Kyle W. Sloop
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View article: Spatially diffuse cAMP signalling with oppositely biased GLP-1 receptor agonists in β-cells despite differences in receptor localisation
Spatially diffuse cAMP signalling with oppositely biased GLP-1 receptor agonists in β-cells despite differences in receptor localisation Open
View article: Long-acting GIPR agonist LY3537021 reduces body weight and fasting blood glucose in patients with T2D: Preclinical development and phase 1 randomized ascending dose studies
Long-acting GIPR agonist LY3537021 reduces body weight and fasting blood glucose in patients with T2D: Preclinical development and phase 1 randomized ascending dose studies Open
View article: α cells use both PC1/3 and PC2 to process proglucagon peptides and control insulin secretion
α cells use both PC1/3 and PC2 to process proglucagon peptides and control insulin secretion Open
α cells secrete proglucagon peptides to regulate nutrient metabolism. Recent findings support an α cell–to–β cell axis that is mediated by paracrine signaling through the glucagon receptor and glucagon-like peptide 1 (GLP-1) receptor in β …
View article: Glycaemic and bodyweight effects of <i>GIPR</i> coding variation reflect differences in both surface expression and intrinsic functional impairment
Glycaemic and bodyweight effects of <i>GIPR</i> coding variation reflect differences in both surface expression and intrinsic functional impairment Open
The glucose-dependent insulinotropic polypeptide receptor (GIPR) is the target of several approved and investigational drugs for type 2 diabetes and obesity. Missense coding variation in GIPR could confer phenotypic effects through altered…
View article: β Cell Gαs signaling is critical for physiological and pharmacological enhancement of insulin secretion
β Cell Gαs signaling is critical for physiological and pharmacological enhancement of insulin secretion Open
The incretin peptides glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors coordinate β cell secretion that is proportional to nutrient intake. This effect permits consistent and restricted glucose excursions …
View article: A Contemporary Rationale for Agonism of the GIP Receptor in the Treatment of Obesity
A Contemporary Rationale for Agonism of the GIP Receptor in the Treatment of Obesity Open
In combatting the obesity crisis, leveraging mechanisms that lower body weight is critical. The finding that treatment with tirzepatide, a glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptor agon…
View article: Publisher Correction: GIPR agonism and antagonism decrease body weight and food intake via different mechanisms in male mice
Publisher Correction: GIPR agonism and antagonism decrease body weight and food intake via different mechanisms in male mice Open
View article: GIPR agonism and antagonism decrease body weight and food intake via different mechanisms in male mice
GIPR agonism and antagonism decrease body weight and food intake via different mechanisms in male mice Open
Agonists and antagonists of the glucose-dependent insulinotropic polypeptide receptor (GIPR) enhance body weight loss induced by glucagon-like peptide-1 receptor (GLP-1R) agonism. However, while GIPR agonism decreases body weight and food …
View article: Glucose-dependent insulinotropic polypeptide (GIP)
Glucose-dependent insulinotropic polypeptide (GIP) Open
View article: The physiological impact of an N‐terminal Halo‐tag on glucose‐dependent insulinotropic polypeptide receptor function in mice
The physiological impact of an N‐terminal Halo‐tag on glucose‐dependent insulinotropic polypeptide receptor function in mice Open
View article: Characterization of LY3324954 a long-acting glucagon-receptor agonist
Characterization of LY3324954 a long-acting glucagon-receptor agonist Open
View article: <i>In vivo</i> functional profiling and structural characterisation of the human <i>GLP1R</i> A316T variant
<i>In vivo</i> functional profiling and structural characterisation of the human <i>GLP1R</i> A316T variant Open
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective therapies for type 2 diabetes (T2D) and obesity, yet patient responses are variable, with GLP1R gene variation potentially linked to therapeutic outcomes. A GLP1R natural m…
View article: Class B1 GPCRs: insights into multireceptor pharmacology for the treatment of metabolic disease
Class B1 GPCRs: insights into multireceptor pharmacology for the treatment of metabolic disease Open
The secretin-like, class B1 subfamily of seven transmembrane-spanning G protein-coupled receptors (GPCRs) consists of 15 members that coordinate important physiological processes. These receptors bind peptide ligands and use a distinct mec…
View article: Effect of Food Consumption on the Pharmacokinetics, Safety, and Tolerability of Once-Daily Orally Administered Orforglipron (LY3502970), a Non-peptide GLP-1 Receptor Agonist
Effect of Food Consumption on the Pharmacokinetics, Safety, and Tolerability of Once-Daily Orally Administered Orforglipron (LY3502970), a Non-peptide GLP-1 Receptor Agonist Open
ClinicalTrials.gov identifiers, NCT03929744 and NCT05110794.
