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Lifestyle intervention for prevention of diabetes: determinants of success for future implementation

Cheryl Roumen, Ellen E Blaak, Eva Corpeleijn
DOI: http://dx.doi.org/10.1111/j.1753-4887.2009.00181.x 132-146 First published online: 1 March 2009

Abstract

Lifestyle interventions are reported to reduce the risk of type 2 diabetes in high-risk individuals after mid- and long-term follow-up. Information on determinants of intervention outcome and adherence and the mechanisms underlying diabetes progression are valuable for a more targeted implementation. Weight loss seems a major determinant of diabetes risk reduction, whereas physical activity and dietary composition may contribute independently. Body composition and genetic variation may also affect the response to intervention. Lifestyle interventions are cost-effective and should be optimized to increase adherence and compliance, especially for individuals in the high-risk group with a low socioeconomic status, so that public health policy can introduce targeted implementation programs nationwide. The aims of this review are to summarize the mid- and long-term effects of lifestyle interventions on impaired glucose tolerance and type 2 diabetes mellitus and to provide determinants of intervention outcome and adherence, which can be used for future implementation of lifestyle interventions.

  • determinants of success
  • diabetes risk
  • impaired glucose tolerance
  • implementation
  • lifestyle intervention

INTRODUCTION

The World Health Organization has predicted a global increase in diabetes prevalence of 39% between the years 2000 and 2030, which will increase the absolute number to 366 million people.1 Impaired glucose tolerance (IGT), impaired fasting glucose (IFG), and IGT/IFG combined predict the development of type 2 diabetes over 6 years with 9.1% progression for IFG, 32.5% progression for IGT, and 64.5% progression for combined IGT/IFG.2 IGT is characterized by insulin resistance and reduced β-cell glucose sensitivity,35 which may develop over many years. Lifestyle intervention may improve the metabolic profile and reverse the progression towards diabetes (Figure 1).5

Figure 1

Transition from normal glucose tolerance to diabetes mellitus type 2: three-step model. The development of normal glucose tolerance to impaired glucose tolerance and type 2 diabetes mellitus can be affected by age, genes, and lifestyle. It is (partly) reversible by healthy changes in lifestyle.

Adapted from Saad et al. (1999)5

In this manuscript, we summarize the mid- and long-term effects of lifestyle interventions in subjects with IGT to lifestyle intervention outcome, i.e., changes in glucose tolerance or diabetes incidence. In order to develop implementation strategies, it is important to know which factors determine the effectiveness of and adherence to the intervention. Therefore, we provide information on lifestyle factors, i.e., (central) obesity, physical activity, dietary patterns,29 on metabolic factors and genetic variation. Implementation of lifestyle interventions in general healthcare services will only start after lifestyle interventions have proven to be cost-effective. Therefore, this subject is discussed in a separate section. To conclude, this manuscript provides summary paragraphs regarding the long-term effects of lifestyle interventions and the major determinants of intervention outcome and adherence. In addition, the cost-effectiveness of lifestyle interventions and additional implementation strategies for the future are discussed and summarized; the strategies for implementation include socioeconomic, social, and psychological factors.

LIFESTYLE INTERVENTIONS: EFFECT ON DIABETES INCIDENCE AND 2-HOUR GLUCOSE CONCENTRATIONS

Tables 1 and 2 provide summaries of the lifestyle intervention studies performed to date to prevent type 2 diabetes in IGT subjects. The inclusion criteria were studies that lasted longer than 1 year and that investigated the effect of exercise and/or dietary intake on 2-h glucose concentration as an intermediate endpoint (Table 1) or diabetes incidence as a primary endpoint (Table 2).

View this table:
Table 1

Summary of lifestyle intervention studies to prevent type 2 diabetes with a minimal follow-up of 1 year and with change in 2-h glucose as an endpoint.

ReferenceCountry/studyStudy designFollow-upInclusion criteriaIntervention type(s)EX interventionDIET interventionChange in 2-h plasma glucose
Lindström et al. (2003)10Finland/DPS, KuopioRCT3 yearsIGT; age 40–64 years; BMI ≥ 25 kg/m2EX + DIETEncouragement to increase overall physical activity + circuit exercise sessions offeredWeight reduction through a healthy dietEX + DIET −0.5 ± 2.4 mmol/l versus −0.1 ± 2.2 mmol/l CON, n.s.
Swinburn et al. (2001)11New ZealandRCT1 year intervention and 4 year follow-upIGTDIETN/AMonthly group education sessions for reduced-fat eatingDIET after 5 years 1.02 ± 0.40 mmol/L versus 2.30 ± 0.54 mmol/L CON, P < 0.05
Lindahl et al. (1999)12SwedenRCT1 yearIGT; age 30–60 years; BMI ≥ 27 kg/m2EX + DIETEncouragement to increase physical activity + free exercise sessions first monthWeight reduction through healthy low-energy, low-fat dietEX + DIET −0.7 mmol/l, n.s.
Carr et al. (2005)13USARCT2 yearsIGTEX + DIETWalking/ jogging at 70% of HR for 1 h, 3 days/weekEncouragement to follow energy-balanced American Heart Foundation Step 2 dietEX −0.6 mmol/L, n.s.
Oldroyd et al. (2006)14EnglandRCT2 yearsIGTEX + DIETEncouragement to engage in 20–30 min aerobic activity 2–3 days/week + discount offered at local gymsWeight reduction through healthy low-energy, low-fat dietEX + DIET 0.2 mmol/L, n.s.
Roumen et al. (2008)15The Netherlands/SLIMRCT3 yearsIGT; age >40 years; BMI ≥ 25 kg/m2EX + DIETEncouragement to exercise for 30 min/day at moderate intensity + free exercise sessionsWeight reduction through healthy low-energy, low-fat dietEX + DIET −0.04 mmol/L, P < 0.05
  • Abbrevitions: BMI, body mass index; DIET, dietary; DM2, type 2 diabetes mellitus ; DPS, Diabetes Prevention Study; EX, exercise; HR, heart rate reserve; IGT, impaired glucose tolerance; LCD, low-calorie diet; LTPA, leisure time physical activity; N/A, not applicable; n.s., no significant difference between groups; RCT, randomized controlled trial; SLIM, Study on Lifestyle Intervention and Impaired Glucose tolerance Maastricht.

