Incretin-responsive human pancreatic adipose tissue organoids: a functional model for fatty pancreas research DOI Creative Commons

Estela Lorza‐Gil,

Olaf Strauß,

Eckart Ziegler

et al.

Molecular Metabolism, Journal Year: 2024, Volume and Issue: 91, P. 102067 - 102067

Published: Nov. 14, 2024

Infiltration of adipocytes into the pancreatic parenchyma has been linked to impaired insulin secretion in individuals with increased genetic risk T2D and prediabetic conditions. However, study this ectopic fat depot limited by lack suitable vitro models. Here, we developed a novel 3D model functionally mature human adipose tissue organoids aggregating tissue-derived stromal vascular fraction (SVF) cells differentiating them over 19 days. These carry biological properties situ fat, presenting levels adipogenic markers comparable native improved lipolytic anti-lipolytic response compared conventional 2D cultures. The harbour small population immune cells, mimicking vivo environment. Furthermore, they express GIPR, allowing investigation incretin effects fat. In accordance, GIP dual GLP1R/GIPR agonist tirzepatide stimulate lipolysis but had distinct on expression proinflammatory cytokines. This organoid is valuable tool metabolic impact signalling tissue, revealing potential therapeutic targets incretins beyond islets. donor-specific memory these enables examination fat-islet crosstalk donor-related context.

Language: Английский

Glucose-dependent insulinotropic polypeptide (GIP) DOI Creative Commons
Timo D. Müller, Alice E. Adriaenssens,

Bo Ahrén

et al.

Molecular Metabolism, Journal Year: 2025, Volume and Issue: 95, P. 102118 - 102118

Published: Feb. 28, 2025

Glucose-dependent insulinotropic polypeptide (GIP) was the first incretin identified and plays an essential role in maintenance of glucose tolerance healthy humans. Until recently GIP had not been developed as a therapeutic thus has overshadowed by other incretin, glucagon-like peptide 1 (GLP-1), which is basis for several successful drugs to treat diabetes obesity. However, there rekindling interest biology recent years, great part due pharmacology demonstrating that both GIPR agonism antagonism may be beneficial treating obesity diabetes. This apparent paradox reinvigorated field, led new lines investigation, deeper understanding GIP. In this review, we provide detailed overview on multifaceted nature discuss implications signal modification various diseases. Following its classification hormone, emerged pleiotropic hormone with variety metabolic effects outside endocrine pancreas. The numerous render interesting candidate development pharmacotherapies obesity, diabetes, drug-induced nausea bone neurodegenerative disorders.

Language: Английский

Citations

3
The other side of the incretin story: GIPR signaling in energy homeostasis DOI
Susana Castelo Branco Ramos Nakandakari, Andin Fosam, Rachel J. Perry

et al.

Cell Metabolism, Journal Year: 2025, Volume and Issue: 37(1), P. 1 - 3

Published: Jan. 1, 2025

Language: Английский

Citations

1
Binding Kinetics, Bias, Receptor Internalization and Effects on Insulin Secretionin vitroandin vivoof a Novel GLP-1R/GIPR Dual Agonist, HISHS-2001 DOI Creative Commons
Yusman Manchanda, Ben Jones, Gaëlle Carrat

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 17, 2025

Abstract The use of incretin analogues has emerged in recent years as an effective approach to achieve both enhanced insulin secretion and weight loss type 2 diabetes (T2D) patients. Agonists which bind stimulate multiple receptors have shown particular promise. However, off target effects, including nausea diarrhoea, remain a complication using these agents, modified versions with optimized pharmacological profiles and/or biased signaling at the cognate are increasingly sought. Here, we describe synthesis properties molecule binds glucagon-like peptide-1 (GLP-1) glucose-dependent insulinotropic polypeptide (GIP) (GLP-1R GIPR) enhance secretion. HISHS-2001 shows increased affinity GLP-1R, well tendency towards reduced internalization recycling this receptor versus FDA-approved dual GLP-1R/GIPR agonist tirzepatide. also displayed significantly greater bias cAMP generation β-arrestin recruitment compared In contrast, G αs was lower tirzepatide but higher GIPR. Administered obese hyperglycaemic db/db mice, circulating whilst lowering body HbA1c similar efficacy substantially doses. Thus, represents novel improved profile.

Language: Английский

Citations

1
The GIP receptor activates futile calcium cycling in white adipose tissue to increase energy expenditure and drive weight loss in mice DOI
Xinxin Yu,

Shiuhwei Chen,

Jan‐Bernd Funcke

et al.

Cell Metabolism, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 1, 2024

Language: Английский

Citations

7
Recent advances in incretin-based therapy for MASLD: from single to dual or triple incretin receptor agonists DOI
Giovanni Targher, Alessandro Mantovani, Christopher D. Byrne

et al.

