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

Campbell, Jonathan E.; Müller, Timo D.; Finan, Brian; DiMarchi, Richard D.; Tschöp, Matthias H.; D’Alessio, David A.

doi:10.1016/j.cmet.2023.07.010

Cited by 45 publications

(14 citation statements)

References 89 publications

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“…Thus, future investigations into the timescales of stress adaptations’ initiation and persistence are motivated by not only fundamental biological understanding but also the longer-term clinical relevance of whether hepatocyte tissue memory and lasting maladaptive phenotypes may be seeded prior to disease diagnosis. With weight loss capable of stabilizing or even reversing histologic features of MASLD, whether and to what degree hepatocytes’ memory of chronic stress is reversible or establishes lasting (mal)adaptive responses even after return to normal weights could shape long-term implications of ongoing trials and novel therapeutic avenues for MASLD 111,151,152 .…”

Section: Discussionmentioning

confidence: 99%

Chronic metabolic stress drives developmental programs and loss of tissue functions in non-transformed liver that mirror tumor states and stratify survival

Tzouanas,

Sherman,

Shay

et al. 2023

Preprint

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Under chronic stress, cells must balance competing demands between cellular survival and tissue function. In metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD/NASH), hepatocytes cooperate with structural and immune cells to perform crucial metabolic, synthetic, and detoxification functions despite nutrient imbalances. While prior work has emphasized stress-induced drivers of cell death, the dynamic adaptations of surviving cells and their functional repercussions remain unclear. Namely, we do not know which pathways and programs define cellular responses, what regulatory factors mediate (mal)adaptations, and how this aberrant activity connects to tissue-scale dysfunction and long-term disease outcomes. Here, by applying longitudinal single-cell multi-omics to a mouse model of chronic metabolic stress and extending to human cohorts, we show that stress drives survival-linked tradeoffs and metabolic rewiring, manifesting as shifts towards development-associated states in non-transformed hepatocytes with accompanying decreases in their professional functionality. Diet-induced adaptations occur significantly prior to tumorigenesis but parallel tumorigenesis-induced phenotypes and predict worsened human cancer survival. Through the development of a multi-omic computational gene regulatory inference framework and humanin vitroand mousein vivogenetic perturbations, we validate transcriptional (RELB, SOX4) and metabolic (HMGCS2) mediators that co-regulate and couple the balance between developmental state and hepatocyte functional identity programming. Our work defines cellular features of liver adaptation to chronic stress as well as their links to long-term disease outcomes and cancer hallmarks, unifying diverse axes of cellular dysfunction around core causal mechanisms.

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Section: Discussionmentioning

confidence: 99%

Chronic metabolic stress drives developmental programs and loss of tissue functions in non-transformed liver that mirror tumor states and stratify survival

Tzouanas,

Sherman,

Shay

et al. 2023

Preprint

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“…Understanding this nuanced interplay between AI, gene length, and DHS abundance can open avenues for more individualized therapeutic interventions. For instance, such a well-known protein-coding gene, GLP1R, one of major drug targets for diabetes and obesity[49], is identified to have high allelic imbalance in cis-regulatory variants and associated with type 2 diabetes, which implies potentially large difference in expression level between individuals with reference allele and risk alleles. This precision might manifest in targeted treatments using pharmacological agents or advanced gene editing technologies at single cell.…”

Section: Discussionmentioning

confidence: 99%

Context Dependent Perturbation of Allelic Expression Imbalance Reveals Novel Candidate Therapeutic Targets for Metabolic diseases

Moon,

Park

2023

Preprint

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Not all alleles express equally. Allelic imbalance (AI) denotes variations in gene expression based on the inherited versions, or alleles, of those genes. While AI has the potential to shed light on many complex diseases, its specific role in obesity and connection with gene regulation remains largely elusive. In this study, we delve into AI’s correlation with gene expression in obesity and its potential ramifications for susceptibility to associated health complications. By melding transcriptomic and epigenomic data through a colocalization approach, we discerned significant variations in the length and functional roles of both coding and noncoding differentially expressed genes across AI spectrums. Further, our examination unveiled DNaseI hypersensitive sites in close association with genetic markers identified in large-scale association studies (GWAS-identified SNPs) and polygenic risk variants, emphasizing the importance of length-dependent regulation and allelic interactions. These discoveries not only expand our understanding of the genetic underpinnings of obesity but also highlight new paths for personalized diagnostics and treatments. Our findings robustly advocate for intensified research for integration of rare pathogenic variants into the intricate interplay between genes and the environment.

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“…Currently, the superiority of GLP-1RAs in cardiovascular protection is primarily focused on diabetes-related conditions, as demonstrated above. However, recent findings have revealed that apart from their hypoglycemic effects, GLP-1RAs also have therapeutic efficacy in weight loss ( Campbell et al, 2023 ). Basic research show their potential anti-inflammatory effects in obesity-related heart disease and advantages in ASCVD and aged animal models ( Withaar et al, 2023 ).…”

Section: Cardiorenal Protection Of Sglt2i Glp-1ras and Dpp-4imentioning

confidence: 99%

Emerging role of antidiabetic drugs in cardiorenal protection

Fu,

Huo,

Mao

et al. 2024

Front. Pharmacol.

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The global prevalence of diabetes mellitus (DM) has led to widespread multi-system damage, especially in cardiovascular and renal functions, heightening morbidity and mortality. Emerging antidiabetic drugs sodium-glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1RAs), and dipeptidyl peptidase-4 inhibitors (DPP-4i) have demonstrated efficacy in preserving cardiac and renal function, both in type 2 diabetic and non-diabetic individuals. To understand the exact impact of these drugs on cardiorenal protection and underlying mechanisms, we conducted a comprehensive review of recent large-scale clinical trials and basic research focusing on SGLT2i, GLP-1RAs, and DPP-4i. Accumulating evidence highlights the diverse mechanisms including glucose-dependent and independent pathways, and revealing their potential cardiorenal protection in diabetic and non-diabetic cardiorenal disease. This review provides critical insights into the cardiorenal protective effects of SGLT2i, GLP-1RAs, and DPP-4i and underscores the importance of these medications in mitigating the progression of cardiovascular and renal complications, and their broader clinical implications beyond glycemic management.

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

Cited by 45 publications

References 89 publications

Chronic metabolic stress drives developmental programs and loss of tissue functions in non-transformed liver that mirror tumor states and stratify survival

Chronic metabolic stress drives developmental programs and loss of tissue functions in non-transformed liver that mirror tumor states and stratify survival

Context Dependent Perturbation of Allelic Expression Imbalance Reveals Novel Candidate Therapeutic Targets for Metabolic diseases

Emerging role of antidiabetic drugs in cardiorenal protection

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