Management of type 2 diabetes mellitus in self-motivated patients: optimized diet, exercise, and medication for weight loss and cardiometabolic fitness.

C L I N I C A L F E AT U R E S

The Physician and Sportsmedicine Downloaded from informahealthcare.com by Nyu Medical Center on 04/30/15 For personal use only.

Management of Type 2 Diabetes Mellitus in SelfMotivated Patients: Optimized Diet, Exercise, and Medication for Weight Loss and Cardiometabolic Fitness

DOI: 10.3810/psm.2014.11.2091

Daniel A. Nadeau, MD Kris V. Iyer Endowed Chair in Diabetes Care, Mary and Dick Allen Diabetes Center, Hoag Hospital, Newport Beach, CA

Abstract: Type 2 diabetes mellitus (T2DM) is a growing public health problem with significant lifetime health care costs. The majority of Americans do not achieve minimal targets for exercise, and individuals with T2DM typically engage in less exercise than the general adult population. However, those patients with T2DM who are sufficiently self-motivated to manage their condition have the potential to reverse diabetes and prevent its complications through behavioral and pharmacologic interventions. Marked improvements are possible through increased awareness and selection of healthy eating options, a willingness to incorporate vigorous exercise into their lifestyle, and the use of newer medications that essentially eliminate the risk of hypoglycemia while facilitating weight loss and the achievement of ideal glucose targets. For self-motivated patients, daily aerobic activity of 45 to 60 minutes per day may be a suitable target. For those who have cardiovascular clearance, high-intensity interval training accomplishes high levels of cardiometabolic fitness with shorter training periods by alternating moderate and intense exertion. Suitable medications that have a low risk of hypoglycemia during exercise include metformin, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and sodium-glucose linked transporter-2 inhibitors. Specific daily caloric goals and incorporation of a mainly plant-based diet should be considered as a primary target for diabetes management. Self-management is important to achieving diabetes treatment goals, and mobile applications can be useful tools to support lifestyle changes in patients with T2DM. Keywords: diabetes mellitus, type 2; motivation; exercise; weight loss; physical fitness

Introduction

Correspondence: Daniel A. Nadeau, MD, Mary and Dick Allen Diabetes Center at Hoag Hospital, 520 Superior Avenue, #150, Newport Beach, CA 92663. Tel: 949-764-6204 Fax: 949-642-7703 E-mail: [email protected]

Type 2 diabetes mellitus (T2DM) is now a worldwide pandemic growing at an alarming rate.1 In 2010, the prevalence of diabetes mellitus among children and adults in the United States was an estimated 25.8 million, approximately 8.3% of the population.1 The incidence is estimated to reach 21% to 33% of the population by 2050.2 Proper nutrition and intense exercise, coupled with newer and better pharmacotherapy, are integral components in the reduction of the risk of this disease.3–5 Unfortunately, overall dietary patterns in the United States remain poor, and approximately 80% of Americans do not achieve minimal targets for exercise6; moreover, individuals with T2DM typically engage in less exercise than the general adult population.7 However, some studies have shown that highly self-motivated patients with T2DM have the potential to reverse diabetes and prevent complications (eg, cardiovascular events,

© The Physician and Sportsmedicine, Volume 42, Issue 4, November 2014, ISSN – 0091-3847 49 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.


Daniel A. Nadeau

neuropathy, retinopathy) with vigorous exercise,8,9 although the results are inconsistent.5,10 The 2013 American Diabetes Association (ADA) nutrition guidelines recommend a healthy diet that contains appropriate portion sizes of high nutritional density foods that help establish and attain individualized glycemic, blood pressure, and lipid goals, and achieve and maintain body weight goals; this may help to delay or prevent complications of diabetes.11 Individuals with diabetes should be aware of caloric content, selection of healthy eating options (eg, whole foods), and avoidance of processed foods and saturated fat.11 Regular exercise in adults with T2DM has been associated with improvement in blood glucose levels,7,12 metabolic profile (ie, triglyceride and total cholesterol levels),13 adiposity and body mass index,14,15 inflammatory markers,8,14 cardiovascular risk,14 and general well-being.13 Furthermore, regular exercise can help reduce the risk of T2DM.16,17 When only sulfonylureas and insulin were available for the treatment of T2DM, these medications proved counterproductive for achievement of weight loss goals and increased the risk of hypoglycemia. Newer medications, such as glucagon-like peptide-1 receptor agonists (GLP-1-RAs), facilitate weight loss and have little to no risk of hypoglycemia, while helping achieve ideal glucose targets. These novel agents can assist motivated patients in achieving their weight loss goals. Improvements in “patient empowerment,” increased exercise, and better compliance can result in better glycated hemoglobin (HbA1c) control.18 This review explores the literature in this challenging and emerging area, and suggests a strategy that will make the role of exercise central to the management of diabetes. This approach focuses on patients who are sufficiently selfmotivated to actively participate in the management of their diabetes. The goal of this work is not to recommend methods through which physicians may attempt to increase motivation in patients with low motivation, but rather to describe options for behavioral and pharmacologic interventions that physicians may recommend to patients who already have high levels of self-motivation. With active participation in their diabetes management, such highly self-motivated patients may be able to arrest or even reverse the development of T2DM.

Motivation and Exercise in Patients With Diabetes

Other than education and “self-empowerment,” detailed information about motivators that promote physical activity in individuals with T2DM are limited. In clinical practice, 50

