Lifestyle Approaches and Glucose Intolerance

China Da Qing Diabetes Prevention Study

The Da Qing Study randomized (by clinic) 577 Chinese adults with IGT (WHO criteria) to a control group or any of 3 treatment interventions (diet, exercise, or diet plus exercise). ⁵ These individuals had a mean age of 45 years and body mass index (BMI) of 26 kg/m². The dietary intervention focused on increasing vegetables, reducing consumption of alcohol and simple sugars, and encouraging overweight individuals (BMI ≥25 kg/m²) to lose weight. The exercise group was instructed to increase their daily activity by the equivalent of 20 minutes of moderate activity, such as brisk walking, and the diet plus exercise group was asked to follow both the exercise regimen and dietary modification. After adjustments for differences in baseline BMI and fasting glucose, the intervention groups showed a 31% (diet only), 46% (exercise only), and 42% (diet plus exercise) significant reduction in the risk of developing T2D when compared with the control group at the 6-year follow-up period. Thus, the effectiveness of the diet intervention were similar to the exercise intervention and an additive effect was not present when the interventions were combined (diet plus exercise). Interestingly, in a multivariate analysis that controlled for age and clustering by clinic, individuals in the lifestyle intervention group (all 3 interventions combined) had a 51% lower incidence of diabetes at the 6-year evaluation period and a 43% lower incidence over the 20-year period (14 years after the intervention ceased) when compared with the control group. ¹³ These results demonstrate that the benefits from a lifestyle modification intervention can be maintained long-term after the active intervention period has ceased.

Finnish Diabetes Prevention Study

The Finnish Diabetes Prevention Study randomized 522 middle-aged (mean age = 55 years) and overweight/obese (mean BMI = 31 kg/m²) individuals with IGT (WHO criteria) to either the intensive lifestyle intervention or control groups. ⁴ The lifestyle intervention provided individualized counseling focused on achieving a weight loss goal of 5% or more of total body weight, reducing fat intake, increasing fiber intake, and increasing physical activity (30 minutes per day of moderate exercise). At 4 years, the cumulative incidence of T2D was 11% in the intervention group and 23% in the control group. Overall, the incidence of diabetes was 58% lower in the intervention group than in the control group. Three years following the active intervention (7-year follow-up), the incidence of diabetes was still lower in the intervention group (4.3 per 100 person-years) when compared with the control group (7.4 per 100 person-years), indicating a 43% reduction in the relative risk of T2D. ¹² It is important to note that the impact of lifestyle changes in reducing the incidence of diabetes was maintained for at least 3 years following the discontinuation of the intensive lifestyle intervention.

The Diabetes Prevention Program (DPP)

To date, one of the largest randomized controlled clinical trials is the US DPP. ⁶ This study was conducted in 3234 adults (mean age = 51 years; mean BMI = 34 kg/m²) with IFG and IGT (ADA criteria). The individuals were randomized to 1 of 3 groups, which included placebo, metformin (results reviewed in the pharmaceutical section), or intensive lifestyle intervention. Here, 68% of the participants were women, and 45% were from minority groups that have an increased risk of developing T2D. The 2 major goals of the DPP lifestyle intervention were a minimum of 7% weight loss through a low-calorie and low-fat diet and a minimum of 150 min/wk of physical activity similar in intensity to brisk walking. After an average follow-up period of 2.8 years, the intensive lifestyle intervention had a 58% reduction in the incidence of T2D when compared with the placebo group. Furthermore, reversion to normal glucose tolerance occurred in approximately 30% of the individuals in the lifestyle intervention arm, as compared with approximately 18% in the control arm (fasting and postload glucose concentrations). Lifestyle changes worked particularly well for participants aged 60 years and older, thus, reducing their diabetes risk by 71%. Approximately 5% of the lifestyle intervention group developed diabetes each year during the study period compared with 11% of those in the placebo group. Also, 50% of the lifestyle intervention group achieved the goal of at least 7% weight reduction, and 74% met the goal of at least 150 min/wk of moderately intensive activities. Although weight loss was a predictor of reduced diabetes incidence in the lifestyle intervention group, improvements in insulin sensitivity and insulin secretion may also be independent predictors of a beneficial outcome. ²¹

Delay or prevention of T2D by lifestyle intervention can persist for at least 10 years in US adults. The long-term effect of the DPP lifestyle intervention was assessed 7 years later following the intervention (10-year follow-up). The DPP Outcomes Study (DPPOS) found that diabetes incidence was reduced by 34% in the lifestyle intervention group when compared with the placebo group. ¹⁴ Also, high-risk individuals who achieved normal glucose regulation status at least once during the DPP clinical trial had a 56% lower risk of diabetes compared with individuals with consistent prediabetes during the subsequent follow-up in DPPOS. ²²