View this table:
Table 2

Summary of lifestyle intervention studies to prevent type 2 diabetes with a minimum follow-up of 1 year and with diabetes incidence as an endpoint.

ReferenceCountry/studyStudy designLength of follow-upInclusion criteriaIntervention type(s)EX interventionDIET interventionRelative risk reduction of type 2 diabetes versus control
Eriksson and Lindgärde (1991)17Sweden/Malmö Feasibility StudyNon-RCT5 yearsIGTEX + DIETEncouragement to increase physical activityHealthy dietary advice63%*
Pan et al. (1997)18China/Da Qing IGT and Diabetes StudyRCT6 yearsIGTEX alone; EX + DIETEncouragement to exercise 1 unit/dayBMI ≥ 25 kg/m2weight loss through reduced energy intake42%*
Tuomilehto et al. (2001)19Finland/DPSRCT3.2 yearsIGTEX + DIETEncouragement to exercise 30 min/day at moderate intensityWeight reduction ≥ 5% through healthy low-energy diet58%*
Knowler et al. (2002)20USA/DPPRCT2.8 yearsIGTEX + DIET; metforminEncouragement to exercise 150 min/week at moderate intensityWeight reduction > 7% through healthy low-energy, low-fat diet58% EX + DIET*; 31% metformin*
Lindstrom et al. (2006)21Finland/DPS, KuopioRCT7 years (4 years intervention + 3 years follow-up)IGT; age 40–64 years; BMI ≥ 25 kg/m2Post-hoc analysisEncouragement to increase overall physical activity + circuit exercise sessions offeredWeight reduction through a healthy diet43%*
Li et al. (2008)22China/Da Qing IGT and Diabetes StudyRCT20 years (6 years intervention + 14 years follow-up)IGTEX alone; EX + DIETEncouragement to exercise 1 unit/dayWeight loss through reduced energy intake43%*
Kosaka et al. (2005)23JapanRCT, intensive versus non-intensive lifestyle intervention4 yearsIGT menEX + DIETEncouragement to exercise 30–40 min/day at moderate intensityBMI < 22 kg/m2 through a healthy diet67%*
Ramachandran et al. (2006)24India, IDPP-1Prospective community-based30 monthsIGTEX + DIET; metformin alone; EX + DIET + metforminEncouragement to exercise 30 min/day at moderate intensityHealthy dietary advice29% EX + DIET* ; 28% EX + DIET + metformin*
Hamman et al. (2006)30USA, DPPCox hazard regression in intervention arm3.2 yearsIGT, only intervention groupEX + DIETEncouragement to exercise 150 min/week at moderate intensityWeight reduction > 7% through healthy low-energy, low-fat diet16% per kg weight loss*
Laaksonen et al. (2005)52Finland, DPSRCT4.1 yearsIGT; age 40–64 years; BMI ≥ 25 kg/m2EX + DIETEncouragement to exercise 30 min/day at moderate intensityWeight reduction ≥ 5% through healthy low-energy dietEX LTPA to moderate-vigorous or strenuous-structured 63–65%*
  • * P < 0.05, significant difference between groups.

  • 1 unit = 30 min mild exercise, 20 min moderate exercise, 10 min strenuous exercise, or 5 min very strenuous exercise.

  • Abbreviations: DIET, dietary; DM2, type 2 diabetes mellitus; DPP, Diabetes Prevention Program; DPS, Diabetes Prevention Study; EX, Exercise; HR, heart rate reserve; IGT, impaired glucose tolerance; LCD, low-calorie diet; LTPA, leisure time physical activity; N/A, not applicable; RCT, randomized controlled trial.

