Advances in Research on Type 2 Diabetes Mellitus Targets and Therapeutic Agents

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(17), С. 13381 - 13381

Опубликована: Авг. 29, 2023

Diabetes mellitus is a chronic multifaceted disease with multiple potential complications, the treatment of which can only delay and prolong terminal stage disease, i.e., type 2 diabetes (T2DM). The World Health Organization predicts that will be seventh leading cause death by 2030. Although many antidiabetic medicines have been successfully developed in recent years, such as GLP-1 receptor agonists SGLT-2 inhibitors, single-target drugs are gradually failing to meet therapeutic requirements owing individual variability, diversity pathogenesis, organismal resistance. Therefore, there remains need investigate pathogenesis T2DM more depth, identify targets, provide improved glycemic control solutions. This review presents an overview mechanisms action development latest agents targeting years. It also discusses emerging target-based therapies new targets emerged within last three aim our theoretical basis for further advancement targeted T2DM.

Язык: Английский

---

SGLT2 inhibitors: from glucose-lowering to cardiovascular benefits

Cardiovascular Research, Год журнала: 2024, Номер 120(5), С. 443 - 460

Опубликована: Март 8, 2024

Abstract An increasing number of individuals are at high risk type 2 diabetes (T2D) and its cardiovascular complications, including heart failure (HF), chronic kidney disease (CKD), eventually premature death. The sodium-glucose co-transporter-2 (SGLT2) protein sits in the proximal tubule human nephrons to regulate glucose reabsorption inhibition by gliflozins represents cornerstone contemporary T2D HF management. Herein, we aim provide an updated overview pleiotropy gliflozins, mechanistic insights delineate related (CV) benefits. By discussing evidence obtained preclinical models landmark randomized controlled trials, move from bench bedside across broad spectrum cardio- cerebrovascular diseases. With trials confirming a reduction major adverse CV events (MACE; composite endpoint death, non-fatal myocardial infarction, stroke), SGLT2 inhibitors strongly mitigate for hospitalization diabetics non-diabetics alike while conferring renoprotection specific patient populations. Along four pathophysiological axes (i.e. systemic, vascular, cardiac, renal levels), into key mechanisms that may underlie their beneficial effects, gliflozins’ role modulation inflammation, oxidative stress, cellular energy metabolism, housekeeping mechanisms. We also discuss how this drug class controls hyperglycaemia, ketogenesis, natriuresis, hyperuricaemia, collectively contributing pleiotropic effects. Finally, evolving data setting diseases arrhythmias presented potential implications future research clinical practice comprehensively reviewed.

Язык: Английский

---

Applications of SGLT2 inhibitors beyond glycaemic control

Nature Reviews Nephrology, Год журнала: 2024, Номер 20(8), С. 513 - 529

Опубликована: Апрель 26, 2024

Язык: Английский

---

Inhibition of sodium-glucose cotransporter 2 suppresses renal stone formation

Pharmacological Research, Год журнала: 2022, Номер 186, С. 106524 - 106524

Опубликована: Окт. 28, 2022

Nephrolithiasis is a common renal disease with no effective medication. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, an anti-diabetic agent, have diuretic and anti-inflammatory properties could prevent nephrolithiasis. Here, we investigated the potential of SGLT2 inhibition against nephrolithiasis using large-scale epidemiological data, animal models, cell culture experiments. This study included data diabetic patients (n = 1,538,198) available in Japanese administrative database divided them according to inhibitor prescription status. For experiments, calcium oxalate stones were induced by ethylene glycol Sprague-Dawley rats, phlorizin, SGLT1/2 inhibitor, was used for treatment. The effects SGLT2-specific stone formation assessed SGLT2-deficient mice human proximal tubular line, HK-2. prevalence men significantly lower group than non-SGLT2 group. Phlorizin attenuated downregulated kidney injury molecule 1 (Kim1) osteopontin (Opn) expression unchanged water intake urine volume. It suppressed inflammation macrophage marker expression, suggesting role reducing inflammation. resistant glyoxylic acid-induced reduced Opn damages. High glucose-induced upregulation OPN CD44 surface adhesion upon SGLT2-silencing HK-2 cells. Overall, our findings identified that prevents may be promising therapeutic approach

Язык: Английский

---

Mechanisms of benefits of sodium-glucose cotransporter 2 inhibitors in heart failure with preserved ejection fraction

