The Role of FTO Gene Polymorphism and Insulin Preparation in Obesity in Children With Type 1 Diabetes Mellitus
Condition: Type 1 Diabetes Mellitus
MeSH terms: Diabetes Mellitus; Obesity; Diabetes Mellitus, Type 1; Pediatric Obesity
Study type: Observational

Summary: 
      The project aims at assessment of the effect of the FTO gene polymorphism and the type of
      treatment on the development of overweight/obesity and features of metabolic syndrome in
      children with type 1 diabetes.

      Gene polymorphism including some genetic variants may predispose to the development of
      cardiovascular diseases and their complications. The A allele of the FTO gene predisposing to
      obesity occurs in approximately 40% of the European population and each copy of this allele
      can increase BMI by 0.1 Z-score i.e. by 0.4 kg/m2. Insulin therapy in diabetic patients may
      result in excess body weight gain. Therefore we need studies involving large groups of
      children and assessing cardiovascular risk factors in type 1 diabetes along with their
      genetic associations.

      Patients: The study will include 1500 children with type 1 diabetes, aged 6-18 years.
      Reference group will be made of 1500 children in whom type 1 diabetes was excluded. The
      following variables will be assessed in the treatment group: 1) Anthropometric data and
      questionnaire data: age, sex, body height and weight, body mass index (BMI), waist and hip
      circumferences, arm and thigh circumferences, family history of overweight/obesity, type 1 or
      2 diabetes or cardiovascular disease, 2) Primary disease characteristics: age of the disease
      onset, treatment regimen, mean daily insulin consumption per kg body weight, brands of
      insulin products, glycated haemoglobin, BMI from the first 3-6 months following diabetes
      onset, diet, conversion of these data into actual and ideal calorie intake 3) Laboratory data
      - lipid profile and blood pressure (average of three measurements). Methodology: Gene
      polymorphism analysis in the extracted DNA will be made with the real-time PCR method using
      TaqMan 7900 HT by Applied Biosystems. Correlations between the FTO gene polymorphism and
      clinical variables such as BMI (including BMI increase since the disease onset), body weight
      and height, waist and hip circumferences, arm and thigh circumferences, and blood pressure
      will be assessed by a professional statistician with a specially dedicated software. Moreover
      parameters such as diet and metabolic control will be assessed. As regards insulin therapy
      the following variables will be analysed: insulin injection device, therapy regimen
      (intensive versus functional; brands and types of insulin products: human insulin versus
      insulin analogue), consumption of insulin. All of the above listed variables will be
      correlated with the genotypes found in the gene polymorphism analysis. The study has been
      approved by Bioethics Committee of the Medical University in Białystok.

      Results: The authors of the project expect that the effect of the FTO gene polymorphism on
      overweight/obesity and features of metabolic syndrome in children with type 1 diabetes will
      be shown. Moreover the project will enable assessment of the effect of the therapeutic
      regimen, including the type of insulin product, on body weight increase in the course of type
      1 diabetes treatment in the context of the FTO gene polymorphism. Confirmation of the above
      associations and identification of a group at risk of excess body weight increase in the
      course of insulin therapy may help physicians, parents and patients to avoid this
      complication. Therefore clinical benefit of this project will include identification - based
      on the genetic assays results - of a group of type 1 diabetic children particularly likely to
      develop overweight, obesity and other cardiovascular risk factors.
    

Detailed description: 
      Aim:

      The project aims at assessment of the effect of the FTO gene polymorphism and the type of
      treatment on the development of overweight/obesity and features of metabolic syndrome in
      children with type 1 diabetes. Particular objective of the project is providing an answer to
      the question: Are type 1 diabetic children who are carriers of the AA genotype of the FTO
      gene polymorphism (rs9939609) at risk of more weight gain in the course of insulin therapy
      when compared to carriers of the TA and TT genotypes of this polymorphism ? Background: Gene
      polymorphism including some genetic variants may predispose to the development of
      cardiovascular diseases and their complications. A great advance in studies on genetic
      susceptibility to obesity was the discovery of the gene called FTO - fat mass and obesity
      associated gene. The A allele of the FTO gene predisposing to obesity occurs in approximately
      40% of the European population and each copy of this allele can increase BMI by 0.1 Z-score
      i.e. by 0.4 kg/m2. However, there are very few data on the impact of human genome on body
      weight change following particular intervention.