Glucose tolerance

There is evidence that lifestyle intervention leads to an improvement in glucose tolerance, measured as the 2-h plasma glucose concentration after a 75-g glucose load. Lifestyle interventions generally aim to achieve a body-weight loss of at least 5%, through a healthy diet and energy restriction, and to increase physical activity of moderate intensity to at least 30 min a day (Table 3). The healthy diet most often refers to a total fat intake of less than 30% of energy consumed (E%), a saturated fat intake of less than 10 E%, and fiber intake of at least 15 g per 1000 kcal. In the Diabetes Prevention Study (DPS), 2-h glucose levels tended to decrease more in the intervention as compared to the control group after 3 years of lifestyle intervention.10 In New Zealand, a 1-year lifestyle intervention directed at reducing fat intake by educating IGT participants on dietary fat intake, showed a lower increase in 2-h glucose levels in the intervention group after a follow-up period of 5 years11 (P < 0.01, Table 1). Three smaller diet and exercise intervention studies, one in Swedish participants, one in Japanese Americans, and one in British subjects with IGT, demonstrated reduced body weight1214 and improved insulin sensitivity, but no significant differences in 2-h glucose changes after 2 years.13,14 In Japanese Americans, central adiposity measured with computed tomography was reduced and the incremental area under the curve for glucose during an oral glucose tolerance test (OGTT) was improved after 6 months in the diet-plus-endurance-training group versus the diet-plus-stretching (control) group.13 The Dutch Study on Lifestyle Intervention and Impaired Glucose Tolerance, Maastricht (SLIM) evaluated a combined diet-and-exercise lifestyle intervention in IGT subjects. After 3 years, the postprandial glucose concentration was 0.8 mmol/L lower in the lifestyle group compared to the control group, representing a substantial reduction of diabetes risk.15

View this table:
Table 3

Common features of lifestyle interventions.

FeatureRecommendation
Body weight loss≥5%
Dietary guidelines
 Carbohydrates±55 E%
 Total fat<30 E%
  Saturated fat≤10 E%
  Cholesterol<33 mg/MJ
 Protein10–15 E%
 Fiber3 g/MJ a day
Exercise30 min of moderate physical activity a day at least 5 days a week

Most, but not all, studies show a beneficial effect of lifestyle intervention on glucose tolerance. Sample size and a short follow-up period of 1–2 years may explain part of the variation in effect size. Differences in baseline characteristics between intervention and control group subjects, like waist circumference,13 fasting glucose and insulin levels,12 and percentage of subjects engaging in physical activity at least once a week,14 may have influenced the effect of lifestyle interventions on 2-h glucose levels. Interestingly, a lack of significant effect on 2-h glucose is not necessarily related to a lack of effect on diabetes risk reduction. In the DPS, the reduction in 2-h glucose levels was not significant10 (0.4 mM difference between intervention and control), but risk reduction was 58% (Table 2). Part of the risk reduction may be mediated via other pathways than 2-h glucose, e.g., via subclinical inflammatory factors16 or preservation of β-cell function.4

Diabetes incidence

The Malmö study17 and the Chinese Da Qing IGT and Diabetes study18 were two of the first studies to show that a diet-and-exercise program during a follow-up period of 6 years reduced risk for type 2 diabetes by more than 50% and 42%, respectively. More recently, both the Finnish Diabetes Prevention Study (DPS)19 and the Diabetes Prevention Program (DPP) in the USA20 confirmed the beneficial effect of lifestyle and showed a diabetes risk reduction of 58% in IGT subjects who received a lifestyle intervention consisting of dietary and exercise advice during a follow-up period of 3.2 and 2.8 years, respectively. Interestingly, in an additional follow-up, the DPS showed that even after 3 years, cessation of a 4-year lifestyle program (total follow-up, 7 years), diabetes risk was still reduced at a level of 43%.21 The Chinese Da Qing IGT and Diabetes study found the same diabetes risk reduction after a 14-year follow-up of a 6-year lifestyle intervention.22 A 4-year randomized controlled trial in Japan reduced diabetes risk by 67.4% using a combination of dietary and exercise advice given to IGT men,23 and the Indian Diabetes Prevention Program (IDPP-1) reduced diabetes risk by 28.5% after 3 years with its diet-and-exercise intervention.24 Thus, lifestyle changes in IGT subjects reduce or delay the development of type 2 diabetes. The risk reduction achieved in studies that follow the lifestyle criteria listed in Table 3 (the DPP,20 DPS,19 and SLIM15) was approximately 58% after 3 years of follow-up. Although all studies show a beneficial lifestyle effect, the risk reduction ranges from 28% to 67%. Differences in risk reduction may be due to different population characteristics, ethnicity, duration of the lifestyle intervention and follow-up, and the lifestyle goals targeted.

A recent systematic review and meta-analysis indicates that lifestyle interventions seem at least as effective as pharmacological interventions, e.g., with Orlistat (Hoffman-La Roche, USA), a drug that reduces intestinal fat absorption.25 In the DPP, Metformin (Bristol Myers Squibb, USA), a drug that suppresses hepatic glucose production, was less effective for reducing type 2 diabetes risk (–31%) than lifestyle intervention.20

In general, lifestyle changes in subjects with IGT considerably reduce or delay the development of type 2 diabetes and are at least equally as effective as pharmacological interventions.

DETERMINANTS OF INTERVENTION OUTCOME AND ADHERENCE

The progression towards type 2 diabetes can be influenced by lifestyle components such as body weight, dietary composition, and physical activity. Positive changes in all of these factors may contribute to improved glucose metabolism and response and adherence to the lifestyle intervention.

