Hypothalamic sex-specific metabolic shift by canagliflozin during aging

GeroScience, Год журнала: 2024, Номер 46(5), С. 4479 - 4493

Опубликована: Май 27, 2024

The hypothalamus undergoes significant changes with aging and plays crucial roles in age-related metabolic alterations. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are anti-diabetic agents that promote glucose excretion, homeostasis. Recent studies have shown a SGLT2i, Canagliflozin (Cana), can extend the median survival of genetically heterogeneous UM-HET3 male mice improve central control via increases hypothalamic insulin responsiveness aged males, as well reduced age-associated inflammation. We studied long- short-term effects Cana on mice. Starting treatment from 7 months age, we show 4 weeks significantly body weight fat mass but not female was associated enhanced tolerance sensitivity observed by 12 months. Indirect calorimetry showed increased energy expenditure male, mice, at age. Long-term rates both sexes, markedly increasing formation orexigenic anorexigenic projections to paraventricular nucleus (PVH) mostly females 25 Hypothalamic RNA-sequencing analysis revealed sex-specific genes signaling pathways related signaling, glycogen catabolic pathway, neuropeptide mitochondrial function upregulated Cana, males showing more pronounced sustained effect age groups. Overall, our data provide critical evidence for mechanisms affected during suggesting key targets Cana-induced neuroprotection control.

Язык: Английский

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Effect of dapagliflozin on proteomics and metabolomics of serum from patients with type 2 diabetes

Diabetology & Metabolic Syndrome, Год журнала: 2023, Номер 15(1)

Опубликована: Дек. 4, 2023

Sodium-glucose co-transporter 2 (SGLT2) inhibitors reduced the risk of cardiovascular and renal outcomes in patients with type diabetes (T2D), but underlying mechanism has not been well elucidated. The circulating levels proteins metabolites reflect overall state human body. This study aimed to evaluate effect dapagliflozin on proteome metabolome newly diagnosed T2D.A total 57 T2D were enrolled, received 12 weeks treatment (10 mg/d, AstraZeneca). Serum investigated at baseline after treatment.Dapagliflozin significantly decreased HbA1c, BMI, HOMA-IR (all p < 0.01). Multivariate models indicated clear separations proteomics metabolomics data between treatment. A 38 differentially abundant including 23 increased 15 proteins, 35 17 18 metabolites, identified. In addition influencing glucose metabolism (glycolysis/gluconeogenesis pentose phosphate pathway), sex hormone-binding globulin, transferrin receptor protein 1, disintegrin, metalloprotease-like decysin-1 apolipoprotein A-IV levels, complement C3, fibronectin, afamin, attractin, xanthine, uric acid levels.The changed These changes might be associated beneficial outcomes.

Язык: Английский

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The latest emerging drugs for the treatment of diabetic cardiomyopathy

Expert Opinion on Pharmacotherapy, Год журнала: 2024, Номер 25(6), С. 641 - 654

Опубликована: Апрель 12, 2024

Introduction Diabetic cardiomyopathy (DCM) is a serious complication of diabetes mellitus involving multiple pathophysiologic mechanisms. In addition to hypoglycemic agents commonly used in diabetes, metabolism-related drugs, natural plant extracts, melatonin, exosomes, and rennin-angiotensin-aldosterone system are cardioprotective DCM. However, there lack systematic summarization drugs for

Язык: Английский

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Sodium-glucose cotransporter-2 inhibitors protect tissues via cellular and mitochondrial pathways: Experimental and clinical evidence

World Journal of Experimental Medicine, Год журнала: 2024, Номер 14(2)

Опубликована: Июнь 13, 2024

Mitochondrial dysfunction is a key driver of cardiovascular disease (CVD) in metabolic syndrome and diabetes. This promotes the production reactive oxygen species (ROS), which cause oxidative stress inflammation. Angiotensin II, main mediator renin-angiotensin-aldosterone system, also contributes to CVD by promoting ROS production. Reduced activity sirtuins (SIRTs), family proteins that regulate cellular metabolism, worsens stress. Reduction energy mitochondria common feature all disorders. High SIRT levels 5’ adenosine monophosphate-activated protein kinase signaling stimulate hypoxia-inducible factor 1 beta, ketosis. Ketosis, turn, increases autophagy mitophagy, processes clear cells debris protect against damage. Sodium-glucose cotransporter-2 inhibitors (SGLT2i), class drugs used treat type 2 diabetes, have beneficial effect on these mechanisms. Randomized clinical trials shown SGLT2i improves cardiac function reduces rate renal events. increase mitochondrial efficiency, reduce inflammation, strengthen tissues. These findings suggest hold great potential for treatment CVD. Furthermore, they are proposed as anti-aging drugs; however, rigorous research needed validate preliminary findings.