Obesity

Excess body weight is an important modifiable risk factor for individuals with a high-risk of developing T2D. The incidence of T2D rises as obesity prevalence increases. ³⁶ One of the many important benefits of weight loss is diabetes prevention. In the Finnish Diabetes Prevention Study and DPP clinical trials, the lifestyle modification interventions resulted in weight loss and reduced risk of T2D in individuals with IGT.^4,6,16,18 During the first year of the Finnish Diabetes Prevention Study, ⁴ the participants’ body weight decreased on average by 4.2 kg in the intervention group and 0.8 kg in the control group. Most of the weight reduction was maintained during the second year, and by the end of the second year the mean weight loss was approximately 3.5 kg in the intervention group and approximately 0.8 kg in the control group. During the 4-year follow-up assessment, a sustained weight reduction in participants with IGT resulted in insulin sensitivity improving by 64%, whereas insulin sensitivity deteriorated by 24% with weight gain. ³⁷ Additionally, insulin sensitivity was inversely correlated with body weight. ³⁷ In a similar study (DPP), ⁶ the lifestyle intervention group had a significantly greater average weight loss (5.6 kg) than the metformin (2.1 kg) and placebo (0.1 kg) groups. The individuals in the lifestyle intervention had a 16% average reduction in risk of T2D per kilogram of weight loss. ³⁸ Also, studies of diabetes prevention in Japan ¹⁶ and Sweden ¹⁸ confirmed the benefit of lifestyle modification programs, and the weight loss was associated with the diabetes risk reductions.

Severe obesity can be difficult to treat through lifestyle modification alone. When lifestyle modification interventions are insufficient, then bariatric surgery can be used to achieve weight-loss goals. There is evidence suggesting that bariatric surgery can be successful in preventing diabetes. In the Swedish Obese Subjects (SOS) intervention study,^39-41 obese individuals underwent adjustable or nonadjustable banding, vertical-banded gastroplasty, or gastric bypass operations. The bariatric surgery group had greater weight loss, lower blood glucose and insulin levels, and lower incidence of diabetes when compared with the control group (no surgery group). ⁴⁰ The mean changes in body weight after 2, 10, 15, and 20 years were −23%, −17%, −16%, and −18% in the surgery group and 0%, 1%, −1%, and −1% in the control group, respectively. ³⁹ Bariatric surgery reduced the long-term incidence of diabetes by 78% in obese individuals. ⁴¹ These results certainly suggest that severe obesity can be treated with bariatric surgery and that weight loss results in a marked reduction in the incidence of diabetes. However, individuals should be cautious when undergoing weight loss surgery because of increased morbidity and mortality rates from the surgical procedure.

Unhealthy Eating Habits

Although obesity is an important risk factor for T2D, ³⁶ eating habits are also believed to play a role in the development of T2D. Dietary modification, including a reduction in total calories and fat (also saturated fat) and an increase in fiber and whole grains, has been successful in reducing the risk of T2D. ⁵ Similar results were found when diet modification was combined with physical activity (ie, lifestyle intervention).^4,6 However, there is evidence suggesting that neither total fat nor carbohydrate, as proportions of total energy intake, play a major part in the development of T2D,^8,42-44 thus suggesting that the quality of fat and carbohydrates may be more important than the quantity. Also, emerging evidence found that dietary patterns (ie, combination of different foods or food groups) may be associated with diabetes.^45,46

Physical Inactivity

A protective effect of physical activity or exercise (used interchangeably) on the risk of developing T2D is biologically plausible. ⁸⁰ Skeletal muscle represents the predominant site of insulin resistance in diabetes, and exercising has been shown to improve insulin sensitivity in this tissue.^81,82 The current joint position stand statement from the American College of Sports Medicine and ADA recommends ≥150 min/wk of moderate- to vigorous-intensity physical activity as part of lifestyle changes to prevent T2D in a high-risk population. ⁸³

Exercising can improve glycemic control and prevent or delay the onset of T2D.^4-6,84 Lifestyle modification interventions in high-risk individuals that included groups with exercise only and the combination of exercise and dietary modification reduced the risk of T2D by 42% to 58%.^4-6 Weight loss is the dominant predictor of a reduced risk of T2D, but increased physical activity reduced the risk of T2D even when weight loss goals were not achieved or adjusted for in the model.^38,85 Also, physical activity has been shown to improve insulin sensitivity independent of weight loss.^86,87

