Preventing Type 2 Diabetes
Targeting Abdominal Obesity
- Elevated waist circumference, a crude anthropometric index of the absolute amount of intra-abdominal adipose tissue, better predicts the risk of developing the metabolic syndrome and related disorders than BMI.
- A preferential loss of intra-abdominal adipose tissue can improve cardiometabolic risk markers and insulin resistance variables.
- Several lifestyle intervention trials have highlighted the fact that increasing physical activity and adopting healthy eating habits can reduce body weight and waist circumference and lower the risk of developing diabetes in patients with impaired glucose tolerance.
- Even without weight loss, physical activity can reduce intra-abdominal adipose tissue and improve indices of plasma glucose-insulin homeostasis.
- Pharmacological compounds aimed at reducing intra-abdominal fat deposition need to be developed and used in conjunction with lifestyle modification therapies to reduce the risk and complications of type 2 diabetes.
- Data on the pharmacological treatment of intra-abdominal obesity is needed.
Targeting Abdominal Obesity to Manage the Metabolic Syndrome
There is a wealth of evidence suggesting that intra-abdominal (visceral) adipose tissue, insulin resistance, and the development of the metabolic syndrome and/or type 2 diabetes are closely linked (1, 2). In addition to its ties to abdominal obesity, the metabolic syndrome has also been linked to blood lipid disorders, an inflammatory and pro-thrombotic state, hypertension, and insulin resistance. In this regard, Palaniappan et al. (3) found that the best predictors of incident metabolic syndrome over a 5 year follow-up were waist circumference, HDL cholesterol, and proinsulin levels. They examined a sample of 714 men aged 54.4 ± 8.5 years at the beginning of follow-up who participated in the Insulin Resistance Atherosclerosis (IRAS) Study. The authors suggested that steps should be taken to address components of the metabolic syndrome, such as waist circumference, in order to reduce the risk of developing the syndrome and related complications such as type 2 diabetes and cardiovascular disease. This study also showed that waist circumference was a better predictor of metabolic syndrome than directly measuring insulin sensitivity with an oral glucose tolerance test. The contribution of various lifestyle and therapeutic interventions to reducing body weight, abdominal fat in particular, and preventing insulin resistance and type 2 diabetes is examined below.
Although each component of the metabolic syndrome can be targeted separately through pharmacotherapy, it is also possible to take a more global therapeutic approach to treating the metabolic syndrome and/or type 2 diabetes by focusing on reducing excess atherogenic/diabetogenic intra-abdominal adipose tissue, which is often present in patients with the clustering abnormalities of this syndrome. The causes of this preferential adipose tissue accumulation include an obesogenic and diabetogenic diet, a low level of physical activity leading to a positive energy balance, and genetic susceptibility. These causes should all be targeted to reduce the risk of developing the metabolic syndrome and type 2 diabetes (4). As depicted in Figure 1, abdominally obese individuals should be encouraged to increase their daily energy expenditure in order to decrease intra-abdominal adipose tissue and improve their plasma lipoprotein-lipid profile and indices of plasma glucose-insulin homeostasis. Typically, this loss of intra-abdominal adipose tissue reduces free fatty acid flux to the liver, which slows hepatic VLDL production, lowers plasma triglyceride and apolipoprotein B levels, and increases HDL cholesterol concentrations (5). It also changes the pattern of adipose tissue secretory products, causing interleukin-6 levels to fall and adiponectin concentrations to rise, which improves insulin sensitivity (6, 7). The end product of abdominal fat loss is a reduction in CRP levels.
Several studies have highlighted the benefits of lifestyle changes in preventing type 2 diabetes in subjects with impaired glucose tolerance (IGT). The first large study to illustrate the key role played by a lifestyle modification program in preventing diabetes among individuals with glucose intolerance was the Finnish Diabetes Prevention Study (8). In that study, a sample of 522 middle-aged men and women, who were all overweight with IGT, were randomly assigned to an intervention group designed to lower total intake of fat (especially saturated fats) to less than 30% of energy consumed, increase intake of dietary fibre, and ensure participants took part in moderate exercise for at least 30 minutes per day. Over the study follow-up period, the overall cumulative incidence of diabetes dropped by 58% in the lifestyle modification group, with the reduction directly linked to lifestyle changes. Cumulative diabetes incidence was 11% and 23% for the intervention and control groups, respectively. Significantly, the lifestyle intervention program reduced waist circumference by 4.4 ± 5.2 cm and improved both glucose-insulin homeostasis variables and lipoprotein-lipid parameters associated with the metabolic syndrome. Based on these results, the authors concluded that 22 subjects with IGT must be treated with lifestyle interventions to prevent one case of diabetes.