Body weight and diabetes risk

Body mass index (BMI) and body weight gain are strongly associated with diabetes risk.26 Weight gain of 11–20 kg in 14 years of follow-up increased age-adjusted relative diabetes risk 5.4-fold in female nurses who had normal weight (BMI 22–25 kg/m2) at age 18 years relative to nurses with normal weight at age 18 years who had no weight gain or a weight loss of more than 5 kg. In addition to overall obesity, body fat distribution, especially increased intra-abdominal fat, is a predictor of type 2 diabetes.27,28 The BMI of middle-aged women at midlife strongly predicts 3-year incidence rates of type 2 diabetes,29 whereas annual weight changes during this period did not significantly affect the onset of type 2 diabetes.29

The effect of changes in body weight on diabetes risk

In the lifestyle intervention group of the DPP, weight loss was the dominant predictor of reduced diabetes risk, with a 16% reduction observed for every kilogram of weight loss during the 3.2-year follow-up.30 Thereafter, in the 4-year follow-up, insulin sensitivity in the entire group (intervention plus control) improved by 64% in the highest tertile of weight-loss subjects, but deteriorated by 24% in those who gained weight, while insulin secretion remained unchanged in IGT subjects who managed to lose weight.31 Overall, weight loss is a major contributor in the prevention of type 2 diabetes mellitus.

In addition to weight loss, changes in body fat distribution may influence diabetes risk. It has been shown that a relatively minor loss of body weight (−3%), which was accompanied by a major reduction in visceral fat mass (−12%) and liver fat content (−33%), was associated with improved insulin sensitivity.32,33 However, to bring the visceral depot to normal levels, subjects with upper-body obesity, i.e., those with a larger visceral depot than subjects with lower-body obesity, may need to lose larger amounts of body weight compared to subjects with lower-body obesity.34 The loss of visceral fat seems to be predominantly determined by the initial amount of fat in the visceral fat depot.35,36 Subjects with high visceral adipose tissue and liver fat or a high BMI score may lose body weight and visceral fat more easily, but this does not imply metabolic benefits.32 Even after weight loss, fat deposition in these subjects is above average, which may not make a metabolic difference, because an improvement in insulin sensitivity may require a reduction in ectopic fat deposition below a specific threshold.32 Overall, with regard to body-fat distribution, lifestyle interventions have led to a reduced diabetes risk, in parallel with reductions in preferentially visceral fat as well as subcutaneous fat and total body fat.13,37 It is still unclear to what extent body fat distribution adds to the metabolic benefits of lifestyle interventions. Therefore, no clear suggestions can be made at this point regarding body fat distribution as a determinant of intervention outcome.

The relationship between increased adiposity and insulin resistance and diabetes may, on one hand, be explained by an increased lipid overflow in the circulation. Normally, adipose tissue functions as a “metabolic buffer” trapping dietary fatty acids, whilst in insulin-resistant conditions, this buffering action is impaired, resulting in exposure of non-adipose tissues like muscle and liver to excessive fluxes of lipids. Accumulation of lipids in these tissues plays a critical role in the etiology of insulin resistance and type 2 diabetes mellitus.3843 On the other hand, the relationship between adiposity and insulin resistance may be explained by an alteration in the production of inflammatory factors. Inflammatory factors, which can be produced by adipose tissue as well as numerous other cell types, may have autocrine effects (i.e., effects on gene expression and lipid and glucose metabolism)44 or may be secreted as endocrine factors influencing energy and substrate metabolism and insulin sensitivity in other tissues, like skeletal muscle and liver.45 For example, baseline levels of adiponectin, an adipose-derived adipokine, seemed to be a strong predictor of incident diabetes in the DPP.46 Considerable weight loss seems to restore high adiponectin levels,47,48 but lifestyle interventions according to general guidelines do not seem to have a relevant effect on adiponectin in diabetic patients,49 IGT subjects,50 or obese subjects.51 Leptin, another adipokine, seems to also be related to improvements in insulin sensitivity, independent of changes in body composition.50

The effect of changes in physical activity on diabetes risk

To design optimal guidelines for physical activity as part of lifestyle programs, it is important to define the independent effect of physical activity on the risk of type 2 diabetes. Post-hoc analysis of 487 IGT men and women in the DPS on whom data of leisure-time physical activity were available revealed that individuals with the highest increase in their level of moderate-to-vigorous physical activity were 63–65% less likely to develop type 2 diabetes during the 4.1-year follow-up compared to individuals with the lowest increase in physical activity.52 Similarly, in the DPP, indexes that reflect autonomic function and fitness improved (i.e., heart rate decreased and heart rate variability increased) during a 3.2-year intervention and were inversely related to diabetes risk, independent of weight change.53 In the Chinese Da Qing IGT and Diabetes Study,18 diet and exercise were as effective as exercise alone for preventing the progression of IGT to type 2 diabetes. Results from the Dutch SLIM study54 and the Oslo Diet and Exercise study55 showed that the combination of diet and exercise had the greatest effect in improving glucose tolerance and preventing type 2 diabetes. These post-hoc analyses show that exercise contributes to the improvement of glucose metabolism, independent of weight loss52 and therefore seems to have an additive effect on diabetes prevention. Besides reducing diabetes risk, increased exercise training results in improved fitness in a dose-dependent manner,56 which may positively influence daily-life activities. Physical activity is also an important predictor of weight maintenance after weight loss.57 To conclude, besides body weight loss, physical activity is an independent contributor to improvement of glucose metabolism. There are indications that moderate-to-vigorous physical activity, especially, helps prevent type 2 diabetes.

