The effect of 6-day subcutaneous glucose-dependent insulinotropic polypeptide infusion on time in glycaemic range in patients with type 1 diabetes: a randomised, double-blind, placebo-controlled crossover trial

Heimbürger, Sebastian M. Nguyen; Hoe, Bjørn; Nielsen, Chris N.; Bergmann, Niklas; Hartmann, Bolette; Holst, Jens J.; Vilsbøll, Tina; Dejgaard, Thomas F.; Christensen, Mikkel B.; Knop, Filip K.

doi:10.1007/s00125-021-05547-8

Cited by 8 publications

(5 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In animal models, GIP receptor modulation affects appetite, food intake and memory functions via centrally located GIP receptors in several brain areas 60,80 . In humans, GIP has, to date, not shown any weight‐ or appetite‐reducing effects 3,61,65 . On the contrary, two rare loss of function GIP receptor variants are associated with lower body mass index (BMI) 42 .…”

Section: Therapeutic Effects Of Glp‐1 and Gipmentioning

confidence: 99%

“…For GIP, no therapeutic compound that only targets the GIP receptor is available. Thus, only acute studies of the effects of natural GIP are available, apart from a single study with a 6‐day infusion of GIP in patients with type 1 diabetes 65,66 . Recently (May 2023), Novo Nordisk announced termination of the development of a once‐weekly GIP receptor agonist (NNC0480‐0389) because of a lack of effect on glycaemia and body weight following 34 weeks of treatment with or without concomitant treatment with the GLP‐1 receptor agonist semaglutide in patients with type 2 diabetes 67 .…”

Section: Therapeutic Effects Of Glp‐1 and Gipmentioning

confidence: 99%

“…Thus, only acute studies of the effects of natural GIP are available, apart from a single study with a 6-day infusion of GIP in patients with type 1 diabetes. 65,66 Recently (May 2023), Novo Nordisk announced termination of the development of a onceweekly GIP receptor agonist (NNC0480-0389) because of a lack of effect on glycaemia and body weight following 34 weeks of treatment with or without concomitant treatment with the GLP-1 receptor agonist semaglutide in patients with type 2 diabetes. 67 By contrast, Eli Lilly and Company presented body weight loss and reduced fasting plasma glucose using a long-acting GIP analogue (LY3537021) for 2 months in both patients with type 2 diabetes and healthy individuals.…”

Section: Therapeutic Effects Of Glp-1 and Gipmentioning

confidence: 99%

“…60,80 In humans, GIP has, to date, not shown any weight-or appetite-reducing effects. 3,61,65 On the contrary, two rare loss of function GIP receptor variants are associated with lower body mass index (BMI). 42 Moreover, in a small study, a 6-hour GIP infusion resulted in increased triglyceride content in subcutaneous adipose tissue in patients with type 2 diabetes and obesity, but not in lean individuals, individuals with obesity, or lean patients with type 2 diabetes.…”

Section: Body Weight and Adipose Tissuementioning

confidence: 99%

See 3 more Smart Citations

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

Gasbjerg

Meier

Holst

et al. 2023

Diabetes Obesity Metabolism

Self Cite

View full text Add to dashboard Cite

Tirzepatide is a unimolecular co‐agonist of the glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP) receptors recently approved for the treatment of type 2 diabetes by the US Food and Drug Administration and the European Medicine Agency. Tirzepatide treatment results in an unprecedented improvement of glycaemic control and lowering of body weight, but the contribution of the GIP receptor‐activating component of tirzepatide to these effects is uncertain. In this review, we present the current knowledge about the physiological roles of the incretin hormones GLP‐1 and GIP, their receptors, and previous results of co‐targeting the two incretin hormone receptors in humans. We also analyse the molecular pharmacological, preclinical and clinical effects of tirzepatide to discuss the role of GIP receptor activation for the clinical effects of tirzepatide. Based on the available literature on the combination of GLP‐1 and GIP receptor activation, tirzepatide does not seem to have a classical co‐activating mode of action in humans. Rather, in vitro studies of the human GLP‐1 and GIP receptors reveal a biased GLP‐1 receptor activation profile and GIP receptor downregulation. Therefore, we propose three hypotheses for the mode of action of tirzepatide, which can be addressed in future, elaborate clinical trials.

show abstract

Section: Therapeutic Effects Of Glp‐1 and Gipmentioning

confidence: 99%

Section: Therapeutic Effects Of Glp‐1 and Gipmentioning

confidence: 99%

Section: Therapeutic Effects Of Glp-1 and Gipmentioning

confidence: 99%

Section: Body Weight and Adipose Tissuementioning

confidence: 99%

See 2 more Smart Citations

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

Gasbjerg

Meier

Holst

et al. 2023

Diabetes Obesity Metabolism

Self Cite

View full text Add to dashboard Cite

show abstract

“…GLP-1 receptor agonists (GLP-1RAs) are extensively used in the treatment of type 2 diabetes and are also emerging as a promising therapy to maintain residual beta-cell function in newly diagnosed type 1 diabetes [30]. The glucagonotropic effect of GIP at low glucose concentrations holds promise to reduce the risk of hypoglycaemia in type 1 diabetes [31], though GIP alone may not be sufficiently effective [32]. Single-molecule dual GIP and GLP-1 receptor agonists are currently under extensive development and are considered crucial for the advancement of diabetes management, with tirzepatide already approved to date [33, 34], though their effects on alpha-cell function and hypoglycaemia are often overlooked.…”

