The role of clinical response to metformin in patients newly diagnosed with type 2 diabetes: a monotherapy study

Abstract

A major predicament in certain users of metformin, which is one of the most commonly used antihyperglycemic agents for type 2 diabetes (T2DM) treatment, is the lack of appropriate response to the drug. We evaluated the role of metformin response and OCT1 (organic cation transporter1) Met420del polymorphism in a monotherapy study (metformin therapy for 12 weeks) on patients newly diagnosed with T2DM. Based on the response to metformin, patients (n = 108) were divided into two groups: responders (n = 49) and non-responders (n = 59). HbA1c levels were determined by affinity technique. The OCT1-Met420del polymorphism was genotyped by PCR-based restriction fragment length polymorphism. There was a significant association between the variable response with HbA1c and fasting blood sugar (FBS) (Wilks' λ = 0.905, p = 0.01). Responders had significantly lower HbA1c and FBS levels compared with non-responders (η (2) = 0.087, p = 0.004 for HbA1c and η (2) = 0.055, p = 0.022 for FBS). The interaction treatment-response increased the effect sizes from 32 to 58 % for HbA1c. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) values were significantly lower in the responder group than in the non-responders (η (2) = 0.067, p = 0.01 for ALT and η (2) = 0.052, p = 0.025 for AST). This observational study showed that the variant OCT1-Met420del may be more effective on plasma glucose than HbA1c. The variable response could account for a significant proportion of the variance in HbA1c levels observed following treatment with metformin. Metformin shows a significantly greater effect on ALT and AST in responders than in non-responders.

The variant organic cation transporter 2 (OCT2)–T201M contribute to changes in insulin resistance in patients with type 2 diabetes treated with metformin

“…The synthetic biguanide is a good substrate for organic cation transporters (OCTs) [8]. OCTs mediate electrogenic transport of small cationic compounds, including endogenous compounds (e.g., serotonin and dopamine), and clinically important drugs (e.g., metformin) [8,9].…”

“…The synthetic biguanide is a good substrate for organic cation transporters (OCTs) [8]. OCTs mediate electrogenic transport of small cationic compounds, including endogenous compounds (e.g., serotonin and dopamine), and clinically important drugs (e.g., metformin) [8,9]. OCT2 is a member of the OCT family, which is mainly expressed in the basolateral membrane of the proximal tubule epithelial cells where it mediates the entry of metformin and other cationic compounds into the renal epithelium [6,8].…”

Allele frequency and genotype distribution of a common variant in the 3´-untranslated region of the SLC22A3 gene in patients with type 2 diabetes: Association with response to metformin

“…[78] In general, the mechanisms of metformin action include reduction of hepatic glucose production, increased glucose uptake in skeletal tissue, suppression of the intestinal absorption of glucose, and improvement of insulin sensitivity. [910] Metformin reduces triglyceride (TG) levels, free fatty acids, and low-density lipoprotein (LDL) in plasma and increases high-density lipoprotein (HDL). [11] Due to slight hydrophobic property, metformin needs a transporter to cross plasma membrane into the cell.…”

Drug Transporters and Na+/H+Exchange Regulatory Factor PSD-95/Drosophila Discs Large/ZO-1 Proteins

“…OCT1 and OCT2 are drug transporters of emerging clinical significance because of their potential influence on drug disposition and response. For example, OCT1 is an important factor in the pharmacotherapy of diabetes and chronic myeloid leukemia (Grinfeld et al, 2013;Koren-Michowitz et al, 2014;Mahrooz et al, 2015). OCT1 is thought to be liver specific; it is predominately expressed on basolateral/ sinusoidal membranes of hepatocytes and mediates drug uptake (Gorboulev et al, 1997;Zhang et al, 1997).…”