European Heart Journal, Год журнала: 2023, Номер 44(37), С. 3640 - 3651

Опубликована: Июнь 13, 2023

For decades, heart failure with preserved ejection fraction (HFpEF) proved an elusive entity to treat. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have recently been shown reduce the composite of hospitalization or cardiovascular death in patients HFpEF landmark DELIVER and EMPEROR-Preserved trials. While improvements blood sugar, pressure, attenuation kidney disease progression all may play some role, preclinical translational research identified additional mechanisms these agents. The SGLT2 intriguingly induce a nutrient-deprivation hypoxic-like transcriptional paradigm, increased ketosis, erythropoietin, autophagic flux addition altering iron homeostasis, which contribute improved cardiac energetics function. These agents also epicardial adipose tissue alter adipokine signalling, role reductions inflammation oxidative stress observed inhibition. Emerging evidence indicates that drugs impact cardiomyocyte ionic homeostasis although whether this is through indirect via direct, off-target effects on other ion channels has yet be clearly characterized. Finally, myofilament stiffness as well extracellular matrix remodelling/fibrosis heart, improving diastolic established themselves robust, disease-modifying therapies recent trial results are incorporated into clinical guidelines, will likely become foundational therapy HFpEF.

Язык: Английский

---

SGLT2 Inhibitors in Diabetic and Non-Diabetic Chronic Kidney Disease

Biomedicines, Год журнала: 2023, Номер 11(2), С. 279 - 279

Опубликована: Янв. 19, 2023

Results from recent randomized controlled trials on inhibitors of the sodium-glucose cotransporter 2 (SGLT2) have determined a paradigm shift in treatment patients with type diabetes mellitus. These agents been shown not only to ameliorate metabolic control, but also independently protect cardiovascular events and reduce progression chronic kidney disease (CKD) these patients. The magnitude nephroprotective effect observed studies is likely make SGLT2 most impactful drug class for diabetic CKD since discovery renin-angiotensin system inhibitors. Even more surprisingly, slow non-diabetic individuals varying degrees proteinuria, suggesting that activation involved pathogenesis independent its etiology. As indications continue expand, it still unclear whether benefits may extend at lower risk if their association other confer additional protection.

Язык: Английский

---

The case for a ketogenic diet in the management of kidney disease

BMJ Open Diabetes Research & Care, Год журнала: 2024, Номер 12(2), С. e004101 - e004101

Опубликована: Апрель 1, 2024

Ketogenic diets have been widely used for weight loss and are increasingly in the management of type 2 diabetes. Despite evidence that ketones multiple positive effects on kidney function, common misconceptions about ketogenic diets, such as high protein content acid load, prevented their widespread use individuals with impaired function. Clinical trial focusing major adverse events is sparse. The aim this review to explore a diet, an emphasis pleiotropic actions ketones, health. Given minimal concerns relation potential renoprotective future studies should evaluate safety efficacy interventions disease.

Язык: Английский

---

SGLT2 Inhibitor Use and Risk of Dementia and Parkinson Disease Among Patients With Type 2 Diabetes

Neurology, Год журнала: 2024, Номер 103(8)

Опубликована: Сен. 18, 2024

Despite the mechanistic potential of sodium-glucose cotransporter 2 inhibitor (SGLT2i) to improve neurologic outcomes, efficacy SGLT2i in neurodegenerative disorders among patients with type diabetes is not well established. This population-based cohort study aimed investigate association use risks incident dementia and Parkinson disease (PD) diabetes.

Язык: Английский

---

Canagliflozin regulates metabolic reprogramming in diabetic kidney disease by inducing fasting-like and aestivation-like metabolic patterns

Diabetologia, Год журнала: 2024, Номер 67(4), С. 738 - 754

Опубликована: Янв. 18, 2024

Язык: Английский

---

Sodium-Glucose-Cotransporter-2 Inhibitor Therapy and Intermitted Fasting in Cardiorenal Syndrome: The Role of Glucose-Mediated Oxidative Stress

Journal of Clinical Medicine, Год журнала: 2025, Номер 14(3), С. 746 - 746

Опубликована: Янв. 24, 2025

Cardiorenal syndrome (CRS) is a complex clinical disorder characterized by the interplay between heart and kidney dysfunction. This condition exacerbated comorbidities such as diabetes mellitus, which contribute to glucose-mediated oxidative stress, further complicating management of CRS. The CRS has evolved with discovery sodium-glucose-cotransporter-2 (SGLT2) inhibitors, have been established effective agents in reducing hyperglycemia demonstrated cardiorenal protective effects. Concurrently, intermittent fasting gained attention an intervention without pharmacological treatment for its metabolic benefits, including improved glucose metabolism insulin regulation sensitivity, both potential reduction stress. review provides summary current findings on roles SGLT2 inhibitors managing CRS, particular focus We evaluate mechanisms these interventions exert their effects, identify gaps research, offer recommendations future studies. While demonstrate more research needed elucidate long-term efficacy, safety, synergistic

Язык: Английский

---