Long-term prospective studies showed that increasing physical activity reduced the risk of diabetes. In the British Regional Heart Study Cohort, ⁸⁸ a substantial fall in risk of diabetes was observed in men engaged in moderate levels of physical activity relative to physically inactive men (after adjusting for age and BMI). In the US NHS Cohort, ⁸⁹ the risk of developing T2D was lower (33% reduction) among the women engaging in vigorous exercise at least once weekly compared with women not engaging in exercise weekly (still apparent after adjusting for BMI). Both moderate walking and vigorous activity have been associated with a decreased risk, and greater volumes of physical activity may provide the most prevention. ⁹⁰ Numerous epidemiological studies that focused on sedentary behavior indicated that increased physical activity reduced the risk of diabetes, whereas sedentary behaviors (such as watching television) increased the risk.^91-93 Similar to low levels of physical activity, a low level of cardiorespiratory fitness (determined by a maximal exercise test on a treadmill) is also a risk factor for T2D, and increasing levels of cardiorespiratory fitness can lower the incidence rates of T2D.^94-98

Smoking and Alcohol Consumption

Apart from obesity, unhealthy eating habits, and physical inactivity, there are other modifiable risk factors for T2D such as cigarette smoking and heavy alcohol consumption. Smoking and alcohol consumption represent a potentially important risk factor for T2D, especially because 52% (alcohol users) and 18% (smokers) of US adults are currently engaging in these unhealthy behaviors (National Health Interview Survey, 2012). ⁹⁹ Although cigarette smoking is well documented as a risk factor for cardiovascular disease, its association with T2D is less clear. Also, the association between alcohol use and T2D has been inconsistent in the literature.

There is evidence that suggests smoking is associated with an increase in the risk of T2D^100-105 and also linked to insulin resistance.^106,107 Smoking cessation is often accompanied by substantial weight gain, ¹⁰⁴ and obesity is an important risk factor for the development of diabetes. ¹⁰⁸ In the British Regional Heart Study, ¹⁰⁴ men who stopped smoking during the first 5 years of follow-up showed significant weight gains, which resulted in a higher risk of diabetes than continuing smokers. However, the benefits of smoking cessation were apparent in those who stopped smoking over 5 years ago; also, it took 20 years for the risk of diabetes to revert to that of never smokers. In the same study, when the current cigarette smokers were compared with the never smokers, the smokers had a higher risk of diabetes (even after adjustments for age, BMI, and other potential confounders). Data from the US NHS ¹⁰³ and Health Professionals’ Follow-up Study, ¹⁰² showed at the follow-up period a relative risk of 1.42 in women and 1.94 in men who smoked ≥25 cigarettes/d compared with nonsmokers. More recent investigations, for example, the Coronary Artery Risk Development in Young Adults (CARDIA) Study ¹⁰¹ indicated that 16.7% of individuals with normal glucose tolerance at baseline developed glucose intolerance at the 15-year follow-up. Consequently, the incidence of glucose intolerance was the highest among smokers (21.8%) and lowest in the never smokers without any exposure to secondhand smoke (11.5%).

Although evidence suggests that light to moderate alcohol consumption is associated with reduced risk of diabetes, heavy alcohol intake increases diabetes risk. There was a 30% to 40% reduced risk of T2D among those individuals consuming 1 to 4 drinks/d, and this reduction in risk was less or no longer existed in individuals consuming >4 drinks/d.^102,109 Also, in the Atherosclerosis Risk in Communities (ARIC) Study, ¹¹⁰ women and men consuming a moderate amount of alcohol (7.1-14 drinks/wk) were not at higher risk of developing T2D compared with their counterparts consuming little alcohol (≤1 drink/wk). However, men consuming >21 drinks/wk were about 50% more likely to develop T2D when compared with their counterparts consuming less alcohol (≤1 drink/wk). These findings were consistent with earlier results reported by Holbrook et al, ¹¹¹ which found that alcohol intake was a risk factor for the development of T2D in men, but not in women.

Pharmaceutical Treatments

Pharmacological treatments targeted at improving insulin sensitivity and glucose homeostasis in vivo have represented the conventional approach by most physicians. Several studies have measured the effects of various drug interventions on the development of T2D in people with IGT. Specifically, oral diabetes drugs such as metformin (a biguanide), troglitazone (a thiazolidinedione), acarbose (an α-glucosidase inhibitor), and orlistat (an intestinal lipase inhibitor) have reduced the incidence of T2D in individuals with IGT.