only a small percentage of the population with T2DM is sufficiently self-motivated to undertake a rigorous exercise program to increase their cardiometabolic fitness level and to perhaps change the impact of T2DM on their life. In a cross-sectional study of subjects at high risk for diabetes, physically active individuals reported that exercise was a high priority, believed that physical activity influenced weight, were less concerned about injuries, and made time for physical activity.19 Individuals with at least a high school diploma were more physically active than those without a high school diploma. Thus, more education about the importance of physical activity may be needed, particularly in people with a sedentary lifestyle. In the Finnish Diabetes Prevention Study, the main motivator for physical activity was quality of life, including health and mental and physical well-being, particularly among older individuals.20 Other motivators included weight management, ability to exercise, and independence; regular counseling was important for promoting exercise among older people. The risk of T2DM increases with age. In older adults, the acceptance of an exercise program may be more difficult because of their age and lower weight-carrying capacity. A 12-month study in older adults ($ 50 years) with T2DM who were treated with insulin found that exercise itself elevated motivation for increased exercise ($ 3 hours/week) more than 2-fold.21 Regular exercise was confirmed in 67% and 65% of the patients at 3- and 12-month poststudy follow-up sessions, respectively, compared with 27% of patients who did not participate in any exercise at the start of the study. Metabolic control improved and the use of insulin was significantly reduced in those who exercised; better metabolic control may have also been a factor in increasing exercise time. In a focus group–based assessment of physical activity and barriers compared with facilitators to exercise in overweight adults with T2DM both during and after participation in a supervised exercise program that included stretching for 15 minutes and exercise on a treadmill, stationary bicycle, or cross trainer for 45 minutes, participants reported that motivation was the most important factor in adhering to a simple long-term exercise program (eg, walking). Patients’ motivation was inferred through questions about program attendance (ie, “What may explain the finding that some patients were not able to attend at least 75% of the sessions?” “From your experience with the program, what might have facilitated attending at least 75% of the sessions?” “Why have you decided to continue [or stop] exercising?”) Other reported factors included fitting with the patient’s daily schedule and the proximity of the exercise location.22

© The Physician and Sportsmedicine, Volume 42, Issue 4, November 2014, ISSN – 0091-3847 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.


T2DM in Self-Motivated Patients

A qualitative study of couples aged . 50 years where one or both partners had T2DM used a framework derived from social cognitive theory to assess the role of collective efficacy in adhering to exercise for married adults living with diabetes.23 For those with diabetes, motivation to exercise and the effort put forth to adhere to an exercise regimen was higher when both individuals shared beliefs about exercise.23 It is possible that there may be gender differences in motivation for physical activity in patients with T2DM; among active members of a patients’ association in France who were contacted by the organizers for potential participation in an interview-based study, females reported that the emotional support from being part of group, positive body image, and a sense of well-being were motivating factors, whereas males emphasized disease control and health-promoting behaviors.24 Thus, it may be necessary to individualize exercise programs, especially in older patients.

Types of Exercise

The ADA recommends that individuals with diabetes perform $ 150 minutes of moderate-intensity aerobic physical activity (50%−70% of maximum heart rate) per week, spread over $ 3 days, with # 2 consecutive days without exercise, and moderate-to-vigorous intensity resistance training $ 2 days a week in the absence of contraindications.4 As discussed elsewhere,25 people who have succeeded in maintaining considerable weight loss routinely achieve approximately 7 hours of exercise each week; likewise, 40 to 60 minutes of aerobic physical activity per day has been suggested as a goal for preventing and managing youth-onset T2DM.26 Increasing physical activity also improves cardiometabolic fitness and decreases cardiovascular risk in subjects with or at risk for T2DM.26–28 The benefit of physical exercise as a potential therapy for patients with T2DM, particularly as a long-term regimen, is an area of increasing clinical interest.27 For patients with cardiovascular clearance, high-intensity interval training (HIIT) enables high levels of fitness to be achieved with shorter training periods by alternating moderate (ie, 80% of maximal heart rate) and intense (ie, 95% of maximal heart rate) exertion. For example, rather than 7 minutes of continuous moderate exercise (CME) alone, one approach would be a 7-minute aerobic workout comprising a warmup of 60 seconds of moderate exercise, followed by alternating 30-second intervals of intense versus moderate exercise for an additional 6 minutes. During exercise, pushing the body beyond its comfort zone has clear-cut benefits,29 which may at least partly explain the positive effects of HIIT. In a study involving subjects with metabolic syndrome,

after a 10-minute warm-up, the HIIT group exercised at 90% maximal heart rate (HRmax) for 4 minutes followed by 3 minutes at 70% HRmax; this was repeated 4 times, followed by a 5-minute cool-down. The CME group exercised at 70% HRmax for 45 minutes. The HIIT group showed greater improvements in insulin sensitivity, aerobic capacity, and high-density lipoprotein cholesterol levels, as well as lower blood glucose levels than did the CME group. Aerobic capacity improved by 35% with HIIT compared with 16% with CME.30 It has also been found that HIIT may provide a more enjoyable workout than CME, with a feeling of exhilaration that makes regular exercise easier.31,32 Resistance training engaging the upper body, lower body, and core muscle groups on 2 to 3 nonconsecutive days per week has been recommended for people with T2DM.25 Homebased training with resistance machines and free weights alone may be insufficient to maintain blood glucose control in the long term33; however, such training regimens increase strength and mass of the muscle groups engaged. Increasing resistance or weight can attenuate insulin resistance in obese adults with T2DM,34 and combining resistance training with aerobic exercise in a physical activity regimen leads to greater benefits such as the potential for cardiovascular risk reduction. Additionally, instruction and supervision by a qualified trainer has been recommended for most individuals with T2DM to maximize health benefits (eg, blood glucose control, blood pressure management, and lipids), to reduce cardiovascular risk, and to minimize potential injury.27 A combination of aerobic training and resistance training has been shown both by the important Italian Diabetes and Exercise Study (IDES) trial and by a systematic review to provide significant benefits and is recommended for individuals with diabetes.35,36 Aerobic exercise (eg, swimming, running, or using a bicycle, treadmill, or elliptical machine) increases the function of the heart, lungs, and muscle through activation of large muscle groups (eg, upper body, lower body, or core) to meet the heightened oxygen demands while providing cardiorespiratory benefits. Because maintenance of weight loss and increasing physical activity are key goals in managing T2DM and decreasing cardiovascular risk, it is my opinion that for highly self-motivated patients an optimal target for daily aerobic activity to increase cardiometabolic fitness may be 40 to 60 minutes per day. Resistance training may appeal particularly to individuals with T2DM, elderly individuals, or those with sedentary lifestyles; it may include the use of various exercise machines, lifting free-weights (eg, dumbbells), or doing calisthenics (eg, sit-ups, push-ups, crunches, and lunges). Although multiple approaches may


Daniel A. Nadeau

be taken by highly self-motivated patients, in my opinion, with cardiovascular clearance, resistance training may be undertaken to muscle exhaustion and might target major muscle groups (eg, upper body, lower body, and core) 237–39 or, ideally, 340–42 times a week. Each session should include $ 1 set of 10 to 15 repetitions, with sufficient weight to lead to muscle fatigue by the end of each set37,40,41,43; 3 to 4 sets is recommended for optimal strength gains.44