One of the underlying mechanisms by which physical activity may contribute to type 2 diabetes prevention is via improved capacity to oxidize fatty acids.5860 Free fatty acid (FFA) oxidation is reduced in subjects with type 2 diabetes mellitus and impaired glucose tolerance (IGT) and it has been shown that a combined diet and physical activity intervention program can prevent further deterioration of impaired fatty acid oxidation during exercise in subjects with IGT.61 An improved utilization of fatty acids for energy may reduce the accumulation of lipids and lipotoxic intermediates in skeletal muscle and thereby improve insulin sensitivity.6264 Additionally, it has been suggested that training can bring about improvements in the regulation of hepatic glucose output.65,66

With respect to duration and intensity, the guidelines of the International Diabetes Federation (IDF) and the American College of Sports Medicine prescribe at least 30min of moderate-intensity physical activity on most, preferably all, days of the week.6,67 However, in formerly obese or overweight subjects 60–90 min/day or 45–60 min/day of moderate-intensity physical activity are recommended, respectively, to prevent further weight gain.68 To date, a recent review indicated that 30 min/day of moderate- or high-level physical activity is an effective and safe way to prevent type 2 diabetes in all populations.69 There is enough evidence to justify that physical activity has an additive effect when combined with a dietary intervention and should be included in lifestyle programs, despite the uncertainty about the exact duration and intensity to effectively prevent diabetes.70

With respect to the kind of physical activity, a recent trial showed the greatest improvement in hemoglobin A1c levels of patients with type 2 diabetes when the physical activity consisted of combined aerobic and resistance training.71 Recent guidelines on physical activity and public health in older adults from the American College of Sports Medicine and the American Heart Association also recommend muscle strengthening and balance exercise as an integrated part of physical activity intervention in older adults.72,73

Lifestyle interventions face the challenge of increasing adherence and compliance to the program, and it seems that men and women with lower initial BMI may be more likely to meet activity goals.74 However, reaching the recommended physical activity level for the majority of people at risk for diabetes may be quite a challenge, since the majority (61%) of individuals in the United States who either have diabetes or are at highest risk for diabetes do not engage in regular physical activity.75 On the other hand, in the Nurses’ Health Study it was shown that even among women who did not perform vigorous physical activity, diabetes risk was reduced by 26% after 8 years of follow-up for those who had walked most relative to those who walked least.76 This seems to indicate that even small but sustained increases in physical activity are beneficial in the long-term; exemplifying that physical activity should be included in lifestyle programs. Since there is a high degree of heterogeneity among high-risk subjects, i.e., with regard to comorbidity and muscle strength, as is the case for diabetic patients, the exercise intervention should become more individualized to optimize its therapeutic value.73 A personalized activity plan may be one of the ways to achieve the physical activity recommendations.72

The effect of changes in dietary composition on diabetes risk

Dietary factors related to the development of type 2 diabetes, besides energy intake restriction, include total fat intake, fat quality, fiber, glycemic index/glycemic load, alcohol consumption, and coffee consumption.7 A Western diet, emphasizing red meat, French fries, and high-fat dairy products has been associated with increased diabetes risk,77,78 while a “prudent” diet, emphasizing fruits, vegetables, fish, and whole grains has been associated with a reduced diabetes risk.7982 The Women's Health study, a large prospective study, showed a relative risk of 1.28 for women in the highest quintile of red meat consumption, versus the lowest quintile.83 Short-term dietary changes towards high-carbohydrate and low glycemic index seem to improve β-cell function in IGT subjects.84 Dietary fibers can reduce the rate of glucose absorption in the intestine, thereby lowering postprandial glycemic and insulinemic responses.85 Total fat intake is also an important risk factor for the development of type 2 diabetes, as its energy density favors increased food intake and obesity. In the San Louis Valley Diabetes Study, a 40-g higher fat intake corresponded with a sixfold increase in diabetes risk in IGT subjects following adjustment for obesity and markers of glucose metabolism (i.e., fasting glucose and insulin).9 An ad libitum reduced-fat diet without energy restriction has been shown to produce a moderate weight reduction of between 3 and 5 kg.86,87 In agreement with these findings, results from the DPS in 500 IGT subjects (intervention plus control group) during a 4.1-year follow-up suggest that a high-fiber, low-fat diet predicts sustained weight loss and reduces the development of type 2 diabetes, even after adjustment for other risk factors such as physical activity.88 In addition, the quality of dietary fat modifies diabetes risk. In particular, an excess of saturated fat may have detrimental effects on skeletal muscle insulin sensitivity.3840 Insulin sensitivity improved when saturated fatty acids in the diet were replaced either by monounsaturated fat89 or polyunsaturated fat.90 Unsaturated fatty acids may influence diabetes risk by increasing the fluidity of membranes, thereby facilitating membrane signalling, including insulin signalling,91 and/or by influencing the regulation of genes involved in the breakdown and oxidation of fatty acids.92 The relation between insulin sensitivity and n-3 polyunsaturated fatty acids is less clear, but most studies using a euglycemic hyperinsulinemic clamp have found no effect of n-3 polyunsaturated fatty acids on insulin sensitivity in healthy or diabetic subjects.8993 Recent interest has developed for specific fatty acids, and for enzymes that alter the saturation of ingested fatty acids, the so-called desaturase enzymes.94 In the SLIM study, lifestyle-induced changes in insulin sensitivity were partly related to changes in the fatty acid profile of serum cholesteryl esters and, in particular, to changes in desaturase activities.95

To conclude, multiple components of a healthy diet, e.g., high fiber and a low saturated fat intake, reduce diabetes risk and contribute to sustained weight loss; they should therefore be included in long-term lifestyle interventions. Composition of the diet plays a key role in diabetes prevention, primarily to sustain weight loss in the long term and secondarily to initiate weight loss and diabetes risk reduction.

