The Study Aims to Investigate the Effects of Oral Inositols on Insulin-resistance in Children With Obesity.

Study Overview
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Brief Summary
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The study aims to investigate the effects of oral inositols on insulin-resistance and metabolic variables (triglycerides, total cholesterol, HDL cholesterol) in children aged 8-12 years with obesity and insulin-resistance.

Detailed Description
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Insulin-resistance is a condition, frequently related to obesity, that leads to cardio-metabolic complications in both children and adults, such as type 2 diabetes, hypertension, dyslipidemia and NAFLD. The best method to lower insulin-resistance is losing weight and doing physical activity, however changing lifestyle statistically reduces excess weight mildly. Also the genetic predisposition for a positive caloric balance, the difficulty in doing physical activity regularly and the metabolic and neuroendocrine responses aimed at preserving energy make it difficult to lose weight and/or improve one's insulin sensitivity. Infact, 80% of children chronicize their obesity into adulthood. For this reason, treatment should be based on both lifestyle changes and complementary approaches. Nutraceuticals can regulate physiological functions and are ideal candidates for children, since they are highly tolerated. Myo-inositol and D-chiro-inositol are stereoisomers of sugar which, in combination with diacylglycerol (DAG), produce phosphatidylinositol (PI), precursor in the signalling of insulin and other hormones (growth factors and FSH). The insulin receptors leads to PI phosphorylation in PIP3, which activates kinases, such as Akt, that cause nuclear (cell proliferation) and cytoplasmatic (activation of glycogen synthetase) effetcs. It also activates phospholipase C, which hydrolyses PIP2 into DAG and IP3. IP3 leads to calcium liberation and moves GLUT4 to the surface of the cell membrane. Inositols are also precursors of inositol-6 phosphate, which is important to promote adipocytes differentiation and fat oxidation. Level A evidence shows that dietary supplements with one or both inositols used in women with PCOS to improve ovarian function, are highly effective also on insulin-sensitivity. The aim of this study is to compare the efficacy of inositols versus placebo on insulin-resistance, measured with the HOMA-IR index, in a sample of children with obesity. As a secondary outcome, the study aims to enlight potential improvements in triglycerides, total cholesterol and HDL cholesterol. This is a randomized, double-blind trial involving 56 children with obesity, aged 8 to 12 years, with insulin-resistance. The children will be randomized into two groups, receiving either a mixture of inositols or placebo, for a period of 3 months (90 days). During these 3 months, the children will be evaluated twice by dietitians (on day 45 and on day 90). Glucose, insulin and lipid profile will be assessed 0 to 30 days before the study beginning and at day 90 of the treatment period. During the visits, dietitians will take the anthropometric measurements, review the lifestyle goals and verify if the treatment is followed correctly (no more than one missed intake per week). The mixture of inositols used contains 4000 mg of myo-inositol and 300 mg of D-chiro-inositol. The chosen dosages are based on two italian studies on young women with PCOS, where it's shown their effectiveness on matabolic risk factors and their high toerance. No dosage variation is required for the trial, since the weight of the evalueted children is similar to adults weight and there aren't differences in the clearance of the supplement. Side effects are rare (<1/1000) and mild (bloating, nausea and stomach ache). The difference in the pre-post treatment HOMA-IR and lipids changes between the two arms will be analyzed with the Student t Test for independent samples, presuming a gaussian distribution of the variable changes. The expected change difference between arms considered clinically significant and used to calculate the arm size is at least 1 standard deviation. The supplement will be considered tollerable if the frequency of side effects will be not significantly different between the two arms.

Official Title
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Effects of Inositols on Insulin Resistance in Children With Obesity (ONIRICO Trial)

Conditions
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Obesity, Prediabetic State, Dyslipidemias, Insulin Resistance

Intervention / Treatment
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* Dietary Supplement: INOSITOLS
* Dietary Supplement: CELLULOSE


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age under 12 and over 8 years Presence of obesity defined by BMI > 95th percentile of BMI based on the growth curves of the Italian Society of Pediatric Endocrinology and Diabetology (Cacciari curves) Presence of HOMA-IR value (insulin x glycaemia/22.5: marker of insulin resistance) > 75th percentile of a reference pediatric population from Verona Exclusion Criteria: Diabetes mellitus Current chronic disease with systemic inflammation Use of drugs acting on insulin sensitivity (e.g. steroids) Use of food or vitamin supplements up to one month before blood sampling Puberty in progress

Ages Eligible for Study
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Minimum Age: 8 Years
Maximum Age: 12 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
Interventional Model Description: The children will be randomized into two arms, receiving either a mixture of inositols or placebo, for a period of 3 months.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: INOSITOLS<br>4000 mg of myo-inositol and 300 mg of D-chiro-inositol. Once a day for 90 days. | Dietary Supplement: INOSITOLS<br>* 4000 mg of myo-inositol and 300 mg of D-chiro-inositol. Once a day for 90 days.<br>|
| Placebo Comparator: PLACEBO<br>Cellulose 4.3 grams once a day for 90 days. | Dietary Supplement: CELLULOSE<br>* 4.3 grams of cellulose once a day for 90 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy on insulin-resistance, measured with the HOMA-IR index | Difference in HOMA-IR index change across arms | 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvements in triglycerides, total cholesterol and HDL cholesterol. | Difference in changes of metabolic variables over time across arms | 90 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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INOSITOLS