title: Individualized therapy for type 2 diabetes: clinical implications of pharmacogenetic data.
abstract: Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance, abnormally elevated hepatic glucose production, and reduced glucose-stimulated insulin secretion. Treatment with antihyperglycemic agents is initially successful in type 2 diabetes, but it is often associated with a high secondary failure rate, and the addition of insulin is eventually necessary for many patients, in order to restore acceptable glycemic control and to reduce the risk of development and progression of disease complications. Notably, even patients who appear to have similar requirements of antidiabetic regimens show great variability in drug disposition, glycemic response, tolerability, and incidence of adverse effects during treatment. Pharmacogenomics is a promising area of investigation and involves the search for genetic polymorphisms that may explain the interindividual variability in antidiabetic therapy response. The initial positive results portend that genomic efforts will be able to shed important light on variability in pharmacologic traits. In this review, we summarize the current understanding of genetic polymorphisms that may affect the responses of subjects with T2DM to antidiabetic treatment. These genes belong to three major classes: genes involved in drug metabolism and transporters that influence pharmacokinetics (including the cytochrome P450 [CYP] superfamily, the organic anion transporting polypeptide [OATP] family, and the polyspecific organic cation transporter [OCT] family); genes encoding drug targets and receptors (including peroxisome proliferator-activated receptor gamma [PPARG], the adenosine triphosphate [ATP]-sensitive potassium channel [K(ATP)], and incretin receptors); and genes involved in the causal pathway of T2DM that are able to modify the effects of drugs (including adipokines, transcription factor 7-like 2 (T cell specific, HMG-box) [TCF7L2], insulin receptor substrate 1 [IRS1], nitric oxide synthase 1 (neuronal) adaptor protein [NOS1AP], and solute carrier family 30 (zinc transporter), member 8 [SLC30A8]). In addition to these three major classes, we also review the available evidence on novel genes (CDK5 regulatory subunit associated protein 1-like 1 [CDKAL1], insulin-like growth factor 2 mRNA binding protein 2 [IGF2BP2], potassium voltage-gated channel, KQT-like subfamily, member 1 [KCNQ1], paired box 4 [PAX4] and neuronal differentiation 1 [NEUROD1] transcription factors, ataxia telangiectasia mutated [ATM], and serine racemase [SRR]) that have recently been proposed as possible modulators of therapeutic response in subjects with T2DM.
authors.affiliation: Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy.
authors.forename: Gaia Chiara
authors.initials: GC
authors.lastname: Mannino
authors.forename: Giorgio
authors.initials: G
authors.lastname: Sesti
mesh_terms: D054392:Adipokines / Q000235:genetics / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000235:genetics*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D054795:Incretins / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000097:blood / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance; D000078790:Insulin Secretion; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D054409:Nicotinamide Phosphoribosyltransferase / Q000235:genetics / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D019998:Racemases and Epimerases / Q000235:genetics / Q000378:metabolism; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics / Q000378:metabolism; D000071246:Uncoupling Protein 2; D012359:tRNA Methyltransferases; D000099300:Serine Racemase
chemical_list: D054392:Adipokines; D051360:Cyclin-Dependent Kinase 5; D007004:Hypoglycemic Agents; D054795:Incretins; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D007335:Insulin-Like Growth Factor II; D007473:Ion Channels; D024101:Mitochondrial Proteins; D054409:Nicotinamide Phosphoribosyltransferase; D052248:Nitric Oxide Synthase Type I; D047495:PPAR gamma; D019998:Racemases and Epimerases; D058118:Transcription Factor 7-Like 2 Protein; D000071246:Uncoupling Protein 2; D012359:tRNA Methyltransferases; D000099300:Serine Racemase; C035170:IGF2 protein, human; C526292:IRS1 protein, human; C544894:TCF7L2 protein, human; C496320:NOS1 protein, human; C495905:CDK5 protein, human; C525110:CDKAL1 protein, human