Activation of the insulin receptor by insulin-like growth factor 2 DOI Creative Commons
Weidong An, Catherine Hall, Jie Li

и другие.

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Март 23, 2024

Abstract Insulin receptor (IR) controls growth and metabolism. Insulin-like factor 2 (IGF2) has different binding properties on two IR isoforms, mimicking insulin’s function. However, the molecular mechanism underlying IGF2-induced activation remains unclear. Here, we present cryo-EM structures of full-length human long isoform (IR-B) in both inactive IGF2-bound active states, short (IR-A) state. Under saturated IGF2 concentrations, IR-A IR-B adopt predominantly asymmetric conformations with or three IGF2s bound at site-1 site-2, which differs from that insulin forms an exclusively T-shaped symmetric conformation. exhibits a relatively weak to site-2 compared insulin, making it less potent promoting full activation. Cell-based experiments validated functional importance distinct sites optimal signaling trafficking. In state, C-terminus α-CT contacts FnIII-2 domain same protomer, hindering its threading into C-loop IGF2, thus reducing association rate IR-B. Collectively, our studies demonstrate by reveal basis affinity

Язык: Английский

Altered glucose metabolism in Alzheimer's disease: Role of mitochondrial dysfunction and oxidative stress DOI
Saikat Dewanjee, Pratik Chakraborty, Hiranmoy Bhattacharya

и другие.

Free Radical Biology and Medicine, Год журнала: 2022, Номер 193, С. 134 - 157

Опубликована: Окт. 4, 2022

Язык: Английский

Процитировано

133
Mechanisms underlying the pathophysiology of type 2 diabetes: From risk factors to oxidative stress, metabolic dysfunction, and hyperglycemia DOI
Jéssica Ellen Barbosa de Freitas Lima, Natália Moreira, Elza Tiemi Sakamoto‐Hojo

и другие.

Mutation Research/Genetic Toxicology and Environmental Mutagenesis, Год журнала: 2021, Номер 874-875, С. 503437 - 503437

Опубликована: Дек. 14, 2021

Язык: Английский

Процитировано

112
Inter-organ crosstalk during development and progression of type 2 diabetes mellitus DOI Open Access
Georgia Xourafa,

Melis Korbmacher,

Michael Roden

и другие.

Nature Reviews Endocrinology, Год журнала: 2023, Номер 20(1), С. 27 - 49

Опубликована: Окт. 16, 2023

Язык: Английский

Процитировано

102
Protective Factors and the Pathogenesis of Complications in Diabetes DOI Creative Commons
Marc Gregory Yu, Daniel Gordin, Jialin Fu

и другие.

Endocrine Reviews, Год журнала: 2023, Номер 45(2), С. 227 - 252

Опубликована: Авг. 25, 2023

Chronic complications of diabetes are due to myriad disorders numerous metabolic pathways that responsible for most the morbidity and mortality associated with disease. Traditionally, divided into those microvascular macrovascular origin. We suggest revising this antiquated classification vascular, parenchymal, hybrid (both vascular parenchymal) tissue origin, since profile ranges from involving only tissues mostly parenchymal organs. A major paradigm shift has occurred in recent years regarding pathogenesis complications, which focus shifted studies on risks interplay between risk protective factors. While factors clearly important development chronic diabetes, have established equally significant modulating severity complications. These responses may help explain differential even lack pathologies, some tissues. Nevertheless, despite growing number field, comprehensive reviews their mechanisms action not available. This review thus focused clinical, biochemical, molecular support idea endogenous factors, roles initiation progression diabetes. In addition, also aimed identify main needs field future studies.

Язык: Английский

Процитировано

71
Insulin Resistance: The Increased Risk of Cancers DOI Creative Commons

Leszek Szablewski

Current Oncology, Год журнала: 2024, Номер 31(2), С. 998 - 1027

Опубликована: Фев. 13, 2024

Insulin resistance, also known as impaired insulin sensitivity, is the result of a decreased reaction signaling to blood glucose levels. This state observed when muscle cells, adipose tissue, and liver improperly respond particular concentration insulin. resistance related increased plasma levels (hyperinsulinemia) may cause metabolic impairments, which are pathological states in obesity type 2 diabetes mellitus. Observations cancer patients confirm that hyperinsulinemia major factor influencing obesity, diabetes, cancer. Obesity have been reported risks initiation, progression, metastasis several cancers. However, both aforementioned pathologies independently additionally increase risk. The disorders associated with poor outcomes treatment. For example, suffering from higher recurrence rates their overall survival reduced. In these associations between risk, an overview various pathogenic mechanisms play role development discussed.

Язык: Английский

Процитировано

38
Cellular and Molecular Mechanisms of Insulin Resistance DOI Creative Commons
Preethi Chandrasekaran, Ralf Weiskirchen

Current Tissue Microenvironment Reports, Год журнала: 2024, Номер 5(3), С. 79 - 90

Опубликована: Фев. 21, 2024

Abstract Purpose of Review Although the molecular mechanism insulin resistance involves multiple factors and several intrinsic extrinsic mechanisms have been identified, this comprehensive review provides key information on some core complex interactions molecules involved in signaling pathways resistance. Recent Findings Diabetes Mellitus, most common metabolic disorder, is one greatest global medical challenges at present. There has a significant increase complications associated with diabetes such as heart disorders, stroke, neuropathy, dyslipidemia, dysfunction-associated steatotic liver disease, nephropathy. This calls for immediate strategic action to combat disorder. Insulin resistance, characteristic marker type 2 condition which regulation glucose metabolism body tissues, liver, adipose tissue, skeletal muscle, becomes disrupted. It generally hyperglycemia, hyperinsulinemia, hyperlipidemia, impaired homeostasis. Summary Understanding pathophysiological critical developing new therapeutic strategies treat polygenic multifactorial condition. Impairment caused by lipotoxicity, increased adiposity, enhanced inflammatory signaling, endoplasmic reticulum stress, adipokines, mitochondrial dysfunction, free fatty acids, dysfunctional signaling.

