Pharmacogenetics of Oral Antidiabetic Drugs

Abstract

Oral antidiabetic drugs (OADs) are used for more than a half-century in the treatment of type 2 diabetes. Only in the last five years, intensive research has been conducted in the pharmacogenetics of these drugs based mainly on the retrospective register studies, but only a handful of associations detected in these studies were replicated. The gene variants in CYP2C9, ABCC8/KCNJ11, and TCF7L2 were associated with the effect of sulfonylureas. CYP2C9 encodes sulfonylurea metabolizing cytochrome P450 isoenzyme 2C9, ABCC8 and KCNJ11 genes encode proteins constituting ATP-sensitive K+ channel which is a therapeutic target for sulfonylureas, and TCF7L2 is a gene with the strongest association with type 2 diabetes. SLC22A1, SLC47A1, and ATM gene variants were repeatedly associated with the response to metformin. SLC22A1 and SLC47A1 encode metformin transporters OCT1 and MATE1, respectively. The function of a gene variant near ATM gene identified by a genome-wide association study is not elucidated so far. The first variant associated with the response to gliptins is a polymorphism in the proximity of CTRB1/2 gene which encodes chymotrypsinogen. Establishment of diabetes pharmacogenetics consortia and reduction in costs of genomics might lead to some significant clinical breakthroughs in this field in a near future.

Using Personalized Medicine in the Management of Diabetes Mellitus

“…Polymorphisms in CYP2C9 were shown to be one of the reasons behind the variability in elimination rates for most SUs . Two CYP2C9 reduced function variants of interest, CYP2C9*2 (rs1799853) and CYP29*3 (rs1057910), are associated with decreased clearance and increased area under the curve (AUC) of SUs in healthy volunteers …”

Type 2 diabetes mellitus: Clinical aspects of genetics, nutrigenetics, and pharmacogenetics

“…Генетический вклад в ответ на прием ПСМ выявлен при оценке полиморфизмов генов, включенных в процесс секре-ции инсулина -гена ABCC8, кодирующего субстрат рецептора сульфонилмочевины SUR1, и гена KCNJ11, кодирующего субъе-диницу KIR6.2 зависимых от АТФ калиевых каналов (данные де-терминанты важны также при рассмотрении неонатального СД и моногенных форм СД-2). При этом у носителей аллеля риска ге-на TCF7L2 отмечается менее выраженный терапевтический ответ на прием ПСМ, в то время как аллели риска развития СД-2 генов ABCC8/KCNJ11 ассоциируются с более сильным ответом [31,36]. Выявлены и генетические локусы, определяющие фармакологи-ческий ответ при приеме глинидов [37].…”

Polimorfismo Val/Met en gen OCT1 de respuesta a metformina en muestras de Lima y Puno. Enfoque farmacogenético de la diabetes

“…La metf ormina mejora la sensibilidad y disminuye la resistencia a la insulina presente en esta patología. Asimismo, ti ene efectos benefi ciosos como la disminución de los niveles de lípidos, prevención de algunas complicaciones vasculares y mínimo riesgo de producir hipoglucemia (11) . La acción principal de la metf ormina es disminuir la producción de glucosa hepáti ca inhibiendo la gluconeogénesis sin producir hipoglucemia.…”

“…A nivel periférico, en los tejidos musculares y grasos, facilita el transporte de glucosa mediante el aumento de la acti vidad ti rosina quinasa en los receptores de insulina y opti mizando la función de los transportadores. Además, no se metaboliza en el cuerpo, siendo efi cientemente excretado en la orina (11,12) . Los transportadores de cati ones orgá-nicos (OCTs), proteínas de la familia de genes SLC22 (solute carrier family 22), movilizan moléculas polares a través de la membrana celular en disti ntos órga-nos, y han sido implicados en la distribución de la metf ormina.…”