Clinical trial NCT02679989: The Impact Of An Intermittent Energy Restricted Diet On Insulin Sensitivity In Men and Women With Central Obesity
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Obesity, Abdominal
Keywords: Insulin sensitivity
Weight loss
Intermittent fasting
Sympathetic nervous system
Lead sponsor: King's College London
Sponsor class: OTHER
Collaborators: name: LighterLife (UK) Ltd
First posted: 2016-02-11
Enrollment: 42
Sex: ALL
Minimum age (years): 35
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Revised QUICKI (RQUICKI)
timeFrame: Baseline
measure: RQUICKI
timeFrame: day 29
measure: RQUICKI
timeFrame: day 31
Secondary outcomes:
measure: Plasma glucose concentration
timeFrame: Baseline
measure: Plasma glucose concentration
timeFrame: day 29
measure: Plasma glucose concentration
timeFrame: day 31
measure: Plasma insulin concentration
timeFrame: Baseline
measure: Plasma insulin concentration
timeFrame: day 29
measure: Plasma insulin concentration
timeFrame: day 31
measure: Plasma non-esterified fatty acid concentration
timeFrame: Baseline
measure: Plasma non-esterified fatty acid concentration
timeFrame: day 29
measure: Plasma non-esterified fatty acid concentration
timeFrame: day 31
measure: Plasma total cholesterol concentration
timeFrame: Baseline
measure: Plasma total cholesterol concentration
timeFrame: day 29
measure: Plasma total cholesterol concentration
timeFrame: day 31
measure: Plasma low density lipoprotein (LDL) cholesterol concentration
timeFrame: Baseline
measure: Plasma LDL cholesterol concentration
timeFrame: day 29
measure: Plasma LDL cholesterol concentration
timeFrame: day 31
measure: Plasma high density lipoprotein (HDL) cholesterol concentration
timeFrame: Baseline
measure: Plasma HDL cholesterol concentration
timeFrame: day 29
measure: Plasma HDL cholesterol concentration
timeFrame: day 31
measure: Plasma triglyceride concentration
timeFrame: Baseline
measure: Plasma triglyceride concentration
timeFrame: day 29
measure: Plasma triglyceride concentration
timeFrame: day 31
measure: Plasma total cholesterol:HDL cholesterol ratio
timeFrame: Baseline
measure: Plasma total cholesterol:HDL cholesterol ratio
timeFrame: day 29
measure: Plasma total cholesterol:HDL cholesterol ratio
timeFrame: day 31
measure: Homeostasis model assessment estimated insulin resistance (HOMA-IR)
timeFrame: Baseline
measure: Homeostasis model assessment estimated insulin resistance (HOMA-IR)
timeFrame: day 29
measure: Homeostasis model assessment estimated insulin resistance (HOMA-IR)
timeFrame: day 31
measure: Plasma adiponectin concentration
timeFrame: Baseline
measure: Plasma adiponectin concentration
timeFrame: day 29
measure: Plasma adiponectin concentration
timeFrame: day 31
measure: Plasma leptin concentration
timeFrame: Baseline
measure: Plasma leptin concentration
timeFrame: day 29
measure: Plasma leptin concentration
timeFrame: day 31
measure: Plasma interleukin-6 concentration
timeFrame: Baseline
measure: Plasma interleukin-6 concentration
timeFrame: day 29
measure: Plasma interleukin-6 concentration
timeFrame: day 31
measure: Plasma beta-hydroxybutyrate concentration
timeFrame: Baseline
measure: Plasma beta-hydroxybutyrate concentration
timeFrame: day 29
measure: Plasma beta-hydroxybutyrate concentration
timeFrame: day 31
measure: Plasma norepinephrine concentration
timeFrame: Baseline
measure: Plasma norepinephrine concentration
timeFrame: day 29
measure: Plasma norepinephrine concentration
timeFrame: day 31
measure: Plasma soluble alpha-klotho concentration
timeFrame: Baseline
measure: Plasma soluble alpha-klotho concentration
timeFrame: day 29
