes management. If you haven’t found any that you enjoy much, choose some new ones to take out for a test run (so to speak).
Spice It Up: It’s essential for motivation to mix your workouts up with different activities. People commonly complain about exercise being boring. Feelings of boredom with your program can be the result of repeating the same exercises each day. To make it more exciting, try different physical activities for varying durations and at different intensities. Knowing that you don’t have to do the same workout day after day is motivating by itself.
Have a Plan B: Always have a backup plan that includes other activities you can do in case of inclement weather or other barriers to your planned exercise. For example, if a sudden snowstorm traps you at home on a day you planned to swim laps at the pool, be ready to walk on the treadmill or substitute some resistance activities. You can always distract yourself during your second-choice exercise to make the time pass more pleasantly. Read a book or magazine, watch your favorite TV program, listen to music or a book on tape, or talk with a friend on the phone while you’re working out.
Get an Exercise Buddy (or Several): You don’t need to go it alone when being active. Having a regular (and reliable) exercise buddy increases your likelihood of participating, and it also makes your activities more social and fun. Get your spouse, family members, friends, and co-workers to join in your physical activities, regardless of what time of day you do them. Having a good social network to support your new or renewed exercise habit helps you adhere to it over the long run.
Schedule It: Put your planned exercise down on your calendar or to-do list like you would other appointments. You show up for your doctor appointments, so why should scheduling your physical activity be any different? Never make the mistake of assuming it’ll happen just because you claim that you want to do it a certain number of days per week or month. It takes some planning ahead and the commitment to make it a priority.
Set Goals and Reward Yourself: Setting goals helps keep your interest up. For instance, if you walk for exercise, you may want to get a pedometer and set a goal of adding in 2,000 more steps each day. Break your larger goals into smaller, realistic stepping-stones (such as daily and weekly physical activity goals) for all your active lifestyle changes, and use SMART goals. Trackers, activity logs, and other motivational tools are also widely available online. Tip: Reward yourself when you reach your exercise goals (but preferably not with food).
Get More Spontaneous Physical Activity: You don’t have to work out at a high intensity to help diabetes and weight management. You can also add physical movement all day long doing anything you want to, including gardening, housework, and many other spontaneous physical activities. For instance, if you have a sedentary desk job take the stairs rather than the elevator whenever you can. Walk to someone else’s office or the neighbor’s house to deliver a message instead of relying on the phone or email. Or park your car at the far end of the parking lot and walk the extra distance. Guess what? You’ve just gotten yourself more active without giving it much thought.
Take Small Steps: If you get out of your normal activity routine and are having trouble getting restarted, simply take small steps in that direction. You may need to start back at a lower intensity by using lighter weights, less resistance, or a slower walking speed. Starting out slowly with small steps helps you avoid burnout, muscle soreness, and injury. Even doing only 5 to 10 minutes at a time (rather than 30 or more) is fine. After you’re up and moving, you may feel good enough to exceed the time you planned on doing in the first place. The key is to begin by any means possible.

Get Off the Couch and Work Your Core

plank-fitness-muscular-exercising-163437.jpegIf you suffer from diabetes, you already know that staying fit greatly benefits your health. Yet, many of the complications caused by diabetes can make it difficult to get the exercise you need; in fact, they can make a normal exercise routine difficult or even dangerous. For example, peripheral neuropathy (numbness in the feet caused by nerve damage) may affect your balance and put you at risk for a fall, or could lead to slow-healing ulcers that keep you inactive. On top of that, diabetes patients may have heart disease symptoms or vision problems that make getting up and going for a walk more risky than helpful.

The good news is that these complications don’t have to prevent you from doing safe and healthy exercise. You can still get a beneficial workout—minus the risks—by exercising your core. Even though a lot of people with diabetes think having neuropathy or other complications means they have to be a couch potato, that’s just not true. Just because you can’t get outside for a brisk walk or run doesn’t mean you can’t get fit. Exercising your core is a safe way to improve your strength and stability so you can better handle your daily life—right from your own home.

