The Biased G-Protein-Coupled Receptor Agonism Bridges the Gap between the Insulin Receptor and the Metabolic Syndrome.

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arginine vasopressin 1 endocrinologydiseasesdrugs
hyperandrogenism 2 endocrinologydiseases
hyperglycemia 1 endocrinologydiseases
metabolic syndrome 22 endocrinologydiseases
obesity 12 endocrinologydiseases
polycystic ovary syndrome 1 endocrinologydiseases
type 2 diabetes mellitus 1 endocrinologydiseases
Insulin 9 endocrinologydiseasesdrugs
hyperinsulinemia 2 endocrinologydiseases
diabetes mellitus 3 endocrinologydiseases

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Insulin 124 Journal of Molecular SciencesThe Biased G-Protein-Coupled Receptor Agonism Bridges the Gap between the Insulin Receptor and the Metabolic SyndromeIryna LiauchonakFady DawoudYatin RiatBessi QorriManpreet SambiJustin
Insulin 937 nicole.mendonza@queensu.ca (N.M.)Publication date (epub): 2/2018Publication date (collection): 2/2018Abstract Insulin signaling, as mediated through the insulin receptor (IR), plays a critical role in metabolism. Aberrations
Insulin 5649 GPCR-biased agonism for the insulin receptor may play a role.2. Mechanism of Action2.1. An Overview of Normal Insulin Receptor SignalingThe insulin receptor is synthesized as a preproreceptor. Following cleavage of a signal
Insulin 10353 resistance through the over-activation of IR signaling.4. Metabolic Syndrome and the Relationship between Insulin Receptor (IR) in Mitigating a Pathological PhenotypeDue to metabolic syndrome being a combination of
Insulin 13498 production in the fasting state may constitute possible explanations for the observed effects of irbesartan. Insulin resistance is proposed to be a significant driver of cardiovascular disease [[22]]. Recent reports have
Insulin 39025 in insulin signaling may contribute to the neurocognitive deficits seen in these patients (Figure 7). Insulin receptors are dispersed throughout the brain but are more pronounced in the hippocampus, olfactory bulb,
Insulin 43667 exacerbating disease conditions related to the insulin receptor. Figure 1Overview of insulin signaling. (A) Insulin binding to the IRα and (B) potentiates GPCR signaling that activates MMP9 (1). Active MMP9 relieves
Insulin 46552 decreases in specific functions of the organs participating in metabolism in response to Ghrelin. IGF, Insulin growth factor; CNS, central nervous system.Figure 6Proposed GHSR induced mechanism of signal transduction
Insulin 47031 for the disassociation of the IRS1-PI3K-AKT pathway. Taken in part from Murata et al. [[64]].Figure 7 Insulin signaling linking Type II diabetes and Alzheimer’s disease. Alterations in glucose homeostasis have
arginine vasopressin 33528 to GPCR agonist neuropeptides gastrin-releasing peptide, neuromedin B, gastrin, cholecystokinin, and arginine vasopressin [[74]]. Interfering with this neuropeptide signaling, as well as intricate connections with other signaling
Select Disease Character Offset Disease Term Instance
diabetes mellitus 3106 defined as the combination of conditions that increase the risk of cardiovascular disease and type two diabetes mellitus (T2DM) [[2]]. However, the specific underlying biochemical and cellular properties of IR signaling that
diabetes mellitus 10709 the activity of the IR have been correlated with several pathologies including hypertension, type 2 diabetes mellitus , and obesity [[2],[9]], in addition to cardiovascular disease and diseases of the gastrointestinal (GI)
diabetes mellitus 38732 β amyloid toxicity, oxidative stress, and ischemia [[95]]. However, patients with type I or type II diabetes mellitus have been shown to suffer from cognitive regression [[96]]. These findings suggest that alterations
hyperandrogenism 35077 T2DM [[79]]. While its etiology remains unknown, it is characterized by severe insulin resistance, hyperandrogenism , menstrual disorders, and polycystic ovaries that can be seen with ultrasound [[80],[81]]. These abnormal
hyperandrogenism 35469 androgen levels and exacerbated clinical symptoms [[80]].PCOS is characterized by hyperinsulinemia and hyperandrogenism , the latter of which has been associated with an overexpression of ovarian RAS (OVRAS) [[82]]. Due to
hyperglycemia 25313 insulin sensitivity. Cani et al. reported that mice experiencing inflammation had increased weight, hyperglycemia , and hyperinsulinemia while mice with mutant CD14 proteins did not develop insulin resistance or diabetes
