Chronic Disease of Diabetes

Diabetes is a chronic disease caused by defects in insulin secretion, leading to increased blood glucose levels. It can be classified into two types: Type 1 Diabetes (T1D), caused by a deficiency of insulin, and Type 2 Diabetes (T2D), caused by insulin resistance. T2D is the most common type of diabetes, accounting for at least 90% of all cases. According to the International Diabetes Foundation, the number of people with T2D was found to increase in most countries as of 2017 (IDF, 2018).

Approximately, 352 million people were at risk of developing the disease. The number of people suffering with T2D was predicted to increase from 285 million to 438 million in another 20 years (Semiz et al., 2013).

Currently, T2D can be treated by modifying the lifestyle through exercise, diet, and the use of oral antidiabetic drugs (OAD). The treatment aims to lower the blood glucose level to normal levels. If lifestyle modification fails to treat T2D, a pharmacological method is used instead. Pharmacogenetics is a branch of pharmacology concerned with the variability in drug response due to genetic factors. In patients treated with OADs, a significant fraction of genetic variability was noticed in genes related to the response of OADs. The interindividual variability can be determined by single nucleotide polymorphisms (SNPs) (Pollastro et al., 2015). Hence, the aim of pharmacogenetics is to link the genetic variability related to the activity of OADs.

T2D can be treated with sulfonylureas, biguanides, thiazolidinediones (TZDs), insulin, amylin analogues, ß-glucosidase inhibitors, dipeptidyl peptidase 4 (DPP4) inhibitors, and incretin hormone mimetics. The most commonly used OAD classes are sulfonylureas, biguanides, and thiazolidinediones.

The most common sulfonylurea agents are tolbutamide, gliclazide, glibenclamide, and glimepiride (Distefano and Watanabe, 2010). Sulfonylureas stimulate the secretion of insulin from pancreatic ß-cells by binding to the sulfonylurea receptor (SUR1). The secretion of glucose-stimulated insulin pancreatic ß-cells is modulated by the ATP-dependent potassium channel (KATP) composed of SUR1, which are encoded by the KCNJ11 and ABCC8 genes. Binding of sulfonylureas to the KATP channel closes the channel, depolarizes the cell, leading to the opening of voltage-gated Ca2+ channels. An increase in intracellular calcium triggers the release of insulin from the ß-pancreatic cells (Semiz et al., 2013).

It was found that mutations in KCNJ11 and ABCC8 genes cause neonatal diabetes mellitus. In KCNJ11, the K (Lys) allele at the common Glu23Lys polymorphism was related to an increased risk of T2D (Huang and Florez, 2011). Mutations in KCNJ11 lead to the continual opening of the KATP channel which inhibits the production of insulin by the pancreatic ß-cells (Distefano and Watanabe, 2010).

Biguanides

Metformin is a commonly used biguanide drug as a first-line treatment for T2D. The main role of metformin is the inhibition of hepatic glycogenesis. Besides, it also increase insulin sensitivity, improve glucose uptake, and decrease gastrointestinal glucose absorption. Metformin activates adenosine monophosphate-activated protein kinase (AMPK) by inhibiting mitochondrial complex 1 (Semiz et al., 2013). The effect of metformin on glucose is not affected by genetic variants in genes encoding metabolizing enzymes because metformin is not metabolized in the liver, but it is excreted in the urine (Pollastro et al., 2015). The figure shows the main proteins involved in the metabolism of OADs.

The transport of metformin is mediated by carrier proteins. The hepatic uptake and renal uptake of metformin are facilitated by the Organic Cation Transporter 1 (OCT1), encoded by the SLC22A1 gene, and Organic Cation Transport 2 (OCT2), encoded by SLC22A2 respectively. OCT1 is expressed in the liver, and OCT2 is expressed mainly in the kidney. The excretion of metformin into urine is facilitated by Multidrug and Toxin Extrusion Transporter 1 (MATE1), encoded by SLC47A1, which is found in the renal proximal tubule cells (Semiz et al., 2013). Variants in SLC22A1 of OCT1 were linked to variation in its response. Gene polymorphism in the transporters may be linked to the variation in the drug response (Dawed et al., 2016).

