Impact of Exercise Intervention on the Phenome

Study Overview
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Brief Summary
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It is an open-label, parallel-group, randomized controlled clinical trial, which is designed to enroll people with different glucose metabolism status who are also overweight or obese, including people with normal glucose metabolism, pre-diabetes patients and newly diagnosed type 2 diabetes patients. The patients are randomized to an enhanced physical activity intervention (high-intensity interval training exercise prescription combined with resistance training) or standard education group (diabetes health education only, including lifestyle education and guidance) for 12 weeks. This trial intends to compare the influence of enhanced physical activity treatment with that of a standard education on liver steatosis, serum glucose and lipids level, insulin sensitivity, cardiovascular metabolic parameters, metabolic molecules, and gut microbiota profile et al.

Detailed Description
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The trial will recruit 270 patients from 2 hospitals within the China Diabetes Clinical Research Network. Eligible criteria include men and women aged 18-65 years; with normal glucose metabolism or pre-diabetes or newly diagnosed type 2 diabetes; no insulin treatment; BMI ≥23 kg/m2 and <40 kg/m2. Main exclusion criteria include severe cardiovascular diseases, uncontrolled hypertension, and other serious illness. The proposed trial has 90% statistical power to detect an absolute 3.0% reduction of liver triglyceride level changes between intensive physical activity intervention and standard education groups at a 2-sided significance level of 0.05. To achieve the proposed study objectives, we plan to perform the following specific aims: Recruit 270 study participants who meet the eligibility criteria, including 90 people with normal glucose metabolism, 90 pre-diabetes patients and 90 newly diagnosed type 2 diabetes patients, and randomly assign 135 to the enhanced physical activity intervention group and 135 to the standard education group for 12 weeks; Employ a study-wide strategy to encourage standard of care for all participants for the treatment of type 2 diabetes and other metabolic disorders; Obtain clinical data on study outcomes for up to 12 months of follow-up among all trial participants; Perform strict quality control procedures for intervention and data collection; Conduct data analysis according to the intention-to-treat principle; Disseminate the study findings to influence clinical practice and clinical guidelines. The results will be analyzed to examine the pan-omics changes after the interventions and clarify their predictive benefits on the effects of the interventions.

Official Title
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Impact of Exercise Intervention on the Phenome (Metabolism and Predictive Complications) in Well Characterised Pre-diabetes and New Onset Type 2 Diabetes Cohorts in China

Conditions
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Overweight and Obesity, Physical Activity

Intervention / Treatment
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* Behavioral: Enhanced physical activity intervention
* Behavioral: Standard education


