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