Using a similar approach, the Diabetes Prevention Program randomly assigned 3,234 participants with IGT to a placebo with standard lifestyle recommendations, the antihyperglycemic agent metformin with standard lifestyle recommendations, or a lifestyle modification program designed to achieve and maintain a 7% body weight reduction (9). During the 4 year follow-up, diabetes incidence dropped by 58% and 31% for the lifestyle and metformin groups respectively, as compared to the placebo (Figure 2). Compared to the metformin group, a greater number of subjects in the lifestyle group had normal post-load glucose values at the end of the follow-up. Similarly, compared to the placebo, the lifestyle group experienced a 41% reduction in metabolic syndrome incidence and the metformin group experienced a 17% reduction. Among features of the metabolic syndrome, both intervention groups saw their HDL cholesterol levels rise and their waist circumference and fasting glucose levels improve. However, only the lifestyle intervention group experienced a decrease in triglyceride levels and blood pressure (10).
In the Indian Diabetes Prevention Programme (IDPP-1), Ramachadran et al. (11) tested the effect of lifestyle intervention and metformin treatment on reducing the onset of diabetes in native Asian Indians with IGT. They randomized 531 subjects in four groups: 1- a control group, 2- lifestyle modifications, 3- treatment with metformin, and 4- lifestyle modifications and treatment with metformin. The 3 year cumulative incidences of diabetes for the four groups were 55.0%, 39.3%, 40.5%, and 39.5% respectively. The authors concluded that both lifestyle modifications and metformin treatment reduced the risk of diabetes and that there were no additional benefits to combining both treatments.
The Da Qing IGT and Diabetes Study sought to determine whether combining diet and exercise could reduce the overall incidence of diabetes in 577 men and women with IGT from the city of Da Qing, China (12). Subjects were randomized to a control group or to one of three lifestyle intervention groups (diet only, exercise only, or diet plus exercise). In the control group, the cumulative 6 year incidence was 67.7%, whereas the incidence was 43.8%, 41.1%, and 46.0% in the diet group, exercise group, and diet-plus-exercise group respectively. These results provide substantial evidence in support of the importance of lifestyle recommendations focusing on physical activity and healthy eating among IGT subjects who are at increased risk of developing type 2 diabetes.
In another investigation, Ross et al. (13) randomized 52 obese men (BMI 31.3 ± 2.0 kg/m2, waist circumference 110.1 ± 5.8 cm) to four study groups: 1- diet-induced weight loss, 2- exercise-induced weight loss, 3- exercise without weight loss, and 4- a control group. During the 3 month intervention program, body weight decreased by an average of 7.5 kg in both weight loss groups. Waist circumference also decreased in the weight loss groups. Subcutaneous and intra-abdominal fat decreased in both weight loss groups. Although more subcutaneous adipose tissue was lost, the relative proportion of intra-abdominal fat loss was greater than the relative proportion of subcutaneous fat loss. Furthermore, subcutaneous and intra-abdominal adipose tissue decreased in the exercise without weight loss group. In both weight loss groups, the relative reduction in intra-abdominal fat was greater than the relative reduction in subcutaneous fat, as illustrated in Figure 3. Although no association was observed between total and abdominal subcutaneous fat and measures of insulin sensitivity, there was a significant relationship between corresponding changes in intra-abdominal fat and glucose area under the curve during an oral glucose tolerance test (r=0.35) and glucose disposal (r=-0.49).
The authors concluded that increasing daily energy expenditure through exercise reduces intra-abdominal adiposity and improves insulin sensitivity, even in the absence of weight loss. It also prevents weight regain in men. Although this study was conducted in a relatively small sample of men, it supports the notion that targeting intra-abdominal adiposity can prevent the development of insulin resistance. This paves the way to larger lifestyle intervention trials to examine whether increasing energy expenditure without necessarily decreasing energy intake can prevent type 2 diabetes among high-risk abdominally obese, dyslipidemic individuals.
In the Women’s Healthy Lifestyle Project, Simkin-Silverman et al. (14) randomly assigned 535 healthy premenopausal women to either a control group or a behavioural, dietary, and physical activity program with modest weight loss goals. Although the intervention group did not lose weight (as opposed to the control group, which had slightly elevated body weight at the end of the 5 year follow-up), the waist circumference of women in the intervention group decreased by 2.9 ± 5.3 cm, suggesting that weight gain and increased waist circumference during peri- to postmenopause can be prevented with a long-term dietary and physical activity intervention program. Furthermore, women who lost weight did not lower their fasting glucose values. However, women who did not lose weight or who gained weight had slightly higher fasting glucose values during follow-up.
Pharmacotherapy for the Prevention of Type 2 Diabetes
Although the pharmacological arsenal to decrease body weight and intra-abdominal adipose tissue remains limited, a few pharmacological compounds have been shown to reduce atherogenic intra-abdominal fat. For example, rimonabant, a selective cannabinoid receptor-1 (CB1) blocker, has been shown to reduce food intake in both rodents and humans (15, 16). For the RIO-Diabetes trial, Scheen et al. (17) randomized 692 patients to rimonabant 5 mg/day, rimonabant 20 mg/day, or a placebo and followed these patients for a year. They reported that patients treated with rimonabant 20 mg/day decreased their body weight by 5.3 ± 5.2 kg and their waist circumference by 5.2 ± 6.1 cm. Patients treated with rimonabant 20 mg/day also had increased HDL cholesterol levels as well as decreased triglyceride, C-reactive protein, and HbA1C levels. The changes in HbA1C levels were directly associated with body weight loss. Further studies are required to do the following: 1) evaluate rimonabant’s ability to prevent diabetes rather than treat diabetes and its metabolic complications and 2) investigate whether rimonabant can reduce intra-abdominal adipose tissue as assessed using imaging techniques.
