Effect of Melatonin and Metformin on Glycemic Control Genotoxicity and Cytotoxicity Markers in Patients With Prediabetes

Study Overview
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Brief Summary
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Melatonin is a hormone that regulates the circadian cycle in addition to having an antioxidant effect. Patients with prediabetes state, has a deregulation of glucose metabolism and an overproduction of reactive oxygen species caused by levels of hyperglycemia that generate DNA modification in pancreatic beta cells, which leads to apoptosis and a deficient production of insulin. The administration of metformin and melatonin could be a possibility to treat and reverse the prediabetic state decreasing the glycemic levels and reactive oxygen species production.

Detailed Description
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A randomized, double blind, placebo-controlled, pilot clinical trial will carried out in 42 patients with a diagnosis of prediabetes, according to the American Diabetes Association criteria. The patients will be divide in three groups administrating metformin plus placebo, melatonin plus placebo or melatonin plus metformin. The intervention will be with 500 mg lengthed release tablets of metformin once a day in the morning, per 90 days, 5 mg lengthed release capsules of melatonin one a day in the night per 90 days and calcined magnesia as a placebo. Before and after the intervention, will be evaluate: fasting plasma glucose, blood glucose after an oral glucose tolerance test, A1c hemoglobin fraction, micronuclei frequency, nuclear anomalies frequency, insulin secretion and insulin sensitivity, weight, height, body mass index, triglycerides, total cholesterol, high-density lipoprotein, low-density lipoprotein, creatinine, uric acid, and sleep quality.

Official Title
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Effect of the Administration of Melatonin and Metformin on Glycemic Control, Genotoxicity and Cytotoxicity Markers in Patients With Prediabetes: Pilot Study

Conditions
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PreDiabetes

Intervention / Treatment
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* Drug: melatonin
* Drug: metformin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age beween 30 to 60 years old. Diagnosis of Prediabetes state according to the American Diabetes Association criteria. Without pharmacological treatment. Body mass index between 25 to 34.9 Kg/m2 Sign informed consent Exclusion Criteria: Patients with pharmacological treatment. Pregnant woman Patients with autoimmune, cancer, reumatic diases history or with pharmaceutical treatment Workers on night or changing shifts. Subjects that have been exposed to radiation Dyslipidemia: Total cholesterol >250mg/dL, Triglycerides >500 mg/dL. Subjects that have travel to other place with a different time zone. Patients with diagnosis of insomnia Patients with a glomerular filtration <60 ml/min using the Cockroft-Gault Formula.