Язык: Английский

Процитировано

27
Phosphorylation Codes in IRS-1 and IRS-2 Are Associated with the Activation/Inhibition of Insulin Canonical Signaling Pathways DOI Creative Commons

Anabel Martínez Báez,

Guadalupe Ayala, Adolfo Pedroza-Saavedra

и другие.

Current Issues in Molecular Biology, Год журнала: 2024, Номер 46(1), С. 634 - 649

Опубликована: Янв. 9, 2024

Insulin receptor substrates 1 and 2 (IRS-1 IRS-2) are signaling adaptor proteins that participate in canonical pathways, where insulin cascade activation occurs, as well non-canonical which phosphorylation of is carried out by a diverse array receptors including integrins, cytokines, steroid hormones, others. IRS subject to spectrum post-translational modifications essential for their activation, encompassing events distinct tyrosine, serine, threonine residues. Tyrosine residue intricately linked the its interaction with SH2 domains within proteins, PI3K. Conversely, serine assumes different function, serving attenuate effects insulin. In this review, we have identified over 50 residues IRS-1 been reported undergo orchestrated kinases, thereby engendering or inhibition pathways. Furthermore, delineate 10 tyrosine at IRS-2 response insulin, process signal transduction subsequent

Язык: Английский

Процитировано

19
Macrophages, Low-Grade Inflammation, Insulin Resistance and Hyperinsulinemia: A Mutual Ambiguous Relationship in the Development of Metabolic Diseases DOI Open Access
Gerhard P. Püschel,

Julia Klauder,

J Henkel

и другие.

Journal of Clinical Medicine, Год журнала: 2022, Номер 11(15), С. 4358 - 4358

Опубликована: Июль 27, 2022

Metabolic derangement with poor glycemic control accompanying overweight and obesity is associated chronic low-grade inflammation hyperinsulinemia. Macrophages, which present a very heterogeneous population of cells, play key role in the maintenance normal tissue homeostasis, but functional alterations resident macrophage pool as well newly recruited monocyte-derived macrophages are important drivers development inflammation. While metabolic dysfunction, insulin resistance damage may trigger or advance pro-inflammatory responses macrophages, itself contributes to resulting Macrophages express receptors whose downstream signaling networks share number knots pathways pattern recognition cytokine receptors, shape polarity. The shared allow enhance attenuate both anti-inflammatory responses. This supposedly physiological function be impaired by hyperinsulinemia macrophages. review discusses mutual ambiguous relationship inflammation, resistance, insulin-dependent modulation activity focus on adipose liver.

Язык: Английский

Процитировано

71
Modulation of the Inflammatory Response in Polycystic Ovary Syndrome (PCOS)—Searching for Epigenetic Factors DOI Open Access
Dariusz Szukiewicz,

Seweryn Trojanowski,

Anna Kociszewska

и другие.

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(23), С. 14663 - 14663

Опубликована: Ноя. 24, 2022

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. Despite its incidence, poorly understood and remains underdiagnosed, female patients are diagnosed with a delay. The heterogenous nature this complex results from combined occurrence genetic, environmental, endocrine, behavioral factors. Primary clinical manifestations PCOS derived excess androgens (anovulation, polycystic morphology, lack or scanty, irregular menstrual periods, acne hirsutism), whereas secondary include multiple metabolic, cardiovascular, psychological disorders. Dietary lifestyle factors play important roles development course PCOS, which suggests strong epigenetic environmental influences. Many studies have shown association between chronic, low-grade inflammation both ovarian tissue throughout body. In vast majority patients, elevated values inflammatory markers their gene been reported. Development vicious cycle chronic state additionally stimulated by hyperinsulinemia obesity. Changes DNA methylation, histone acetylation noncoding RNA levels presented review context oxidative stress, reactive oxygen species, signaling PCOS. Epigenetic modulation androgenic activity response to also discussed.

Язык: Английский

Процитировано

44
State of the Science on Brain Insulin Resistance and Cognitive Decline Due to Alzheimer’s Disease DOI Creative Commons
Elizabeth M. Rhea,

Manon Leclerc,

Hussein N. Yassine

и другие.

Aging and Disease, Год журнала: 2023, Номер unknown, С. 0 - 0

Опубликована: Янв. 1, 2023

Type 2 diabetes mellitus (T2DM) is common and increasing in prevalence worldwide, with devastating public health consequences. While peripheral insulin resistance a key feature of most forms T2DM has been investigated for over century, research on brain (BIR) more recently developed, including the context non-diabetes states. Recent data support presence BIR aging brain, even states, found that may be Alzheimer’s disease (AD) contributes to cognitive impairment. Further, therapies used treat are now being AD treatment prevention, insulin. In this review, we offer definition BIR, present evidence AD; discuss expression, function, activation receptor (INSR) brain; how could develop; tools study BIR; correlates current hallmarks; regional/cellular involvement BIR. We close discussion resilience both AD, can improved better understand future avenues research. Overall, review position paper highlights as plausible therapeutic target prevention decline dementia due AD.

Язык: Английский

Процитировано

37