The Impact Of An Intermittent Energy Restricted Diet On Insulin Sensitivity In Men and Women With Central Obesity (Met-IER)

A Randomised Controlled Trial Assessing The Impact Of An Intermittent Energy Restricted Diet On Weight Loss, Insulin Sensitivity and Heart Rate Variability In Men and Women With Central Obesity

An intermittent energy restricted (IER) diet may modify cardio-metabolic disease risk factors compared to an energy-matched continuous energy restricted (CER) diet. A randomised controlled parallel design trial will determine the impact of a short-term IER diet (2 consecutive days of very low calorie diet (VLCD), 5 days moderate energy restriction each week for a 4 week period), compared to a CER diet, on insulin sensitivity in healthy (disease-free) subjects with central obesity.

Study Overview

• Status: Completed
• Conditions: Obesity, Abdominal
• Intervention / Treatment: Behavioral: Intermittent Energy Restriction; Behavioral: Continuous Energy Restriction

Detailed Description

Prediabetes rates in England have showed a marked increase, more than tripling between 2003 and 2011. It is characterised by an impaired fasting glucose or impaired glucose tolerance that increases the risk of progression to type 2 diabetes (T2D). It has been estimated that approximately 90% of T2D is attributed to excess weight. Central obesity is a primary driver of increased cardiometabolic risk due to its lipotoxicity effects, promoting a proinflammatory state that facilitates insulin resistance and beta cell dysfunction. A high waist circumference measurement, indicative of central obesity, is associated with increased risk of cardiovascular diseases and T2D, and is a stronger predictor of T2D than BMI. BMI has limitations as an indicator of adiposity since it doesn't distinguish lean from fat mass, and does not indicate body fat distribution. Conventionally, continuous energy restriction (CER) diets have been used for weight loss, which consist of a constant daily energy deficit relative to total energy expenditure. The impact on weight loss and health of an intermittent energy restriction (IER) approach has only rarely been investigated (although the "5:2 diet" has been popularised in lifestyle books aimed at the general public). An IER diet consists of a predefined period of time severely restricting energy intake, alternated with a period of greater energy intake. This approach was shown to confer metabolic benefits in overweight and obese women at risk of breast cancer with baseline BMI of 2445 (Harvie et al., 2013; Harvie et al., 2011).

Rationale: An IER diet using meal replacements (VLCD foodpacks used as total dietary replacements for 2 consecutive days each week, and a food-based energy-restricted diet for the other 5 days of the week) may modify cardio-metabolic disease risk factors compared to an energy-matched CER diet.

Research question: In centrally obese subjects, assessed by a high waist circumference measurement, does adherence to an IER diet have enhanced cardio-metabolic benefits compared to a CER diet? Hypothesis: Increases in insulin sensitivity following a 4 week dietary intervention with an IER weight loss programme will be greater compared to a standard CER programme.

Objectives:

1. A randomised controlled parallel design trial will determine the impact of a short-term IER diet compared to a CER diet on primary outcome variables (insulin sensitivity) in healthy subjects with a high waist circumference.
2. To assess the impact of an IER diet on secondary outcome variables, including body composition, heart rate variability (HRV, a measure of cardiac autonomic function, including parasympathetic and sympathetic activity), blood pressure, vascular function, other markers of insulin resistance, inflammation/adipokines, plasma lipid profile, plasma norepinephrine, ketosis, the gut microbiome and cognitive function in healthy subjects with a high waist circumference.

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United Kingdom
  • England
    • London, England, United Kingdom, SE1 9NH
      • Diabetes & Nutritional Sciences Division, King's College London, Franklin-Wilkins Buiding, 150 Stamford St.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Aged >35-75 years
• Waist circumference above cut-off for high risk of cardio-metabolic disease of >102 cm in men with a Europid, Black African and Caribbean, and other ethnic background and >88 cm in women with a Europid, Black African and Caribbean, and other ethnic background (WHO, 2008), and ≥90 cm in men and ≥80 cm in women with an Asian background (South Asian and East Asian) (Misra et al., 2009).

REFERENCES Misra A, Chowbey P, Makkar BM, Vikram NK, Wasir JS, Chadha D, et al. (2009). Consensus statement for diagnosis of obesity, abdominal obesity and the metabolic syndrome for Asian Indians and recommendations for physical activity, medical and surgical management. The Journal of the Association of Physicians of India 57: 163170.

WHO (2008). Waist circumference and waist-hip ratio: report of a WHO expert consultation. Geneva, 8-11 December 2008.

