The importance of glucose‐dependent insulinotropic polypeptide receptor activation for the effects of tirzepatide

Gasbjerg, Lærke S.; Meier, Juris J.; Holst, Jens J.; Knop, Filip K.

doi:10.1111/dom.15216

Cited by 16 publications

(6 citation statements)

References 129 publications

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“…Both GIP and GLP-1 hormones improve glucose tolerance. GIP appears to be the most effective, particularly regarding insulin secretion, whereas the action of GLP-1 is mainly associated with the inhibition of glucagon secretion[ 30 ]. In the present study, plasma active GIP and active GLP-1 Levels were increased by TJ-43 treatment in patients undergoing PpPD (Figure 2 ).…”

Section: Discussionmentioning

confidence: 99%

Rikkunshito increases peripheral incretin-hormone levels in humans and rats

Kono,

Furuya,

Akaike

et al. 2024

World J Methodol

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BACKGROUND It was reported that rikkunshito (TJ-43) improved the cisplatin-induced decreases in the active form of ghrelin in plasma; however, other effects on gastrointestinal hormones have not been investigated. AIM To investigate the effects of TJ-43 on peripheral levels of incretin hormones, including gastric inhibitory polypeptide (GIP) and glucagon-like polypeptide-1 (GLP-1), in humans and rats. METHODS Patients were divided into two groups, namely patients who received TJ-43 immediately following surgery [TJ-43(+) group] and those who received TJ-43 on postoperative day 21 [TJ-43(-) group], and the plasma levels of active GIP and active GLP-1 were assessed. In animal experiments, rats were treated with TJ-43 [rat (r)TJ-43(+) group] or without [rTJ-43(−) group] by gavage for 4 wk, and the plasma active GIP and active GLP-1 levels were measured. The expression of incretin hormones in the gastrointestinal tract and insulin in the pancreas were investigated by immunohistochemistry. Furthermore, the cyclic adenosine monophosphate activities were assessed in pancreatic tissues from rats treated with or without TJ-43 in vivo , and the blood glucose levels and plasma insulin levels were measured in rats treated with or without TJ-43 in oral glucose tolerance tests. RESULTS In humans, the active incretin hormone levels increased, and values were significantly greater in the TJ-43(+) group compared those in the TJ-43(-) group. In rats, the plasma active incretin levels significantly increased in the rTJ-43(+) group compared with those in the rTJ-43(-) group. GIP and GLP-1 expressions were enhanced by TJ-43 treatment. Moreover, plasma insulin levels increased and blood glucose levels were blunted in the rTJ-43(+) group. CONCLUSION The results show that TJ-43 may be beneficial for patients who undergo pancreatic surgery.

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Section: Discussionmentioning

confidence: 99%

Rikkunshito increases peripheral incretin-hormone levels in humans and rats

Kono,

Furuya,

Akaike

et al. 2024

World J Methodol

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“… 60 In this regard, tirzepatide may offer an exciting new option for improving bone health in obesity and diabetes, linked to the combined direct and indirect benefits of GLP-1, and especially GIP, at the level of the skeleton. 118 Although the precise nature of tirzepatide-receptor interactions is under debate, 119 it is interesting to note that other dual- and triple-acting peptide molecules that tend to have GLP-1 receptor signalling as their mainstay have also been developed, 120 with some already progressed to clinical trials. 121 , 122 The overall impact of these compounds on bone in the setting of obesity and diabetes will also be of particular interest, as described below.…”

Section: The Gastrointestinal Tract and Bonementioning

confidence: 99%

“…Given recent approval of tirzepatide for T2DM, 61 , 118 alongside current clinical evaluation of other similar dual- and triple-acting entities, 120 it seems clear that the same rationale could be applied to bone-targeting unimolecular peptides. Consequently, the powerful, and likely complementary effects of GIP and GLP-2 on bone turnover, 89 , 126 support this paradigm.…”

