Wednesday, May 23, 2018

Role of DPP4 in obesity

Dipeptidyl peptidase 4 (DPP4) is an ubiquitous enzyme that regulates incretins (a hormone that stimulates insulin secretion). DPP4 is mainly secreted by endothelial cells and acts as a regulatory protease for cytokines, chemokines, and neuropeptides involved in inflammation, immunity, and vascular function. DPP4 (also known as adenosine deaminase binding protein), is a serine exopeptidase able to inactivate various oligopeptides through the removal of N-terminal dipeptides. Human white preadipocyte and adipocyte cells express DPP4 in high amounts. In humans, the DPP4 gene is located on chromosome 2q23, encoding a protein of 766 amino acids.

DPP4 degrades incretin peptides (e.g. GLP1/glucagon-like peptide 1) and is known for its regulatory effect in glucose metabolism [1]. Recent study found a connection of DPP4 with obesity and the metabolic syndrome or insulin resistance. DPP4 expression and release are higher in obese patients with metabolic syndrome and type 2 diabetes. Researches on DPP4 knockout mice revealed that absence of this enzyme improves glycemic control and leads to reduced fat mass which made DPP4 inhibitors promising candidates for treating human Type 2 diabetes (T2DM). So DPP4 inhibitors are in clinical use as antidiabetic drugs to improve glycemic control by stimulating pancreatic insulin secretion and suppressing glucagon production. Recent research found that adipocytes release DPP4 in a differentiation-dependent manner. Circulating DPP4 concentrations are increased in obese subjects and correlate with fasting plasma insulin, leptin, and adipocyte size in subcutaneous adipose tissue (SAT). DPP4 overexpression in visceral adipose tissue (VAT) is a marker of adipose tissue inflammation, which is known to be associated with insulin resistance and the metabolic syndrome [2].

Several DPP4 inhibitors (vildagliptin, sitagliptin, saxagliptin, linagliptin, and alogliptin) have been launched in the market and are now being used for the treatment of T2DM. All of them have proved efficacy in glycemic control with impressive safety and tolerance profiles. Gliptins (small molecular inhibitors of the peptidase DPP4) can be used as monotherapy or in combination with other oral agents (in dual or triple therapy) and even with insulin [3]. The adipose tissue is a major endocrine and energy storage organ that plays an important role in metabolic systems and insulin action which make this a target for another class of antidiabetics, the glitazones. DPP4 plays a functional role within adipose tissue, because DPP4 inhibition has been seen to prevent adipose tissue inflammation and development of glucose intolerance in high fat diet induced obesity in mice.

References:

1.https://www.hindawi.com/journals/bmri/2015/816164/

2.http://care.diabetesjournals.org/content/36/12/4083

3.https://www.nature.com/articles/srep23074

Wednesday, February 28, 2018

Aspirin: The wonder drug

Aspirin or salicyclate is a non-steroidal anti-inflammatory drug that works as a wonder drug. Its various aspects are:

1. Inhibition of Prostaglandin Synthesis and Antithrombotic action: Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the activity of the enzyme now called cyclooxygenase (COX) which leads to the formation of prostaglandins (PGs) that cause inflammation, swelling, pain and fever.The predominant product of cyclooxygenase in platelets is thromboxane A2 that is necessary for platelet aggregation.

The antithrombotic action of aspirin (acetylsalicylic acid) is due to inhibition of platelet function by acetylation of the platelet cyclooxygenase (COX) at the functionally important amino acid serine at position 529. This prevents the access of the substrate (arachidonic acid) to the catalytic site of the enzyme at tyrosine and results in an irreversible inhibition of platelet-dependent thromboxane formation. Aspirin is an approximately 150- to 200-fold more potent inhibitor of the (constitutive) isoform of the platelet enzyme (COX-1) than the (inducible) isoform (COX-2) which is expressed by cytokines, inflammatory stimuli, and some growth factors [1].

2. Ischemic stroke prevention: Aspirin reduces the incidence of recurrent myocardial infarction and stroke. It also reduces significantly the incidence of a first nonfatal myocardial infarction. Aspirin works by inhibiting platelet function (platelets are the tiny blood cells that trigger blood clotting). Thromboxane B2 (TxB2) is an indicator of platelet activation that drops as platelet function is inhibited by aspirin during heart attack and stroke [2].

3. Aspirin reduces risk of pre-eclampsia: Pre-eclampsia and other hypertensive disorders of pregnancy are leading causes of maternal and infant illness and death globally. Such disorders are estimated to cause 76,000 maternal and 500,000 infant deaths each year, according to the Pre-eclampsia Foundation. Pre-eclampsia is characterized by a sudden increase in blood pressure and protein in the urine, which can occur after the 20th week of pregnancy and often results in pre-term birth [3]. It can lead to eclampsia, renal or liver failure, cardiac, pulmonary and other maternal health complications. Low-dose aspirin (81 mg) initiated in early pregnancy is an efficient method of reducing the incidence of preeclampsia and IUGR (intrauterine growth restriction). Preeclampsia is associated with an imbalance of increased thromboxane and decreased prostacyclin and an abnormal increase of lipid peroxides (lipid peroxides are toxic compounds that damage cells and inhibit prostacyclin synthesis) [4]. The protective effect of aspirin is mediated by a decrease in thromboxane A2 production without a reduction in prostacyclin production, which thus prevents the vasoconstriction and coagulation problems that are characteristic of preeclampsia.

Though aspirin has several health benefits, combining this drug with other anticoagulant drug (ibuprofen or heparin) may result into internal/gastrointestinal bleeding that could be life threatening.