Statement of significance:
In 2021, the International Diabetes Federation (IDF) predicted a five-fold increase in the worldwide adult population of diabetes mellitus to 783 million in 2045; of which type II diabetes mellitus (T2DM) is said to account for approximately 90% of all cases. T2DM is characterized as a chronic disease and is diagnosed with increased levels of blood glucose or hyperglycemia. Since no cure exists, efforts to control and treat T2DM have escalated. Treatment with glucagon-like peptide-1 receptor (GLP-1R) agonists have dramatically transformed patient care guidelines for T2DM. In comparison to the other anti-hyperglycemic medications, GLP-1R agonists have established an increased capability to target directly or indirectly six out of the eight core defects associated with T2DM, also portraying beneficial cardiovascular and renal outcomes. The focus of research thus needs to shift from investigating the pharmacological effects of GLP-1R agonists, to understanding the underlying molecular mechanisms. In this exploratory study, we aimed to assess the effect of treatment with GLP-1R agonists on the urinary peptidome of T2DM patients, in an untargeted peptidomics approach. The urinary peptides identified indicate potential effect of GLP-1R agonists on reduction of insulin resistance and inflammation in the context of prevention, delaying the progression and management of T2DM.
Introduction
In 2021, the International Diabetes Federation predicted a five-fold increase in the worldwide adult population of diabetes mellitus, from 150 million in 2000[1] to 783 million in 2045[2]; of which type II diabetes mellitus (T2DM) is said to account for approximately 90% of all cases[3]. T2DM is characterized as a chronic disease[4] and is diagnosed with increased levels of blood glucose or hyperglycemia[5]. T2DM has been associated with macrovascular complications, such as atherosclerosis, myocardial infarction and diabetic foot syndrome; as well as microvascular complications, such as neuropathy, retinopathy, and nephropathy[6-8]. Approximately 44% of all T2DM cases have been linked to obesity, correlating an exponential increase in their worldwide prevalence[9, 10]. Additionally, the World Health Organization predicts 57.8% of the world population to be overweight and obese by 2030[11].
Since no cure exists, efforts to control and treat T2DM have escalated[12]. The American Diabetes Association recommends healthy lifestyle changes as the first-in-line response, followed by metformin-based pharmaceutical interventions[13]. The approach of lowering glucose plasma levels remains the most sought-after treatment and has recently witnessed novel and effective advances. These alongside metformin, commonly include treatment with glucagon-like peptide-1 receptor (GLP-1R) agonists, sodium-glucose co-transporter-2 (SGLT-2) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors and insulin pumps followed by continuous monitoring of glucose levels[8]. Furthermore, research focusing on treatment paradigms targeting the ‘ominous octet’ of T2DM, implicated in the development and progression of hyperglycemia, has gained momentum in the last couple of decades.
The GLP-1R agonists have dramatically transformed patient care guidelines for T2DM[14]. In comparison to the other antihyperglycemic medications, GLP-1R agonists have established an increased capability to target directly or indirectly six out of the eight core defects (‘ominous octet’) associated with T2DM[15-17]. In response to food intake, the intestinal L-cells dependent secretion of GLP-1 is significantly impaired in T2DM patients, which affects the pancreatic β cells dependent insulin secretion; eventually resulting in hyperglycemia[18-20]. The synthetically produced GLP-1R agonists stimulate GLP-1R, in a similar fashion as the native GLP-1. Treatment benefits of peptide-based GLP-1R agonists include glycemic control, weight loss, delayed onset of macroalbuminuria, prevention of clinical hyperglycemic episodes and cardiovascular events, and reduced estimated glomerular filtration rate (eGFR) decline; that in turn indirectly result in the inhibition of glucagon secretion and increased secretion of insulin with minimal hypoglycemic risks[8, 21-23].
Since their first approval in 2005, seven GLP-1R agonists drugs have been developed for glycemic control in T2DM patients. In 2021, Trujilloet al. , described fourteen head-to-head trials conducted on these seven GLP-1R agonists, the results of which continue to establish the benefits of this class of drugs in treatment of T2DM patients. The authors further highlighted studies that have published beneficial cardiovascular and renal outcomes of the treatment; however, the results, in terms of the magnitude for glycemic control and adverse effects are not consistent[24]. The focus of research thus needs to shift from investigating the pharmacological effects of GLP-1R agonists, to understanding the underlying molecular mechanisms.
Recent advances in the analyses of urinary peptidome, have paved way for the detection of alterations at both pathological as well as physiological levels in chronic diseases[25]. Urine-based omics studies have especially garnered relevance, due to the ease of sample collection, longer stability of the peptides, complex composition (from blood, kidney, and bladder) and the possibility of larger cohort studies because of its non-invasive approach. In addition, the water soluble and charged nature of urinary peptides enable their uncomplicated mass spectrometric (MS) based detections[26]. The urinary peptidomic analysis in this study was performed by a capillary electrophoresis coupled to mass spectrometry (CE-MS) technique, which supports the identification of naturally occurring urinary peptides and peptidomic changes in response to drug interventions[27]. Therefore, in this exploratory study, we aimed to assess the effect of treatment with GLP-1R agonists on the urinary peptidome of T2DM patients, in an untargeted peptidomics approach.
Materials and Methods