Medical Risks Associated With Exercise

Prevention of hypoglycemia is important in the management of patients with diabetes mellitus, particularly during and after intense exercise. Thus, a balance must be achieved between insulin use, carbohydrate intake, and exercise. Exercise participation can be further complicated by the presence of comorbidities (eg, cardiovascular disease [CVD], hypertension, neuropathy, or microvascular changes). Before beginning an exercise program, individuals with diabetes should be assessed for conditions that may contraindicate exercise, predispose them to injury, require pre-exercise treatment, or are associated with an increased risk of CVD.40 Current guidelines recommend formal exercise stress testing before initiating a moderate-intensity exercise program; electrocardiogram stress testing may be indicated for individuals aged . 40 years, or those aged . 30 years with hypertension, a history of smoking, dyslipidemia, retinopathy, neuropathy, or disease duration of . 10 years.25

Role of Diet/Nutrition

In the United States, diets rich in animal products have contributed to the increased incidence of obesity and T2DM. The nutrition recommendations described here are supported primarily by findings of the Harvard School of Public Health and the 2013 ADA nutrition guidelines. It should be emphasized that early referral to a registered dietitian or a certified diabetes educator is recommended to assist patients through individualized nutritional counseling. A review and meta-analysis of 3 cohort studies, including data from Harvard’s Nurses’ Health Studies I and II (n = 79 570 women and n = 87 504 women, respectively) and Health Professionals’ Follow-Up Study (n = 37 083 men), found that individuals who ate red or processed meat had a higher risk of T2DM.45 Specifically, results of the meta-analysis of follow-up data indicated that, among a total of 442 101 patients and 28 228 cases of diabetes, 3.5 ounces of red meat or 1.8 ounces of processed meat (ie, a hot dog or 2 slices of bacon) daily led to a 19% and 51% increase in T2DM risk, 52

respectively.45 Similarly, a meta-analysis of 12 cohort studies estimated the relative risk of T2DM associated with high versus low total meat consumption (17% risk) and high versus low consumption of red (21% risk) and processed (41% risk) meat.46 Further, a small study (18 subjects were enrolled, 17 completed the study) suggested that eating processed foods results in increased energy absorption,47 which may contribute to associated weight gain and increased diabetes risk. The 2013 ADA nutrition guidelines recommend that distribution of protein, cholesterol, and fat (ie, macronutrients) should be based on individualized assessment of current eating patterns, preferences, and metabolic goals; evidence suggests that there is no ideal percentage of calories from each macronutrient that is applicable to all people with diabetes.11 Plant-based diets consisting of whole grains, fruits, vegetables, legumes, and nuts, which have long been used for weight loss,48 also increase insulin sensitivity and reduce CVD risk factors.49 Specifically, a 22-week randomized trial in 99 patients with T2DM who were stable on medication and were assigned to a low-fat, low glycemic index, vegan diet, or a portion-controlled omnivorous diet following the 2003 ADA guidelines found that the vegan group had a significantly greater decrease in HbA1c compared with the ADA diet group (1.23% vs 0.38%, respectively; P = 0.01). Moreover, average weight loss was significantly higher with the vegan diet (6.5 kg vs 3.1 kg; P , 0.001). Furthermore, patients on the vegan diet had reduced diabetes medication requirements (43% vs 26%).50 Such changes were generally maintained for more than 18 months,49 illustrating the importance of dietary choices for T2DM management. Despite some clear health benefits, a strict vegan diet is not realistic for most patients, and maintaining a restrictive or radically altered dietary profile may be challenging for many patients in the long-term; a less restrictive, primarily plant-based diet that includes fish and other healthy protein seems prudent in such cases. In either case, in my experience, whole grains should be emphasized. Eliminating refined carbohydrates and using whole grains is now supported by the recent ADA recommendations to “minimize” intake of processed carbohydrates.11 The ADA recommends that people with prediabetes (impaired glucose tolerance, impaired fasting glucose, or HbA1c levels between 5.7% and 6.4%, but not yet at the diagnostic threshold for T2DM) or confirmed T2DM should receive ongoing support, which includes individualized nutritional guidance targeting weight loss (7% of body weight), increased physical activity (150 min/week moderate activity). Metformin therapy should also be considered.51




Ideally, the nutritional guidance would be provided by a registered dietitian familiar with the concepts of nutritional management of diabetes.4 Strong counseling support is central to these programs; however, for most patients such a system may not be available, limiting the longer term effectiveness of this intervention in the “real world.” In such situations, it may become necessary to add drug therapy for patients with high glucose readings or those who are not meeting their glycemic and weight targets. I recommend weight loss for overweight or obese individuals at risk of or diagnosed with T2DM; strategies should include behavior modification and physical activity. Setting specific daily caloric goals is helpful in achieving targets. For most women, a target of 1200 kcal/ day is a good starting point; for men, 1500 kcal/day is appropriate, but for patients weighing . 100 kg (220 pounds), the target can be increased to 1800 kcal/day. Therefore, healthy daily menus of 1200, 1500, and 1800 kcal provide guidance for most patients. If weight loss of $ 1 to 2 pounds/week is not achieved, reducing calories by 200 to 300 calories per day seems reasonable. Saturated fats (, 7% of total calories) should be a small part of the overall calorie intake, and no amount of hydrogenated or “trans” fat should be considered safe. A traditional Mediterranean diet, with its focus on vegetables, fruits, whole grains, beans, legumes, and healthy proteins, in line with the new ADA recommendations,11 may help patients achieve their glycemic control and weight loss goals. Individuals at risk of T2DM should consume more whole fruit, specifically blueberries, grapes, and apples; fruit juice alone has been associated with a higher risk of developing T2DM in an analysis of data from the Nurses’ Health Studies and the Health Professionals Follow-Up Study involving almost 3.5 million person-years of follow-up.52 As noted previously, among individuals with diabetes, adherence to dietary guidelines is much greater than adherence to an exercise regimen.53