Genetic susceptibility

Genetic variability may partly explain why there are non-responders to lifestyle treatment despite compliance and adherence to the lifestyle intervention program. In the DPS, numerous genes have been examined for their effect on diabetes incidence and intervention success (for a review of genes investigated in the DPS, see Weyrich et al.96). An interaction with intervention outcome has been found for the TT genotype of SNP rs12255372 in the TCF7L2 gene, which was associated with 2.85-fold increased risk of incident type 2 diabetes in the control subjects of the DPS, but not in the intervention subjects.97 The TCF7L2 gene is presumed to play a role in the first-phase insulin release.97 A similar pattern was found for a single nucleotide polymorphism (SNP), the X/Ala genotype of the PPARγ-2 Pro12Ala SNP, which was associated with increased diabetes risk in the control group, whereas there was no newly diagnosed diabetes in the Ala/Ala genotype subjects of the intervention group.98 One explanation is that subjects with the Ala12 allele are more responsive to weight reduction and physical activity than subjects with the Pro/Pro genotype; thus, although they suffer a greater number of bad lifestyle habits, they profit more from the lifestyle intervention.

A large study that investigates the interaction between exercise training and genes, is the Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) Family Study.99 Multiple genes related to the response of an exercise program were identified, including several quantitative trait loci on chromosome 1p, 3q, 6p, 7q, 10p, 12q, and 19q in white participants,100,101 the -514 C > T SNP in the hepatic lipase gene in both white and black individuals101 and the rs2180062 and rs9018 of the four-and-a-half LIM domains 1 gene.102

The Tübinger Lifestyle Intervention Program103 followed the lifestyle protocol from the Finnish DPS study (weight loss, increased physical activity, and healthy diet).19 They showed that the minor G allele of SNP rs2267668 in PPARD and the minor serine-encoding allele of the common Gly482Ser SNP in PPARGC1A were independently associated with a lower increase in individual anaerobic threshold,104 indicating that these alleles impair the effectiveness of aerobic training. In addition, low-level skeletal muscle mitochondrial function was detected in vitro in young carriers of the G allele of the rs2267668 SNP of PPARD. They also showed that variation in the adiponectin receptor 1 gene predicted the improvement of insulin sensitivity and the reduction of liver fat after lifestyle intervention.105 The adiponectin receptor 1 may have a putative role in the development of body size, as has been suggested by the Finnish DPS.106

To conclude, genetic variation can play a role in the response to a lifestyle intervention. Some SNPs may increase the vulnerability for lifestyle factors. This means that these individuals run an increased risk for developing type 2 diabetes with adverse lifestyle behavior and, at the same time, may benefit more from lifestyle intervention. Other SNPs increase diabetes risk independent of lifestyle factors. Studies involving interactions between genes and lifestyle intervention response are still limited and need confirmation in large cohorts. When more conclusive evidence is provided, the effectiveness of tailored lifestyle programs should be tested in subgroups with genotypes that are associated with adequate and impaired metabolic response to a lifestyle intervention.96

COSTS AND COST-EFFECTIVENESS

The potential benefits of lifestyle intervention are substantial, but so are the costs for implementing such programs. In return, the potential for cost savings from the prevention or delay of type 2 diabetes and its complications is also considerable. Although several studies have shown effectiveness over longer periods (up to 6 years), it is important for policy makers and healthcare providers to predict its effectiveness in 10, 20, or 30 years’ time. To assist policy makers, researchers have developed computer models that simulate the progression of diabetes, expenditures on diabetes care, and effects of interventions. Two principal types of diabetes models exist. The Markov model simulates transitions from one disease state to another (e.g., from IGT to type 2 diabetes) as chance events. A second novel type of model, named Archimedes, integrates detailed biological and administrative information in complex differential equations to simulate pathophysiological processes (e.g., postprandial glucose disposal) that change over time and can lead to disease.107

The results of the DPP and DPS have been used extensively for cost-effectiveness analyses using both models, resulting in different outcomes. The outcome depends on many factors, such as the assumptions for the natural progression of glycemia and the effectiveness of the lifestyle intervention, the time horizon that is used (30 years or until death after diagnosis), characteristics of included patients (age, degree of obesity, ethnicity, gender), and the costs of the lifestyle program, which depend on the approach used (group or individual counseling) and country in which the implementation will take place.108

The DPP developed an analysis based on the Markov model in conjunction with a lifetime horizon and a societal perspective. The cost was calculated at $8800 per quality-adjusted life-year (QALY) for the lifestyle intervention and the per-person saving associated with metformin was $29,900 for the lifetime horizon;109 both figures fall within a range generally accepted as being cost-effective.110 When using the Archimedes model with time horizons of 10, 20, and 30 years and a societal perspective, the cost per QALY of beginning the intensive lifestyle intervention in subjects with IGT was $62,600, and $35,400 for metformin over 30 years, when compared with no intervention.111 The cost per QALY for an intensive lifestyle intervention that was started after the onset of diabetes was $24,500.111 The Archimedes model adopted more conservative assumptions for the development of diabetes and its complications, which may have reduced the cost-effectiveness of the intervention. Both studies underline that lifestyle intervention will substantially reduce the proportion of patients at risk for developing diabetes, postpone the onset of diabetes from 7 or 8 to 14 or 18 years, and lead to fewer complications, longer life, and improved quality of life.