Core exercises are an important part of a well-rounded fitness program for diabetes patients. Your body core, including the muscles around your trunk, is particularly important to keep strong so you can go about your normal daily activity and prevent falls and injuries, particularly as you age. The best part? They are easy to do on your own in your home, and you don’t even need to purchase any equipment to perform them. However, once you become more advanced, you can accelerate your workouts using a gym ball or dumbbells.

Ready to get a strong core and improve your stability and overall wellness? Here are ten core exercises that I recommend highly for people with diabetes (or anyone for that matter).

Look for illustrated versions of these core exercises in Chapter 21 (“Ten Easy Exercises to Build a Strong Core without Leaving the House”) in Diabetes & Keeping Fit for Dummies by Dr. Sheri Colberg available online at Amazon.com or Dummies.com.

(1) Abdominal Squeezes. This exercise is great for working your abdominals and getting your core as strong as possible. If you’re female and have gone through a pregnancy, getting these muscles in shape doing these squeezes is a must.

  1. Put one of your hands against your upper stomach and the other facing the other direction below your belly button.
  2. Inhale to expand your stomach.
  3. Exhale and try to pull your abdominal muscles halfway toward your spine. This is your starting position.
  4. Contract your abdominal muscles more deeply in toward your spine while counting to two.
  5. Return to the starting position from Step 3 for another count of two.

Work up to doing 100 repetitions per workout session.

(2) Plank or Modified Plank. Nobody likes doing planks, but they get the job done when it comes to boosting the strength of your core. Both planks and modified planks work multiple areas, including your abdominals, lower back, and shoulders.

  1. Start on the floor on your stomach and bend your elbows 90 degrees, resting your weight on your forearms.
  2. Place your elbows directly beneath your shoulders and form a straight line from your head to your feet.
  3. Hold this position as long as you can.

Repeat this exercise as many times as possible during each workout.

(3) Side Planks. A modification of regular planks, this side plank exercise works some of the same and some slightly different muscles that include your abdominals, oblique abdominal muscles, sides of hips, gluteals, and shoulders. Try doing some of both types for the best results.

  1. Start out on the floor on your side with your feet together and one forearm directly below your shoulder.
  2. Contract your core muscles and raise your hips until your body is in a straight line from head to feet.
  3. Hold this position without letting your hips drop for as long as you can.
  4. Repeat Steps 1 through 3 on the other side.

Switch back and forth between sides as many times as you can.

(4) Bridging. If you work on your abdominal strength, you also need to build the strength in your lower back to keep things balanced. Bridging is a good exercise to do that as it works your buttocks (including gluteals), low back, and hip extensors. Remember to breathe in and out throughout this exercise.

  1. Keeping your shoulders on the floor, slowly raise your buttocks from the floor with your stomach tight and your lower back straight.
  2. Gently lower your back to the ground.
  3. Repeat Steps 1 and 2.

(5) Pelvic Tilt. An easy exercise to do, the pelvic tilt works your lower back and lower part of your abdominals.

  1. Lie on your back on the floor with your knees bent and feet flat on the floor.
  2. Place your hands either by your sides or supporting your head.
  3. Tighten your bottom, forcing your lower back flat against the floor, and then relax.
  4. Repeat Steps 2 and 3 as many times as you can.

(6) Superhero Pose. Whether you want to leap tall building with a single bound or not, try doing this superhero pose exercise to get a stronger core. It works many areas, including your lower back, upper back, back of shoulders, and gluteals.

  1. Lie on your stomach with your arms straight out in front of your head on the floor.
  2. Rest your chin on the floor between your arms.
  3. Keeping your arms and legs straight, simultaneously lift your feet and your hands as high off the floor as you can. Aim for at least three inches.
  4. Hold that position (sort of a superhero flying position) for 10 seconds if possible, and then relax your arms and legs back onto the floor.