Use of Technology to Manage Diet and Exercise

Self-management is important for achieving diabetes treatment goals, and mobile applications (apps) can be useful tools for lifestyle changes in patients with T2DM. To date, however, published studies describing the specific role of these apps and devices in improving diabetes control or promoting long-term adherence to exercise regimens are limited, in part because many of these tools are relatively new. In a review of mobile health apps, the management of diabetes had the greatest number of apps available.54 A few years

ago, expensive dietary analysis programs were not readily available to patients. But now it is remarkably easy to capture calories associated with diet and exercise on apps such as Loseit! and MyFitnessPal on smart phones and computers. Other apps support self-management tasks, such as physical exercise, insulin dosage or medication, blood glucose monitoring, blood pressure monitoring, and diet.55 These apps also provide valuable notifications and alerts, enabling health care provider feedback and decision support, and integration with social media; their use has been shown to have a positive impact on HbA1c, weight, and blood pressure.56 In addition, the perceived usefulness of these apps among individuals with T2DM or those at risk for T2DM is high and implies a potentially greater role in self-management.57 The use of mobile technology, remote coaching, and incentives in sedentary adults with elevated saturated fat and low fruit/vegetable intake has been associated with an increase in consumption of fruits/vegetables and an increase in physical activity.58 The elderly face particularly strong barriers to exercise, including comorbid conditions, as well as impaired reaction time, coordination, cognition, gait, and balance. A mobile training app called Active Lifestyle aims to improve balance and strength in the elderly; it assists, monitors, and motivates the user to follow personalized training plans autonomously at home while interacting socially with other participants.59 In a pilot study of this app, adherence to the training plans among users was 89% for balance exercises and 60% for strength exercises.59 The majority of participants (64%) reported feeling increased motivation to exercise; 91% felt motivated by being part of a virtual exercise group and being able to monitor their performance in real time; although baseline motivation was not assessed, patients reported that they did not feel motivated to exercise without the app.59 These findings indicate the clinical utility of mobile apps in motivating individuals with T2DM to increase physical activity and consume a healthy diet, but next-generation apps would ideally include behavior modification techniques as well.

Role of Medications

The goal of pharmacotherapy in self-motivated patients is to control blood glucose without causing hypoglycemia and to help facilitate weight loss to achieve a body weight as close to ideal as possible. The relationship between HbA1c levels and weight loss has been detailed elsewhere3; available T2DM medications are summarized in Table 1. At the time of diagnosis of T2DM, initiation of lifestyle interventions should be coupled with diet and


54 Closes KATP channels on β-cell plasma membranes ↑ Insulin secretion Activates PPAR-γ ↑ Insulin sensitivity

Thiazolidinediones (pioglitazone, rosiglitazone)

Activates dopaminergic receptors Alters hypothalamic regulation of metabolism ↓ Hepatic glucose production

Inhibits SGLT-2, responsible for glucose reabsorption ↑ Urinary glucose excretion ↓ Plasma glucose

Activates GLP-1 receptors ↑ GLP-l response ↑ Insulin secretion ↓ Glucagon secretion ↓ Gastric emptying ↑ Satiety Inhibits DPP-4 activity ↑ Active GLP-1 concentration ↑ Insulin secretion ↓ Glucagon secretion Directly activates insulin receptor ↓ Hepatic glucose production ↓ Lipolysis

Activates AMPK ↓ Hepatic glucose production ↑ Insulin sensitivity ↓ Insulin resistance ↑ GLP-1 levels?

MOA/effects

Not recommended Sulfonylureas (glyburide, glipizide, glimepiride)

Acceptable Dopamine agonists (bromocriptine)

SGLT-2 inhibitors (dapagliflozin, canagliflozin, empagliflozin)

Long-acting insulin analogues (glargine, detemir)

DPP-4 inhibitors (sitagliptin. saxagliptin, linagliptin)

GLP-1 receptor agonists (exenatide LAR, exenatide bid, liraglutide)

Recommended Biguanides (metformin)

Class (medication)

Table 1. Medications Available to Treat T2DM

No hypoglycemia Durable ↑ HDL-C levels ↓ TG levels ↓ All-cause mortality (pioglitazone)

Low cost Long-term safety established

Weight neutral No hypoglycemia ↓ CV events

↓ Weight No hypoglycemia

Weight neutral No to low risk of hypoglycemia Oral administration β-cell survival Sustained glycemic improvements

Weight neutral No to low risk of hypoglycemia ↓ CV events Low cost Oral administration Long-term safety known ↓ Weight No to low risk of hypoglycemia Improved (β-cell function/survival Potential CV benefit

Advantages

↑ Weight Hypoglycemia HbA1c reductions not durable Conflicting data on CVD risk ↑ Weight Edema, heart failure ↑ Risk of myocardial infarction Bone fractures ↑ LDL-C levels

Dizziness/syncope Nausea Fatigue Rhinitis

Varies

↑ Weight Injectable Hypoglycemia Training required Associated stigma Fluid retention Vulvovaginitis, balanitis, and lower UTIs

Pioglitazone: 15–45 mg daily Rosiglitazone: # 8 mg/day

1–40 mg daily

0.8–4.8 mg daily

NA

Saxagliptin: 2.5–5 mg daily; sitagliptin: 100 mg daily; linagliptin: 5 mg daily

Exenatide bid: 10–20 μg daily; exenatide LAR: 2 mg weekly; liraglutide: 0.6, 1.2, 1.8 mg/day

500–2550 mg daily

Dosage

Cases of pancreatitis observed Allergic and hypersensitivity reactions Long-term safety unknown

GI AEs (diarrhea, cramping) Lactic acidosis (rare) Vitamin B12 deficiency Contraindications: reduced kidney, liver, cardiac function, history of lactic acidosis, hypoxemia GI AEs (nausea, vomiting) Cases of acute pancreatitis and medullary thyroid cell carcinoma observed Injectable Long-term safety unknown

Disadvantages


Daniel A. Nadeau


↑ Weight similar to long-acting analogues Injectable Training required Associated stigma

GI AEs: nausea, vomiting Hypoglycemia Injectable Long-term safety unknown Only used with insulin Administration frequency ↑ Weight Hypoglycemia Administration frequency

Hypoglycemia likely in combination with other drugs GI AEs

N/A

Repaglinide: 1.5–12 mg daily Nateglinide: 120–360 mg daily

60–120 μg daily

25–100 mg 3 times daily

Adapted from Nadeau DA. Physiologic and weight-focused treatment strategies for managing type 2 diabetes mellitus: the metformin, glucagon-like peptide-1 receptor agonist, and insulin (MGI) approach. Postgrad Med. 2013;125(3): 112–126.3 Abbreviations: AE, adverse event; AMPK, adenosine monophosphate–activated protein kinase; CV, cardiovascular; CVD, cardiovascular disease; DPP-4, dipeptidyl peptidase-4; GI, gastrointestinal; GLP-1, glucagon-like peptide-1; HbA1c, glycated hemoglobin; HDL-C, high-density lipoprotein cholesterol; KATP, adenosine triphosphate–sensitive potassium; LAR, long-acting release; LDL-C, low-density lipoprotein cholesterol; MOA, mechanism of action; NA, not applicable; PPAR, peroxisome proliferator–activated receptor; SGLT-2, sodium-glucose cotransporter; T2DM, type 2 diabetes mellitus; TG, triglyceride; UTI, urinary tract infection.

