<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03264001</url>
  </required_header>
  <id_info>
    <org_study_id>NEB</org_study_id>
    <nct_id>NCT03264001</nct_id>
  </id_info>
  <brief_title>Effects of Progressive Negative Energy Balance on Glucose Tolerance, Insulin Sensitivity, and Beta-cell Function</brief_title>
  <official_title>Effects of Progressive Negative Energy Balance Induced by Diet or Exercise on Glucose Tolerance, Insulin Sensitivity, and Beta-cell Function</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Clinical Nutrition Research Centre, Singapore</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Clinical Nutrition Research Centre, Singapore</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Type 2 diabetes results from a combination of peripheral insulin resistance and beta-cell&#xD;
      dysfunction, and manifests as fasting and postprandial hyperglycemia. In Singapore, despite&#xD;
      the relatively low prevalence of overweight and obesity, the prevalence of type 2 diabetes is&#xD;
      disproportionately high and is expected to double in the near future. This indicates that&#xD;
      insulin resistance and beta-cell dysfunction are widely prevalent even among individuals who&#xD;
      are not overweight or obese. Still, weight loss induced by a variety of ways (calorie&#xD;
      restriction, exercise, surgery, etc.) is considered the cornerstone of diabetes treatment.&#xD;
      This underscores the importance of negative energy balance in improving metabolic function.&#xD;
      In fact, negative energy balance induced by calorie restriction can improve metabolic&#xD;
      function acutely, i.e. within 1-2 days and before any weight loss occurs. Likewise, negative&#xD;
      energy balance induced by a single session of aerobic exercise improves metabolic function&#xD;
      over the next few days. However, the magnitude of negative energy balance that needs to be&#xD;
      achieved in order to improve metabolic function, as well as possible dose-response&#xD;
      relationships, are not known. Furthermore, the comparative efficacy of calorie restriction&#xD;
      vs. exercise in improving metabolic function has never been directly assessed.&#xD;
&#xD;
      Accordingly, a better understanding of the effects of acute negative energy balance induced&#xD;
      by calorie restriction or aerobic exercise on insulin sensitivity and beta-cell function will&#xD;
      have important implications for public health, by facilitating the design of effective&#xD;
      lifestyle (diet and physical activity) interventions to prevent or treat type 2 diabetes.&#xD;
&#xD;
      To test these hypotheses, whole-body insulin sensitivity, the acute insulin response to&#xD;
      glucose, and the disposition index (i.e. beta-cell function), will be determined the morning&#xD;
      after a single day of progressively increasing negative energy balance (equivalent to 20% or&#xD;
      40% of total daily energy needs for weight maintenance) induced by calorie restriction or&#xD;
      aerobic exercise.&#xD;
&#xD;
      Results from this project are expected to result in the better understanding of the effects&#xD;
      of negative energy balance induced by diet and exercise on metabolic function. Therefore,&#xD;
      this project may help in the design of effective lifestyle intervention programs for the&#xD;
      prevention and treatment of type 2 diabetes.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Metabolic dysfunction, obesity, and type 2 diabetes The incidence of overweight and obesity&#xD;
      has been increasing during the past 2-3 decades in Singapore, and is expected to rise further&#xD;
      in the future. By the year 2050, it is estimated that more than half of the population will&#xD;
      be overweight or obese, defined as having a body mass index (BMI, calculated as the weight in&#xD;
      kilograms divided by the square of height in meters) equal to or greater than 25 kg/m2. This&#xD;
      is likely responsible, at least in part, for the concomitant increase in obesity-related&#xD;
      co-morbid conditions, and particularly type 2 diabetes. The relationship between BMI and the&#xD;
      risk for type 2 diabetes in populations from the Asia-Pacific region is linear within a wide&#xD;