Exclusion Criteria:

• Kidney or cardiovascular disease, cancer, diabetes, gastrointestinal or chronic liver disease;
• previous bariatric surgery or other major surgery (e.g. organ transplantation);
• unable to provide written informed consent;
• have significant psychiatric disorder (e.g. schizophrenia, anxiety, panic disorder, attention deficit disorder, post-traumatic stress disorder, obsessive compulsive disorder) or uncontrolled depression;
• participated in a weight management drug trial in the previous 3 months;
• have binge eating behaviour;
• have uncontrolled epilepsy;
• alcohol or substance abuse;
• currently pregnant, lactating, or planning pregnancy within the study period;
• are using medication clinically deemed to affect metabolic rate and weight (e.g. beta blockers, corticosteroids, diuretics, etc);
• lactose intolerant.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intermittent Energy Restriction; Weight loss intervention: Intermittent Energy Restriction	Behavioral: Intermittent Energy Restriction; Dietary advice to follow 5:2 diet supported by physical activity advice and motivational group support sessions
Active Comparator: Continuous Energy Restriction; Weight loss intervention: Continuous Energy Restriction	Behavioral: Continuous Energy Restriction; Dietary advice to follow daily energy restricted diet supported by physical activity advice and motivational group support sessions

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Revised QUICKI (RQUICKI)	Marker of insulin sensitivity	Baseline
RQUICKI	Marker of insulin sensitivity	day 29
RQUICKI	Marker of insulin sensitivity	day 31

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Body weight		Baseline
Waist circumference		Baseline
Hip circumference		Baseline
Plasma glucose concentration	Fasting	Baseline
Plasma adiponectin concentration	Fasting	Baseline
Plasma leptin concentration	Fasting	Baseline
Plasma total cholesterol concentration	Fasting	Baseline
Plasma low density lipoprotein (LDL) cholesterol concentration	Fasting	Baseline
Plasma high density lipoprotein (HDL) cholesterol concentration	Fasting	Baseline
Plasma triglyceride concentration	Fasting	Baseline
Plasma total cholesterol:HDL cholesterol ratio	Fasting	Baseline
Body mass index (BMI)		Baseline
Plasma glucose concentration	Fasting	day 29
Plasma glucose concentration	Fasting	day 31
Plasma insulin concentration	Fasting	Baseline
Plasma insulin concentration	Fasting	day 29
Plasma insulin concentration	Fasting	day 31
Plasma non-esterified fatty acid concentration	Fasting	Baseline
Plasma non-esterified fatty acid concentration	Fasting	day 29
Plasma non-esterified fatty acid concentration	Fasting	day 31
Plasma total cholesterol concentration	Fasting	day 29
Plasma total cholesterol concentration	Fasting	day 31
Plasma LDL cholesterol concentration	Fasting	day 29
Plasma LDL cholesterol concentration	Fasting	day 31
Plasma HDL cholesterol concentration	Fasting	day 29
Plasma HDL cholesterol concentration	Fasting	day 31
Plasma triglyceride concentration	Fasting	day 29
Plasma triglyceride concentration	Fasting	day 31
Plasma total cholesterol:HDL cholesterol ratio	Fasting	day 29
Plasma total cholesterol:HDL cholesterol ratio	Fasting	day 31
Homeostasis model assessment estimated insulin resistance (HOMA-IR)	Fasting (calculated from insulin and glucose)	Baseline
Homeostasis model assessment estimated insulin resistance (HOMA-IR)	Fasting (calculated from insulin and glucose)	day 29
Homeostasis model assessment estimated insulin resistance (HOMA-IR)	Fasting (calculated from insulin and glucose)	day 31
Plasma adiponectin concentration	Fasting	day 29
Plasma adiponectin concentration	Fasting	day 31
Plasma leptin concentration	Fasting	day 29
Plasma leptin concentration	Fasting	day 31
Plasma interleukin-6 concentration	Fasting	Baseline
Plasma interleukin-6 concentration	Fasting	day 29
Plasma interleukin-6 concentration	Fasting	day 31
Plasma beta-hydroxybutyrate concentration	Fasting	Baseline
Plasma beta-hydroxybutyrate concentration	Fasting	day 29
Plasma beta-hydroxybutyrate concentration	Fasting	day 31
Plasma norepinephrine concentration	Fasting	Baseline
Plasma norepinephrine concentration	Fasting	day 29
Plasma norepinephrine concentration	Fasting	day 31
Plasma soluble alpha-klotho concentration	Fasting	Baseline
Plasma soluble alpha-klotho concentration	Fasting	day 29
Plasma soluble alpha-klotho concentration	Fasting	day 31
Body weight		day 29
Body weight		day 31
BMI		day 29
BMI		day 31
Waist circumference		day 29
Waist circumference		day 31
Hip circumference		day 29
Hip circumference		day 31
Percentage body fat		Baseline
Percentage body fat		day 29
Percentage body fat		day 31
Percentage lean body mass		Baseline
Percentage lean body mass		day 29
Percentage lean body mass		day 31
Heart rate variability (resting)	supine	Baseline
Heart rate variability (resting)	supine	day 29
Heart rate variability (resting)	supine	day 31
Heart rate variability (ambulatory)		24 h recording at baseline
Heart rate variability (ambulatory)		24 h recording on day 29
Heart rate variability (ambulatory)		24 h recording on day 31
Heart rate variability (sleep-time)		Baseline
Heart rate variability (sleep-time)		day 29
Heart rate variability (sleep-time)		day 31
Heart rate variability (during mental stress)		Baseline
Heart rate variability (during mental stress)		day 29
Heart rate variability (during mental stress)		day 31
Ambulatory blood pressure 24 h		24 h analysis at baseline
Ambulatory blood pressure daytime		Daytime analysis at baseline
Ambulatory blood pressure night-time		Night-time analysis at baseline
Ambulatory blood pressure 24 h		24 h analysis on day 29
Ambulatory blood pressure daytime		daytime analysis on day 29
Ambulatory blood pressure night-time		night-time analysis on day 29
Ambulatory blood pressure 24 h	24 h	24 h analysis on day 31
Ambulatory blood pressure daytime	day time	Daytime analysis on day 31
Ambulatory blood pressure night-time	night-time	Night-time analysis on day 31
Digital volume pulse - stiffness index (SI)	Stiffness index	Baseline
Digital volume pulse - SI	Stiffness index	day 29
Digital volume pulse - SI	Stiffness index	day 31
Digital volume pulse - reflection index (RI)	reflection index	Baseline
Digital volume pulse - RI	reflection index	day 29
Digital volume pulse - RI	reflection index	day 31
Mnemonic Similarity Test		Baseline
Mnemonic Similarity Test		day 29
Mnemonic Similarity Test		day 31
Power of food scale	questionnaire	Baseline
Power of food scale	questionnaire	day 29
Power of food scale	questionnaire	day 31
COPE (not an acronym)	questionnaire	Baseline
COPE	questionnaire	day 29
COPE	questionnaire	day 31