(7) Knee Push-Ups. Push-ups are hard to do if you haven’t built up the strength in your shoulders yet, so this knee version is an easier way to start for most people. This exercise works your chest, front of shoulders, and back of upper arms.

  1. Get on your hands and knees on the floor or a mat.
  2. Place your hands shoulder-width apart on the floor.
  3. Tighten your abdominal muscles to straighten your lower back and lower yourself down toward the floor as far as you can without touching.
  4. Push yourself back up until your arms are extended, but don’t lock your elbows.

(8) Suitcase Lift. This exercise is the proper way to lift items from the floor. Before you begin, place dumbbells or household items slightly forward and between your feet on the floor. You work the same muscles used in doing squats (lower back and lower body) with this activity.

  1. Stand in an upright position with your back and arms straight, with your hands in front of your abdomen.
  2. Bending only your knees, reach down to pick up the dumbbells.
  3. Grab the dumbbells or items in both hands and then push up with your legs and stand upright, keeping your back straight.

(9) Squats with Knee Squeezes. These squats are not your normal squats. They’re more like a combination of squatting and wall sitting with a twist. You work the front and back of thighs, inner thighs (adductors), hip flexors and extensors all with this one exercise.

  1. Stand with your back against the wall, with your feet aligned with your knees and straight out in front of you.
  2. Place a ball or pillow between your knees and hold it there with your legs.
  3. Inhale to expand your stomach and then exhale and contract your abdominal muscles.
  4. Bend your knees and lower yourself into a squat. To avoid injuring your knees, don’t bend them more than 90 degrees.
  5. Squeeze the ball with your thighs, drawing your stomach muscles more deeply toward your spine.
  6. Do as many squeezes as you can up to 20 and then return to the starting position.

(10) Lunges. Lunges are a common activity to work on the front and back of thighs, hip flexors and extensors, abdominals and lower back all with one exercise. Do them with proper form to avoid aggravating your knees, though.

  1. Keep your upper body straight, with your shoulders back and relaxed and chin up.
  2. Pick a point to stare at in front of you so you don’t keep looking down, and engage your core.
  3. Step forward with one leg, lowering your hips until both knees are bent at about a 90-degree angle. Make sure your front knee is directly above your ankle, not pushed out too far, and don’t let your back knee touch the floor.
  4. Focus on keeping your weight on your heels as you push back up to the starting position.

Even though diabetes sometimes presents tough fitness challenges, you can use these core-strengthening exercises to maintain fitness in spite of any mobility issues you’re facing right now. Whether you still active or sedentary, working your core is a safe and smart way to improve your balance, keep you as fit as possible, and elevate your overall quality of life.

Exercise and Statins: Revisited

Exercise and statins 

I chronicled someone with type 1 diabetes whose ability to exercise was compromised by his use of statins. Statins are medications prescribed to lower cholesterol levels or abnormal levels of blood fats, given to lower your risk of heart attack and stroke. Examples include Altoprev, Crestor, Lescol, Lipitor, Livalo, Mevacor, Pravachol, and Zocor.

The updated cholesterol guidelines have led to even more adults with diabetes and prediabetes being put on these medications. For anyone unwilling or unable to change diet and lifestyles sufficiently or with genetically high levels of blood lipids, the experts have claimed that the benefits of statins likely greatly exceed the risks. If those risks include the risk of becoming more inactive, then I vehemently disagree with this claim.

This issue is resurfacing for discussion because of a recent study in JAMA Internal Medicine online. That study examined statin treatment among adults aged 65 to 74 years and 75 years and older when used to prevent heart attacks. The statin in in the study was pravastatin (Pravachol), and the adults already had elevated LDL levels and hypertension in most cases. Interestingly, over a six-year period, taking that statin did not lower the risk of having a coronary heart disease event compared to usual care in these older individuals (some of whom likely had diabetes or prediabetes, although this was not stated).

