The Impact Of An Intermittent Energy Restricted Diet On Insulin Sensitivity In Men and Women With Central Obesity

Study Overview
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Brief Summary
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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
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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: 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. 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.

Official Title
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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

Conditions
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Obesity, Abdominal

Intervention / Treatment
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* Behavioral: Intermittent Energy Restriction
* Behavioral: Continuous Energy Restriction


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 75 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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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 |
| --- | --- | --- |
| Plasma glucose concentration | Fasting | 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 | Baseline | 
| Plasma total cholesterol concentration | Fasting | day 29 | 
| Plasma total cholesterol concentration | Fasting | day 31 | 
| Plasma low density lipoprotein (LDL) cholesterol concentration | Fasting | Baseline | 
| Plasma LDL cholesterol concentration | Fasting | day 29 | 
| Plasma LDL cholesterol concentration | Fasting | day 31 | 
| Plasma high density lipoprotein (HDL) cholesterol concentration | Fasting | Baseline | 
| Plasma HDL cholesterol concentration | Fasting | day 29 | 
| Plasma HDL cholesterol concentration | Fasting | day 31 | 
| Plasma triglyceride concentration | Fasting | Baseline | 
| Plasma triglyceride concentration | Fasting | day 29 | 
| Plasma triglyceride concentration | Fasting | day 31 | 
| Plasma total cholesterol:HDL cholesterol ratio | Fasting | Baseline | 
| 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 | Baseline | 
| Plasma adiponectin concentration | Fasting | day 29 | 
| Plasma adiponectin concentration | Fasting | day 31 | 
| Plasma leptin concentration | Fasting | Baseline | 
| 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 |  | Baseline | 
| Body weight |  | day 29 | 
| Body weight |  | day 31 | 
| Body mass index (BMI) |  | Baseline | 
| BMI |  | day 29 | 
| BMI |  | day 31 | 
| Waist circumference |  | Baseline | 
| Waist circumference |  | day 29 | 
| Waist circumference |  | day 31 | 
| Hip circumference |  | Baseline | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Insulin sensitivity, Weight loss, Intermittent fasting, Sympathetic nervous system