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1.
Bioorg Med Chem ; 100: 117630, 2024 Feb 15.
Article in English | MEDLINE | ID: mdl-38330849

ABSTRACT

Tirzepatide, the first approved dual GLP-1/GIP receptor agonist (RA), has achieved better clinical outcomes than other GLP-1RAs. However, it is an imbalanced dual GIP/GLP-1 RA, and it remains unclear whether the degree of imbalance is optimal. Here, we present a novel long-acting dual GLP-1/GIP RA that exhibits better activity than tirzepatide toward GLP-1R. A candidate conjugate, D314, identified via peptide design, synthesis, conjugation, and experimentation, was evaluated using chronic studies in db/db and diet induced obese (DIO) mice. D314 achieved favorable blood glucose and body weight-lowering effects, equal to those of tirzepatide. Its half-life in dogs (T1/2: 78.3 ± 14.01 h) reveals its suitability for once-weekly administration in humans. This preclinical study suggests the potential role of D314 as an effective agent for treating T2DM and obesity.


Subject(s)
Diabetes Mellitus, Type 2 , Glucagon-Like Peptide 1 , Receptors, Gastrointestinal Hormone , Animals , Dogs , Humans , Mice , Blood Glucose , Diabetes Mellitus, Type 2/drug therapy , Glucagon-Like Peptide 1/agonists , Glucagon-Like Peptide-1 Receptor/agonists , Hypoglycemic Agents/pharmacology , Obesity/drug therapy , Receptors, Gastrointestinal Hormone/agonists , Receptors, Gastrointestinal Hormone/therapeutic use
3.
Curr Opin Cardiol ; 38(6): 539-545, 2023 Nov 01.
Article in English | MEDLINE | ID: mdl-37792556

ABSTRACT

PURPOSE OF REVIEW: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for the management of type 2 diabetes (T2D) and obesity, and some are recommended for cardiorenal risk reduction in T2D. To enhance the benefits with GLP-RA mono-agonist therapy, GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor co-agonists are in development to capitalize on the synergism of GLP-1 and GIP agonism. We review the mechanisms of action and clinical data for GLP-1/GIP receptor co-agonists in T2D and obesity and their potential role in cardiovascular protection. RECENT FINDINGS: Tirzepatide, a first-in-class unimolecular GLP-1/GIP receptor co-agonist, is approved for T2D and is awaiting approval for obesity management. Phase 3 trials in T2D cohorts revealed significant reductions in glycemia and body weight and superiority compared with GLP-1R mono-agonism with semaglutide. Tirzepatide has demonstrated significant body weight reductions in individuals with obesity but not diabetes. It enhances lipid metabolism, reduces blood pressure, and lowers liver fat content. Pooled phase 2/3 data showed cardiovascular safety in T2D while a post hoc analysis suggested tirzepatide slows the decline of kidney function in T2D. SUMMARY: GLP-1/GIP receptor co-agonists are a novel addition to the diabetes and obesity armamentarium. The cardiorenal-metabolic benefits position them as promising multiprong tools for metabolically complex individuals with chronic vascular complications.


Subject(s)
Diabetes Mellitus, Type 2 , Receptors, Gastrointestinal Hormone , Humans , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Glucagon-Like Peptide 1/metabolism , Glucagon-Like Peptide 1/pharmacology , Glucagon-Like Peptide 1/therapeutic use , Receptors, Gastrointestinal Hormone/agonists , Receptors, Gastrointestinal Hormone/therapeutic use , Obesity/complications , Obesity/drug therapy
4.
Proc Natl Acad Sci U S A ; 119(13): e2116506119, 2022 03 29.
Article in English | MEDLINE | ID: mdl-35333651

ABSTRACT

SignificanceTirzepatide 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 investigational agent has proven superior to selective GLP-1R agonists in clinical trials in subjects with type 2 diabetes mellitus. Intriguingly, although tirzepatide closely resembles native GIP in how it activates the GIPR, it differs markedly from GLP-1 in its activation of the GLP-1R, resulting in less agonist-induced receptor desensitization. We report how cryogenic electron microscopy and molecular dynamics simulations inform the structural basis for the unique pharmacology of tirzepatide. These studies reveal the extent to which fatty acid modification, combined with amino acid sequence, determines the mode of action of a multireceptor agonist.


Subject(s)
Diabetes Mellitus, Type 2 , Receptors, Gastrointestinal Hormone , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Gastric Inhibitory Polypeptide/metabolism , Gastric Inhibitory Polypeptide/pharmacology , Gastric Inhibitory Polypeptide/therapeutic use , Glucagon-Like Peptide-1 Receptor/metabolism , Humans , Incretins/pharmacology , Receptors, Gastrointestinal Hormone/agonists , Receptors, Gastrointestinal Hormone/metabolism , Receptors, Gastrointestinal Hormone/therapeutic use
5.
Clin Transl Gastroenterol ; 13(4): e00474, 2022 04 01.
Article in English | MEDLINE | ID: mdl-35297797

ABSTRACT

INTRODUCTION: Gastroparesis is a serious medical condition characterized by delayed gastric emptying and symptoms of nausea, vomiting, bloating, fullness after meals, and abdominal pain. METHODS: To ascertain the genetic risk factors for gastroparesis, we conducted the largest thus far whole-genome sequencing study of gastroparesis. We investigated the frequency and effect of rare loss-of-function variants in patients with both idiopathic and diabetic gastroparesis enrolled in a clinical study of gastroparesis. RESULTS: Among rare loss-of-function variants, we reported an increased frequency of a frameshift mutation p.Leu202ArgfsTer105, within the motilin receptor gene, variant rs562138828 (odds ratio 4.9). We currently replicated this finding in an independent large cohort of gastroparesis samples obtained from patients participating in the ongoing phase III gastroparesis clinical study. DISCUSSION: Motilin receptor is an important therapeutic target for the treatment of hypomotility disorders. The identified genetic variants may be important risk factors for disease as well as may inform treatments, especially those targeting motilin receptor.