So, if statins don’t always prevent coronary events and may keep you from being active and naturally lowering your cardiovascular risk with physical activity, why take them at all? It may be that glucose, blood pressure, and cholesterol all need to be aggressively managed to see benefits, but then why not try to do that with exercise and physical activity (which can lower all three)? As I stated before, likely the greatest risk factor for heart disease is physical inactivity, so prescribing statins that make people sedentary is counterproductive. At least have them try another medication to see if it has a lesser negative impact on being active.

We already know that many statins increase the risk of developing type 2 diabetes. A recent meta-analysis of 20 studies just reported an increased risk of new-onset diabetes from 9% to 13% associated with statins in just one year, and this could be an underestimation of the risk of developing type 2 diabetes due to statins. Diabetes is known to be a strong and independent risk factor by itself for cardiovascular disease. Does this make the “cure” for high LDL-cholesterol worse than the condition itself?

As a group of medications, statins are recognized for frequently causing muscle and joint issues. Muscular effects from statin use, such as unexplained muscle pain and weakness, are common and may result from a compromised ability to generate energy. The occurrence of muscular conditions like myalgia, mild myositis, severe myositis, and rhabdomyolysis, although relatively rare, is doubled by diabetes. Others have an increased susceptibility to exercise-induced muscle injury when taking statins. Other symptoms, such as muscle cramps during or after exercise, nocturnal cramping, and general fatigue, generally resolve when people stop taking them. It is also concerning that long-term use of statins negatively impacts the organization of collagen and decreases the biomechanical strength of the tendons, making them more predisposed to ruptures. Statin users experience more spontaneous ruptures of both their biceps and Achilles tendons.

You should talk with your doctors about whether it may be possible to manage your heart disease risk without taking statins long-term for this reason. If you experience any of these symptoms, bring up possibly switching to another cholesterol-lowering drug. A newer one on the market that is not a statin is Repatha and is worth a look if such medications absolutely have to be taken. Instead of blocking LDL production by the liver, Repatha apparently is an injectable antibody that helps the liver clear bad LDL-cholesterol from your blood. While its musculoskeletal effects remain to be determined (if any), it appears that it is unlikely to do more harm than statins. It’s worth considering…

Finding Fitness Professionals Trained in Diabetes–It’s Hard!

Personal training 3One in three Americans has diabetes or prediabetes. You would think that finding a fitness professional—a personal trainer, physical therapist, or other allied fitness and health trainer—that knows enough about diabetes to be helpful wouldn’t be that hard, right? Think again.

Why does it matter whether your trainer knows about diabetes? Well, if you had severe arthritis in your knees, you’d want a trainer who knows enough to avoid making you do certain activities that might be injury-inducing (burpees come to mind). The same goes if you have diabetes. Over the years, I have just heard of too many trainers ending up getting their clients injured because they didn’t understand that diabetes makes people more prone to overuse injuries, or that certain medications increase the risk for activity-associated hypoglycemia, or that most people with type 2 diabetes who are overweight and sedentary are going to be demotivated or injured by being forced to train like they do on “The Biggest Loser” (even though trainers shouting at people makes for good reality TV).

Many professional fitness organizations certify trainers and other fitness professionals, including the American College of Sports Medicine (ACSM), American Council on Exercise (ACE), National Academy of Sports Medicine (NASM), Athletics and Fitness Association of America (AFAA), International Sports Sciences Association (ISSA), and at least 30 other groups that offer certifications for personal trainers, health coaches, and other allied professions. The certification requirements vary widely by organization, however, and most (but not all) require continuing education to maintain the certification. Some offer full training courses, while others barely meet minimal standards. The premier certifying organizations are ACSM and ACE at present.

One problem is that it’s not easy to identity certified fitness professionals who are knowledgeable about working with people with diabetes (all types and ages). What’s more, very few diabetes training programs are available for fitness professionals, and most trainers are more interested in learning more about training techniques that they can use in their prescribed workouts than chronic diseases. I personally have been on a crusade for the past two years trying to offer expert training for fitness professionals about working with diabetic clients. I finally got a program done for ACSM online as of February 2017 and will shortly have programs offered through ACE and others as well (check on Diabetes Motion Academy for these and other programs).

