Metformin Gastrointestinal Intolerance: Measurement of Mitochondrial Complex I
Condition: Diabetes Mellitus, Type 2; Metformin Adverse Reaction
MeSH terms: Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Early Phase 1

Summary: 
      Metformin is associated with a high degree of gastrointestinal intolerance, which limits the
      effective use of the medication. It is proposed to be an inhibitor of liver mitochondrial
      glycerophosphate dehydrogenase which results in partial blockade of mitochondrial complex 1
      and inhibition of metabolism of lactate to pyruvate. There is also evidence that it is
      accumulated in gastrointestinal cells, and that there are certain genotypes associated with
      inclusion or lack of exclusion of the metformin from these cells. To validate this hypothesis
      investigators propose to give metformin after a standard meal test to see if there is the
      accumulation of lactic acid in those with gastrointestinal intolerance to metformin, compared
      to those without intolerance, and to determine if these elevations of lactic acid and GI
      symptoms are associated with genetic predispositions.

      Aims:

        1. To determine if the GI intolerance to metformin is associated with post meal elevations
           of lactic acid.

           a. The test will measure the inhibition of mitochondrial complex 1 levels of lactate to
           pyruvate compared with non- intolerant subjects.

        2. To determine if individuals with gastrointestinal symptoms and elevated lactate/pyruvate
           ratios have genetic variation in the organic cation transporters.
    

Detailed description: 
      Metformin is the primary drug of choice for management of type 2 diabetes mellitus. Most
      recent evidence suggest that the drug is a noncompetitive inhibitor of mitochondrial
      glycerophosphate dehydrogenase which modifies mitochondrial complex 1 in the liver, reducing
      the generation of NADH, increasing the ratio of lactate to pyruvate, and reducing
      gluconeogenesis. Metformin which is a guanidine/ biguanide analog is not metabolized in vivo
      and is cleared by the kidney. It has a limited degree of mitochondrial inhibition, and only
      becomes toxic when serum levels accumulate in renal failure. Other guanidine analogs, such as
      fenformin or galegine, however may be associated with irreversible complete mitochondrial
      blockade and lactic acidosis.

      The incidence of gastrointestinal intolerance to the drug can range between 10% and 30%. It
      is postulated that the gastrointestinal enterocyte may accumulate the metformin. It is
      postulated that metformin uptake and accumulation may be exacerbated in those with genetic
      predispositions for certain organic transporters which are involved in the uptake and removal
      of metformin in cells. Metformin appears to be taken up from the intestine by plasma
      monoamine transporter (PMAT; SLC29A4), organic cation transporter 1 (OCT1; SCLC22A1) and
      organic cation transporter 3 (OCT3; SLC22A3) and actively removed from target tissues by
      multi-antimicrobial extrusion protein 1 (MATE1; SLC47A1) and eliminated by the urinary
      multi-antimicrobial extrusion protein 2 (MATE2; SCL47A2). Although certain genotypes are
      associated with a high incidence of intolerance, the gene low gene frequency does not explain
      the high degree of intolerance in the population.

      ii) Innovation: The plan is to develop a test to evaluate whether there is accumulation of
      lactic acid after a therapeutic dose of metformin and whether the levels of lactic acid are
      higher in subjects with GI intolerance than those not intolerant. The hypothesis is that
      there is increased generation of lactic acid in those intolerant individuals, independent of
      glucose lowering effect on liver metabolism. Investigators propose to measure the generation
      of lactate/pyruvate (L/P, mitochondrial complex 1), in those with and without clinically
      known metformin gastrointestinal symptoms. Investigators will correlate gastrointestinal
      symptoms with L/P ratios. Investigators will also evaluate for genomic susceptibility for the
      origin transporters with comparison to the metformin tolerance test generation of lactic
      acid.

      iii) Approach: Investigators wish to develop a pilot project of 24 subjects who will complete
      the protocol. Subject will be seen in the Endocrinology clinic of St. Louis University, and
      investigators will recruit 12 subjects who have clinical symptoms of gastrointestinal
      symptoms (diarrhea or bloating) and 12 subjects who are tolerant. Subjects will be randomized
      to receive a fasting standard dose of 1000 mg brand metformin (Glucophage) or comparable
      placebo on day one and then the alternate medicine on a second day. The study drug will be
      given with Diabetasourse meal (standard meal) which will provide carbohydrates to challenge
      the mitochondrial system [2]. Bloods for glucose, L/P, will be obtained at 0, 30 60 90 and
      120 minutes. Symptoms of gastrointestinal effects will be documented by a Likert type
      questionnaire. Outcomes will be 1) the effect of metformin vs. placebo on the meal tolerance
      glucose levels 2) the effect of metformin on post meal challenge levels of L/P, in intolerant
      vs. tolerant individual and 3) the correlation of gastrointestinal symptoms with changes in
      L/P. From animal data, metformin causes a 2 fold increase in lactic acid at 60 minutes. In
      our laboratory with a normal reference lactic acid of 1.0 mmol/L and a SD=0.725. Twelve pairs
      would be sufficient for a pilot study to determine a difference at an alpha of 0.05 and beta
      of 0.80.
    

Intervention name(s): Metformin; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Metformin 1000mg once; Sugar pill manufactured to mimic metformin 1000mg
Other intervention name(s): Glucophage
Intervention MeSH terms: Metformin
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: Randomized, double blinded, placebo controlled crossover trial
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Screening