Subject(s)
Gastroparesis , Receptors, Gastrointestinal Hormone , Gastroparesis/genetics , Humans , Nausea/genetics , Receptors, Gastrointestinal Hormone/genetics , Receptors, Gastrointestinal Hormone/therapeutic use , Receptors, Neuropeptide , Vomiting/etiology
6.
Crit Care Clin ; 35(2): 341-355, 2019 Apr.
Article in English | MEDLINE | ID: mdl-30784614

ABSTRACT

In health, postprandial glycemic excursions are attenuated via stimulation of insulin secretion, suppression of glucagon secretion, and slowing of gastric emptying. The incretin hormones, glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, are primary modulators of this response. Drugs have recently been developed that exploit the incretin-axis for the management of type 2 diabetes. There is burgeoning interest in the potential of incretin therapies for the management of acute hyperglycemia in the critically ill. This article outlines basic incretin physiology, highlights relevant pharmacology, and briefly summarizes the literature on incretins for glycemic control in the critically ill.


Subject(s)
Blood Glucose/drug effects , Critical Care/methods , Diabetes Mellitus, Type 2/drug therapy , Glycemic Index/drug effects , Hypoglycemic Agents/therapeutic use , Incretins/therapeutic use , Adult , Aged , Aged, 80 and over , Female , Gastric Inhibitory Polypeptide/therapeutic use , Glucagon-Like Peptide 1/therapeutic use , Humans , Male , Middle Aged , Receptors, Gastrointestinal Hormone/therapeutic use
7.
Peptides ; 100: 173-181, 2018 02.
Article in English | MEDLINE | ID: mdl-29412817

ABSTRACT

Glucose-dependent insulinotropic polypeptide (GIP) is an intestinal hormone with a broad range of physiological actions. In the postprandial state, the hormone stimulates insulin secretion and during eu- and hypoglycemia, it stimulates glucagon secretion. In addition, GIP increases triacylglycerol (TAG) uptake in adipose tissue and decreases bone resorption. However, the importance of these actions in humans are not clearly understood as a specific GIP receptor (GIPR) antagonist - an essential tool to study GIP physiology - has been missing. Several different GIPR antagonists have been identified comprising both peptides, vaccines against GIP, GIP antibodies or antibodies against the GIPR. However, most of these have only been tested in rodents. In vitro, N- and C-terminally truncated GIP variants are potent and efficacious GIPR antagonists. Recently, GIP(3-30)NH2, a naturally occurring peptide, was shown to block the GIPR in humans and decrease GIP-induced insulin secretion as well as adipose tissue blood flow and TAG uptake. So far, there are no studies with a GIPR antagonist in patients with type 2 diabetes (T2D), but because the elevations in fasting plasma glucagon and paradoxical postprandial glucagon excursions, seen in patients with T2D, are aggravated by GIP, a GIPR antagonist could partly alleviate this and possibly improve the fasting and postprandial glycemia. Since the majority of patients with T2D are overweight, inhibition of GIP-induced fat deposition may be beneficial as well. Here we summarize the studies of GIPR antagonists and discuss the therapeutic potential of the GIP system in humans.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/therapeutic use , Insulin/metabolism , Receptors, Gastrointestinal Hormone/genetics , Adipose Tissue/drug effects , Adipose Tissue/metabolism , Blood Glucose/drug effects , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/pathology , Gastric Inhibitory Polypeptide/metabolism , Glucagon/metabolism , Glucose/metabolism , Humans , Hypoglycemic Agents/chemistry , Receptors, Gastrointestinal Hormone/antagonists & inhibitors , Receptors, Gastrointestinal Hormone/therapeutic use
8.
Gastroenterol Clin North Am ; 32(2): 707-32, viii-ix, 2003 Jun.
Article in English | MEDLINE | ID: mdl-12858612

ABSTRACT

Motor disorders of the gastrointestinal tract are characterized by definable impairments of gut contractile function. Other conditions exhibit specific disturbances of visceral afferent and efferent activity, which may underlie selected symptom complexes. Medications in several classes have been developed to treat these disorders of gastrointestinal function. Prokinetic agents are effective therapies for ailments with reduced motor function, whereas antispasmodic drugs reduce symptoms in conditions with exaggerated pressure wave activity. Recently, medications designed to blunt transmission in visceral sensory pathways have been proposed for use in the functional bowel disorders. Finally, some patients may benefit from initiation of nonspecific therapies, which have no appreciable effect on gut motor or sensory function.


Subject(s)
Intestinal Diseases/drug therapy , Antidepressive Agents/therapeutic use , Antidiarrheals/therapeutic use , Calcium Channel Blockers/therapeutic use , Gastrointestinal Motility/drug effects , Gastrointestinal Motility/physiology , Humans , Intestinal Diseases/complications , Intestinal Diseases/physiopathology , Muscle Contraction/drug effects , Muscle Contraction/physiology , Neurotransmitter Agents/therapeutic use , Parasympathomimetics/therapeutic use , Receptors, Gastrointestinal Hormone/agonists , Receptors, Gastrointestinal Hormone/therapeutic use , Receptors, Neuropeptide/agonists , Receptors, Neuropeptide/therapeutic use , Somatosensory Disorders/complications , Somatosensory Disorders/drug therapy , Somatosensory Disorders/physiopathology
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