View article: <b>GIPR Agonism Enhances TZD-Induced Insulin Sensitivity in Obese IR Mice</b>
<b>GIPR Agonism Enhances TZD-Induced Insulin Sensitivity in Obese IR Mice</b> Open
Recent studies have found that GIPR agonism can enhance the metabolic efficacy of GLP-1R agonist treatment by promoting both weight-dependent and -independent improvements on systemic insulin sensitivity. These findings have prompted new i…
View article: <b>GIPR Agonism Enhances TZD-Induced Insulin Sensitivity in Obese IR Mice</b>
<b>GIPR Agonism Enhances TZD-Induced Insulin Sensitivity in Obese IR Mice</b> Open
Recent studies have found that GIPR agonism can enhance the metabolic efficacy of GLP-1R agonist treatment by promoting both weight-dependent and -independent improvements on systemic insulin sensitivity. These findings have prompted new i…
View article: GIPR Agonism Enhances TZD-Induced Insulin Sensitivity in Obese IR Mice
GIPR Agonism Enhances TZD-Induced Insulin Sensitivity in Obese IR Mice Open
Recent studies have found that glucose-dependent insulinotropic polypeptide receptor (GIPR) agonism can enhance the metabolic efficacy of glucagon-like peptide–1 receptor agonist treatment by promoting both weight-dependent and -independen…
View article: Pancreatic islet α cell function and proliferation requires the arginine transporter SLC7A2
Pancreatic islet α cell function and proliferation requires the arginine transporter SLC7A2 Open
Interrupting glucagon signaling decreases gluconeogenesis and the fractional extraction of amino acids by liver from blood resulting in lower glycemia. The resulting hyperaminoacidemia stimulates α cell proliferation and glucagon secretion…
View article: Orforglipron ( <scp>LY3502970</scp> ), a novel, oral non‐peptide glucagon‐like peptide‐1 receptor agonist: A Phase 1a, blinded, placebo‐controlled, randomized, single‐ and multiple‐ascending‐dose study in healthy participants
Orforglipron ( <span>LY3502970</span> ), a novel, oral non‐peptide glucagon‐like peptide‐1 receptor agonist: A Phase 1a, blinded, placebo‐controlled, randomized, single‐ and multiple‐ascending‐dose study in healthy participants Open
Aim To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple doses of orforglipron (LY3502970), an oral, non‐peptide glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) in healthy participants. Mate…
View article: The incretin co-agonist tirzepatide requires GIPR for hormone secretion from human islets
The incretin co-agonist tirzepatide requires GIPR for hormone secretion from human islets Open
View article: Orforglipron ( <scp>LY3502970</scp> ), a novel, oral non‐peptide glucagon‐like peptide‐1 receptor agonist: A Phase 1b, multicentre, blinded, placebo‐controlled, randomized, multiple‐ascending‐dose study in people with type 2 diabetes
Orforglipron ( <span>LY3502970</span> ), a novel, oral non‐peptide glucagon‐like peptide‐1 receptor agonist: A Phase 1b, multicentre, blinded, placebo‐controlled, randomized, multiple‐ascending‐dose study in people with type 2 diabetes Open
Aim To report the results of a Phase 1b trial evaluating the safety, pharmacokinetics and pharmacodynamics of orforglipron (LY3502970), an oral, non‐peptide glucagon‐like peptide‐1 receptor agonist (GLP‐1RA), in patients with type 2 diabet…
View article: LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept
LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept Open
View article: Tirzepatide induces a thermogenic-like amino acid signature in brown adipose tissue
Tirzepatide induces a thermogenic-like amino acid signature in brown adipose tissue Open
View article: 14-3-3-zeta mediates GLP-1 receptor agonist action to alter α cell proglucagon processing
14-3-3-zeta mediates GLP-1 receptor agonist action to alter α cell proglucagon processing Open
Recent studies demonstrate that α cells contribute to glucose-stimulated insulin secretion (GSIS). Glucagon-like peptide-1 receptor (GLP-1R) agonists potently potentiate GSIS, making these drugs useful for diabetes treatment. However, the …
View article: GIPR Agonism Inhibits PYY-Induced Nausea-Like Behavior
GIPR Agonism Inhibits PYY-Induced Nausea-Like Behavior Open
The induction of nausea and emesis is a major barrier to maximizing the weight loss profile of obesity medications, and therefore, identifying mechanisms that improve tolerability could result in added therapeutic benefit. The development …
View article: GIPR Agonism Inhibits PYY-Induced Nausea-Like Behavior
GIPR Agonism Inhibits PYY-Induced Nausea-Like Behavior Open
The induction of nausea and emesis is a major barrier to maximizing the weight loss profile of obesity medications, and therefore, identifying mechanisms that improve tolerability could result in added therapeutic benefit. The development …
View article: GIPR Agonism Inhibits PYY-Induced Nausea-Like Behavior
GIPR Agonism Inhibits PYY-Induced Nausea-Like Behavior Open
The induction of nausea and emesis is a major barrier to maximizing the weight loss profile of obesity medications, and therefore, identifying mechanisms that improve tolerability could result in added therapeutic benefit. The development …
View article: Is Glucagon Receptor Activation the Thermogenic Solution for Treating Obesity?
Is Glucagon Receptor Activation the Thermogenic Solution for Treating Obesity? Open
A major challenge of obesity therapy is to sustain clinically relevant weight loss over time. Achieving this goal likely requires both reducing daily caloric intake and increasing caloric expenditure. Over the past decade, advances in phar…
View article: Structural determinants of dual incretin receptor agonism by tirzepatide
Structural determinants of dual incretin receptor agonism by tirzepatide Open
Significance Tirzepatide is a dual agonist of the glucose-dependent insulinotropic polypeptide receptor (GIPR) and the glucagon-like peptide-1 receptor (GLP-1R), which are incretin receptors that regulate carbohydrate metabolism. This inve…
View article: GIPR Function in the Central Nervous System: Implications and Novel Perspectives for GIP-Based Therapies in Treating Metabolic Disorders
GIPR Function in the Central Nervous System: Implications and Novel Perspectives for GIP-Based Therapies in Treating Metabolic Disorders Open
During the past decade, pharmaceutical engineering of unimolecular agents has revealed the therapeutic potential of glucose-dependent insulinotropic polypeptide receptor (GIPR) agonism. From this work, one of the most intriguing findings i…