Gut, Journal Year: 2024, Volume and Issue: unknown, P. gutjnl - 334023

Published: Nov. 26, 2024

Clinically effective pharmacological treatment(s) for metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form steatohepatitis (MASH) represent a largely unmet need in medicine. Since glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been licensed the treatment of type 2 diabetes mellitus obesity, they were one first drug classes to be examined individuals with MASLD/MASH. Successful phase randomised clinical trials these agents resulted progression 3 (principally testing long-term efficacy subcutaneous semaglutide). Over last few years, addition GLP-1RAs, newer glucose-dependent insulinotropic peptide and/or glucagon agonist functions tested, increasing evidence from histological improvements MASLD/MASH, as well benefits on MASLD-related extrahepatic complications. Based this background evidence, single, dual or triple incretin are becoming an attractive promising option MASLD MASH, particularly coexisting obesity mellitus. In narrative review, we examine rapidly expanding body supporting role incretin-based pharmacotherapies delaying reversing MASH progression. We also discuss biology incretins putative hepatoprotective mechanisms managing MASH.

Language: Английский

Citations

4
Greater improvement in insulin sensitivity per unit weight loss associated with tirzepatide versus semaglutide: An exploratory analysis DOI
Kieren J. Mather, Andrea Mari, Govinda J. Weerakkody

et al.

Diabetes Obesity and Metabolism, Journal Year: 2025, Volume and Issue: 27(3), P. 1507 - 1514

Published: Jan. 6, 2025

Abstract Aims To explore the relationship between weight loss and insulin sensitivity in response to tirzepatide or semaglutide. Materials Methods We conducted a post hoc exploratory analysis of 28‐week, double‐blind, randomized trial people with type 2 diabetes treated metformin, 15 mg, semaglutide 1 mg placebo. evaluated change body determined from hyperinsulinemic euglycemic clamp ( M value), mixed‐meal tolerance testing (Matsuda index). Results Tirzepatide was associated greater improvement than assessed using clamps p < 0.001). With tirzepatide, improvements were percent R = −0.656, 0.0001). semaglutide, less strongly correlated −0.268, 0.0820; 0.0242 vs. tirzepatide). In regression analyses, slope value statistically different 0.0461). These relationships also Matsuda index as metric sensitivity, fat mass determinant sensitivity. Conclusions Improvement proportional loss, strength association tirzepatide. analysis, per unit The following treatment not simply attributable loss.

Language: Английский

Citations

0
A dietary intervention following incretin analog treatment restores adipose tissue functions in diet-induced obese mice DOI Creative Commons
Jan Seuntjens,

Jente De Gols,

Bethan K. Davies

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 10, 2025

ABSTRACT Obesity affects more than 15% of the world population and is associated with development glucose intolerance type 2 diabetes. In recent years, incretin analogs are prescribed at a high rate for treatment obesity diabetes due to their potent effects on lowering bodyweight improving homeostasis. However, studies suggest that many patients do not stay analog therapy thereby rapidly regain bodyweight. The non-compliance only drug shortage but also insufficient knowledge long-term therapy. To address this gap provide strategy obesity, we examined withdrawal adipose tissue functions in diet-induced obese mice. Our transcriptome data restored most obesity-mediated deregulated gene expression tissue. genes encoding lipogenic enzymes, downregulated by were treatment. Upon withdrawal, mice displayed rapid regain, impaired function, intolerance. contrast, dietary intervention following tissue, maintained homeostasis, increased lean mass minimized body weight regain. findings revealed highlight importance therapy, which may contribute guidelines obesity.

Language: Английский

Citations

0
The physiological impact of an N‐terminal Halo‐tag on glucose‐dependent insulinotropic polypeptide receptor function in mice DOI Creative Commons

Iona Davies,

Yusman Manchanda, Kyle W. Sloop

et al.

Diabetes Obesity and Metabolism, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 30, 2025

Language: Английский

Citations

0
Short‐term outcomes of switching from GLP‐1 receptor agonists to tirzepatide in type 2 diabetes: A retrospective, observational study in clinical practice DOI
Mari Matsushiro, Yuko Yamaguchi,

Hitoshi Kuwata

et al.

Diabetes Obesity and Metabolism, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 2, 2025

Language: Английский

Citations

0
The role of GIPR in food intake control DOI Creative Commons

Paula-Peace James-Okoro,

Jo E. Lewis, Fiona M. Gribble

et al.

Frontiers in Endocrinology, Journal Year: 2025, Volume and Issue: 16

Published: March 17, 2025

Glucose-dependent insulinotropic polypeptide (GIP) is one of two incretin hormones playing key roles in the control food intake, nutrient assimilation, insulin secretion and whole-body metabolism. Recent pharmacological advances clinical trials show that unimolecular co-agonists target receptors for incretins - GIP glucagon-like peptide 1 (GLP-1) offer more effective treatment strategies obesity type 2 diabetes mellitus (T2D) compared with GLP-1 receptor (GLP1R) agonists alone, suggesting previously underappreciated regulating intake body weight. The mechanisms by which regulates energy balance remain controversial as both agonism antagonism (GIPR) produce weight loss improve metabolic outcomes preclinical models. studies have shown GIPR signalling central nervous system (CNS), especially regions brain regulate balance, essential its action on appetite regulation. This finding has sparked interest understanding engages circuits to reduce In this review, we present knowledge around actions regulation potential GIPR/GLP1R may balance.

Language: Английский

Citations

0