Glucagon and glucagon‐like peptide‐1 dual agonist therapy: A possible future towards fatty kidney disease

European Journal of Clinical Investigation, Год журнала: 2024, Номер unknown

Опубликована: Окт. 13, 2024

Abstract Background Obesity is a growing epidemic affecting approximately 40% of the adult population in developed countries with major health consequences and comorbidities, including diabetes mellitus insulin resistance, metabolically associated fatty liver disease, atherosclerotic cardiovascular cerebrovascular diseases chronic kidney disease. Pharmacotherapies targeting significant weight reduction may have beneficial effects on such though therapeutic options are highly limited. In this narrative review, we aim to evaluate current knowledge regarding dual agonist therapies potential implications for managing Results Conclusion Glucagon‐like peptide‐1 agonists sodium‐glucose cotransporter‐2 inhibitors two novel classes glucose‐lowering medications beneficiary renal outcomes, estimated glomerular filtration rate, albuminuria disease progression. Recently, glucagon‐like glucagon receptors, namely survodutide cotadutide, been evaluated well‐established example visceral obesity. Fatty another concept implicated pathophysiology among patients

Язык: Английский

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Finerenone attenuates downregulation of the kidney GLP-1 receptor and glucagon receptor and cardiac GIP receptor in mice with comorbid diabetes

Diabetology & Metabolic Syndrome, Год журнала: 2024, Номер 16(1)

Опубликована: Ноя. 24, 2024

Abstract Background Several new treatments have recently been shown to heart and kidney protective benefits in people with diabetes. Because these were developed parallel, it is unclear how the different molecular pathways affected by therapies may overlap. Here, we examined effects of mineralocorticoid receptor antagonist finerenone mice comorbid diabetes, focusing on regulation expression glucagon-like peptide-1 (GLP-1R), gastric inhibitory polypeptide (GIPR) glucagon (GCGR), which are targets approved or investigational Methods Male C57BL/6J fed a high fat diet for 26 weeks. Twelve weeks into feeding period, received an intraperitoneal injection streptozotocin before being followed remaining 14 (DMHFD mice). After weeks, containing (100 mg/kg diet) alone further 2 Cell culture experiments performed primary vascular smooth muscle cells (VSMCs), NRK-49 F fibroblasts, HK-2 cells, MDCK cells. Results DMHFD albuminuria, glomerular mesangial expansion, diastolic dysfunction (decreased E/A ratio). Glp1r Gcgr predominantly expressed arteriolar VSMCs distal nephron structures mouse kidneys respectively, whereas Gipr was predominant three transcripts hearts. Kidney cardiac mRNA levels reduced this reduction negated attenuated finerenone. Mechanistically, upregulation profibrotic growth factor Ccn2 kidneys, recombinant CCN2 downregulated respectively. Conclusions Through its anti-fibrotic actions, reverses downregulation diabetic kidney. Both GLP-1R agonists proven cardiorenal benefits, co-agonists under development. The current findings provide preclinical rationale combined use agonist family. They also mechanism action insights potential benefit diabetes whom not be indicated.

Язык: Английский

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Characterization of LY3324954 a long-acting glucagon-receptor agonist

Molecular Metabolism, Год журнала: 2024, Номер 91, С. 102073 - 102073

Опубликована: Ноя. 25, 2024

Glucagon is a crucial regulator of glucose and lipid metabolism as well whole-body energy balance. Thus, modulation glucagon receptor (GCGR) activity in the context single-molecule multi-receptor co-agonists has become an emerging therapeutic target against obesity obesity-associated metabolic dysfunction. To better elucidate role GCGR-signaling when paired with incretin signaling or on its own, we developed, LY3324954, GCGR agonist improved potency selectivity compared to native peptide.

Язык: Английский

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Incretin and glucagon receptor polypharmacology in chronic kidney disease

AJP Endocrinology and Metabolism, Год журнала: 2024, Номер 326(6), С. E747 - E766

Опубликована: Март 13, 2024

Chronic kidney disease is a debilitating condition associated with significant morbidity and mortality. In recent years, the effects of incretin-based therapies, particularly glucagon-like peptide-1 receptor agonists (GLP-1RAs), have garnered substantial interest in management type 2 diabetes obesity. This review delves into intricate interactions between kidney, GLP-1RAs, glucagon, shedding light on their mechanisms action potential benefits. Both GLP-1 known for opposing roles regulating glucose homeostasis, improve systemic risk factors affecting including adiposity, inflammation, oxidative stress, endothelial function. Additionally, these hormones pharmaceutical mimetics may direct impact kidney. Clinical studies provided evidence that incretins, those incorporating glucagon agonism, are likely to exhibit improved outcomes. Although further research necessary, polypharmacology holds promise preserving function through eliciting vasodilatory effects, influencing volume electrolyte handling, improving factors.

Язык: Английский

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GCGR: novel potential therapeutic target for chronic kidney disease

Science China Life Sciences, Год журнала: 2024, Номер 67(7), С. 1542 - 1544

Опубликована: Апрель 26, 2024

Язык: Английский

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Glucagon infusion alters the circulating metabolome and urine amino acid excretion in dogs

Journal of Endocrinology, Год журнала: 2024, Номер 262(2)

Опубликована: Май 30, 2024

Glucagon plays a central role in amino acid (AA) homeostasis. The dog is an established model of glucagon biology, and recently, metabolomic changes people associated with infusions have been reported. also has effects on the kidney; however, urinary AA concentrations remain under investigation. Therefore, we aimed to fill these gaps canine by determining plasma metabolome measuring urine concentrations. Employing two constant rate (CRI) - low-dose (CRI-LO: 3 ng/kg/min) high-dose (CRI-HI: 50 five research beagles, monitored interstitial glucose conducted untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) samples collected pre- post-infusion. CRI-HI induced transient peak (90-120 min), returning near baseline infusion end, while only CRI-LO resulted 372 significantly altered metabolites, primarily reductions (333). Similarly, affected 414 369 reductions, evidenced distinct clustering post-infusion via data reduction (PCA sPLS-DA). notably decreased circulating levels, impacting various AA-related energy-generating metabolic pathways. Urine analysis revealed increased 3-methyl-l-histidine glutamine, alanine These findings demonstrate glucagon's glucose-independent modulation highlight dog's relevance as translational for biology. Understanding contributes managing dysregulated conditions informs treatments

Язык: Английский

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Uninephrectomy and sodium‐glucose cotransporter 2 inhibitor administration delay the onset of hyperglycemia

Physiological Reports, Год журнала: 2024, Номер 12(21)

Опубликована: Ноя. 1, 2024

The kidneys are essential for glucose homeostasis, as they perform gluconeogenesis, utilize glucose, and reabsorb glucose. Reabsorption is performed by SGLT2, which responsible about 90%. However, little known how renal handling altered in patients with chronic kidney disease (CKD). SGLT2 inhibitors have demonstrated efficacy suppressing CKD progression clinical trials, but their mechanisms not fully understood. Therefore, this study aimed to evaluate each uninephrectomy (UNx) inhibitor affects blood concentrations SGLTs dynamics rats type 2 diabetes mellitus. Male were divided into four treatment groups: sham + placebo, dapagliflozin, UNx dapagliflozin. There few group differences food intake or body weight, continued rise the whereas was delayed several weeks largely suppressed mRNA expression significantly lower group, SGLT1 did differ. Dapagliflozin alter expression. In animal models of diabetes, reabsorption appears likely be a major contributor development hyperglycemia.

Язык: Английский

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