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 60 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: melatonin plus metformin<br>It will be indicate metformin 850 mg tablets, once a day in the morning (before breakfast) per 90 days. Will administrate melatonin 5 mg lengthed release capsules, once a day in the night (before bedtime) per 90 days. | Drug: melatonin<br>* The administration of melatonin will be indicated at night before bedtime to avoid alterations of the circadian cycle. It will be contained in bottles labeled Medication 2 to maintain the masking. This intervention will be indicated in two groups (Melatonin plus metformin and Melatonin plus placebo)<br>* Other names: Cronocaps;Drug: metformin<br>* For the intervention with metformin, prolonged-release tablets will be used to reduce adverse effects and improve adherence to treatment. It will be contained in bottles labeled Medication 1 to maintain masking. This intervention will be indicated in two groups (Melatonin plus metformin and metformin plus placebo)<br>* Other names: Ifor;|
| Active Comparator: metformin plus placebo<br>It will be indicate metformin 850 mg tablets, once a day in the morning (before breakfast) per 90 days. Will administrate homologated placebo once a day in the night (before bedtime) per 90 days. | Drug: metformin<br>* For the intervention with metformin, prolonged-release tablets will be used to reduce adverse effects and improve adherence to treatment. It will be contained in bottles labeled Medication 1 to maintain masking. This intervention will be indicated in two groups (Melatonin plus metformin and metformin plus placebo)<br>* Other names: Ifor;Drug: Placebo<br>* The placebo may be contained in bottles labeled Medication 1 or Medication 2 depending on the time of administration, and the group in which it is used. Placebo will be used in two groups (Melatonin plus placebo and Metformin plus placebo)<br>* Other names: Calcined magnesia;|
| Experimental: melatonin plus placebo<br>It will be indicate homologated placebo once a day in the morning (before breakfast) per 90 days. Will administrate melatonin 5 mg lengthed release capsules, once a day in the night (before sleep) per 90 days. | Drug: melatonin<br>* The administration of melatonin will be indicated at night before bedtime to avoid alterations of the circadian cycle. It will be contained in bottles labeled Medication 2 to maintain the masking. This intervention will be indicated in two groups (Melatonin plus metformin and Melatonin plus placebo)<br>* Other names: Cronocaps;Drug: Placebo<br>* The placebo may be contained in bottles labeled Medication 1 or Medication 2 depending on the time of administration, and the group in which it is used. Placebo will be used in two groups (Melatonin plus placebo and Metformin plus placebo)<br>* Other names: Calcined magnesia;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fasting plasma glucose (FPG) | The FPG will be evaluate in a blood sample after a 8 - 12 hour fasting period. Will be use a fotometric quantification of glucose levels in plasma sample and will report in mg/dL. | Baseline to week 12 | 
| Blood Glucose level after an Oral Glucose tolerance Test | Will estimate the glucose levels at 2 hours after administration of 75 grams of anhydrid dextrosa. The result will report in mg/dL. | Baseline to week 12 | 
| A1c Hemoglobin Fraction (HbA1C) | HbA1c will be measured with High-performance liquid chromatography technique from a blood sample. The result will report in percentage (%). | Baseline to week 12 | 
| Micronuclei frequency | The frequency of micronuclei will be measured from a cytological sample obtained from the oral epithelium by careful scraping of both cheeks. A fluorescence technique will be performed using acridine orange, as well as a Giemsa-Wrigth stain. The result will be reported in micronucleus frequency per 1000 cells. | Baseline to week 12 | 
| Nuclear anomalies frequency | The nuclear anomalies frequency will be measured from a cytological sample obtained from the oral epithelium by careful scraping of both cheeks. A fluorescence technique will be performed using acridine orange, as well as a Giemsa-Wrigth stain. They will be divided according to their morphology (multinucleated cells, pyknotic nucleus, karyorrhexis, caryolysis, nuclei buds, condensed chromatin) and will be reported by the number of findings per 1000 cells. | Baseline to week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Body height | It will be determined using the electric bioimpedance scale with electrical stadiometer. The measurement will be made with the patient standing on the marks on the bioimpedance scale, in an upright position. This determination will be reported in meters (m) with a minimum precision of 0.01 meters. | Baseline to week 12 | 
| Body weight | t will be determined using the electric bioimpedance scale with electrical stadiometer. The measurement will be made with the patient standing on the marks on the bioimpedance scale, in an upright position. This determination will be reported in kilograms (Kg). | Baseline to week 12 | 
| Body mass index | The calculation will be made using the results of the weight, and height. From these results will be calculated by dividing the weight obtained over the square of the height. This index will be reported in kilograms per square meter (kg / m2) | Baseline to week 12 | 
| Insulin Secretion | The calculation will be made using the insulogenic index, using the values obtained in the oral glucose tolerance test, and determining the insulin levels in plasma at 120 minutes and at the baseline measurement, as well as the glucose levels obtained at the 120 minutes and at the baseline measurement. | Baseline to week 12 | 
| Baseline Insulin Secretion | It will be use the Stumvoll index for the calculation of this parameter. | Baseline to week 12 | 
| Insulin sensitivity | For the calculation of this parameter the Matsuda index will be used, from the values obtained and applying the formula. | Baseline to week 12 | 
| Total Cholesterol | The determination of total cholesterol will be made from a blood sample with the patient fasting between 8 to 12 hours. Samples will be analyzed by spectrophotometry. The result will be reported in milligrams per deciliter (mg / dL). | Baseline to week 12 | 
| High-density lipoprotein (HDL) | The determination of HDL will be made from a blood sample with the patient fasting between 8 to 12 hours. Samples will be analyzed by spectrophotometry. The result will be reported in milligrams per deciliter (mg / dL). | Baseline to week 12 | 
| Low-density lipoprotein | LDL will be calculated using the Friedewald formula from the results obtained of total cholesterol, HDL and triglycerides. The result will be expressed in milligrams per deciliter (mg / dl). | Baseline to week 12 | 
| Triglycerides | The determination of triglycerides will be made from a blood sample with the patient fasting between 8 to 12 hours. Samples will be analyzed by spectrophotometry. The result will be reported in milligrams per deciliter (mg / dL). | Baseline to week 12 | 
| Serum Lactate | The determination of serum lactate will be made from a blood sample with the patient fasting between 8 to 12 hours. Samples will be analyzed by spectrophotometry. The result will be reported in millimoles per Liter (mg / dL). | Baseline to week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Melatonin, Metformin, Pre Diabetes, PreDiabetes, Micronuclei, Genotoxicity Markers, Cytotoxicity Markers