measure: Plasma soluble alpha-klotho concentration
timeFrame: day 31
measure: Body weight
timeFrame: Baseline
measure: Body weight
timeFrame: day 29
measure: Body weight
timeFrame: day 31
measure: Body mass index (BMI)
timeFrame: Baseline
measure: BMI
timeFrame: day 29
measure: BMI
timeFrame: day 31
measure: Waist circumference
timeFrame: Baseline
measure: Waist circumference
timeFrame: day 29
measure: Waist circumference
timeFrame: day 31
measure: Hip circumference
timeFrame: Baseline
measure: Hip circumference
timeFrame: day 29
measure: Hip circumference
timeFrame: day 31
measure: Percentage body fat
timeFrame: Baseline
measure: Percentage body fat
timeFrame: day 29
measure: Percentage body fat
timeFrame: day 31
measure: Percentage lean body mass
timeFrame: Baseline
measure: Percentage lean body mass
timeFrame: day 29
measure: Percentage lean body mass
timeFrame: day 31
measure: Heart rate variability (resting)
timeFrame: Baseline
measure: Heart rate variability (resting)
timeFrame: day 29
measure: Heart rate variability (resting)
timeFrame: day 31
measure: Heart rate variability (ambulatory)
timeFrame: 24 h recording at baseline
measure: Heart rate variability (ambulatory)
timeFrame: 24 h recording on day 29
measure: Heart rate variability (ambulatory)
timeFrame: 24 h recording on day 31
measure: Heart rate variability (sleep-time)
timeFrame: Baseline
measure: Heart rate variability (sleep-time)
timeFrame: day 29
measure: Heart rate variability (sleep-time)
timeFrame: day 31
measure: Heart rate variability (during mental stress)
timeFrame: Baseline
measure: Heart rate variability (during mental stress)
timeFrame: day 29
measure: Heart rate variability (during mental stress)
timeFrame: day 31
measure: Ambulatory blood pressure 24 h
timeFrame: 24 h analysis at baseline
measure: Ambulatory blood pressure daytime
timeFrame: Daytime analysis at baseline
measure: Ambulatory blood pressure night-time
timeFrame: Night-time analysis at baseline
measure: Ambulatory blood pressure 24 h
timeFrame: 24 h analysis on day 29
measure: Ambulatory blood pressure daytime
timeFrame: daytime analysis on day 29
measure: Ambulatory blood pressure night-time
timeFrame: night-time analysis on day 29
measure: Ambulatory blood pressure 24 h
timeFrame: 24 h analysis on day 31
measure: Ambulatory blood pressure daytime
timeFrame: Daytime analysis on day 31
measure: Ambulatory blood pressure night-time
timeFrame: Night-time analysis on day 31
measure: Digital volume pulse - stiffness index (SI)
timeFrame: Baseline
measure: Digital volume pulse - SI
timeFrame: day 29
measure: Digital volume pulse - SI
timeFrame: day 31
measure: Digital volume pulse - reflection index (RI)
timeFrame: Baseline
measure: Digital volume pulse - RI
timeFrame: day 29
measure: Digital volume pulse - RI
timeFrame: day 31
measure: Mnemonic Similarity Test
timeFrame: Baseline
measure: Mnemonic Similarity Test
timeFrame: day 29
measure: Mnemonic Similarity Test
timeFrame: day 31
measure: Power of food scale
timeFrame: Baseline
measure: Power of food scale
timeFrame: day 29
measure: Power of food scale
timeFrame: day 31
measure: COPE (not an acronym)
timeFrame: Baseline
measure: COPE
timeFrame: day 29
measure: COPE
timeFrame: day 31
Other outcomes:
measure: Adverse events
timeFrame: Baseline until endpoint: day 31 (+/-1 day)
Locations:
city: London
country: United Kingdom
facility: Diabetes & Nutritional Sciences Division, King's College London, Franklin-Wilkins Buiding, 150 Stamford St.
state: England
Study officials:
affiliation: King's College London
name: Wendy Hall, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.