When the DPS results were applied to a Swedish setting, the cost-effectiveness analysis based on the Markov model predicted that the program would be cost-saving from the healthcare payers’ perspective.112 In the Netherlands, two different approaches for healthcare interventions were evaluated: a community-based approach targeted at the general population with a high number needed to treat (300–1500 individuals) but low costs per individual;113 and a healthcare intervention approach aimed at high-risk individuals with a low number needed to treat (7–30 individuals) but relative high costs per individual.54 Both approaches were evaluated using a Markov-type, multistate transition model, which describes the development over time of demography, risk factor prevalence, disease incidence, and mortality in the Dutch population.114 Both approaches were cost-effective in the range of €5,600–€9,900 per person, per year.114

To design cost-effective lifestyle interventions, the effectiveness of lifestyle intervention for different subgroups may need to be taken into account. The results from the DPP show no differences in progression towards type 2 diabetes among ethnic groups once individuals are identified as impaired glucose tolerant.115 However, age may be important: Metformin was only cost-effective in IGT subjects under the age of 65 years, while lifestyle intervention was effective in all age groups.109 Metformin had a greater impact on costs in younger and more obese subjects, whereas lifestyle intervention was more effective in subjects with a BMI below 30 kg/m2.108 Further identification of factors that modify intervention outcome may increase the efficacy of tailored advice, thereby improving cost-effectiveness.

In general, the implementation of lifestyle intervention as a therapy to prevent and postpone type 2 diabetes and its complications looks promising, and cost-effectiveness seems acceptable. In particular, differences in the effectiveness of lifestyle intervention between groups and countries, and the approach used for implementation (group or individual counseling), will influence the cost-effectiveness. In Finland, a large 4-year implementation trial was recently started to evaluate different approaches for lifestyle intervention in the healthcare system.116 It is expected to provide valuable information about the barriers, strategies, and costs of lifestyle implementation in a real-life setting.

IMPLEMENTATION STRATEGIES

Lifestyle interventions are cost-effective in reducing the risk for type 2 diabetes over the long term. The next question is how to implement a lifestyle intervention in the general public health setting in a way that is most successful. The high-risk approach has the advantage over a community-based strategy in the sense that tailored advice can increase personal risk awareness of diabetes as well as the magnitude and durability of behavioral changes; in comparison, a community-based strategy will prompt the individual to undertake action to a lesser extent.

Recently, the IDF has proposed a simple three-step plan for the prevention of type 2 diabetes in high-risk individuals: first, identification of those who may be at increased risk; second, measurement of risk; and third, intervention to prevent the development of type 2 diabetes.6

For identification, the IDF recommends brief questionnaires with criteria regarding obesity, family history, age, cardiovascular history, gestational history, and drug history to assess the level of risk. These questionnaires are simple, practical, non-invasive, and inexpensive. In Finland, a type 2 diabetes risk assessment form has already been developed which assesses diabetes risk based on age, BMI, waist circumference, physical activity, fruit and vegetable intake, blood pressure medication, previous high blood glucose (i.e., during pregnancy or illness), and family history of type 2 diabetes; the data is then used to calculate the so-called FINDRISC score.117 A recent post-hoc analysis of the DPS results shows that the FINDRISC score may be useful in identifying high-risk groups most likely to benefit from intensive lifestyle intervention to prevent type 2 diabetes.118

For measurement of risk, the IDF recommends the measurement of venous fasting plasma glucose levels. If plasma glucose levels are above 6.1 mmol/L, a 2-h OGTT is recommended to detect cases of IGT and undiagnosed diabetes.

For intervention, the IDF recommends gradual weight loss, improvement of dietary composition, and an increase in physical activity to 30 min of moderate-intensity physical activity per day on most days of the week.6 Similar recommendations appear in recent reviews evaluating diet, glucose tolerance, and type 2 diabetes.119,120 Furthermore, although smoking is not usually included as part of a lifestyle intervention program, it is an important lifestyle-related risk factor for diabetes. Since quitting smoking may lead to weight gain,121 special attention is necessary with regard to weight control.122 Lifestyle intervention programs can be suitable for this.

However, merely providing the method of implementation will not be sufficient for successfully implementing lifestyle interventions. To achieve and sustain lifestyle changes throughout the lifespan, intervention mapping can be used as a tool for the development of health promotion interventions.123 However, efforts from the individual, the practitioner, the community, and policy makers fulfill a key role in giving high-risk individuals tailored advice and encouragement to decrease their diabetes risk.

To increase sustainable lifestyle changes, first, the individual should be aware of his/her increased risk for type 2 diabetes and his/her lifestyle. This can be achieved, for example, by the general practitioner who asks at-risk individuals if they have family or friends who suffer from the disease. In a recent cross-sectional study, African Americans with a family history of diabetes were more aware of diabetes risk factors and were more likely to engage in certain health behaviors than were subjects without a family history of the disease.124

Second, motivational interviewing by nurse practitioners can be applied to assist individuals aiming to achieve a positive attitude towards changes in diet, physical activity, or the social aspects associated with it. An individual's intentional behavior stage, as identified by the transtheoretical model of behavior change, does influence preparedness for lifestyle changes (for more information with regard to exercise see the review of Nigg125). In subjects with type 2 diabetes at different behavioral stages, the action stage was associated with healthier eating than the pre-action stage.126 In the action stage, defined as undertaking action for less than 6 months, people are active; in the pre-action stages (precontemplation, contemplation, and preparation), individuals are either not yet active or have no intention to become active – although those in the contemplation or preparation phases have the intention to become active within 6 months or 1 month, respectively.127 Knowing the behavioral stage of the individual gives the advantage of formulating specific advice. Altogether, tailored information and advice may increase the intention to adopt a certain lifestyle aspect.125,128

Third, general practitioners should be both aware of and convinced of the clinical significance of IGT and reducing the incidence of type 2 diabetes by targeting lifestyle interventions to patients who are at risk.129 Practitioners or dieticians should inform subjects about the importance of reading food labels and understanding portion size.130 Therefore, it is desired that practitioners have skills that include assessment of dietary history and physical activity counseling or the willingness to refer patients to professionals who have those skills, such as dieticians and physiotherapists. A Finnish study evaluating lifestyle counseling in primary care has recently shown a lack of communication skills on the part of nurses and physicians counseling subjects with diabetes and IGT with regard to diet and physical activity.131 Improving communication skills, e.g., by teaching the motivational interviewing approach to healthcare professionals, may therefore improve intervention outcome.

To conclude, high-risk screening and tailored advice seem to have potential for success. In addition, general measures from the food industry and government, e.g., lowering prices for healthy food, may also help stimulate an active and healthy lifestyle.6

CONCLUSION

The studies mentioned in this review clearly illustrate that improvements in lifestyle can have a large and beneficial impact on diabetes risk. Very promising are new data on the long-term effects of lifestyle programs, showing a sustained reduction in diabetes risk, even after counseling was stopped.21,23 Lifestyle intervention can additionally have a positive impact on cardiovascular risk profile132 and features of the metabolic syndrome.133 Therefore, we conclude that lifestyle interventions can reduce the risk of diabetes substantially in subjects with impaired glucose tolerance, especially when the interventions include a combined diet and exercise program. We underscore the importance of cost-effective changes in lifestyle that are sustainable over a long period.

With regard to determinants of intervention outcome, weight loss seems to be the most important factor for reducing diabetes risk. At the same time, physical activity has proven to be an important contributor, independent of obesity. Relatively small changes in physical activity that are prolonged over several years seem to contribute to a reduction in diabetes risk, although moderate-to-vigorous physical activity seems to have a larger effect. Changes in dietary composition are important for sustaining achieved weight loss in the long term, but they also initiate weight loss and reduce diabetes risk. Body composition and genetic variation seem to modulate the effect of lifestyle intervention on metabolic benefits; however, no conclusive data are yet available on either subject to allow evidence-based recommendations to be made. More large studies are required in order to elucidate the major modulators and the ways in which they interact with lifestyle effects.

With respect to determinants of adherence, this review shows that lifestyle intervention outcome is not just the result of an individual's motivation; it is also the result of a variety of metabolic, genetic, and socioeconomic factors.134136 Increasing self-efficacy, motivational readiness, and social activities,137 decreasing perceived stress,126 exemplifying the importance of prevention, and giving tailored personal advice may comprise the first step toward increasing adherence. As an alternative when lifestyle intervention is not effective, it may be necessary to prescribe medication or to enact public health policy changes in order to make the cultural environment more favorable. Furthermore, future publications should include concise and conclusive reporting on risk genotypes and reasons for non-adherence for one or both of the following reasons: 1) so lifestyle interventions can be adjusted for those less likely to adhere to and benefit from them; or 2) so the environment can be adjusted to increase adherence and compliance, especially for the lower socioeconomic classes.

To conclude, lifestyle intervention programs are feasible and cost-effective for the long term and will probably be the most important tool for alleviating the burden of diabetes and related complications in the future, and to sustain healthy aging. Thus, the question is no longer whether lifestyle interventions might be effective, but under which circumstances they will be most effective.

Abbreviations:

ADA
American Diabetes Association
BMI
body mass index
CVD
cardiovascular disease
DPP
Diabetes Prevention Program
DPS
Diabetes Prevention Study
Glut4
glucose transporter 4
HDL
high-density lipoprotein
IDF
International Diabetes Federation
IDPP-1
Indian Diabetes Prevention Program-1
IFG
impaired fasting glucose
IGT
impaired glucose tolerance
LDL
low-density lipoprotein
NGT
normal glucose tolerance
OGTT
oral glucose tolerance test
QALY
quality-adjusted life-year
SLIM
Study on Lifestyle intervention and Impaired Glucose Tolerance, Maastricht
SNP
single nucleotide polymorphism
VLDL
very-low-density lipoprotein.

REFERENCES

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