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

March 10, 2018 updated by: Faidon Magkos, Clinical Nutrition Research Centre, Singapore

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

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.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Actual)

61

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Singapore
      • Singapore, Singapore, 117609
        • Clinical Nutrition Research Centre

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

19 years to 63 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Diet-induced negative energy balance
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
20% and 40% reduction of daily energy needs for weight maintenance
Experimental: Exercise-induced negative energy balance
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
20% and 40% reduction of daily energy needs for weight maintenance

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Insulin sensitivity
Time Frame: 4-6 weeks
Insulin sensitivity index (i.e. Si) will be determined by using minimal modeling analysis of the IVGTT data.
4-6 weeks
Beta-cell function
Time Frame: 4-6 weeks
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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Clinical Nutrition Research Centre, Singapore

Investigators

  • Principal Investigator: Faidon Magkos, PhD, Clinical Nutrition Research Centre

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 4, 2017

Primary Completion (Anticipated)

July 31, 2018

Study Completion (Anticipated)

December 31, 2018

Study Registration Dates

First Submitted

August 18, 2017

First Submitted That Met QC Criteria

August 24, 2017

First Posted (Actual)

August 28, 2017

Study Record Updates

Last Update Posted (Actual)

March 13, 2018

Last Update Submitted That Met QC Criteria

March 10, 2018

Last Verified

March 1, 2018

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NEB

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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