      range of BMI values (from ~21 kg/m2 to ~34 kg/m2), so that for every 2 kg/m2 increase in BMI&#xD;
      (which corresponds to ~6 kg for a normal-weight person of average stature), the risk for&#xD;
      developing type 2 diabetes rises by ~27 %. In Singapore, the prevalence of type 2 diabetes is&#xD;
      expected to double from 7.3 % in 1990 to ~15 % in 2050, predominantly as a result of the&#xD;
      fattening of the population. Remarkably, however, the prevalence of type 2 diabetes in&#xD;
      Singapore is similar to that in the Unites States, even though the prevalence of overweight&#xD;
      and obesity (BMI ≥25 kg/m2) is approximately half. This corroborates findings from many&#xD;
      studies demonstrating that markers of metabolic dysfunction and particularly hyperglycemia,&#xD;
      hyperinsulinemia, and insulin resistance, are highly prevalent among Singaporean adults, even&#xD;
      among people who are not overweight or obese. This likely results in increased risk for&#xD;
      developing type 2 diabetes. These observations underscore the importance of metabolic&#xD;
      dysfunction independent of body weight per se.&#xD;
&#xD;
      Metabolic effects of weight loss The pathogenesis of type 2 diabetes involves peripheral&#xD;
      insulin resistance (i.e. resistance of peripheral tissues and particularly skeletal muscle to&#xD;
      the glucose uptake-promoting effect of insulin) and inadequate secretion of insulin from the&#xD;
      pancreatic beta-cells upon glucose stimulation, leading to fasting and postprandial&#xD;
      hyperglycemia. Weight loss, achieved as a result of chronic negative energy balance induced&#xD;
      by a variety of ways (calorie restriction, exercise, pharmacotherapy, bariatric surgery),&#xD;
      improves metabolic function and is considered the cornerstone of diabetes prevention and&#xD;
      management. Part of the beneficial effect of weight loss could be due to the reduction in&#xD;
      total body fat, intra-abdominal fat, and ectopic fat accumulation in metabolically active&#xD;
      organs (e.g. muscle, pancreas, and liver), however acute perturbations in energy balance&#xD;
      (whether positive or negative, for a period of 24-72 hours) can affect insulin action,&#xD;
      beta-cell function, and glycemic control even before any changes in body weight or body fat&#xD;
      distribution occur. For example, one day of overfeeding disrupts 24-hr glucose homeostasis,&#xD;
      and two days of caloric restriction improves insulin action. Likewise, exercise can also lead&#xD;
      to negative energy balance and is a very potent intervention that readily improves metabolic&#xD;
      function and particularly insulin sensitivity, even after just a single session.&#xD;
      Nevertheless, the degree of negative energy balance that needs to be achieved by calorie&#xD;
      restriction or exercise in order to improve insulin action and beta-cell function is not&#xD;
      known, and the dose-response relationship between negative energy balance and metabolic&#xD;
      function remains elusive. Furthermore, the comparative efficacy of calorie restriction and&#xD;
      exercise on improving the mechanisms regulating glucose homeostasis (i.e. insulin sensitivity&#xD;
      and beta-cell function) has not been adequately studied. One study found that for the same&#xD;
      amount weight loss (8-9 % of initial body weight) induced by a low-calorie diet or endurance&#xD;
      exercise, exercise caused a greater reduction in fat mass, a smaller decrease in muscle mass,&#xD;
      and led to a greater increase in insulin-mediated glucose disposal during a&#xD;
      hyperinsulinemic-euglycemic clamp (by ~30 %), and a greater reduction in the total insulin&#xD;
      response to an oral glucose tolerance test (by ~2.5-fold), compared with matched diet-induced&#xD;
      weight loss; although these differences did not reach statistical significance. These&#xD;
      observations raise the possibility that, for the same negative energy balance, exercise may&#xD;
      be more effective than calorie restriction in improving metabolic function; however these&#xD;
      findings are difficult to interpret in the face of the concomitant more favorable changes in&#xD;
      body composition and fat distribution. No study has directly assessed the effects of the same&#xD;