Section: The Gastrointestinal Tract and Bonementioning

confidence: 99%

Gut-Derived Peptide Hormone Analogues and Potential Treatment of Bone Disorders in Obesity and Diabetes Mellitus

Ali,

Flatt,

Irwin

2024

Clin Med Insights Endocrinol Diabetes

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Obesity and diabetes mellitus are prevalent metabolic disorders that have a detrimental impact on overall health. In this regard, there is now a clear link between these metabolic disorders and compromised bone health. Interestingly, both obesity and diabetes lead to elevated risk of bone fracture which is independent of effects on bone mineral density (BMD). In this regard, gastrointestinal (GIT)-derived peptide hormones and their related long-acting analogues, some of which are already clinically approved for diabetes and/or obesity, also seem to possess positive effects on bone remodelling and microarchitecture to reduce bone fracture risk. Specifically, the incretin peptides, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), as well as glucagon-like peptide-2 (GLP-2), exert key direct and/or indirect benefits on bone metabolism. This review aims to provide an initial appraisal of the relationship between obesity, diabetes and bone, with a focus on the positive impact of these GIT-derived peptide hormones for bone health in obesity/diabetes. Brief discussion of related peptides such as parathyroid hormone, leptin, calcitonin and growth hormone is also included. Taken together, drugs engineered to promote GIP, GLP-1 and GLP-2 receptor signalling may have potential to offer therapeutic promise for improving bone health in obesity and diabetes.

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“…After receptor activation, the status can switch to receptor desensitization. Thus, agonists may act as functional antagonists under certain circumstances[ 48 , 49 ]. The compensatory relationship between GLP-1 and GIP might also play a role in the paradoxical agonist-antagonist phenomenon[ 48 ].…”

Section: Pathophysiological Mechanisms and Sites Of Action Of Increti...mentioning

confidence: 99%

Role of incretins and glucagon receptor agonists in metabolic dysfunction-associated steatotic liver disease: Opportunities and challenges

Xie,

Alkhouri,

Elfeki

2024

World J Hepatol

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Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most common chronic liver disease worldwide, paralleling the rising pandemic of obesity and type 2 diabetes. Due to the growing global health burden and complex pathogenesis of MASLD, a multifaceted and innovative therapeutic approach is needed. Incretin receptor agonists, which were initially developed for diabetes management, have emerged as promising candidates for MASLD treatment. This review describes the pathophysiological mechanisms and action sites of three major classes of incretin/glucagon receptor agonists: glucagon-like peptide-1 receptor agonists, glucose-dependent insulinotropic polypeptide receptor agonists, and glucagon receptor agonists. Incretins and glucagon directly or indirectly impact various organs, including the liver, brain, pancreas, gastrointestinal tract, and adipose tissue. Thus, these agents significantly improve glycemic control and weight management and mitigate MASLD pathogenesis. Importantly, this study provides a summary of clinical trials analyzing the effectiveness and safety of incretin receptor agonists in MASLD management and provides an in-depth analysis highlighting their beneficial effects on improving liver function, hepatic steatosis, and intrahepatic inflammation. There are emerging challenges associated with the use of these medications in the real world, particularly adverse events, drug-drug interactions, and barriers to access, which are discussed in detail. Additionally, this review highlights the evolving role of incretin receptor agonists in MASLD management and suggests future research directions.

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The importance of glucose‐dependent insulinotropic polypeptide receptor activation for the effects of tirzepatide

Cited by 16 publications

References 129 publications

Rikkunshito increases peripheral incretin-hormone levels in humans and rats

Rikkunshito increases peripheral incretin-hormone levels in humans and rats

Gut-Derived Peptide Hormone Analogues and Potential Treatment of Bone Disorders in Obesity and Diabetes Mellitus

Role of incretins and glucagon receptor agonists in metabolic dysfunction-associated steatotic liver disease: Opportunities and challenges

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