Response of Individuals With Ataxia-Telangiectasia to Metformin and Pioglitazone
Condition: Ataxia-Telangiectasia
MeSH terms: Ataxia; Cerebellar Ataxia; Ataxia Telangiectasia; Telangiectasis
Study type: Interventional
Phase: Phase 4

Summary: 
      This study aims to investigate the link between the Ataxia Telangiectasia Mutated (ATM) gene
      and metformin response. This link has been identified from large studies of the human genome,
      and this study aims to confirm this link in a clinical study. The ATM gene is involved in DNA
      repair - if a person inherits a "faulty" copy of this gene from both their parents, they have
      a genetic condition called Ataxia-telangiectasia (A-T).

      A-T is associated with, among other things, a resistance to insulin, which causes fatty liver
      and diabetes. This study will recruit people who have A-T, but have not developed diabetes,
      and compare this group to "healthy" controls, i.e. people who do not have A-T or diabetes.
      The study will compare how the groups respond to two drugs used to treat diabetes (metformin
      and pioglitazone), with the intention that this will guide the management of diabetes in A-T.

      This is an, open label unblinded study recruiting 15 people with A-T and 15 age and gender
      matched controls. Each participant will have three study visits to the Clinical Research
      Centre at Ninewells hospital in Dundee - one at baseline, a second after 8 weeks of metformin
      and the final visit after eight weeks of pioglitazone. During each visit we will carry out a
      number of investigations to study the insulin resistance of A-T and how it responds to
      metformin and pioglitazone.
    

Detailed description: 
      Metformin is a commonly-prescribed drug, used as first-line medical management of type 2
      diabetes mellitus (T2DM), but also off-license in non-diabetics for Polycystic Ovary Syndrome
      (PCOS). Over 120 million people worldwide are prescribed metformin. Despite this, its
      mechanism of action is not fully understood. Both tolerance of and response to metformin
      varies greatly from patient to patient, and highlights the need for further research into the
      pharmacokinetics and dynamics of the drug.

      As a team of diabetes researchers, our group have been interested in the genetics of drug
      response in diabetes. A Genome Wide Association Study carried out by members of our group
      highlighted the locus carrying the ATM gene as a potential link to metformin response. We
      have designed this study to investigate this link clinically. In doing so we hope to guide
      the management of diabetes in a condition called Ataxia Telangiectasia.

      ATM (Ataxia Telangiectasia Mutated) is a gene involved in DNA repair - homozygous recessive
      mutations in this gene cause Ataxia Telangiectasia (A-T), which is associated with cerebellar
      ataxia, ocular telangiectasia and lymphoproliferative cancers. The incidence of A-T is
      between 1 in 40,000 to 1 in 100,000 live births, though this increases dramatically with
      consanguineous parents. Interestingly, A-T has also been associated with insulin resistance.
      Both "fatty liver" and diabetes have been documented in this patient group, but there is
      little research into the link between A-T and these conditions. Approximately 1 in 100 people
      are carriers of a loss of function mutation in the ATM gene, which is associated with an
      increased risk of ischaemic heart disease and certain cancers.

      Several studies of ATM deficiency in a mouse model have been carried out. Atm -/- mice
      display an early defect in glucose-stimulated insulin release and later develop
      hyperglycaemia, and insulin resistance[1]. Unpublished data from the McCrimmon Group at
      University of Dundee suggest that mice heterozygous for ATM deficiency have impaired fasting
      glucose, but demonstrated a marked improvement in fasting glucose with metformin. A Cell
      Reports paper, detailing a mouse model of ATM deficiency, demonstrates insulin resistance in
      ATM deficient mice, with a lipodystrophic phenotype[2]. This phenotype (paucity of
      subcutaneous fat, and increased visceral fat) was attenuated by metformin and
      thiazolidinedione (TZD) use.

      A small study published by the Pearson group from University of Dundee, which compared data
      from oral glucose tolerance tests (OGTTs) in A-T patients versus healthy individuals,
      confirmed increased insulin resistance in A-T patients[3]. As mentioned above, a genome wide
      association study, also by the Pearson group, highlights the ATM locus as a potential genetic
      link to metformin response[4, 5]. With the mouse models and information from genetic studies,
      this study now aims to assess insulin resistance in this A-T patient group, and to understand
      how they respond to drugs commonly used to treat insulin resistance / diabetes.

      The potential genetic link between ATM and metformin response will be investigated. Thus far
      it is unclear from the genetic studies how ATM deficiency affects an individual's metformin
      response - is their response greater or less than that of the general population? Similarly,
      magnitude of this response has not been quantified. There are anecdotal reports of patients
      with A-T who have had a marked improvement in glycaemic control with metformin use. Mouse
      model studies have indicated an increased response to metformin in heterozygous ATM deficient
      mice.

      The study will also investigate the response of individuals with A-T to TZDs. Studies of the
      mouse model of A-T has demonstrated response to the TZD pioglitazone,. Of note, pioglitazone
      is now used off-licence in non-diabetics for the treatment of Non-Alcoholic Fatty Liver
      Disease (NAFLD) [6, 7], therefore we know it is safe for use in a non-diabetic cohort.

      This study will assess the effect of ATM deficiency on metformin and pioglitazone response in
      humans, by studying people with A-T, and comparing their response to that of a matched
      control group.

      This study will recruit non-diabetic individuals - 15 cases (people with A-T) vs 15 age and
      gender matched controls - in a crossover design. Participants will be 18 - 30 years of age.
      This age group is most realistic for recruiting patients with "classic", as opposed to "mild
      variant" A-T, as people with classic A-T rarely survive to their 30s. Exclusion of
      individuals with other milder forms of A-T will provide a more detectable difference between
      the two cohorts. Participants will be of white European descent, as this will narrow the
      genetic differences between individuals. Ethnic origin also has an effect on an individual's
      insulin resistance, therefore all the participants should be of the same ethnicity.

      The study is made up of two treatment periods each lasting eight weeks, and separated by a
      one week washout period. Initial treatment shall be with metformin, titrated to 1000mg twice
      daily. The second treatment will be pioglitazone titrated to 30mg once daily.

      The study will last a total of approximately 17 weeks, and involves three visits to the
      Clinical Research Centre at Ninewells hospital in Dundee. The first visit will be the
      longest, lasting 1.5 days, and the other two visits last one full day with a short
      preparatory visit for 30 minutes the day before.

      Multiple methods will be used to investigate the relationship between ATM, diabetes and drug
      response:

        -  Dual tracer mixed meal tests with indirect calorimetry (see Tracer Studies SOP)

        -  MRI (see MRI SOP)

        -  Blood and urine sampling (see Sample Collection SOP)

        -  Fat biopsy (see Fat Biopsy SOP)

      In summary, each individual will have three tracer studies: an initial study at baseline; a
      second after eight weeks of metformin; and a final tracer study after eight weeks of the TZD,
      pioglitazone. Tracer studies involve a standardised meal the night before the study, and
      fasting from midnight in preparation. No alcohol should be consumed for 24 hours before the
      study. On the day of the tracer study two cannulae will be inserted, one in each forearm. One
      cannula will be used to infuse a stable glucose tracer [6,6-2H2] for the duration of the
      eight hour study. After two hours of this infusion, the participant will be fed a mixed meal
      containing [U-13C] glucose (stable). The participant is observed for a further six hours,
      while the [6,6-2H2] glucose infusion continues. Throughout the tracer study, blood will be
      taken from the second cannula at multiple time-points, to allow for measurement of glucose
      (including the tracers), insulin, C-peptide, glucagon, glucagon-like peptide 1 (GLP-1) and
      nonesterified fatty acids (NEFAs). A total of 150ml of blood will be taken during the tracer
      study. Urine is collected in two phases (before and after the meal) during the tracer study,
      for the measurement of glucose excretion. Indirect calorimetry will be used for twenty minute
      episodes at several time-points to measure substrate utilisation during the study. This
      involves the participant wearing a "hood" which is lightweight, and has a see-through visor.
      All of these measurements will enable us to model glucose fluxes in the participant and
      calculate indices of insulin sensitivity. Repetition of the tracer studies on two
      anti-hyperglycaemic agents will provide comparison of these indices on and off treatment.

      At the baseline visit an MRI, blood sampling and fat biopsy will take place during the half
      day visit before the tracer study. This will allow us to assess fat distribution using MRI
      and obtain adipose tissue to carry out lab-based studies to assess the adipocyte function and
      response to metformin and pioglitazone. Blood samples are taken for "safety bloods" (i.e. to
      ensure normal renal function and HbA1c <48mmol/mol) but also for future DNA analysis, to
      confirm the diagnosis in the A-T group, and to check for carrier status of the controls.

      Visits two and three involve a full day at the clinical research centre (CRC) for a tracer
      study. On the day before the tracer, a short half-hour visit to obtain "safety bloods" (in
      this case, to check renal function) and provide the standardised meal is necessary to prepare
      for the tracer study the following day.

      If this study can clinically confirm the hypothesis that individuals with ATM-deficiency
      respond well to either metformin or pioglitazone, and individuals show marked improvement in
      insulin resistance while taking either study drug, this study could direct clinical
      decision-making in the care of patients with A-T and fatty liver / insulin resistance.

      In conjunction with the clinical studies cell experiment studies will be carried out on
      induced pluripotent stem cell (IPSC) derived hepatocytes from individuals with A-T, to assess
      drug response at a cellular level. This will be a collaboration with the Sanger Institute in
      Cambridge, where they have already developed IPSC-derived hepatocytes from the blood of A-T
      patients. These cells will be used to create a drug response model at a cellular level. These
      cell lines are not from our recruited patients directly, but serve as a cellular model of
      A-T. However, we will offer the A-T group the chance to donate blood to the INSIGNIA study,
      run by the Sanger Institute, which is a study focused on the investigation of patterns of
      mutations (signatures) in inherited and other progressive genetic diseases (please see
      INSIGNIA PIS and consent forms). This is optional and taking part in RAMP does not commit
      those with A-T to contributing to INSIGNIA.
    

Intervention name(s): Metformin; Pioglitazone
Intervention type(s): Drug; Drug
Intervention description(s): Metformin will be given orally, regularly for eight weeks. Dose starts at 500mg once daily for one week, increasing by 500mg per week, to final dose of 1000mg twice daily.; Pioglitazone will be given orally, regularly for eight weeks. Dose starts at 15mg once daily and after one week increases to 30mg once daily.
Other intervention name(s): Glucophage; Actos
Intervention MeSH terms: Metformin; Pioglitazone
Allocation: Non-Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment