The dual incretin co-agonist tirzepatide increases both insulin secretion and glucose effectiveness in model experiments in mice

Review Endocrinology & Metabolism

Gut hormone-based pharmacology: novel formulations and future possibilities for metabolic disease therapy

Matthias Tschoep et al.

Summary: GLP-1 receptor agonists are established pharmaceutical therapies for type 2 diabetes and obesity. They reduce glucose levels by simulating GLP-1 action and induce satiety through central actions, leading to weight reduction.

DIABETOLOGIA (2023)

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Article Biochemistry & Molecular Biology

Contribution of GIP and GLP-1 to the Insulin Response to Oral Administration of Glucose in Female Mice

Bo Ahren

Summary: In this study, the contribution of GIP and GLP-1 to insulin response to oral glucose in female mice was investigated using receptor antagonists. It was found that both GIP and GLP-1 are required for a normal incretin effect in female mice, and no other incretin hormone is likely present in this species.

BIOMEDICINES (2023)

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Article Endocrinology & Metabolism

The incretin co-agonist tirzepatide requires GIPR for hormone secretion from human islets

Kimberley El et al.

Summary: This study shows that tirzepatide, through dual activation of GLP-1R and GIPR, is highly effective in treating type 2 diabetes and obesity. It predominantly stimulates insulin secretion through GLP-1R in mouse islets, but enhances hormone secretion through both incretin receptors in human islets.

NATURE METABOLISM (2023)

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Article Cell Biology

GIPR/GLP-1R dual agonist therapies for diabetes and weight loss—chemistry, physiology, and clinical applications

Jonathan E. Campbell et al.

Cell Metabolism (2023)

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Article Endocrinology & Metabolism

Effects of subcutaneous tirzepatide versus placebo or semaglutide on pancreatic islet function and insulin sensitivity in adults with type 2 diabetes: a multicentre, randomised, double-blind, parallel-arm, phase 1 clinical trial

Tim Heise et al.

Summary: Tirzepatide demonstrates remarkable glucose-lowering ability in patients with type 2 diabetes by improving insulin secretion and sensitivity. Compared to other GLP-1 receptor agonists, Tirzepatide shows more significant improvements in glucose metabolism.

LANCET DIABETES & ENDOCRINOLOGY (2022)

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Article Pharmacology & Pharmacy

Tirzepatide: First Approval

Yahiya Y. Syed

Summary: Tirzepatide is a single molecule that combines dual agonism of GIP and GLP-1 receptors, used for the treatment of type 2 diabetes, obesity, cardiovascular disorders, and other conditions. Its first approval in the USA marks a significant milestone in the development of this novel diabetes medication.

DRUGS (2022)

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Article Endocrinology & Metabolism

Discovery of a potent GIPR peptide antagonist that is effective in rodent and human systems

Bin Yang et al.

Summary: This study reports the discovery of a potent, specific, and long-acting GIPR peptide antagonist that effectively blocks GIP action in vitro, ex vivo in human islets, and in vivo in mice while producing additive weight-loss when combined with a GLP-1R agonist in DIO mice.

MOLECULAR METABOLISM (2022)

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Review Cardiac & Cardiovascular Systems

Tirzepatide, a dual GIP/GLP-1 receptor co-agonist for the treatment of type 2 diabetes with unmatched effectiveness regrading glycaemic control and body weight reduction

Michael A. Nauck et al.

Summary: Tirzepatide, the first dual GIP/GLP-1 receptor co-agonist approved for the treatment of type 2 diabetes, has shown to be effective in reducing HbA(1c) and body weight, and has good cardiovascular safety. However, there are still questions regarding its mechanism of action.

CARDIOVASCULAR DIABETOLOGY (2022)

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Article Endocrinology & Metabolism

Management of hyperglycaemia in type 2 diabetes, 2022. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)

Melanie J. Davies et al.

Summary: The American Diabetes Association and the European Association for the Study of Diabetes have updated the consensus statements on the management of hyperglycaemia in type 2 diabetes in adults. The new recommendations focus on social determinants of health, physical activity behaviors, and weight management.

DIABETOLOGIA (2022)

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Review Endocrinology & Metabolism

Glucose effectiveness: Lessons from studies on insulin-independent glucose clearance in mice

Bo Ahren et al.

Summary: In addition to insulin-mediated transport, the non-insulin-mediated glucose disposal known as glucose effectiveness (S-G) plays a significant role in regulating glucose homeostasis. S-G accounts for approximately 70% of glucose disposal and is reduced in conditions such as type 2 diabetes, obesity, and liver cirrhosis. Experimental studies in mice have shown that S-G is independent of glucose levels but can be influenced by factors like insulin secretion, high-fat feeding, and glucagon administration. Understanding the role of S-G in glucose elimination and its regulation may have implications for diabetes development and potential therapeutic interventions.

JOURNAL OF DIABETES INVESTIGATION (2021)

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Review Cell Biology

The many actions of insulin in skeletal muscle, the paramount tissue determining glycemia

Lykke Sylow et al.

Summary: Skeletal muscle is crucial for insulin-stimulated glucose disposal and overall glycemic control. Insulin regulates glucose uptake in skeletal muscle through complex signaling cascades. Understanding insulin's actions in muscle can provide insights into addressing issues with glucose uptake in conditions like diabetes and obesity.

CELL METABOLISM (2021)

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Article Endocrinology & Metabolism

Impact of Incretin Hormone Receptors on Insulin-Independent Glucose Disposal in Model Experiments in Mice

Tina Ovlund et al.

Summary: The study indicates that active GLP-1 receptors are required for insulin-independent glucose elimination, while GIP receptors do not show the same relevance for this process. GLP-1 receptor knockout mice had reduced S-G, while GIP receptor knockout mice showed no difference compared to wildtype mice. This dissociated relevance of two incretin hormone receptor types suggests different roles in glucose disposal.

FRONTIERS IN ENDOCRINOLOGY (2021)

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Article Medicine, Research & Experimental

GIPR agonism mediates weight-independent insulin sensitization by tirzepatide in obese mice

Ricardo J. Samms et al.

Summary: Tirzepatide, a dual GIP and GLP-1 receptor agonist, improves insulin sensitivity in obese mice to a greater extent than GLP-1R agonism. This effect is associated with enhanced glucose disposal in white adipose tissue and reduction of branched-chain amino acids in the circulation. The upregulation of genes related to the catabolism of glucose, lipid, and BCAAs in brown adipose tissue contributes to the improved insulin sensitivity by tirzepatide.

JOURNAL OF CLINICAL INVESTIGATION (2021)

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Article Medicine, Research & Experimental