hyperinsulinemia 25332 sensitivity. Cani et al. reported that mice experiencing inflammation had increased weight, hyperglycemia, and hyperinsulinemia while mice with mutant CD14 proteins did not develop insulin resistance or diabetes [[54]]. These findings
hyperinsulinemia 35448 increased circulating androgen levels and exacerbated clinical symptoms [[80]].PCOS is characterized by hyperinsulinemia and hyperandrogenism, the latter of which has been associated with an overexpression of ovarian RAS
metabolic syndrome 1171 cascade lead to several pathologies, the majority of which are classified under the umbrella term “ metabolic syndrome ”. Although many of these pathologies are associated with insulin resistance, the exact mechanisms
metabolic syndrome 1998 notion that GPCRs can regulate the activation of the IR is particularly significant in relation to metabolic syndrome and other pathologies that develop as a result of alterations in IR signaling. As such, we aim to provide
metabolic syndrome 2202 such, we aim to provide an overview of the physiological and pathophysiological roles of the IR within metabolic syndrome and its related pathologies, including cardiovascular health, gut microflora composition, gastrointestinal
metabolic syndrome 2952 This receptor is of particular relevance due to its crucial role in metabolism and the development of metabolic syndrome . Metabolic syndrome (MetSyn) is defined as the combination of conditions that increase the risk of cardiovascular
metabolic syndrome 5072 between GPCR and IR signaling that could contribute to the development of the complex conditions of metabolic syndrome . Here, we aim to provide an overview of GPCR-biased agonism and its proposed mechanism of action in
metabolic syndrome 5351 We also aim to highlight specific ligands that promote this bias and the critical roles they play in metabolic syndrome . Finally, we aim to expand on several pathologies that are either classified as or are exacerbated by
metabolic syndrome 5472 Finally, we aim to expand on several pathologies that are either classified as or are exacerbated by metabolic syndrome and identify additional disease states on which GPCR-biased agonism for the insulin receptor may play
metabolic syndrome 10420 Syndrome and the Relationship between Insulin Receptor (IR) in Mitigating a Pathological PhenotypeDue to metabolic syndrome being a combination of disorders that involves changes in sensitivity to insulin and by extension, the
metabolic syndrome 15932 mediators and effectors, thereby implicating RAS activation in the development of insulin resistance within metabolic syndrome due to ANG II promoting the pathophysiology of atherosclerosis, hypertension, and congestive heart failure
metabolic syndrome 16402 Metabolic SyndromeMetabolic regulation and inflammation are highly integrated processes contributing to metabolic syndrome , with the prothrombotic and proinflammatory properties of MetSyn having direct implications for conditions
metabolic syndrome 18267 [[23]]. More recently, Talbot and colleagues showed that B1R contributes to insulin resistance and metabolic syndrome while claiming that B2R has been associated with a preventive role in insulin resistance [[44]]. In
metabolic syndrome 20937 [[8]].While the application of GPCR agonists such as BK for the treatment of conditions that fall under metabolic syndrome represents immense potential, patients who suffer from both IBD and metabolic syndrome must be taken
metabolic syndrome 21024 that fall under metabolic syndrome represents immense potential, patients who suffer from both IBD and metabolic syndrome must be taken into special consideration. If GPCR agonists such as BK are deemed as therapeutic targets
metabolic syndrome 21531 models [[37],[38],[39],[40],[41],[42]], and consequently, alternative approaches to the management of metabolic syndrome may be warranted in this population. The link proposed to exist between BK and PI3K via biased GPCR
metabolic syndrome 21771 [[8]] requires further investigation to determine whether GPCR agonists can be used in the treatment of metabolic syndrome in patients with IBD. Based on available preclinical data, it may be the case that exacerbation of IBD
metabolic syndrome 21991 IBD [[41]] may be an unwanted side-effect of GPCR agonist therapy in this subgroup of patients. While metabolic syndrome is serious comorbidity for patients with IBD that should be managed, the use of GPCR agonists may be
metabolic syndrome 22563 not fully understood, it has been implicated in the development of insulin resistance, obesity, and metabolic syndrome , and may be mediated through interactions with the IR or GPCRs [[47]]. For example, there are distinct