      An important problem to be dealt with by physicians and type 1 diabetic patients is
      overweight and obesity. This problem is inevitably associated with insulin therapy and excess
      energy intake. Insulin therapy in diabetic patients may result in excess body weight gain.
      The exact mechanisms underlying this phenomenon are not known. Obesity in patients diagnosed
      with diabetes can be an additional risk factor of cardiovascular disease. Central obesity,
      insulin resistance, dyslipidaemia and arterial hypertension are all the elements of metabolic
      syndrome - a disease that predisposes to the development of cardiovascular disorders.
      Cardiovascular complications are the main cause of morbidity and mortality in adult patients
      with diabetes. However recently repeated attempts have been made to assess these factors also
      in children and adolescents. Overweight and obesity in type 1 diabetes depend among others on
      patients' sex, age and type of treatment. Although the role of gene polymorphism in the
      development of obesity in adults and children is the subject of extensive investigations,
      currently there are no reports that would assess genetic aspects of obesity in treatment of
      type 1 diabetes. Therefore we need studies involving large groups of children and assessing
      cardiovascular risk factors in type 1 diabetes along with their genetic associations.

      Patients: The study will include 1500 children with type 1 diabetes, aged 6-18 years.
      Reference group will be made of 1500 children in whom type 1 diabetes was excluded.

      The following variables will be assessed in the treatment group: 1) Anthropometric data and
      questionnaire data: age, sex, body height and weight, body mass index (BMI) (including
      SDS-BMI), waist and hip circumferences, arm and thigh circumferences, family history of
      overweight/obesity, type 1 or 2 diabetes or cardiovascular disease, 2) Primary disease
      characteristics: age of the disease onset, treatment regimen (intensive insulin therapy
      versus functional insulin therapy with a personal insulin pump), mean daily insulin
      consumption per kg body weight, brands of insulin products, glycated haemoglobin (the last
      available measurement and the mean value from the last year), BMI from the first 3-6 months
      following diabetes onset, diet - consumption of carbohydrate and protein-fat exchanges (only
      in patients using a personal insulin pump), conversion of these data into actual and ideal
      calorie intake 3) Laboratory data: lipid profile (total cholesterol, HDL cholesterol, LDL
      cholesterol, triglycerides) and blood pressure (average of three measurements). In the
      control group anthropometric variables and questionnaire data will be assessed along with
      additional questions.

      Methodology: Gene polymorphism analysis in the extracted DNA will be made with the real-time
      PCR method using TaqMan 7900 HT by Applied Biosystems. Correlations between the FTO gene
      polymorphism and clinical variables such as BMI (including BMI increase since the disease
      onset), body weight and height, waist and hip circumferences, arm and thigh circumferences,
      and blood pressure will be assessed by a professional statistician with a specially dedicated
      software (R-project). Moreover parameters such as diet and metabolic control will be
      assessed. As regards insulin therapy the following variables will be analysed: insulin
      injection device, therapy regimen (intensive versus functional; brands and types of insulin
      products: human insulin versus insulin analogue), consumption of insulin. Out of laboratory
      data, lipid metabolism parameters will be assessed. All of the above listed variables will be
      correlated with the genotypes found in the gene polymorphism analysis. The study has been
      approved by Bioethics Committee of the Medical University in Białystok.

      Results: The authors of the project expect that the effect of the FTO gene polymorphism on
      overweight/obesity and features of metabolic syndrome in children with type 1 diabetes will
      be shown. Moreover the project will enable assessment of the effect of the therapeutic
      regimen, including the type of insulin product, on body weight increase in the course of type
      1 diabetes treatment in the context of the FTO gene polymorphism. Confirmation of the above
      associations and identification of a group at risk of excess body weight increase in the
      course of insulin therapy may help physicians, parents and patients to avoid this
      complication. Therefore clinical benefit of this project will include identification - based
      on the genetic assays results - of a group of type 1 diabetic children particularly likely to
      develop overweight, obesity and other cardiovascular risk factors.
    

Observational model: Case-Control
Time perspective: Cross-Sectional
Sampling method: Non-Probability Sample
Study population: 
        The study will include 1500 children with type 1 diabetes, aged 6-18 years. These will be
        patients from Diabetes Outpatient Clinics and patients hospitalized in Departments of
        Paediatrics, Endocrinology and Diabetology in University and Municipal Hospitals from all
        over Poland (Białystok, Warszawa, Gdańsk, Katowice, Wrocław). Reference group will be made
        of 1500 children from the above mentioned Clinics and Departments in whom type 1 diabetes
        was excluded. In these children diagnostics procedures will be conducted for reasons other
        than body weigh related diseases (excluding simple obesity). The children will not receive
        any treatment that might influence their body weight.
      
Biospecimen description: 
      Small amount of peripheral blood for isolation of DNA for assessment of FTO polymorphism.
    
Keywords: overweight, obesity, children, insulin, pump therapy, FTO