Effects of Progressive Negative Energy Balance on Glucose Tolerance, Insulin Sensitivity, and Beta-cell Function

Study Overview
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Brief Summary
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Type 2 diabetes results from a combination of peripheral insulin resistance and beta-cell dysfunction, and manifests as fasting and postprandial hyperglycemia. In Singapore, despite the relatively low prevalence of overweight and obesity, the prevalence of type 2 diabetes is disproportionately high and is expected to double in the near future. This indicates that insulin resistance and beta-cell dysfunction are widely prevalent even among individuals who are not overweight or obese. Still, weight loss induced by a variety of ways (calorie restriction, exercise, surgery, etc.) is considered the cornerstone of diabetes treatment. This underscores the importance of negative energy balance in improving metabolic function. In fact, negative energy balance induced by calorie restriction can improve metabolic function acutely, i.e. within 1-2 days and before any weight loss occurs. Likewise, negative energy balance induced by a single session of aerobic exercise improves metabolic function over the next few days. However, the magnitude of negative energy balance that needs to be achieved in order to improve metabolic function, as well as possible dose-response relationships, are not known. Furthermore, the comparative efficacy of calorie restriction vs. exercise in improving metabolic function has never been directly assessed. Accordingly, a better understanding of the effects of acute negative energy balance induced by calorie restriction or aerobic exercise on insulin sensitivity and beta-cell function will have important implications for public health, by facilitating the design of effective lifestyle (diet and physical activity) interventions to prevent or treat type 2 diabetes. To test these hypotheses, whole-body insulin sensitivity, the acute insulin response to glucose, and the disposition index (i.e. beta-cell function), will be determined the morning after a single day of progressively increasing negative energy balance (equivalent to 20% or 40% of total daily energy needs for weight maintenance) induced by calorie restriction or aerobic exercise. Results from this project are expected to result in the better understanding of the effects of negative energy balance induced by diet and exercise on metabolic function. Therefore, this project may help in the design of effective lifestyle intervention programs for the prevention and treatment of type 2 diabetes.

Detailed Description
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Metabolic dysfunction, obesity, and type 2 diabetes The incidence of overweight and obesity has been increasing during the past 2-3 decades in Singapore, and is expected to rise further in the future. By the year 2050, it is estimated that more than half of the population will be overweight or obese, defined as having a body mass index (BMI, calculated as the weight in kilograms divided by the square of height in meters) equal to or greater than 25 kg/m2. This is likely responsible, at least in part, for the concomitant increase in obesity-related co-morbid conditions, and particularly type 2 diabetes. The relationship between BMI and the risk for type 2 diabetes in populations from the Asia-Pacific region is linear within a wide range of BMI values (from  21 kg/m2 to  34 kg/m2), so that for every 2 kg/m2 increase in BMI (which corresponds to  6 kg for a normal-weight person of average stature), the risk for developing type 2 diabetes rises by  27 %. In Singapore, the prevalence of type 2 diabetes is expected to double from 7.3 % in 1990 to  15 % in 2050, predominantly as a result of the fattening of the population. Remarkably, however, the prevalence of type 2 diabetes in Singapore is similar to that in the Unites States, even though the prevalence of overweight and obesity (BMI ≥25 kg/m2) is approximately half. This corroborates findings from many studies demonstrating that markers of metabolic dysfunction and particularly hyperglycemia, hyperinsulinemia, and insulin resistance, are highly prevalent among Singaporean adults, even among people who are not overweight or obese. This likely results in increased risk for developing type 2 diabetes. These observations underscore the importance of metabolic dysfunction independent of body weight per se. Metabolic effects of weight loss The pathogenesis of type 2 diabetes involves peripheral insulin resistance (i.e. resistance of peripheral tissues and particularly skeletal muscle to the glucose uptake-promoting effect of insulin) and inadequate secretion of insulin from the pancreatic beta-cells upon glucose stimulation, leading to fasting and postprandial hyperglycemia. Weight loss, achieved as a result of chronic negative energy balance induced by a variety of ways (calorie restriction, exercise, pharmacotherapy, bariatric surgery), improves metabolic function and is considered the cornerstone of diabetes prevention and management. Part of the beneficial effect of weight loss could be due to the reduction in total body fat, intra-abdominal fat, and ectopic fat accumulation in metabolically active organs (e.g. muscle, pancreas, and liver), however acute perturbations in energy balance (whether positive or negative, for a period of 24-72 hours) can affect insulin action, beta-cell function, and glycemic control even before any changes in body weight or body fat distribution occur. For example, one day of overfeeding disrupts 24-hr glucose homeostasis, and two days of caloric restriction improves insulin action. Likewise, exercise can also lead to negative energy balance and is a very potent intervention that readily improves metabolic function and particularly insulin sensitivity, even after just a single session. Nevertheless, the degree of negative energy balance that needs to be achieved by calorie restriction or exercise in order to improve insulin action and beta-cell function is not known, and the dose-response relationship between negative energy balance and metabolic function remains elusive. Furthermore, the comparative efficacy of calorie restriction and exercise on improving the mechanisms regulating glucose homeostasis (i.e. insulin sensitivity and beta-cell function) has not been adequately studied. One study found that for the same amount weight loss (8-9 % of initial body weight) induced by a low-calorie diet or endurance exercise, exercise caused a greater reduction in fat mass, a smaller decrease in muscle mass, and led to a greater increase in insulin-mediated glucose disposal during a hyperinsulinemic-euglycemic clamp (by  30 %), and a greater reduction in the total insulin response to an oral glucose tolerance test (by  2.5-fold), compared with matched diet-induced weight loss; although these differences did not reach statistical significance. These observations raise the possibility that, for the same negative energy balance, exercise may be more effective than calorie restriction in improving metabolic function; however these findings are difficult to interpret in the face of the concomitant more favorable changes in body composition and fat distribution. No study has directly assessed the effects of the same acute negative energy balance induced by calorie restriction or aerobic exercise on metabolic function. Accordingly, a better understanding of the effects of calorie restriction and exercise on insulin sensitivity, beta-cell function and daily glycemic control will have important implications for the design of effective lifestyle intervention targeted at preventing or managing type 2 diabetes. To this end, this study aims to test the following hypotheses: Hypothesis 1: It is hypothesized that a single day of negative energy balance induced by calorie restriction improves intravenous glucose tolerance because of improved beta-cell function without changes in insulin sensitivity. The investigators further hypothesize that this effect requires 20% negative energy balance, and does not improve further with greater energy restriction (40%). Hypothesis 2: It is hypothesized that a single day of negative energy balance induced by aerobic exercise improves intravenous glucose tolerance because of improved insulin sensitivity without changes in beta-cell function. The investigators further hypothesize this effect requires 20% negative energy balance, and improves further with greater energy restriction (40%). Hypothesis 3: It is hypothesized that at any given level of negative energy balance (20% or 40%), calorie restriction has a greater effect than aerobic exercise on beta-cell function, whereas aerobic exercise has a greater effect than calorie restriction on insulin sensitivity.