metabolic syndrome 24653 both GPCR proteins, and the insulin receptor.The development of a low-grade inflammatory state seen in metabolic syndrome represents another mechanism by which the gut microbiome affects insulin metabolism, described as metabolic
metabolic syndrome 25923 concluded that a strong correlation exists between the gut microbiome and the inflammatory state seen in metabolic syndrome and insulin resistance by these interactions. However, additional studies are required to investigate
metabolic syndrome 38284 Potential Implications in Alzheimer’s Disease and NeurocognitionThere is a growing body of evidence that metabolic syndrome and insulin resistance can have an effect on the brain and cause neurocognitive impairment and dementia,
metabolic syndrome 43059 activation patterns can directly or indirectly lead to several pathologies. One such disease state is a metabolic syndrome , a collection of pathologies related to metabolism in addition to other conditions such as PCOS, Alzheimer’s,
metabolic syndrome 46382 action on multiple organs. Most notably, ghrelin modulates eating habits and has been correlated with metabolic syndrome . The arrows indicate the respective increase or decreases in specific functions of the organs participating
obesity 9185 disease progression, particularly as it relates to cardiovascular disease, irritable bowel disease, obesity , polycystic ovarian syndrome (PCOS), pancreatic cancer, and neuropathologies.3. Metabolic SyndromeMetabolic
obesity 9384 SyndromeMetabolic syndrome is defined as a combination of cardio-metabolic risk factors that lead to obesity , T2DM, and hypertension, all of which are primarily characterized by unhealthy body measurements [[2],[9]].
obesity 10732 have been correlated with several pathologies including hypertension, type 2 diabetes mellitus, and obesity [[2],[9]], in addition to cardiovascular disease and diseases of the gastrointestinal (GI) tract. As
obesity 22550 human host are not fully understood, it has been implicated in the development of insulin resistance, obesity , and metabolic syndrome, and may be mediated through interactions with the IR or GPCRs [[47]]. For example,
obesity 23079 findings suggest that the phyla of bacteria found in the human gut are correlated with the development of obesity , implicating the gut flora in insulin metabolism. The link between the IR and GPCR may result in changes
obesity 25554 findings suggest that this inflammatory state caused by certain species of gut bacteria is contributing to obesity and insulin resistance. Also, Brugman et al. [[56]] have shown that by altering the gut microbiome in
obesity 26438 fundus and the anterior pituitary gland, has been shown to play a role in metabolic disorders including obesity and T2DM [[57],[58]]. Endogenous ghrelin stimulates the release of growth hormone (GH) and directly
obesity 27145 alterations are particularly significant because plasma ghrelin levels are inversely correlated with obesity , weight gain, and insulin resistance [[61]]. By extension, abnormally high levels of plasma ghrelin
obesity 27419 and may be regulated through GPCRs and IR cross-talk mechanisms.The proposed link between ghrelin and obesity was evaluated in a study by Tschöp, Smiley, and Heiman [[58]] that showed that ghrelin administration
obesity 29804 ghrelin and insulin-induced increases of PI3K and MAPK may be linked to an energy-rich state such as obesity , as these pathways regulate cell proliferation.When ghrelin-induced IRS1 phosphorylation occurs, it
obesity 30481 Collectively, the ghrelin/GHSR and the PI3K-AKT signaling pathway may suggest a role in the development of obesity . Furthermore, the observations made by Haxho et al. regarding NMBR-MMP9-IRβ crosstalk [[8]] may be
obesity 30954 increase the level of circulating ghrelin and may suggest an underlying link to metabolic diseases such as obesity . Though ghrelin is primarily released through the gastric fundus, it has been found in the hypothalamus,
polycystic ovary syndrome 9952 differential expression of MetSyn observed across individuals and its associated conditions such as polycystic ovary syndrome (PCOS) [[13]]. Therefore, a thorough understanding of insulin resistance and the IR in pathologies that
type 2 diabetes mellitus 10702 alterations in the activity of the IR have been correlated with several pathologies including hypertension, type 2 diabetes mellitus , and obesity [[2],[9]], in addition to cardiovascular disease and diseases of the gastrointestinal (GI)

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