One bright note is the Medical Fitness Network (MFN), a free online resource directory for consumers to locate fitness and allied healthcare professionals who have a background in and provide services for those with chronic disease, medical conditions, disabilities and women’s health issues. MFN donates its service as a database management company to the top medical and health organizations who do not offer resources for locating these professionals. Fitness and healthcare professionals can join to increase their online exposure and credibility for a modest annual fee. It is my hope that some of the larger fitness organizations (like ACSM) will also soon see the value of making diabetes-savvy fitness professionals easier for consumers to find—for the benefit of everyone!

Staying Active with Aging Joints and Diabetes

Using bandsWithout properly functioning joints, our bodies would be unable to bend, flex, or even move. A joint is wherever two bones come together, held in place by tendons that cross the joint and attach muscles to a bone on the other side and ligaments that attach to bones on both sides of the joint to stabilize it. The ends of the bones are covered with cartilage, a white substance. Specialized cells there called chondrocytes produce large amounts of an extracellular matrix composed of collagen fibers, proteoglycan, elastin fibers, and water. Tendons and ligaments are also made up of primarily of collagen.

Joints can be damaged, however, making movement more difficult or painful. Joint cartilage can be damaged by acute injuries (i.e., ankle sprain, tendon or ligament tears) or overuse (related to repetition of joint movements and wear-and-tear over time). Damage to the thin cartilage layer covering the ends of the bones is not repaired by the body easily or well, mainly because cartilage lacks its own blood supply.

Aging alone can cause you to lose some loss of this articular cartilage layer in knee, hip, and other joints—leading to osteoarthritis and joint pain—but having diabetes also potentially speeds up damage to joints. Although everyone gets stiffer joints with aging, diabetes accelerates the usual loss of flexibility by changing the structure of collagen in the joints, tendons, and ligaments. In short, glucose “sticking” to joint surfaces and collagen makes people with diabetes more prone to overuse injuries like tendinitis and frozen shoulder (1; 2). It may also take longer for their joint injuries to heal properly, especially if blood glucose levels are not managed effectively. What’s more, having reduced motion around joints increases the likelihood of injuries, falls, and self-imposed physical inactivity due to fear of falling.

Reduced flexibility limits movement around joints, increases the likelihood of orthopedic injuries, and presents a greater risk of joint-related problems often associated with diabetes, such as diabetic frozen shoulder, tendinitis, trigger finger, and carpal tunnel syndrome. These joint issues can come on with no warning and for no apparent reason, even if an individual exercises regularly and moderately, and they may recur more easily as well (3). It is not always just due to diabetes, though, since older adults without diabetes experience inflamed joints more readily than when they were younger.

So what can you do to keep your joints mobile if you’re aging (as we all are) and have diabetes? Regular stretching to keep full motion around joints can help prevent some of these problems, and also include specific resistance exercises that strengthen the muscles surrounding affected joints. Vary activities to stress joints differently each day. Overuse injuries occur following excessive use the same joints and muscle in a similar way over an extended period of weeks or months, or they can result from doing too much too soon.

Doing moderate aerobic activity that is weight-bearing (like walking) will actually improve arthritis pain in hips and knees (4). People can also try non-weight-bearing activities, such as aquatic activities that allow joints to be moved more fluidly. Swimming and aquatic classes (like water aerobics) in either shallow or deep water are both appropriate and challenging activities to improve joint mobility, overall strength, and aerobic fitness. Walking in a pool (with or without a flotation belt around the waist), recumbent stationary cycling, upper-body exercises, seated aerobic workouts, and resistance activities will give you additional options to try.

Finally, managing blood glucose levels effectively is also important to limit changed to collagen structures related to hyperglycemia. Losing excess weight and keeping body weight lower will decrease the risk for excessive stress on joints that can lead to lower body joint osteoarthritis (5). Simply staying as active as possible is also critical to allowing your joints to age well, but remember to rest inflamed joints properly to give them a chance to heal properly. You may have to try some new activities as you age to work around your joint limitations, but a side benefit is that you may find some of them to be enjoyable!