In the SERENADE trial, rimonabant’s ability to lower HbA1C was tested in 278 newly diagnosed diabetic patients (138 patients were treated with rimonabant and 140 patients with placebo). Compared to the placebo, rimonabant treatment produced a 0.5% greater reduction in HbA1C. The results of the SERENADE trial were very similar to those of RIO-Diabetes in terms of weight reduction, waist circumference, and improvements to HDL cholesterol and triglyceride levels.
Orlistat, a gastrointestinal lipase inhibitor, has been shown to decrease body weight in humans (18). In the XENDOS study (Xenical in the Prevention of Diabetes in Obese Subjects), Torgerson et al. (19) randomized 3,305 obese patients with or without IGT to a lifestyle intervention group, with either a placebo or orlistat 120 mg, three times daily. After the 4 year treatment period, the cumulative incidence of diabetes was 9.0% with placebo and 6.2% with orlistat, for an overall risk reduction of 37.3%. Orlistat was more effective than the placebo in decreasing body weight (5.8 vs. 3.0 kg) and waist circumference (6.4 vs. 4.4 cm). However, diabetes incidence only decreased in patients with IGT at baseline, even if body weight loss was similar in patients with and without IGT.
Thiazolidinediones (TZDs) are peroxisome-proliferator activated receptor-γ (PPAR-γ) agonists that have been shown to improve insulin sensitivity while increasing total body fat in patients with type 2 diabetes (20). Shadid and Jensen (21) tested the difference between diet and exercise and treatment with the PPAR-γ agonist pioglitazone in improving insulin sensitivity and body fat distribution in 39 abdominally obese, insulin-resistant, nondiabetic men and premenopausal women who were randomized to receive either 30 mg/day pioglitazone or a diet and exercise program for 20 weeks. They found that only the diet and exercise group had a reduction of waist circumference, body fat percentage, and intra-abdominal adipose tissue surface as calculated by computed tomography at the L4-L5 level. Similar improvements in insulin resistance markers and other cardiometabolic risk variables were observed in both groups, suggesting that diet and exercise improve insulin sensitivity by mobilizing intra-abdominal adipose tissue.
This improvement may not be related to any loss of intra-abdominal adipose tissue and may instead be related to the subcutaneous fat gain of patients treated with pioglitazone. However, this hypothesis remains to be tested. The TRIPOD (Troglitazone in Prevention of Diabetes) study has also tested the effectiveness of a PPAR-γ agonist, troglitazone, in reducing type 2 diabetes incidence (22). The study sample included high-risk Hispanic women with previous gestational diabetes who were randomized to troglitazone (n=133) and a placebo (n=133). In the median follow-up of 30 months, diabetes incidence was 12.1% in women on placebo and 5.4% in women treated with troglitazone, suggesting that treatment with troglitazone could significantly reduce type 2 diabetes onset in this population. It is important to point out, however, that troglitazone was withdrawn from the market in 2000 because of liver toxicity. In the DREAM trial (Diabetes REduction Assessment with ramipril and rosiglitazone Medication), 5,269 men and women aged 30 years or more with impaired fasting glucose or IGT without prior cardiovascular disease were randomized to receive 8 mg/day of rosiglitazone or a placebo. Rosiglitazone substantially (6%) reduced the risk of developing diabetes over the 4 year follow-up. Waist circumference did not change after treatment with rosiglitazone or the placebo. Interestingly, rosiglitazone treatment significantly increased hip circumference whereas the placebo did not. Rosiglitazone therefore reduced waist-to-hip ratio significantly, suggesting that rosiglitazone treatment can also cause an increase in subcutaneous adipose tissue. In light of this, it is reasonable to believe that rosiglitazone improves cardiometabolic risk profile by 1) creating an anti-atherogenic and anti-diabetogenic energy sink, i.e., subcutaneous fat and 2) mobilizing intra-abdominal adipose tissue.
In summary, pharmacological compounds designed to mobilize atherogenic intra-abdominal fat need to be developed in order to improve the diabetic dyslipidemia and disruption of plasma glucose-insulin homeostasis caused by excess intra-abdominal fat.
Given that abdominal obesity is one of the most prevalent forms of type 2 diabetes, therapeutic approaches should focus on reducing intra-abdominal adipose tissue. This should have an impact on the causal pathways leading to insulin resistance, impaired glucose tolerance, and type 2 diabetes. Very few pharmacological compounds target intra-abdominal adipose tissue directly. Health professionals should focus first on reshaping patient lifestyles through increased physical activity and better eating habits. These measures have proven effective in reducing intra-abdominal fat and should be promoted to the general population as valid ways to prevent obesity-related health problems.
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