      acute negative energy balance induced by calorie restriction or aerobic exercise on metabolic&#xD;
      function.&#xD;
&#xD;
      Accordingly, a better understanding of the effects of calorie restriction and exercise on&#xD;
      insulin sensitivity, beta-cell function and daily glycemic control will have important&#xD;
      implications for the design of effective lifestyle intervention targeted at preventing or&#xD;
      managing type 2 diabetes. To this end, this study aims to test the following hypotheses:&#xD;
&#xD;
      Hypothesis 1: It is hypothesized that a single day of negative energy balance induced by&#xD;
      calorie restriction improves intravenous glucose tolerance because of improved beta-cell&#xD;
      function without changes in insulin sensitivity. The investigators further hypothesize that&#xD;
      this effect requires 20% negative energy balance, and does not improve further with greater&#xD;
      energy restriction (40%).&#xD;
&#xD;
      Hypothesis 2: It is hypothesized that a single day of negative energy balance induced by&#xD;
      aerobic exercise improves intravenous glucose tolerance because of improved insulin&#xD;
      sensitivity without changes in beta-cell function. The investigators further hypothesize this&#xD;
      effect requires 20% negative energy balance, and improves further with greater energy&#xD;
      restriction (40%).&#xD;
&#xD;
      Hypothesis 3: It is hypothesized that at any given level of negative energy balance (20% or&#xD;
      40%), calorie restriction has a greater effect than aerobic exercise on beta-cell function,&#xD;
      whereas aerobic exercise has a greater effect than calorie restriction on insulin&#xD;
      sensitivity.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date type="Actual">April 4, 2017</start_date>
  <completion_date type="Anticipated">December 31, 2018</completion_date>
  <primary_completion_date type="Anticipated">July 31, 2018</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Insulin sensitivity</measure>
    <time_frame>4-6 weeks</time_frame>
    <description>Insulin sensitivity index (i.e. Si) will be determined by using minimal modeling analysis of the IVGTT data.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Beta-cell function</measure>
    <time_frame>4-6 weeks</time_frame>
    <description>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.</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">61</enrollment>
  <condition>Insulin Sensitivity</condition>
  <condition>Glucose Intolerance</condition>
  <condition>Insulin Resistance</condition>
  <condition>Energy Supply; Deficiency</condition>
  <arm_group>
    <arm_group_label>Diet-induced negative energy balance</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Exercise-induced negative energy balance</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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.</description>
  </arm_group>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Negative energy balance</intervention_name>
    <description>20% and 40% reduction of daily energy needs for weight maintenance</description>
    <arm_group_label>Diet-induced negative energy balance</arm_group_label>
    <arm_group_label>Exercise-induced negative energy balance</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Healthy males and females&#xD;
&#xD;
          -  Age between 21-65 years&#xD;
&#xD;
          -  BMI from ≥18 to &lt;30 kg/m2 (BMI is equal to body weight in kilograms divided by height&#xD;
             in metres squared)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Persons with metabolic diseases that require use of medications (e.g. diabetes, heart&#xD;
             disease, hypertension, etc.)&#xD;
&#xD;
          -  Persons using tobacco products (smokes daily or occasionally)&#xD;
&#xD;
          -  Persons who regularly consume alcohol (≥1 drink/day)&#xD;
&#xD;
          -  Women on oral contraceptives or hormone replacement therapy&#xD;
&#xD;
          -  Pregnant or breastfeeding women&#xD;
&#xD;
          -  Persons who have had recent weight loss or gain (≥5% over the past 6 months)&#xD;
&#xD;
          -  Persons with contraindication to calorie restriction (e.g. anemia) or exercise (e.g.&#xD;
