Chronic Disease of Diabetes

Published: 2021-06-25 17:35:04
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Diabetes is a chronic disease caused by defects in insulin secretion leading to increased blood glucose level. It can be classified into two; Type 1 Diabetes (T1D), caused by deficiency of insulin and Type 2 Diabetes (T2D), caused by insulin resistance. T2D is the common types of diabetes that accounts for at least 90% of all cases of diabetes. According to the International Diabetes Foundation, the number of people with T2D was found to increase in most countries as in 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).Presently, T2D can be treated by modification of lifestyle through exercise and diet and using oral antidiabetic drugs (OAD). The treatment aims to lower the blood glucose level to normal levels. If modification of lifestyle fails to treat T2D, pharmacological method is used instead.  Pharmacogenetic 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 oral antidiabetic drugs (OAD). 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.PharmacogeneticsT2D can be treated with sulfonylureas, biguanides, thiazolidinediones (TZDs), insulin, amylin analogues, ?-glucosidase inhibitors, dipeptidyl peptidase 4 (DPP4) inhibitors and incretin hormone mimetics. The most commonly used OAD classes are sulfonylureas, biguanides, and thiazolidinediones.SulfonylureasThe most common sulfonylurea agents are tolbutamide, gliclazide, glibenclamide, and glimepiride (Distefano and Watanabe, 2010). Sulfonylureas stimulates the secretion of insulin from pancreatic ?-cells by binding to sulphonylurea receptor (SUR1). The secretion of glucose-stimulated insulin pancreatic ?-cells is modulated by ATP-dependent potassium channel (KATP) composed of SUR1 which are encoded by the KCNJ11 and ABCC8 gene.  Binding of sulfonylureas to KATP channel closes the channel, depolarizes the cell, leading to opening of voltage-gated Ca2+ channels. An increase in intracellular calcium triggers the release of insulin from the ?-pancreatic cells (Semiz et al., 2013).It was found that mutations in KCNJ11 and ABCC8 genes causes neonatal diabetes mellitus. In KCNJ11, the K (Lys) allele at the common Glu23Lys polymorphism was related to increased risk of T2D (Huang and Florez, 2011). Mutations in KCNJ11 leads to continual opening of the KATP channel which inhibits the production of insulin by the pancreatic ?-cells (Distefano and Watanabe, 2010).BiguanidesMetformin is a commonly used biguanide drug as first line treatment for T2D. The main role of metformin is inhibition of hepatic glycogenesis. Besides, it also increases insulin sensitivity, improves glucose uptake and decreases 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). Figure shows the main proteins involved in metabolism of OADs.The transport of metformin is mediated by carrier proteins. The hepatic uptake and renal uptake of metformin are facilitated Organic cation transporter 1 (OCT1), encoded by 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 was linked to the variation in its response. Gene polymorphism in the transporters may be linked to the variation in drug response (Dawed et al., 2016).ThiazolidinedionesThiazolidinedione increases insulin sensitivity in T2D patients by binding to peroxisome proliferator-activated receptors (PPRAs). There are three types of PPARs: PPAR-?, PPAR-?, and PPAR-?.  TZD is highly specific for PPAR-? which regulates the transcription of genes involved in metabolism of glucose and lipid (Jermolovicius et al., 2017). It increases adipogenesis and fatty acid uptake. This results in reduced amount of fatty acids and lipid available in muscle in liver which increases the insulin sensitivity of the patient to T2D (Semiz et al., 2013). Protein products responsible for absorption of water and sodium are encoded by AQP2 and SLC12A1 genes. Variants in these genes may cause adverse effects (Brunetti et al., 2017). Table summarizes the responses of antidiabetic drugs and genes involved in the responseTable: Responses of antidiabetic drugs and genes involved (Huang and Florez, 2011)DrugsMechanismMain rolePotential adverse effectsGenes affecting response SulfonylureasATP-dependent K channel inhibitionIncrease insulin secretionDecrease glucagon secretionHypoglycemia,allergic reaction to sulfa drugsCYP2C9, ABCC8, KCNJ11, TCF7L2 MetforminAMP-dependent kinase (AMPK) activationIncrease insulin sensitivityDecrease hepatic gluconeogenesisLactic acidosisSLC22A1, SLC47A1, ATM ThiazolidinedionesEnhance PPAR? binding to its DNA response elementIncrease glucose uptake by skeletal muscleIncrease lipolysisDecrease hepatic glucose outputFluid overload, congestive heart failure, fractures, hepatotoxicity,bladder cancerADIPOQ, CYP2C8 InsulinInsulin/IGF-1 receptor pathwayIncrease tissue glucose uptakeHypoglycemia– MeglitinidesATP-dependent K channel inhibitionIncrease insulin secretionDecrease glucagon secretionHypoglycemia– ?-Glucosidase inhibitorsInhibit pancreatic ?-amylase and intestinal ?-glucosidaseGlucose absorption by GI tractHypoglycemia– Amylin mineticsAmylin receptor pathwayDecrease gastric emptying rateIncrease insulin secretionDecrease glucagon secretionHypoglycemia– GLP-1 mimeticsGLP-1 receptor pathway? Glucose-dependent insulin secretionDecrease gastric emptying rate? SatietyDecrease glucagon secretionNausea, vomiting, hypoglycemia, acute pancreatitis,angioedema, anaphylaxis– DPP-IV inhibitorsGLP-1 receptor pathway? Glucose-dependent insulin secretion 

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