Official Title
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Effects of Progressive Negative Energy Balance Induced by Diet or Exercise on Glucose Tolerance, Insulin Sensitivity, and Beta-cell Function

Conditions
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Insulin Sensitivity, Glucose Intolerance, Insulin Resistance, Energy Supply; Deficiency

Intervention / Treatment
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* Behavioral: Negative energy balance


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy males and females Age between 21-65 years BMI from ≥18 to <30 kg/m2 (BMI is equal to body weight in kilograms divided by height in metres squared) Exclusion Criteria: Persons with metabolic diseases that require use of medications (e.g. diabetes, heart disease, hypertension, etc.) Persons using tobacco products (smokes daily or occasionally) Persons who regularly consume alcohol (≥1 drink/day) Women on oral contraceptives or hormone replacement therapy Pregnant or breastfeeding women Persons who have had recent weight loss or gain (≥5% over the past 6 months) Persons with contraindication to calorie restriction (e.g. anemia) or exercise (e.g. asthma)

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Diet-induced negative energy balance<br>For the diet-induced negative energy balance arm, the three trials will include one control trial (isocaloric diet; zero energy balance) and two trials of progressively increasing negative energy balance induced by calorie restriction (20% and 40% reduction of daily energy needs for weight maintenance). With respect to physical activity, all diet trials will be performed under resting conditions. | Behavioral: Negative energy balance<br>* 20% and 40% reduction of daily energy needs for weight maintenance<br>|
| Experimental: Exercise-induced negative energy balance<br>For the exercise-induced negative energy balance arm, the three trials will include one control trial (rest; zero energy balance) and two trials of progressively increasing negative energy balance induced by aerobic exercise (20% and 40% reduction of daily energy needs for weight maintenance); with respect to caloric intake, all exercise trials will be performed under isocaloric conditions. | Behavioral: Negative energy balance<br>* 20% and 40% reduction of daily energy needs for weight maintenance<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin sensitivity | Insulin sensitivity index (i.e. Si) will be determined by using minimal modeling analysis of the IVGTT data. | 4-6 weeks | 
| Beta-cell function | Beta-cell function will be determined as the disposition index (i.e. product of acute insulin response [AIR] and Si) using minimal modeling analysis of the IVGTT data. | 4-6 weeks |