Less hypoglycemia than with long-acting insulin analogues

Closes KATP channels on β-cell plasma membranes ↑ Insulin secretion

Meglitinides (repaglinide. nateglinide)

Multihexamer solubilization technology Directly activates insulin receptor ↓ Hepatic glucose production ↓ Lipolysis

Rapid, short acting

Amylinomimetic; stimulates amylin receptors ↓ Gastric emptying ↑ Satiety ↓ Glucagon secretion

Amylin (pramlintide)

Emerging treatments Ultra–long-acting insulin analogues (insulin degludec)

↓ TG levels ↓ Weight No hypoglycemia Low cost ↓ Weight

Inhibit carbohydrate degradation ↑ Secretion of GLP-1

Alpha-glucosidase inhibitors (acarbose, miglitol)





Daniel A. Nadeau

pharmacologic therapy, unless contraindicated. One approach to pharmacologic therapy, termed the MGI (metformin, GLP1-RA, and insulin) protocol has been described previously.3 In brief, treatment of T2DM is begun with metformin; this drug is the first-line oral therapy for T2DM according to guidelines from several medical professional groups.60–64 An injectable GLP-1-RA could be added immediately if baseline HbA1c is high (ie, . 7.5%)64 or if there is urgency in achieving weight loss targets. For example, underlying weight-related sleep apnea and lower extremity arthritic pain may compel urgent weight loss. As previously discussed, because GLP1-RAs address the core pathophysiologic defects of T2DM (Figure 1),3,65 their early use is reasonable. The GLP-1-RAs stimulate insulin secretion in a glucosedependent manner via pancreatic β cells and enhance glucose sensitivity (defect III on Figure 1), prevent inflammationmediated apoptosis of pancreatic β-cells (defect III), reduce glucagon secretion by pancreatic α cells (defect VI), decrease hepatic glucose production (defect I), replace a deficient GLP-1 response (defect V), initially delay gastric emptying, induce satiety (defect VIII), and result in overall weight loss,65–68 which suggests that the GLP-1-RAs address 5 of

the 8 pathophysiologic defects. Moreover, the GLP-1-RAs reduce triglyceride levels and blood pressure69–71; evidence also suggests that the GLP-1-RAs may facilitate better food choices, aiding in further weight loss, 72 and potentially increasing exercise quantity. Metformin and the GLP-1-RAs are helpful for self-motivated patients with T2DM because they are weight-neutral or may induce weight loss.3 Insulin therapy with or without additional pharmacotherapy may be considered in patients with markedly symptomatic or elevated blood glucose levels or HbA1c. Insulin, if needed, should be initiated in patients with T2DM as the long-acting form at bedtime to reduce hepatic glucose production and reduce the risk of daytime hypoglycemia during exercise. In my experience, dosing can begin at either 10 U at bedtime or 0.2 U/kg and increased by 1 U every day until the morning glucose is , 120 mg/dL. Allowing time for the achievement of weight loss may require slower titration if dramatic alterations in lifestyle are occurring. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are newly available, and when added to metformin and a GLP-1-RA, are powerful adjuncts to current therapy. These

Figure 1. The multifactorial pathogenesis of T2DM. X, T2DM pathologies directly addressed by GLP-1-RAs; x, anecdotal evidence suggests that weight loss induced by GLP-1-RAs may correspond with positive changes in food and exercise choices.

Reprinted from Postgraduate Medicine, 125, Nadeau D. Physiologic and weight-focused treatment strategies for managing type 2 diabetes mellitus: The metformin glucagonlike peptide-1 receptor agonist, and insulin (mgi) approach, 112–126. Copyright 2013, with permission from JTE Multimedia.3 Abbreviations: GLP-1-RA, glucagon-like peptide 1 receptor agonist; T2DM, type 2 diabetes mellitus.

56




agents prevent glucose reabsorption in the proximal tubule of the kidney, leading to glucose (and calorie) loss, significant effects on HbA1c, and overall glucose control; weight loss is observed in some patients. Adverse events include an increased risk of bacterial and mycotic infections; patients who develop mycotic infections may experience recurrent infections.73 Additionally, elderly patients should be cautioned about the possibility of symptoms related to orthostatic hypotension secondary to volume contraction when using SGLT-2 inhibitors.73 The combination of metformin, GLP-1, and SGLT-2 lowers glucose and facilitates weight loss with almost no risk of hypoglycemia; however, the economic cost of treatment may be an important consideration for some patients.

Case Report Patient Demographics and Clinical Characteristics Upon Clinic Arrival

T.M. was a 260-lb (118 kg), 5′10″ (178 cm; body mass index = 37.3), 43-year-old man diagnosed with T2DM 1 month previously, with hypertension, hypercholesterolemia, and concomitant sleep apnea for which he refused to use a continuous positive air pressure machine. He stated he had gained an average of 3 to 5 pounds each year for the previous 5 years, and had “never been able to lose weight.” Current medication included metformin (1000 mg twice daily), plus 2 medications to lower blood pressure and cholesterol levels. Fasting glucose readings were 200 to 230 mg/dL and HbA 1c was 9.7%. He was following the standard American diet and had no regular exercise program other than working on his commercial boat. He described his diabetes as a “wake-up call.”