Язык: Английский

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SGLT2 inhibitor improves kidney function and morphology by regulating renal metabolism in mice with diabetic kidney disease

Journal of Diabetes and its Complications, Год журнала: 2023, Номер 38(2), С. 108652 - 108652

Опубликована: Ноя. 21, 2023

Язык: Английский

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Cardioprotection of Canagliflozin, Dapagliflozin, and Empagliflozin: lessons from preclinical studies

Chemico-Biological Interactions, Год журнала: 2024, Номер 403, С. 111229 - 111229

Опубликована: Сен. 6, 2024

Язык: Английский

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The lower incidence of cervical cancer in type 2 diabetes mellitus with sodium-glucose cotransporter 2 inhibitors utilization

Journal of Cancer, Год журнала: 2024, Номер 15(19), С. 6196 - 6203

Опубликована: Янв. 1, 2024

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are medications with anti-inflammatory effects used to treat type diabetes mellitus (T2DM). Cervical cancer is the most common gynecological and characterized by elevated inflammatory status. Accordingly, this study aimed investigate potential association between SGLT2 inhibitor use cervical development. In retrospective cohort study, female patients T2DM were divided into groups: users a control group of non-SGLT2 users. After propensity score matching, each had 136 212 patients. Cox proportional hazards regression was conducted obtain adjusted hazard ratio (aHR) 95% confidence interval (CI) for groups. Overall, 148 191 cases identified in groups, respectively. The incidence significantly lower than (aHR, 0.77; CI, 0.62-0.96,

Язык: Английский

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Kidney single-cell transcriptomes uncover SGLT2i-induced metabolic reprogramming via restoring glycolysis and fatty acid oxidation

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Ноя. 2, 2023

Abstract Approximately 40% of individuals with chronic kidney disease have type 2 diabetes mellitus, and diabetic is the leading cause end-stage worldwide. Inhibitors sodium-glucose cotransporter (SGLT2) been demonstrated to be effective in glucose control, improving cardiovascular outcomes progression disease. However, protective role SGLT2 inhibition on metabolism not fully understood. To explore these mechanisms further, we conducted analysis publicly available single-cell RNA sequencing data db/db mice treated an inhibitor(dapagliflozin) accompanying controls. We found that proximal tubule cells exhibited impaired glycolysis high fatty acid oxidation compared control mice. reversed this metabolic dysfunction by reducing its substrate accumulation. also upregulates without increasing uptake acids elongation, along low lipotoxicity. Surprisingly, both SGLT2(+) SGLT2(-) show gene consistent changes expression genes, a non-cell autonomous effect dapagliflozin treatment. This study demonstrates via restoring dysfunction.

Язык: Английский

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Toma de posición. Efecto de los iSGLT-2 sobre la presión arterial, el daño vascular, la enfermedad renal y el riesgo cardiovascular asociado

Revista de la Sociedad Argentina de Diabetes, Год журнала: 2023, Номер 57(3)

Опубликована: Дек. 12, 2023

Un nuevo y sorprendente paradigma se ha conformado con la llegada de las “gliflozinas”. Más allá su acción antihiperglucémica, estos fármacos han impactado centralmente en terapéutica alteraciones cardio-vásculo-reno-metabólicas responsables enfermedades más prevalentes que abordamos práctica clínica. Los inhibidores del cotransportador sodio glucosa tipo 2 (iSGLT-2) ayudan a controlar reducir progresión daño órgano blanco. En esta Toma Posición, cuatro Sociedades Médicas vinculadas estas temáticas acordaron plasmar el conocimiento este esperanzador fenómeno generado por 7500 publicaciones difundidas los últimos 10 años sobre beneficio Decidimos revisar manera rigurosa evidencias experimentales múltiples trabajos controlados muestran sus efectos metabólicos, vasculares, cardíacos, renales también celulares, incluyendo aspectos no resueltos advertencias acerca precauciones uso.

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