The ADA recommends that metformin therapy for prevention of T2D may be considered in those with IGT, IFG, or a hemoglobin A1C between 5.7% and 6.4%. ⁹ To date, metformin is the most extensively used and researched pharmacological treatment for people with prediabetes, and its long-term safety has been demonstrated. The DPP and DPPOS clinical lifestyle modification intervention trials found that metformin reduced the incidence of diabetes by 31% at the 2.8-year follow-up and by 18% at the 10-year follow-up when compared with the placebo group.^6,14 Metformin was most effective in more obese (BMI ≥35 kg/m²) and younger (<45 years old) participants, and they experienced reductions in diabetes incidence of 53% and 44%, respectively. In contrast, metformin was less effective in those >60 years old, with a BMI <35 kg/m², and a fasting plasma glucose ≤6.1 mmol/L. ⁶ Gastrointestinal symptoms, including diarrhea, flatulence, nausea, and vomiting, occurred in 77 of every 100 persons on metformin in the study. ⁶ In addition, studies in China and India reported similar reductions in diabetes risk, with the use of metformin as an intervention, as well as improvements in glucose metabolism, such as fasting glucose, glucose tolerance, and insulin sensitivity.^15,112

The drug troglitazone has been shown to improve insulin sensitivity and glucose tolerance in obese individuals with IGT or normal glucose tolerance. ¹¹³ Troglitazone was used as a drug intervention in the DPP trial, and it reduced the development of T2D by 75% when compared with the placebo. ¹¹⁴ However, this drug was discontinued in the DPP trial and withdrawn from the market because of an increased incidence of drug-induced hepatotoxicity. The drug’s action did not persist long-term after it was discontinued, and the diabetes incidence rate was eventually similar to that in the placebo group.

The drug acarbose was studied in a meta-analyses that included people with IGT and IFG, and it was found that the use of acarbose reduced the incidence of T2D. ¹¹⁵ In the Study to Prevent Non-Insulin-Dependent Diabetes (STOP-NIDDM) trial, ¹¹⁶ 1429 participants with IGT were randomized to receive either the α-glucosidase inhibitor acarbose or a placebo. After a mean follow-up of 3.3 years, a 25% relative risk reduction in progression to diabetes was observed in the acarbose-treated group compared with the placebo group. However, almost one-third of the acarbose group was unable to complete the study because of gastrointestinal side effects (eg, flatulence and diarrhea).

Orlistat, a weight-loss drug, has been studied in individuals with IGT. Clinical trials showed improved glucose tolerance and reduced risk of progression from IGT to diabetes among individuals randomized to the orlistat group compared with the placebo group.^117,118 The beneficial health effects of this drug on glucose intolerance may be attributable to the weight loss.

Botanicals

Current pharmacological approaches marketed to control hyperglycemia tend to have untoward side effects,^119-124 thus shifting Americans’ interest to complementary and alternative medicine (CAM). Currently, it is estimated that approximately 38% of adults use CAM in pursuit of achieving good health and well-being. ¹²⁵ Specifically, the most commonly used CAM therapies are nonvitamin, nonmineral, and natural products (especially derived from botanicals) because they are perceived to be less toxic with fewer side effects than synthetic products. Botanicals, such as blueberries, have demonstrated many beneficial antidiabetic properties in rodent and cell culture models.^126-132 In a clinical trial conducted by Stull and Colleagues, ¹³³ daily supplementation of blueberries for 6 weeks improved insulin sensitivity in obese adults with prediabetes. These health benefits may be attributable to the blueberry phenolic bioactive compounds, such as anthocyanins, which are natural dark pigment colors in fruits and vegetables that also have antioxidant properties.^134-136

Likewise, other commonly used botanicals such as fenugreek, bitter melon, and cinnamon have been reviewed by Deng ¹³⁷ and Graf et al. ¹³⁸ The hypoglycemic effects of these botanicals were inconsistent in the literature. However, there were clinical studies that found these botanicals reduced hyperglycemia and improved insulin sensitivity in individuals with glucose intolerance. In a meta-analysis using 15 different Chinese herbal medicines, Grant et al ¹³⁹ found that several Chinese herbal medicines could be considered as potential treatments in people with prediabetes. Specifically, 8 of the 16 clinical trials reviewed showed that individuals consuming Chinese herbal medicines combined with lifestyle modification were more than 2-fold as likely to have their fasting plasma glucose levels reverted to normal levels when compared with lifestyle modification alone. Additionally, individuals receiving Chinese herbs were less likely to progress to diabetes over the duration of the trial.

Caution must be taken when reviewing the data from botanical clinical studies because certain limitations exist, such as small sample sizes and poor experimental designs. Also, there are variations in the participant population, botanical preparation, dose, and treatment duration. Therefore, before recommending botanicals as beneficial for the delay or prevention of diabetes, more botanical research is warranted to better understand their safety efficacy, and mechanisms of action with more well-designed, randomized, and controlled clinical trials.