             asthma)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Faidon Magkos, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Clinical Nutrition Research Centre</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Clinical Nutrition Research Centre</name>
      <address>
        <city>Singapore</city>
        <zip>117609</zip>
        <country>Singapore</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Singapore</country>
  </location_countries>
  <reference>
    <citation>Phan TP, Alkema L, Tai ES, Tan KH, Yang Q, Lim WY, Teo YY, Cheng CY, Wang X, Wong TY, Chia KS, Cook AR. Forecasting the burden of type 2 diabetes in Singapore using a demographic epidemiological model of Singapore. BMJ Open Diabetes Res Care. 2014 Jun 11;2(1):e000012. doi: 10.1136/bmjdrc-2013-000012. eCollection 2014.</citation>
    <PMID>25452860</PMID>
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    <citation>Asia Pacific Cohort Studies Collaboration; Ni Mhurchu C, Parag V, Nakamura M, Patel A, Rodgers A, Lam TH. Body mass index and risk of diabetes mellitus in the Asia-Pacific region. Asia Pac J Clin Nutr. 2006;15(2):127-33.</citation>
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    <citation>Yoon KH, Lee JH, Kim JW, Cho JH, Choi YH, Ko SH, Zimmet P, Son HY. Epidemic obesity and type 2 diabetes in Asia. Lancet. 2006 Nov 11;368(9548):1681-8. doi: 10.1016/S0140-6736(06)69703-1.</citation>
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    <citation>Deurenberg-Yap M, Yian TB, Kai CS, Deurenberg P, VAN Staveren WA. Manifestation of cardiovascular risk factors at low levels of body mass index and waist-to-hip ratio in Singaporean Chinese. Asia Pac J Clin Nutr. 1999 Sep;8(3):177-83. doi: 10.1046/j.1440-6047.1999.00091.x.</citation>
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    <citation>Deurenberg-Yap M, Chew SK, Lin VF, Tan BY, van Staveren WA, Deurenberg P. Relationships between indices of obesity and its co-morbidities in multi-ethnic Singapore. Int J Obes Relat Metab Disord. 2001 Oct;25(10):1554-62. doi: 10.1038/sj.ijo.0801739.</citation>
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    <citation>Luo D, Liu F, Li X, Yin D, Lin Z, Liu H, Hou X, Wang C, Jia W. Comparison of the effect of 'metabolically healthy but obese' and 'metabolically abnormal but not obese' phenotypes on development of diabetes and cardiovascular disease in Chinese. Endocrine. 2015 May;49(1):130-8. doi: 10.1007/s12020-014-0444-2. Epub 2014 Oct 14.</citation>
    <PMID>25312689</PMID>
  </reference>
  <reference>
    <citation>Bradley D, Magkos F, Klein S. Effects of bariatric surgery on glucose homeostasis and type 2 diabetes. Gastroenterology. 2012 Oct;143(4):897-912. doi: 10.1053/j.gastro.2012.07.114. Epub 2012 Aug 8.</citation>
    <PMID>22885332</PMID>
  </reference>
  <reference>
    <citation>Aucott L, Poobalan A, Smith WC, Avenell A, Jung R, Broom J, Grant AM. Weight loss in obese diabetic and non-diabetic individuals and long-term diabetes outcomes--a systematic review. Diabetes Obes Metab. 2004 Mar;6(2):85-94. doi: 10.1111/j.1462-8902.2004.00315.x.</citation>
    <PMID>14746573</PMID>
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  <reference>
    <citation>Maggard-Gibbons M, Maglione M, Livhits M, Ewing B, Maher AR, Hu J, Li Z, Shekelle PG. Bariatric surgery for weight loss and glycemic control in nonmorbidly obese adults with diabetes: a systematic review. JAMA. 2013 Jun 5;309(21):2250-61. doi: 10.1001/jama.2013.4851.</citation>
    <PMID>23736734</PMID>
  </reference>
  <reference>
    <citation>Magkos F, Fraterrigo G, Yoshino J, Luecking C, Kirbach K, Kelly SC, de Las Fuentes L, He S, Okunade AL, Patterson BW, Klein S. Effects of Moderate and Subsequent Progressive Weight Loss on Metabolic Function and Adipose Tissue Biology in Humans with Obesity. Cell Metab. 2016 Apr 12;23(4):591-601. doi: 10.1016/j.cmet.2016.02.005. Epub 2016 Feb 22.</citation>
    <PMID>26916363</PMID>
  </reference>
  <reference>
    <citation>Magkos F, Yannakoulia M, Chan JL, Mantzoros CS. Management of the metabolic syndrome and type 2 diabetes through lifestyle modification. Annu Rev Nutr. 2009;29:223-56. doi: 10.1146/annurev-nutr-080508-141200.</citation>
    <PMID>19400751</PMID>
  </reference>
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    <citation>Gaborit B, Abdesselam I, Kober F, Jacquier A, Ronsin O, Emungania O, Lesavre N, Alessi MC, Martin JC, Bernard M, Dutour A. Ectopic fat storage in the pancreas using 1H-MRS: importance of diabetic status and modulation with bariatric surgery-induced weight loss. Int J Obes (Lond). 2015 Mar;39(3):480-7. doi: 10.1038/ijo.2014.126. Epub 2014 Jul 21.</citation>
    <PMID>25042860</PMID>
  </reference>
  <reference>
    <citation>Kirk E, Reeds DN, Finck BN, Mayurranjan SM, Patterson BW, Klein S. Dietary fat and carbohydrates differentially alter insulin sensitivity during caloric restriction. Gastroenterology. 2009 May;136(5):1552-60. doi: 10.1053/j.gastro.2009.01.048. Epub 2009 Jan 25. Erratum In: Gastroenterology. 2009 Jul;137(1):393. Mayurranjan, Mitra S [corrected to Mayurranjan S Mitra].</citation>
    <PMID>19208352</PMID>
  </reference>
  <reference>
    <citation>Magkos F, Smith GI, Reeds DN, Okunade A, Patterson BW, Mittendorfer B. One day of overfeeding impairs nocturnal glucose but not fatty acid homeostasis in overweight men. Obesity (Silver Spring). 2014 Feb;22(2):435-40. doi: 10.1002/oby.20562. Epub 2013 Sep 10.</citation>
    <PMID>23836730</PMID>
  </reference>
  <reference>
    <citation>Thomas F, Smith GC, Lu J, Babor R, Booth M, Beban G, Chase JG, Murphy R. Differential Acute Impacts of Sleeve Gastrectomy, Roux-en-Y Gastric Bypass Surgery and Matched Caloric Restriction Diet on Insulin Secretion, Insulin Effectiveness and Non-Esterified Fatty Acid Levels Among Patients with Type 2 Diabetes. Obes Surg. 2016 Aug;26(8):1924-31. doi: 10.1007/s11695-015-2038-3.</citation>
    <PMID>26729277</PMID>
  </reference>
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    <citation>Plourde CE, Grenier-Larouche T, Caron-Dorval D, Biron S, Marceau S, Lebel S, Biertho L, Tchernof A, Richard D, Carpentier AC. Biliopancreatic diversion with duodenal switch improves insulin sensitivity and secretion through caloric restriction. Obesity (Silver Spring). 2014 Aug;22(8):1838-46. doi: 10.1002/oby.20771. Epub 2014 Apr 24.</citation>
    <PMID>24760439</PMID>
  </reference>
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    <citation>Magkos, F. and L.S. Sidossis, Exercise and insulin sensitivity. Where do we stand? You'd better run! European Endocrinology, 2008. 4(1): p. 22-25.</citation>
  </reference>
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    <citation>Magkos F, Tsekouras Y, Kavouras SA, Mittendorfer B, Sidossis LS. Improved insulin sensitivity after a single bout of exercise is curvilinearly related to exercise energy expenditure. Clin Sci (Lond). 2008 Jan;114(1):59-64. doi: 10.1042/CS20070134.</citation>
    <PMID>17635103</PMID>
  </reference>
  <reference>
    <citation>Mikines KJ, Sonne B, Farrell PA, Tronier B, Galbo H. Effect of physical exercise on sensitivity and responsiveness to insulin in humans. Am J Physiol. 1988 Mar;254(3 Pt 1):E248-59. doi: 10.1152/ajpendo.1988.254.3.E248.</citation>
    <PMID>3126668</PMID>
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    <citation>Ross R, Dagnone D, Jones PJ, Smith H, Paddags A, Hudson R, Janssen I. Reduction in obesity and related comorbid conditions after diet-induced weight loss or exercise-induced weight loss in men. A randomized, controlled trial. Ann Intern Med. 2000 Jul 18;133(2):92-103. doi: 10.7326/0003-4819-133-2-200007180-00008.</citation>
    <PMID>10896648</PMID>
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    <citation>Weiss EP, Racette SB, Villareal DT, Fontana L, Steger-May K, Schechtman KB, Klein S, Holloszy JO; Washington University School of Medicine CALERIE Group. Improvements in glucose tolerance and insulin action induced by increasing energy expenditure or decreasing energy intake: a randomized controlled trial. Am J Clin Nutr. 2006 Nov;84(5):1033-42. doi: 10.1093/ajcn/84.5.1033.</citation>
    <PMID>17093155</PMID>
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    <citation>Weir JB. New methods for calculating metabolic rate with special reference to protein metabolism. 1949. Nutrition. 1990 May-Jun;6(3):213-21. No abstract available.</citation>
    <PMID>2136000</PMID>
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    <citation>Bergman RN, Ader M, Huecking K, Van Citters G. Accurate assessment of beta-cell function: the hyperbolic correction. Diabetes. 2002 Feb;51 Suppl 1:S212-20. doi: 10.2337/diabetes.51.2007.s212.</citation>