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women aged 18-65 years; Normal glucose metabolism or pre-diabetes or newly diagnosed type 2 diabetes Normal glucose metabolism: FBG<5.6mmol/L and 2h-PG<7.8mmol/L and HbA1c<5.7%; Pre-diabetes: 5.6mmol/L ≤ FBG ≤ 6.9mmol/L and/or 7.8mmol/L ≤ 2h-PG ≤ 11.0mmol/L and/or 5.7% ≤ HbA1c ≤ 6.4%; Newly diagnosed diabetes: o Duration of type 2 diabetes is less than 5 years; No insulin treatment; 23 Kg/m2 ≤ Body mass index (BMI) <40 Kg/m2; Exclusion Criteria: Eligibility Minimum Age: 18 Years Maximum Age: 65 Years Sex: All Gender Based: No Accepts Healthy Volunteers: No Criteria: Inclusion Criteria: Men and women aged 18-65 years; Normal glucose metabolism or pre-diabetes or newly diagnosed type 2 diabetes Normal glucose metabolism: FBG<5.6mmol/L and 2h-PG<7.8mmol/L and HbA1c<5.7%; Pre-diabetes: 5.6mmol/L ≤ FBG ≤ 6.9mmol/L and/or 7.8mmol/L ≤ 2h-PG ≤ 11.0mmol/L and/or 5.7% ≤ HbA1c ≤ 6.4%; Newly diagnosed diabetes: o Duration of type 2 diabetes is less than 5 years; No insulin treatment; 23 Kg/m2 ≤ Body mass index (BMI) <40 Kg/m2; Exclusion Criteria: Severe cardiovascular disease: current angina myocardial infarction or stroke within last six months heart failure (NYHA grading III IV) symptomatic periphery vascular disease Uncontrolled hypertension: systolic blood pressure > 180 mmHg and/or diastolic blood pressure > 100 mmHg; Myocardial ischemia indicated by resting ECG; Cardiac dysfunction indicated by Echocardiogram; Abnormal HS-TNT or NT-proBNP concentration; Foot ulcers, peripheral neuropathy or skeletal disorders; Taking high intensity exercise more than 75 minutes or moderate intensity exercise more than 150 minutes per week during the screening phase ALT or AST levels more than three times the upper limit of the normal range or active liver diseases; eGFR <60 ml/min/1.73 m2, or serum creatinine >1.5 mg/dl for men or 1.3mg/dl for women; or macro albuminuria (urine albumin/creatinine>300mg/g) Malignant tumor in active-stage, or in remission stage but less than 5 years from the most recent treatment Past or present confirmed psychiatric illness or drug dependence; Currently taking medications known to affect weight (e.g. anti thyroid drugs, glucocorticoids); Known to have weight-affecting diseases (e.g. malabsorption, functional bowel disease, uncontrolled low sodium/hyperthyroidism, eating disorders); Known to have metabolism-affecting diseases; Other acute diseases supported by clinical evidence which may contradict to the interventions; Pregnancy, currently trying to become pregnant, or of child-bearing potential and not using birth control; Currently participating in another intervention study; Failure to obtain informed consent from participant; Any factors judged by the clinic team to be likely to limit adherence to interventions; Any other medical condition judged by the clinic team not eligible for the trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Enhanced physical activity group<br>the participants will take high-intensity exercise in accordance with High Intensity Interval Training (HIIT) prescriptions, with maximum heart rate and relative maximal oxygen uptake monitored. They will take both aerobic and resistance training exercise consecutively, and total training time will be expected to reach at least 150 minutes per week. | Behavioral: Enhanced physical activity intervention<br>* the participants will take high-intensity exercise in accordance with High Intensity Interval Training (HIIT) prescriptions, with maximum heart rate and relative maximal oxygen uptake monitored. They will take both aerobic and resistance training exercise consecutively, and total training time will be expected to reach at least 150 minutes per week.<br>|
| Experimental: Standard education group<br>the participants will receive no extra intervention but diabetes health education, which will be carried out in large classrooms, in groups, and over the telephone. The education is mainly consisted of instructions on diabetes prevention according to < Guidelines for prevention and treatment of type 2 diabetes in China (2017 edition)telephone. The education is mainly consisted of instructions on diabetes prevention according to < Guidelines for prevention and treatment of type 2 diabetes in China (2017 edition)>. | Behavioral: Standard education<br>* the participants will receive no extra intervention but diabetes health education, which will be carried out in large classrooms, in groups, and over the telephone. The education is mainly consisted of instructions on diabetes prevention according to < Guidelines for prevention and treatment of type 2 diabetes in China (2017 edition)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in liver steatosis quantified by MRI-PDFF (percentage) |  | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in liver steatosis quantified by MRI-PDFF (percentage) |  | 1 year | 
| Change in the level of fasting blood glucose (mmol/l) |  | 12 weeks and 1 year | 
| Change in the level of plasma glucose of 2 hours post glucose-load (mmol/l) |  | 12 weeks and 1 year | 
| Change in the level of HbA1c (percentage) |  | 12 weeks and 1 year | 
| Change in body mass index (BMI) | Body weight (kg) and height (m) will be combined to report BMI in kg/m^2 | 12 weeks and 1 year | 
| Change in waist circumstance (cm) |  | 12 weeks and 1 year | 
| Change in body fat level (%) | Quantified by bioelectrical impedance analysis in a human body composition analyzer | 12 weeks and 1 year | 
| Change in serum non-HDL-C level (mg/dl) |  | 12 weeks and 1 year | 
| Change in serum total cholesterol level (mg/dl) |  | 12 weeks and 1 year | 
| Change in serum VLDL-C level (mg/dl) |  | 12 weeks and 1 year | 
| Change in serum LDL-C level (mg/dl) |  | 12 weeks and 1 year | 
| Change in serum HDL-C level (mg/dl) |  | 12 weeks and 1 year | 
| Change in serum ApoB level (mg/dl) |  | 12 weeks and 1 year | 
| Change in basal metabolic rate (BMR) (Kcal) | Quantified by bioelectrical impedance analysis in a human body composition analyzer | 12 weeks and 1 year | 
| Change in blood pressure (mmHg) |  | 12 weeks and 1 year | 
| Change in heart rate |  | 12 weeks and 1 year | 
| Change in insulin sensitivity | Quantify by HOMA score, which is calculated multiplying fasting plasma insulin (FPI, mIU/L) by fasting plasma glucose (FPG, mmol/L), then dividing by the constant 22.5, i.e. HOMA-IR = (FPI×FPG)/22.5. | 12 weeks and 1 year | 
| Change in islet β-cell function | Quantify by HOMA score, which is calculated with fasting plasma insulin (FPI, mIU/L) and fasting plasma glucose (FPG, mmol/L), i.e. HOMA-β = 20*FPI/(FPG-3.5). | 12 weeks and 1 year | 
| Change in serum fetuin-A concentration (μg/mL) |  | 12 weeks and 1 year | 
| Change in serum GREM2 concentration (pg/ml) |  | 12 weeks and 1 year | 
| Change in gut hormones, monocyte subtypes and other serum biomarkers |  | 12 weeks and 1 year | 
| Change in metabolic molecules concentration |  | 12 weeks and 1 year | 
| Change in microRNA concentration |  | 12 weeks and 1 year | 
| Change in overall gut microbiota profile | change in gut microbiota composition and proportion of specific gut flora. | 12 weeks and 1 year | 
| Depression | Evaluated with PHQ-9 scores. The PHQ is 59-question instrument, referring to the level of interest in doing things, feeling down or depressed, difficulty with sleeping, energy levels, eating habits, self-perception, ability to concentrate, speed of functioning and thoughts of suicide. Responses range from 0 (Not at all) to 3 (nearly every day).The total sum of the responses suggests varying levels of depression. Scores range from 0 to 27. In general, a total of 10 or above is suggestive of the presence of depression. | 12 weeks and 1 year | 
| Health related quality of life | Evaluated with HQoL scales such as Short Form 12 Health Survey Questionnaire. The SF-12 is 12-question instrument, covering the eight domains of health outcomes, including physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health. Scores range from 0 to 48. A higher score indicates a better health state. | 12 weeks and 1 year | 
| Change in diet pattern | Evaluated with a semiquantitative food frequency questionnaire. | 12 weeks and 1 year | 
| Change in sleeping pattern | Evaluated with Pittsburgh Sleep Quality Index, PSQI. Scores range from 0 to 21. A higher score indicates a worse sleeping pattern. | 12 weeks and 1 year | 
| Change in daily exercise | Evaluated with short form International Physical Activity Questionnaire (IPAQ). | 12 weeks and 1 year | 
| Cardiovascular risk | Evaluated with Framingham Risk Scores. Individuals with low risk have 10% or less CHD risk at 10 years, with intermediate risk 10-20%, and with high risk 20% or more. | 12 weeks and 1 year |