Organic Cation Transporter 1 (OCT1), on Response to Metformin in Healthy Subjects
Condition: Other Conditions That May Be A Focus of Clinical Attention
Study type: Interventional
Phase: Phase 4

Summary: 
      Specific Objectives:

        -  To determine if individuals who carry a decreased or non-functional variant of OCT1
           exhibit differences in the pharmacokinetics of metformin in comparison to individuals
           who carry the common allele.

        -  To determine if individuals who carry the decreased or non-functional variants exhibit
           differences in the response to metformin in comparison to individuals who carry the
           common allele.
    

Detailed description: 
      In the proposed studies, we will address two questions:

      •Do individuals who carry one of OCT1 variants with reduced or no function exhibit
      differences in the pharmacokinetics of metformin in comparison to individuals who carry the
      common allele?

      Compared to wild type mice, Oct1-/- mice have reduced metformin distribution to the liver and
      intestine. We expect a similar pattern between persons who carry the variant OCT1 allele and
      those who carry the common allele. This effect might be reflected by a difference of Tmax or
      Cmax after oral administration of metformin. Other differences in metformin pharmacokinetic
      properties such as volume of distribution, half life and clearance may also be evident.

      •Do individuals who carry the decreased or non-functional variants exhibit differences in the
      response to metformin in comparison to individuals who carry the common allele? Specially, we
      will test the hypothesis that the OCT1-expressing tissues are target organs for metformin,
      and that individuals with the variant transporters may have reduced metformin uptake into
      these sites (is this the correct meaning?) and therefore a reduced drug response to
      metformin.

      In this study, we will evaluate metformin pharmacokinetics and glucose metabolic effects in
      healthy subjects rather than in patients with type 2 diabetes. Our rationale is as follows.
      The hepatic glucose production in diabetic patients is abnormally increased. Metformin
      decreases fasting blood glucose concentration by reducing hepatic glucose production and
      improving glucose utilization. However, the fasting blood glucose concentration is not
      decreased by metformin in non-diabetics who have a normal hepatic glucose production. It was
      suggested that the glucose-lowering effect of metformin was difficult to demonstrate in
      non-diabetics unless glucose concentrations were artificially raised. Although there are
      studies showing that metformin improves the glucose tolerance both in non-diabetics and
      diabetics, the results for non-diabetics have been inconsistent, depending on the variable
      experimental condition. Variation in OCT1 expression and activity may be one of those
      variables, and the time points for blood sampling after drug and glucose (meal) intakes may
      also be important to observe the glucose-lowering effect [16]. In this study, we employ a
      similar study design as that reported [16] to observe the glucose-lowering effect by
      metformin in healthy subjects. Before and after metformin administration, oral glucose
      tolerance test (OGTT) will be conducted. We expect a difference of glucose tolerance between
      different OCT1 genotypes, under the hypothesis that individuals with different OCT1 genotypes
      have different metformin concentrations in the target tissues, and hence have different
      glucose uptakes into (and so utilization in) the target tissues (primary muscle and liver).

      In non-diabetic healthy subjects, metformin significantly attenuated the rise in immediate
      postprandial insulin levels. In this study, we will also determine insulin levels after
      glucose administration. With metformin treatment, we expect to observe significant difference
      in post-glucose-administration insulin levels between individuals with different OCT1
      genotypes.

      When mice were given metformin, the blood lactate concentration significantly increased in
      the wild-type mice, whereas only a slight increase was observed in Oct1-/- mice. This is
      consistent with our hypothesis that OCT1 is a determinant of metformin effect on glucose
      utilization. It will be interesting to compare plasma lactate concentrations after metformin
      treatment between individuals with different OCT1 genotypes.

      Metformin can improve lipid metabolism in obese and diabetics patients, which is reflected by
      the reduced plasma levels of free fatty acid, cholesterol, and triglycerides. However, in
      this study with a single dose of metformin, it may not be possible to observe those effects
      in healthy subjects, although the corresponding concentrations will be measured.
    

Intervention name(s): Metformin
Intervention type(s): Drug
Intervention description(s): 2 doses of Metformin Day 1 1000mg, Day 2 850 mg
Other intervention name(s): Dimethylguanylguanidine; Glucophage
Intervention MeSH terms: Metformin
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Keywords: Healthy controls