    <PMID>11815482</PMID>
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  <reference>
    <citation>Kahn SE, Prigeon RL, McCulloch DK, Boyko EJ, Bergman RN, Schwartz MW, Neifing JL, Ward WK, Beard JC, Palmer JP, et al. Quantification of the relationship between insulin sensitivity and beta-cell function in human subjects. Evidence for a hyperbolic function. Diabetes. 1993 Nov;42(11):1663-72. doi: 10.2337/diab.42.11.1663.</citation>
    <PMID>8405710</PMID>
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    <citation>Boston RC, Stefanovski D, Moate PJ, Sumner AE, Watanabe RM, Bergman RN. MINMOD Millennium: a computer program to calculate glucose effectiveness and insulin sensitivity from the frequently sampled intravenous glucose tolerance test. Diabetes Technol Ther. 2003;5(6):1003-15. doi: 10.1089/152091503322641060.</citation>
    <PMID>14709204</PMID>
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    <citation>Ganda OP, Day JL, Soeldner JS, Connon JJ, Gleason RE. Reproducibility and comparative analysis of repeated intravenous and oral glucose tolerance tests. Diabetes. 1978 Jul;27(7):715-25. doi: 10.2337/diab.27.7.715.</citation>
    <PMID>658617</PMID>
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    <citation>Prigeon RL, Kahn SE, Porte D Jr. Reliability of error estimates from the minimal model: implications for measurements in physiological studies. Am J Physiol. 1994 Feb;266(2 Pt 1):E279-86. doi: 10.1152/ajpendo.1994.266.2.E279.</citation>
    <PMID>8141288</PMID>
  </reference>
  <verification_date>March 2018</verification_date>
  <study_first_submitted>August 18, 2017</study_first_submitted>
  <study_first_submitted_qc>August 24, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 28, 2017</study_first_posted>
  <last_update_submitted>March 10, 2018</last_update_submitted>
  <last_update_submitted_qc>March 10, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">March 13, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Clinical Nutrition Research Centre, Singapore</investigator_affiliation>
    <investigator_full_name>Faidon Magkos</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Insulin Resistance</mesh_term>
    <mesh_term>Glucose Intolerance</mesh_term>
    <mesh_term>Hypersensitivity</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03264001
org study id: NEB
nct id: NCT03264001
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
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.
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.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Insulin sensitivity
time frame: 4-6 weeks
description: Insulin sensitivity index (i.e. Si) will be determined by using minimal modeling analysis of the IVGTT data.
measure: Beta-cell function
time frame: 4-6 weeks
description: 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.
arm group label: Diet-induced negative energy balance
arm group type: Experimental
description: 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.
arm group label: Exercise-induced negative energy balance
arm group type: Experimental
description: 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.
intervention type: Behavioral
intervention name: Negative energy balance
description: 20% and 40% reduction of daily energy needs for weight maintenance
arm group label: Diet-induced negative energy balance
arm group label: Exercise-induced negative energy balance
criteria: 
gender: All
minimum age: 21 Years
maximum age: 65 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Faidon Magkos, PhD
role: Principal Investigator
affiliation: Clinical Nutrition Research Centre
facility: 
country: Singapore
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citation: Magkos F, Yannakoulia M, Chan JL, Mantzoros CS. Management of the metabolic syndrome and type 2 diabetes through lifestyle modification. Annu Rev Nutr. 2009;29:223-56. doi: 10.1146/annurev-nutr-080508-141200.
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responsible party type: Principal Investigator
investigator affiliation: Clinical Nutrition Research Centre, Singapore
investigator full name: Faidon Magkos
investigator title: Principal Investigator
mesh term: Insulin Resistance
mesh term: Glucose Intolerance
mesh term: Hypersensitivity
sharing ipd: No