Pharmacogenetics of Type 2 Diabetes—Progress and Prospects

Abstract

Type 2 diabetes mellitus (T2D) is a chronic metabolic disease resulting from insulin resistance and progressively reduced insulin secretion, which leads to impaired glucose utilization, dyslipidemia and hyperinsulinemia and progressive pancreatic beta cell dysfunction. The incidence of type 2 diabetes mellitus is increasing worldwide and nowadays T2D already became a global epidemic. The well-known interindividual variability of T2D drug actions such as biguanides, sulfonylureas/meglitinides, DPP-4 inhibitors/GLP1R agonists and SGLT-2 inhibitors may be caused, among other things, by genetic factors. Pharmacogenetic findings may aid in identifying new drug targets and obtaining in-depth knowledge of the causes of disease and its physiological processes, thereby, providing an opportunity to elaborate an algorithm for tailor or precision treatment. The aim of this article is to summarize recent progress and discoveries for T2D pharmacogenetics and to discuss the factors which limit the furthering accumulation of genetic variability knowledge in patient response to therapy that will allow improvement the personalized treatment of T2D.

Pharmacogenetics of novel glucose-lowering drugs

“…Moreover, the difference between genotypes in individuals treated with metformin was statistically significantly larger than that in people not treated with glucose-lowering drugs ( p value for interaction <0.01) [ 3 ]. Similar reports exist of genetic variants interfering with metabolic responses to treatment with sulfonylureas and meglitinides [ 4 ].…”

The Current and Potential Therapeutic Use of Metformin—The Good Old Drug

“…Experimental and clinical studies in both healthy volunteers and diabetic patients have shown that specific groups of genes (e.g., the family of SLC genes) are involved in metformin absorption, distribution, metabolism and elimination and, as a result, may affect the pharmacological response to this drug [ 281 , 282 , 283 , 284 , 285 ]. It has also been demonstrated that the polymorphisms of many genes may increase or decrease the therapeutic response to metformin [ 286 ] The most thoroughly investigated gene was SLC22A1 encoding an organic cationic transporter 1(OCT1) which is localized in hepatocytes. OCT1 is responsible primarily for the uptake of metformin by the liver—a main target of the drug action on glucose metabolism.…”

“…OCT1 is responsible primarily for the uptake of metformin by the liver—a main target of the drug action on glucose metabolism. However, the role of SLC22A1 polymorphisms in response to metformin has not been fully clarified [ 283 , 286 , 287 ]. As has recently been demonstrated in a systematic review, which assessed the association between OCT1 polymorphisms and the biochemical and clinical outcomes in metformin users, only some of this gene’s polymorphisms were associated with the variable response to the drug [ 288 ].…”

Genetics of macrovascular complications in type 2 diabetes

“…However, the results of many pharmacogenetic studies conducted in small cohorts were not replicated in larger populations. Also, the inconsistency may be associated with the ethnicity of the population analyzed, which must be taken into account when prescribing personalized therapy[ 155 ].…”