Section: Introductionmentioning

confidence: 99%

Proinflammatory cytokine-induced alpha-cell impairment in human islet microtissues is partially restored by dual incretin receptor agonism

Henriksen,

Rufer,

Title

et al. 2024

Preprint

View full text Add to dashboard Cite

Aims/hypothesisIn type 1 diabetes, the counterregulatory glucagon response to low plasma glucose is impaired. The resulting increased risk of hypoglycaemia necessitates novel strategies to ameliorate alpha-cell impairment. Here, we aimed to establish an in vitro model of alpha-cell impairment in type 1 diabetes using human islet microtissues (MTs) exposed to proinflammatory cytokines. Additionally, we investigated the therapeutic potential of incretin receptor agonists in improving alpha-cell responses to low glucose.MethodsHuman islet MTs were exposed to proinflammatory cytokines (IL-1β, IFN-γ, and TNF-α) for 1 day (short-term) and 6 days (long-term). Alpha-cell function was assessed by sequential glucose-dependent secretion assays at 2.8 and 16.7 mmol/l glucose, followed by glucagon measurements. Additional evaluations included ATP content, caspase-3/7 activity, chemokine secretion, and expression of islet transcription factors and hormones. The effects of incretin receptor agonist treatment (glucose-dependent insulinotropic polypeptide (GIP) analogue [D-Ala2]-GIP ± liraglutide) alongside or after cytokine exposure were also investigated, focusing on low glucose-dependent glucagon secretion.ResultsShort-term cytokine exposure increased glucagon secretion at both 2.8 and 16.7 mmol/l glucose. In contrast, long-term cytokine exposure caused dose-dependent suppression of glucagon secretion at 2.8 mmol/l glucose, resembling a type 1 diabetes phenotype. Long-term cytokine exposure also diminished somatostatin secretion, reduced ATP content, increased caspase 3/7 activity, and decreased islet transcription factor and hormone expression. Despite cytokine-induced impairment, alpha cells partially retained secretory capacity to L-arginine stimulation. Treatment with incretin receptor agonists during long-term cytokine exposure did not prevent alpha-cell impairment. However, acute treatment with [D-Ala2]-GIP ± liraglutide or the single-molecule dual agonist tirzepatide partially restored glucagon secretion at low glucose.Conclusions/interpretationLong-term cytokine exposure of human islet MTs impaired glucagon secretion to low glucose, creating a type 1 diabetes alpha-cell phenotype. This cytokine-induced alpha-cell impairment was partially restored by [D-Ala2]-GIP ± liraglutide and tirzepatide, respectively.Research in contextWhat is already known about this subject?The counterregulatory alpha-cell response to low glucose is impaired in type 1 diabetes, increasing the risk of hypoglycaemia.Limited translatability of rodent islet findings highlights the need for human islet models.Actions of the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) have mainly been studied in the context of type 2 diabetes and hyperglycaemia but less in type 1 diabetes and hypoglycaemia.What is the key question?Can alpha-cell impairment in type 1 diabetes be modelled in vitro by exposing human islet microtissues (MTs) to proinflammatory cytokines, and could incretins protect against this?What are the new findings?Long-term (6-day) exposure to proinflammatory cytokines produces a type 1 diabetes phenotype of alpha-cell impairment to low glucose in islet MTsAcute dual treatment with incretin receptor agonists partially restored glucose-dependent glucagon secretion in cytokine-exposed islet MTs — an effect mainly carried by GIP receptor agonism and not opposed by GLP-1 receptor agonism.How might this impact on clinical practice in the foreseeable future?Investigating incretin receptor agonists in a preclinical in vitro model of alpha-cell impairment may reveal their potential and fast-track their use as safeguards against hypoglycaemia in type 1 diabetes.

show abstract

The Gut-Bone Axis in Diabetes

Maagensen

Helsted

Gasbjerg

et al. 2022

Curr Osteoporos Rep

View full text Add to dashboard Cite

The effect of 6-day subcutaneous glucose-dependent insulinotropic polypeptide infusion on time in glycaemic range in patients with type 1 diabetes: a randomised, double-blind, placebo-controlled crossover trial

Cited by 8 publications

References 14 publications

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

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

Proinflammatory cytokine-induced alpha-cell impairment in human islet microtissues is partially restored by dual incretin receptor agonism

The Gut-Bone Axis in Diabetes

Contact Info

Product

Resources

About