Treatment

After screening for cardiac disease, T.M. was counseled on an aggressive diet and exercise program. He was asked to begin walking for 20 minutes/day, which would increase as he became able to do so. His metformin was continued at the same dose, and liraglutide 0.6 mg daily was initiated and titrated to 1.2 mg after 1 week. The patient had mild nausea that was resolved within 10 days of initiation of treatment with liraglutide. He seemed eager to use a medication that would lower his HbA1c and that might help with weight loss and lifestyle changes. He adopted a whole food, mainly plant-based diet. As encouraged to do so after 3 weeks, he increased his exercise to 40 minutes/day of HIIT, which included a 10-minute warmup and three 5-minute intervals of intense exercise, alternating with three 5-minute

moderate exercise intervals. He also included 4 days of resistance training, with each session lasting approximately 20 minutes, focusing on chest, back, legs, and shoulders on different days, with abdominal exercises twice weekly. At a follow-up visit, his wife reported that his snoring had improved, and T.M. reported being more awake during the day. A repeat polysomnographic study showed a significant reduction in apnea.

Results

After 7 weeks, T.M. had lost 12 pounds, his fasting blood glucose levels were 100 to 110 mg/dL, and his HbA1c was 7.3%. He was optimistic about continuing to lose weight now that his appetite was better controlled.

Conclusion

Type 2 diabetes mellitus is a significant public health problem. For motivated individuals, the severity/progression of the disease can at least be alleviated by making positive changes in diet and exercise. New technology may assist some patients with achieving their objectives, but for others, it may be necessary to initiate pharmacotherapy: the MGI (metformin, GLP-1 RA, and insulin) protocol3 may prove beneficial for many patients who are motivated to make the lifestyle modifications necessary to assist in controlling T2DM.

Acknowledgments

Under the direction of the author, medical editorial support was provided by Sylvia Hanna and Roderick H. Sayce, BSc, MBA, at Complete Publications Solutions, LLC; this support was funded by Novo Nordisk A/S.

Conflict of Interest Statement

Daniel A. Nadeau, MD, has served as a speaker for AstraZeneca, Bristol-Myers Squibb, Janssen, and Novo Nordisk. Dr Nadeau is also an adviser to and stockholder in Novo Nordisk. The content of this manuscript has not been presented elsewhere in whole or in part.

References 1. National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011. Atlanta, GA: Department of Health and Human Services, Centers for Disease Control and Prevention, 2011. 2. Boyle JP, Thompson TJ, Gregg EW, Barker LE, Williamson DF. Projection of the year 2050 burden of diabetes in the US adult population: dynamic modeling of incidence, mortality, and prediabetes prevalence. Popul Health Metr. 2010;8:29.



Daniel A. Nadeau 3. Nadeau DA. Physiologic and weight-focused treatment strategies for managing type 2 diabetes mellitus: the metformin, glucagon-like peptide-1 receptor agonist, and insulin (MGI) approach. Postgrad Med. 2013;125(3):112–126. 4. American Diabetes Association. Standards of medical care in diabetes—2012. Diabetes Care. 2012;35 Suppl 1:S11–S63. 5. Look Ahead Research Group, Wing RR, Bolin P, et al. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med. 2013;369(2):145–154. 6. Centers for Disease Control and Prevention. Adult participation in aerobic and muscle-strengthening physical activities—United States, 2011. Morb Mortal Wkly Rep. 2013;62(17):326–330. 7. Grace SL, Barry-Bianchi S, Stewart DE, Rukholm E, Nolan RP. Physical activity behavior, motivational readiness and self-efficacy among Ontarians with cardiovascular disease and diabetes. J Behav Med. 2007;30(1):21–29. 8. Church TS, Blair SN, Cocreham S, et al. Effects of aerobic and resistance training on hemoglobin A1c levels in patients with type 2 diabetes: a randomized controlled trial. JAMA. 2010;304(20):2253–2262. 9. de Lemos ET, Oliveira J, Pinheiro JP, Reis F. Regular physical exercise as a strategy to improve antioxidant and anti-inflammatory status: benefits in type 2 diabetes mellitus. Oxid Med Cell Longev. 2012;2012:741545. 10. Balducci S, Zanuso S, Cardelli P, et al. Effect of high- versus lowintensity supervised aerobic and resistance training on modifiable cardiovascular risk factors in type 2 diabetes; the Italian Diabetes and Exercise Study (IDES). PLoS One. 2012;7(11):e49297. 11. Evert AB, Boucher JL, Cypress M, et al. Nutrition therapy recommendations for the management of adults with diabetes. Diabetes Care. 2013;36(11):3821–3842. 12. Loimaala A, Groundstroem K, Rinne M, et al. Effect of long-term endurance and strength training on metabolic control and arterial elasticity in patients with type 2 diabetes mellitus. Am J Cardiol. 2009;103(7):972–977. 13. Arora E, Shenoy S, Sandhu JS. Effects of resistance training on metabolic profile of adults with type 2 diabetes. Indian J Med Res. 2009;129(5):515–519. 14. Balducci S, Zanuso S, Cardelli P, et al. Supervised exercise training counterbalances the adverse effects of insulin therapy in overweight/obese subjects with type 2 diabetes. Diabetes Care. 2012;35(1):39–41. 15. Li J, Zhang W, Guo Q, et al. Duration of exercise as a key determinant of improvement in insulin sensitivity in type 2 diabetes patients. Tohoku J Exp Med. 2012;227(4):289–296. 16. Chae JS, Kang R, Kwak JH, et al. Supervised exercise program, BMI, and risk of type 2 diabetes in subjects with normal or impaired fasting glucose. Diabetes Care. 2012;35(8):1680–1685. 17. Payne WR, Walsh KJ, Harvey JT, et al. Effect of a low-resource-intensive lifestyle modification program incorporating gymnasium-based and home-based resistance training on type 2 diabetes risk in Australian adults. Diabetes Care. 2008;31(12):2244–2250. 18. Williams GC, Freedman ZR, Deci EL. Supporting autonomy to motivate patients with diabetes for glucose control. Diabetes Care. 1998;21(10):1644–1651. 19. Donahue KE, Mielenz TJ, Sloane PD, Callahan LF, Devellis RF. Identifying supports and barriers to physical activity in patients at risk for diabetes. Prev Chronic Dis. 2006;3(4):A119. 20. Korkiakangas E, Taanila AM, Keinanen-Kiukaanniemi S. Motivation to physical activity among adults with high risk of type 2 diabetes who participated in the Oulu substudy of the Finnish Diabetes Prevention Study. Health Soc Care Community. 2011;19(1):15–22. 21. Biesenbach G, Bodlaj G, Sedlak M, Pieringer H, Kiesling G. Exercise program for older patients with insulin-treated type 2 diabetes: long-term effects on metabolic control and BMI. Z Gerontol Geriatr. 2009;42(6):465–469. 22. Casey D, De Civita M, Dasgupta K. Understanding physical activity facilitators and barriers during and following a supervised exercise programme in Type 2 diabetes: a qualitative study. Diabet Med. 2010;27(1):79–84.