Other Outcome Measures

Outcome Measure	Time Frame
Adverse events	Baseline until endpoint: day 31 (+/-1 day)

Collaborators and Investigators

• Sponsor: King's College London
• Collaborators: LighterLife (UK) Ltd

Publications and helpful links

General Publications

• Allaf M, Elghazaly H, Mohamed OG, Fareen MFK, Zaman S, Salmasi AM, Tsilidis K, Dehghan A. Intermittent fasting for the prevention of cardiovascular disease. Cochrane Database Syst Rev. 2021 Jan 29;1(1):CD013496. doi: 10.1002/14651858.CD013496.pub2.
• Harvie M, Wright C, Pegington M, McMullan D, Mitchell E, Martin B, Cutler RG, Evans G, Whiteside S, Maudsley S, Camandola S, Wang R, Carlson OD, Egan JM, Mattson MP, Howell A. The effect of intermittent energy and carbohydrate restriction v. daily energy restriction on weight loss and metabolic disease risk markers in overweight women. Br J Nutr. 2013 Oct;110(8):1534-47. doi: 10.1017/S0007114513000792. Epub 2013 Apr 16.
• Harvie MN, Pegington M, Mattson MP, Frystyk J, Dillon B, Evans G, Cuzick J, Jebb SA, Martin B, Cutler RG, Son TG, Maudsley S, Carlson OD, Egan JM, Flyvbjerg A, Howell A. The effects of intermittent or continuous energy restriction on weight loss and metabolic disease risk markers: a randomized trial in young overweight women. Int J Obes (Lond). 2011 May;35(5):714-27. doi: 10.1038/ijo.2010.171. Epub 2010 Oct 5.
• Kim C, Pinto AM, Bordoli C, Buckner LP, Kaplan PC, Del Arenal IM, Jeffcock EJ, Hall WL, Thuret S. Energy Restriction Enhances Adult Hippocampal Neurogenesis-Associated Memory after Four Weeks in an Adult Human Population with Central Obesity; a Randomized Controlled Trial. Nutrients. 2020 Feb 28;12(3):638. doi: 10.3390/nu12030638.
• Pinto AM, Bordoli C, Buckner LP, Kim C, Kaplan PC, Del Arenal IM, Jeffcock EJ, Hall WL. Intermittent energy restriction is comparable to continuous energy restriction for cardiometabolic health in adults with central obesity: A randomized controlled trial; the Met-IER study. Clin Nutr. 2020 Jun;39(6):1753-1763. doi: 10.1016/j.clnu.2019.07.014. Epub 2019 Jul 30.

Helpful Links

• Primary publication

Study record dates

Study Major Dates

• Study Start: February 1, 2016
• Primary Completion (Actual): July 1, 2016
• Study Completion (Actual): July 1, 2016

Study Registration Dates

• First Submitted: January 22, 2016
• First Submitted That Met QC Criteria: February 8, 2016
• First Posted (Estimate): February 11, 2016

Study Record Updates

• Last Update Posted (Actual): September 17, 2019
• Last Update Submitted That Met QC Criteria: September 13, 2019
• Last Verified: July 1, 2016

More Information

Terms related to this study

• Keywords: Weight loss; Insulin sensitivity; Intermittent fasting; Sympathetic nervous system
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Overnutrition; Nutrition Disorders; Overweight; Body Weight; Hyperinsulinism; Hypersensitivity; Obesity; Insulin Resistance; Obesity, Abdominal
• Other Study ID Numbers: Met-IER2016

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED