Metformin Gastrointestinal Intolerance: Measurement of Mitochondrial Complex I

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.

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.

Eligibility Criteria:
Inclusion Criteria:

1. Diabetes mellitus
2. Tolerance to meformin
3. Intolerance to metformin

Exclusion Criteria:

1. Exclusion: Pregnant or nursing mothers
2. Those not competent to provide informed consent
3. Known systemic allergy (not intolerance) to metformin
4. Congestive heart failure NYHA class III-IV
5. Renal impairment,EGFRr\<45ml/min
6. Liver cirrhosis