58

23. Beverly EA, Wray LA. The role of collective efficacy in exercise adherence: a qualitative study of spousal support and type 2 diabetes management. Health Educ Res. 2010;25(2):211–223. 24. Ferrand C, Perrin C, Nasarre S. Motives for regular physical activity in women and men: a qualitative study in French adults with type 2 diabetes, belonging to a patients’ association. Health Soc Care Community. 2008;16(5):511–520. 25. Colberg SR, Albright AL, Blissmer BJ, et al. Exercise and type 2 diabetes: American College of Sports Medicine and the American Diabetes Association: joint position statement. Exercise and type 2 diabetes. Med Sci Sports Exerc. 2010;42(12):2282–2303. 26. McGavock J, Sellers E, Dean H. Physical activity for the prevention and management of youth-onset type 2 diabetes mellitus: focus on cardiovascular complications. Diab Vasc Dis Res. 2007;4(4):305–310. 27. Balducci S, Sacchetti M, Haxhi J, et al. Physical exercise as therapy for type 2 diabetes mellitus. Diabetes Metab Res Rev. 2014;30 Suppl 1:13–23. 28. Ross R, Janiszewski PM. Is weight loss the optimal target for obesityrelated cardiovascular disease risk reduction? Can J Cardiol. 2008;24 Suppl D:25D–31D. 29. Kessler HS, Sisson SB, Short KR. The potential for high-intensity interval training to reduce cardiometabolic disease risk. Sports Med. 2012;42(6):489–509. 30. Tjonna AE, Lee SJ, Rognmo O, et al. Aerobic interval training versus continuous moderate exercise as a treatment for the metabolic syndrome: a pilot study. Circulation. 2008;118(4):346–354. 31. Bartlett JD, Close GL, MacLaren DP, et al. High-intensity interval running is perceived to be more enjoyable than moderate-intensity continuous exercise: implications for exercise adherence. J Sports Sci. 2011;29(6):547–553. 32. Guiraud T, Nigam A, Gremeaux V, et al. High-intensity interval training in cardiac rehabilitation. Sports Med. 2012;42(7):587–605. 33. Dunstan DW, Daly RM, Owen N, et al. Home-based resistance training is not sufficient to maintain improved glycemic control following supervised training in older individuals with type 2 diabetes. Diabetes Care. 2005;28(1):3–9. 34. Willey KA, Singh MA. Battling insulin resistance in elderly obese people with type 2 diabetes: bring on the heavy weights. Diabetes Care. 2003;26(5):1580–1588. 35. Balducci S, Zanuso S, Nicolucci A, et al. Effect of an intensive exercise intervention strategy on modifiable cardiovascular risk factors in subjects with type 2 diabetes mellitus: a randomized controlled trial: the Italian Diabetes and Exercise Study (IDES). Arch Intern Med. 2010;170(20):1794–1803. 36. Hovanec N, Sawant A, Overend TJ, Petrella RJ, Vandervoort AA. Resistance training and older adults with type 2 diabetes mellitus: strength of the evidence. J Aging Res. 2012;2012:284635. 37. Albright A, Franz M, Hornsby G, et al. American College of Sports Medicine position stand. Exercise and type 2 diabetes. Med Sci Sports Exerc. 2000;32(7):1345–1360. 38. Haskell WL, Lee IM, Pate RR, et al. Physical activity and public health: updated recommendation for adults from the American College of Sports Medicine and the American Heart Association. Med Sci Sports Exerc. 2007;39(8):1423–1434. 39. Nelson ME, Rejeski WJ, Blair SN, et al. Physical activity and public health in older adults: recommendation from the American College of Sports Medicine and the American Heart Association. Med Sci Sports Exerc. 2007;39(8):1435–1445. 40. Sigal RJ, Kenny GP, Wasserman DH, Castaneda-Sceppa C. Physical activity/exercise and type 2 diabetes. Diabetes Care. 2004;27(10):2518–2539. 41. Sigal RJ, Kenny GP, Wasserman DH, Castaneda-Sceppa C, White RD. Physical activity/exercise and type 2 diabetes: a consensus statement from the American Diabetes Association. Diabetes Care. 2006;29(6):1433–1438. 42. Dunstan DW, Daly RM, Owen N, et al. High-intensity resistance training improves glycemic control in older patients with type 2 diabetes. Diabetes Care. 2002;25(10):1729–1736.



T2DM in Self-Motivated Patients 43. Gordon BA, Benson AC, Bird SR, Fraser SF. Resistance training improves metabolic health in type 2 diabetes: a systematic review. Diabetes Res Clin Pract. 2009;83(2):157–175. 44. Colberg SR, Sigal RJ, Fernhall B, et al. Exercise and type 2 diabetes: the American College of Sports Medicine and the American Diabetes Association: joint position statement. Diabetes Care. 2010;33(12):e147–e167. 45. Pan A, Sun Q, Bernstein AM, et al. Red meat consumption and risk of type 2 diabetes: 3 cohorts of US adults and an updated meta-analysis. Am J Clin Nutr. 2011;94(4):1088–1096. 46. Aune D, Ursin G, Veierod MB. Meat consumption and the risk of type 2 diabetes: a systematic review and meta-analysis of cohort studies. Diabetologia. 2009;52(11):2277–2287. 47. Barr SB, Wright JC. Postprandial energy expenditure in whole-food and processed-food meals: implications for daily energy expenditure. Food Nutr Res. 2010;54. doi: 10.3402/fnr.v54i0.5144. 48. Berkow SE, Barnard N. Vegetarian diets and weight status. Nutr Rev. 2006;64(4):175–188. 49. Barnard ND, Cohen J, Jenkins DJ, et al. A low-fat vegan diet improves glycemic control and cardiovascular risk factors in a randomized clinical trial in individuals with type 2 diabetes. Diabetes Care. 2006;29(8):1777–1783. 50. Barnard ND, Cohen J, Jenkins DJ, et al. A low-fat vegan diet and a conventional diabetes diet in the treatment of type 2 diabetes: a randomized, controlled, 74-wk clinical trial. Am J Clin Nutr. 2009;89(5):1588S–1596S. 51. American Diabetes Association. Standards of medical care in diabetes— 2013. Diabetes Care. 2013;36 Suppl 1:S11–S66. 52. Muraki I, Imamura F, Manson JE, et al. Fruit consumption and risk of type 2 diabetes: results from three prospective longitudinal cohort studies. BMJ. 2013;347:f5001. 53. Oftedal B, Bru E, Karlsen B. Motivation for diet and exercise management among adults with type 2 diabetes. Scand J Caring Sci. 2011;25(4):735–744. 54. Martinez-Perez B, de la Torre-Diez I, Lopez-Coronado M. Mobile health applications for the most prevalent conditions by the World Health Organization: review and analysis. J Med Internet Res. 2013;15(6):e120. 55. El-Gayar O, Timsina P, Nawar N, Eid W. Mobile applications for diabetes self-management: status and potential. J Diabetes Sci Technol. 2013;7(1):247–262. 56. Ma Y, Olendzki BC, Chiriboga D, et al. PDA-assisted low glycemic index dietary intervention for type II diabetes: a pilot study. Eur J Clin Nutr. 2006;60(10):1235–1243. 57. Tatara N, Arsand E, Bratteteig T, Hartvigsen G. Usage and perceptions of a mobile self-management application for people with type 2 diabetes: qualitative study of a five-month trial. Stud Health Technol Inform. 2013;192:127–131. 58. Spring B, Schneider K, McFadden HG, et al. Multiple behavior changes in diet and activity: a randomized controlled trial using mobile technology. Arch Intern Med. 2012;172(10):789–796. 59. Silveira P, van het Reve E, Daniel F, Casati F, de Bruin ED. Motivating and assisting physical exercise in independently living older adults: a pilot study. Int J Med Inform. 2013;82(5):325–334.

60. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia. 2012;55(6):1577–1596. 61. Qaseem A, Humphrey LL, Sweet DE, et al. Oral pharmacologic treatment of type 2 diabetes mellitus: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2012;156(3):218–231. 62. Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009;32(1):193–203. 63. Handelsman Y, Mechanick JI, Blonde L, et al. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for developing a diabetes mellitus comprehensive care plan. Endocr Pract. 2011;17 Suppl 2:1–53. 64. Garber AJ, Abrahamson MJ, Barzilay JI, et al. AACE comprehensive diabetes management algorithm 2013. Endocr Pract. 2013;19(2):327–336. 65. Defronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58(4):773–795. 66. Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet. 2002;359(9309):824–830. 67. Madsbad S, Krarup T, Deacon CF, Holst JJ. Glucagon-like peptide receptor agonists and dipeptidyl peptidase-4 inhibitors in the treatment of diabetes: a review of clinical trials. Curr Opin Clin Nutr Metab Care. 2008;11(4):491–499. 68. Ferdaoussi M, Abdelli S, Yang JY, et al. Exendin-4 protects beta-cells from interleukin-1 beta-induced apoptosis by interfering with the c-Jun NH2-terminal kinase pathway. Diabetes. 2008;57(5):1205–1215. 69. Garber A, Henry R, Ratner R, et al. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet. 2009;373(9662):473–481. 70. Vilsboll T, Zdravkovic M, Le-Thi T, et al. Liraglutide, a long-acting human glucagon-like peptide-1 analog, given as monotherapy significantly improves glycemic control and lowers body weight without risk of hypoglycemia in patients with type 2 diabetes. Diabetes Care. 2007;30(6):1608–1610. 71. Moretto TJ, Milton DR, Ridge TD, et al. Efficacy and tolerability of exenatide monotherapy over 24 weeks in antidiabetic drug-naive patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther. 2008;30(8):1448–1460. 72. Dickson SL, Shirazi RH, Hansson C, et al. The glucagon-like peptide 1 (GLP-1) analogue, exendin-4, decreases the rewarding value of food: a new role for mesolimbic GLP-1 receptors. J Neurosci. 2012;32(14):4812–4820. 73. Invokana. Canagliflozin. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2013.


Remission of recently diagnosed type 2 diabetes mellitus with weight loss and exercise.

Nutritional management of type 2 diabetes mellitus and obesity and pharmacologic therapies to facilitate weight loss.

Short-term safety, tolerability and efficacy of a very low-calorie-ketogenic diet interventional weight loss program versus hypocaloric diet in patients with type 2 diabetes mellitus.

Distorted self-perceived weight status and underestimation of weight status in diabetes mellitus type 2 patients.

Management of hospitalized type 2 diabetes mellitus patients.

Exenatide Effects on Cardiometabolic Risk and Weight in Adolescents with Morbid Obesity and Type 2 Diabetes Mellitus: Two Case Reports.

Obesity, weight loss and prognosis in type 2 diabetes.

Exercise Therapy for Management of Type 2 Diabetes Mellitus: Superior Efficacy of Activity Monitors over Pedometers.

Physical exercise as therapy for type 2 diabetes mellitus.

Improvements in insulin sensitivity after aerobic exercise and weight loss in older women with a history of gestational diabetes and type 2 diabetes mellitus.

Predictors of Diet-Induced Weight Loss in Overweight Adults with Type 2 Diabetes.

Prevalence of lean type 2 diabetes mellitus in recently diagnosed type 2 diabetes mellitus patients.

Diet and exercise interventions for preventing gestational diabetes mellitus.

Qigong Exercises for the Management of Type 2 Diabetes Mellitus.

[Guidelines for the management of diabetes mellitus type 2].

High protein weight loss diets in obese subjects with type 2 diabetes mellitus.

Effect of diet on type 2 diabetes mellitus: a review.

Adiposity, hypertension and weight management behaviours in Ghanaian type 2 diabetes mellitus patients aged 20-70 years.

Effect of diet on type 2 diabetes mellitus: A review.

Cardiovascular control during exercise in type 2 diabetes mellitus.

Glycemic targets and medication limitations for type 2 diabetes mellitus in the older adult.

Randomization to a low-carbohydrate diet advice improves health related quality of life compared with a low-fat diet at similar weight-loss in Type 2 diabetes mellitus.

Laparoscopic sleeve gastrectomy: perioperative outcomes, weight loss and impact on type 2 diabetes mellitus over 2 years.

Clinical Evaluation of OneTouch Diabetes Management Software System in Patients with Type 2 Diabetes Mellitus.