Thiazolidinediones

Thiazolidinedione increases insulin sensitivity in T2D patients by binding to peroxisome proliferator-activated receptors (PPRAs). There are three types of PPARs: PPAR-?, PPAR-?, and PPAR-?. Thiazolidinediones (TZD) are highly specific for PPAR-?, which regulates the transcription of genes involved in the metabolism of glucose and lipids (Jermolovicius et al., 2017). It increases adipogenesis and fatty acid uptake. This results in a reduced amount of fatty acids and lipid available in muscle and liver, which increase the insulin sensitivity of T2D patients (Semiz et al., 2013). Protein products responsible for the absorption of water and sodium are encoded by the AQP2 and SLC12A1 genes. Variants in these genes may cause adverse effects (Brunetti et al., 2017). The table summarizes the responses of antidiabetic drugs and the genes involved in the response.

Table: Responses of Antidiabetic Drugs and Genes Involved (Huang and Florez, 2011)

Drugs
Mechanism
Main Role
Potential Adverse Effects
Genes Affecting Response

Sulfonylureas
ATP-Dependent K Channel Inhibition
Increase Insulin Secretion
Decrease Glucagon Secretion
Hypoglycemia, Allergic Reaction to Sulfa Drugs
CYP2C9, ABCC8, KCNJ11, TCF7L2

Metformin
AMP-Dependent Kinase (AMPK) Activation
Increase Insulin Sensitivity
Decrease Hepatic Gluconeogenesis
Lactic Acidosis
SLC22A1, SLC47A1, ATM

Thiazolidinediones
Enhance PPAR? binding to its DNA Response Element
Increase Glucose Uptake by Skeletal Muscle
Increase Lipolysis
Decreased Hepatic Glucose Output
Fluid overload, congestive heart failure, fractures, hepatotoxicity, bladder cancer
ADIPOQ, CYP2C8
 
Insulin
Insulin/IGF-1 receptor pathway
Increase in tissue glucose uptake
Hypoglycemia
 
Meglitinides
ATP-dependent K channel inhibition
Increase in insulin secretion
Decrease in glucagon secretion
Hypoglycemia
 
?-Glucosidase inhibitors
Inhibit pancreatic ?-amylase and intestinal ?-glucosidase
Glucose absorption by GI tract
Hypoglycemia
 
Amylin minetics
Amylin receptor pathway
Decrease in gastric emptying rate
Increase in insulin secretion
Decrease in glucagon secretion
Hypoglycemia
 
GLP-1 mimetics
GLP-1 receptor pathway
? Glucose-dependent insulin secretion
Decrease in gastric emptying rate
? Satiety
Decrease in glucagon secretion
Nausea, vomiting, hypoglycemia, acute pancreatitis, angioedema, anaphylaxis
 
DPP-IV inhibitors
GLP-1 receptor pathway
? Glucose-dependent insulin secretion

1. Types of diabetes. Retrieved from International Diabetes Federation web : https://www.idf.org/aboutdiabetes/what-is-diabetes/types-of-diabetes.html
2. Brunetti, A., Chiefari, E. & Foti, D. P. (2017). Pharmacogenetics in type 2 diabetes: still a conundrum in clinical practice. Expert Review of Endocrinology & Metabolism, 12 (3), 155-158.
3. Distefano, J. K. & Watanabe, R. M. (2010). Pharmacogenetics of Anti-Diabetes Drugs. Pharmaceuticals (Basel, Switzerland), 3 (8), 2610-2646.
4. Huang, C. & Florez, J. C. (2011). Pharmacogenetics in type 2 diabetes: potential implications for clinical practice. Genome Medicine, 3 (11), 76.
5. Jermolovicius, L. A., Cantagesso, L. C. M., do Nascimento, R. B., de Castro, E. R., dos S. Pouzada, E. V. & Senise, J. T. (2017). Microwave fast-tracking biodiesel production. Chemical Engineering and Processing: Process Intensification, 122, 380-388.
6. Semiz, S., Dujic, T. & Causevic, A. (2013). Pharmacogenetics and personalized treatment of type 2 diabetes. Biochemia Medica, 23 (2), 154.
7. Dawed, A., Zhou, K., & Pearson, E. (2016). Pharmacogenetics in type 2 diabetes: influence on response to oral hypoglycemic agents. Pharmacogenomics and Personalized Medicine, 9, 17-29.
8. Jose, C. F. (2017). Pharmacogenetics in type 2 diabetes: precision medicine or discovery tool? Diabetologia, 60, 800 - 807.

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