Metformin & Inflammation in Pre-diabetic Children
Condition: Glucose Intolerance; Inflammation; Diabetes
MeSH terms: Glucose Intolerance; Inflammation
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      Hypothesis. To determine the effect of metformin on the concentrations of resistin and other
      insulin resistance or inflammatory markers (C-reactive protein, cytokines, body weight,
      HbA1c, among others) in minors with glucose intolerance.

      Children with glucose intolerance are given either metformin or placebo for 12 consecutive
      weeks.

      High sensitivity C-reactive protein, TNF-alpha, IL-6, IL1-beta, resistin, leptin,
      adiponectin, glucose, insulin, HbA1c, lipid profile and transaminases are measured at the
      beginning and at the end of the period. Statistical analysis: t Student test; Friedman and
      Kruskal Wallis test are used. Variables are adjusted for: sex, age, baseline BMI and
      percentage weight change.
    

Detailed description: 
      Experimental, double-blind, randomized, prospective, placebo-controlled study. Patients aged
      4-17 years old are selected from the endocrine outpatient clinic of the Hospital de Pediatria
      del CMN "Siglo XXI", and both patients and parents sign informed consent. They are scheduled
      for a fasting oral glucose tolerance test (OGTT) with 1.75 mg/kg of oral glucose. A blood
      sample is taken from antecubital vein at baseline and 120 minutes.

      A high carbohydrate diet is indicated for 3 days prior to the test. All patients diagnosed
      with glucose intolerance are invited to participate. All followed an aerobic program of 30 to
      45 minutes every day, an isocaloric diet from the moment of inclusion throughout the study
      period, in order to decrease the effect of nutrition modification in the metabolic and
      vascular parameters. A complete medical history is taken, recording family background of
      diabetes plus blood pressure, heart rate and Tanner stage13. Age, body weight, height, waist
      circumference are measured and recorded in percentile according to age and gender, and the
      body mass index is calculated (kg/m2), and recorded in percentile according to reference
      values of the Center for the Disease Control, Atlanta, GA14. Subjects are randomized for
      metformin or placebo. Both metformin and placebo are placed in capsules with gelatin to blind
      their aspect. Treatments are administered during 3 months. Children are evaluated monthly,
      measuring transaminases, glucose, creatinine, and uric acid. Measurements of C reactive
      protein, cytokines, adipokines, insulin concentrations, HbA1c levels and lipid profile are
      made at the beginning and end of the study. Insulin resistance was assayed by HOMA-IR index.
      Beta cell function is determined by using HOMA-β. These are complemented with an evaluation
      of diet, physical activity, and physical examination.

      Treatment assignment: Two groups are formed, randomly assigned using a table of random
      numbers previously designed with the Epistat statistic package (Round Rock, Texas). When the
      screening finished, every child receives a consecutive number. This number corresponds to an
      envelope with a card identifying his/her medication flasks, containing 60 tablets of 850 mg
      or placebo. The content of the capsules is not identified, so both the physician and the
      patient are blinded. A blinded member of the study prepared the flasks and labeled them.

      Participants take the capsules twice daily, at breakfast and dinner. They are instructed to
      take medication with meals in order to decrease the possibility of adverse effects (nausea,
      meteorism, diarrhea), which are checked during every visit. Hepatic function is monitored
      during the study.

      FPG, total cholesterol, HDL-cholesterol, triglycerides, liver function tests and creatinine
      are measured using the Synchron CX analyzer (Beckman Systems, Fullerton CA), according to the
      standard protocols. The coefficients of variation for cholesterol and HDL-cholesterol are
      3.3% and 2.5% respectively. Plasma leptin, adiponectin and insulin concentrations are
      measured in duplicate by radioinmmunoassay (Linco Research Inc, St Charles, MO). HbA1c is
      determined in whole blood using ion exchange high performance liquid chromatography (normal
      range 4-6). Plasma resistin is measured using Human Resistin Elisa Kit (PeproTech, Rock Hill,
      NJ, USA) read by Multiscan EX, Lab Systems, USA). Plasma IL-6, IL1-b, TNF-α concentrations
      are determined by ELISA using Quantike HS Human Immunoassay Kits (R&D Systems, Minneapolis,
      MN, USA), plasma C-reactive protein (hs-CRP) is measured using a highly sensitive human CRP
      ELISA Kit (Alpha diagnostic international, San Antonio, TX, USA ) according to the
      manufacturer's instructions and are read by an ELISA reader (Sunrise, Tecan USA, Durham
      NC,USA).
    

Intervention name(s): Metformin; placebo
Intervention type(s): Drug; Drug
Intervention description(s): 850 mg of metformin twice daily over 12 weeks; 850 mg gel capsules with starch (6.8 calories)as placebo
Other intervention name(s): Diet and physical activity; Diet and physical activity
Intervention MeSH terms: Metformin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Prevention
Keywords: Metformin, inflammation; resistin; impaired glucose tolerance; children