References:

  1. Abate M, Schiavone C, Pelotti P, Salini V: Limited joint mobility in diabetes and ageing: Recent advances in pathogenesis and therapy. Int J Immunopathol Pharmacol 2011;23:997-1003
  2. Ranger TA, Wong AM, Cook JL, Gaida JE: Is there an association between tendinopathy and diabetes mellitus? A systematic review with meta-analysis. Br J Sports Med 2015;
  3. Rozental TD, Zurakowski D, Blazar PE: Trigger finger: Prognostic indicators of recurrence following corticosteroid injection. J Bone Joint Surg Am 2008;90:1665-1672
  4. Rogers LQ, Macera CA, Hootman JM, Ainsworth BE, Blairi SN: The association between joint stress from physical activity and self-reported osteoarthritis: An analysis of the Cooper Clinic data. Osteoarthritis Cartilage 2002;10:617-622
  5. Magrans-Courtney T, Wilborn C, Rasmussen C, Ferreira M, Greenwood L, Campbell B, Kerksick CM, Nassar E, Li R, Iosia M, Cooke M, Dugan K, Willoughby D, Soliah L, Kreider RB: Effects of diet type and supplementation of glucosamine, chondroitin, and msm on body composition, functional status, and markers of health in women with knee osteoarthritis initiating a resistance-based exercise and weight loss program. J Int Soc Sports Nutr 2011;8:8

Exercise Management in Type 1 Diabetes: A Consensus Statement

JDRF Consensus Statement Cover

Above you see part of the first page of a new consensus statement that comes from many of the individuals involved with the creation and launch of the new JDRF PEAK Performance Program, aimed at educating both clinicians and people with type 1 diabetes how to manage the complexities of being active. In my opinion, this recently published consensus statement on exercise and type 1 diabetes is long overdue and much needed. I managed to get the American Diabetes Association to let me chair an updated position statement (see my November blog) and include type 1 diabetes in it but, unfortunately, never just one addressing type 1 and exercise alone so this JDRF one fills a huge void.

The past decade has seen a growing number of publications related to diabetes management during exercise in people who have to either inject or pump insulin to stay alive. As you well know, whether insulin is injected or pumped, it is not being delivered where it normally ends up in a body that can release its own insulin, and this altered insulin delivery leads to alterations in hormones and blood glucose management by the liver. Normally, your liver would be able to either release or store glucose to keep your levels constant, but not without these proper hormonal signals.

Consequently, the only way you can keep your blood glucose levels normal (or near normal) with exercise is to take in carbohydrate/food, lower circulating insulin levels, or both during activities. Given that exercise is a huge stressor to normal metabolic control of blood glucose, it can make your diabetes more difficult to manage–even though exercising is generally beneficial for a number of other health reasons. This new consensus statement does an excellent job of covering all of the potential effects of engaging in differing physical activities, along with comprehensive management strategies involving changes in food intake and adjustments in basal and/or bolus insulin dosing. It also points out the many areas that need additional (or even any) research with regard to exercising with type 1 diabetes, either to enhance health or sports performance. Read it now if you haven’t already for some great advice!

Reference:

(1) Riddell MC, Gallen IW, Smart CE, Taplin CE, Adolfsson P, Lumb AN, Kowalski A, Rabasa-Lhoret R, McCrimmon RJ, Hume C, Annan F, Fournier PA, Graham C, Bode B, Galassetti P, Jones TW, Millán IS, Heise T, Peters AL, Petz A, Laffel LM. Exercise management in type 1 diabetes: a consensus statement, Lancet Diabetes Endocrinol. 2017 Jan 23. pii: S2213-8587(17)30014-1. doi: 10.1016/S2213-8587(17)30014-1. [Epub ahead of print]