The PI3K/AKT pathway in obesity and type 2 diabetes

International Journal of Biological Sciences, Journal Year: 2018, Volume and Issue: 14(11), P. 1483 - 1496

Published: Jan. 1, 2018

Obesity and type 2 diabetes mellitus are complicated metabolic diseases that affect multiple organs characterized by hyperglycaemia.Currently, stable effective treatments for obesity not available.Therefore, the mechanisms leading to more ways treat should be identified.Based on accumulated evidences, PI3K/AKT signalling pathway is required normal metabolism due its characteristics, imbalance leads development of mellitus.This review focuses role in skeletal muscle, adipose tissue, liver, brain pancreas, discusses how this affects aforementioned diseases.We also summarize evidences recently identified therapeutic targets as mellitus.PI3K/AKT damaged various tissues body result insulin resistance, turn, resistance exacerbates pathway, forming a vicious circle.

Language: Английский

---

Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease

Endocrine Reviews, Journal Year: 2018, Volume and Issue: 39(4), P. 489 - 517

Published: April 24, 2018

The ability to efficiently adapt metabolism by substrate sensing, trafficking, storage, and utilization, dependent on availability requirement, is known as metabolic flexibility. In this review, we discuss the breadth depth of flexibility its impact health disease. Metabolic essential maintain energy homeostasis in times either caloric excess or restriction, low high demand, such during exercise. liver, adipose tissue, muscle govern systemic manage nutrient uptake, transport, expenditure communication via endocrine cues. At a molecular level, relies configuration pathways, which are regulated key enzymes transcription factors, many interact closely with mitochondria. Disrupted flexibility, inflexibility, however, associated pathological conditions including syndrome, type 2 diabetes mellitus, cancer. Multiple factors dietary composition feeding frequency, exercise training, use pharmacological compounds, influence will be discussed here. Last, outline important advances research medical horizons translational aspects.

Language: Английский

---

Growth differentiation factor 15 is a myomitokine governing systemic energy homeostasis

The Journal of Cell Biology, Journal Year: 2016, Volume and Issue: 216(1), P. 149 - 165

Published: Dec. 16, 2016

Reduced mitochondrial electron transport chain activity promotes longevity and improves energy homeostasis via cell-autonomous –non-autonomous factors in multiple model systems. This mitohormetic effect is thought to involve the unfolded protein response (UPRmt), an adaptive stress-response pathway activated by proteotoxic stress. Using mice with skeletal muscle–specific deficiency of Crif1 (muscle-specific knockout [MKO]), integral large mitoribosomal subunit (39S), we identified growth differentiation factor 15 (GDF15) as a UPRmt-associated cell–non-autonomous myomitokine that regulates systemic homeostasis. MKO were protected against obesity sensitized insulin, associated elevated GDF15 secretion after UPRmt activation. In ob/ob mice, administration recombinant decreased body weight improved insulin sensitivity, which was attributed oxidative metabolism lipid mobilization liver, muscle, adipose tissue. Thus, potent signal safeguards onset resistance.

Language: Английский

---

Mitochondrial (Dys)function and Insulin Resistance: From Pathophysiological Molecular Mechanisms to the Impact of Diet

Frontiers in Physiology, Journal Year: 2019, Volume and Issue: 10

Published: May 3, 2019

Mitochondrial dysfunction has been implicated in the pathogenesis of insulin resistance, hallmark type 2 diabetes mellitus (T2DM). However, cause-effect relationship remains to be fully elucidated. Compelling evidence suggest that boosting mitochondrial function may represent a valuable therapeutic tool improve sensitivity. Mitochondria are highly dynamic organelles which adapt short- and long-term metabolic perturbations by undergoing fusion fission cycles, spatial rearrangement electron transport chain complexes into supercomplexes as well biogenesis governed peroxisome proliferator-activated receptor γ co-activator 1 α (PGC 1α). these processes appear dysregulated diabetic individuals. Herein we describe mechanistic link between resistance skeletal muscle alongside intracellular pathways orchestrating bioenergetics. We then review current on nutritional tools, including fatty acids, amino caloric restriction food bioactive derivatives enhance sensitivity therapeutically targeting

Language: Английский

---

Cinnamaldehyde in diabetes: A review of pharmacology, pharmacokinetics and safety

Pharmacological Research, Journal Year: 2017, Volume and Issue: 122, P. 78 - 89

Published: May 30, 2017

Language: Английский

---

Mitochondrial dysfunction: mechanisms and advances in therapy

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: May 15, 2024

Abstract Mitochondria, with their intricate networks of functions and information processing, are pivotal in both health regulation disease progression. Particularly, mitochondrial dysfunctions identified many common pathologies, including cardiovascular diseases, neurodegeneration, metabolic syndrome, cancer. However, the multifaceted nature elusive phenotypic threshold dysfunction complicate our understanding contributions to diseases. Nonetheless, these complexities do not prevent mitochondria from being among most important therapeutic targets. In recent years, strategies targeting have continuously emerged transitioned clinical trials. Advanced intervention such as using healthy replenish or replace damaged mitochondria, has shown promise preclinical trials various Mitochondrial components, mtDNA, mitochondria-located microRNA, associated proteins can be potential agents augment function immunometabolic diseases tissue injuries. Here, we review current knowledge pathophysiology concrete examples We also summarize treat perspective dietary supplements targeted therapies, well translational situation related pharmacology agents. Finally, this discusses innovations applications transplantation an advanced promising treatment.

Language: Английский

---

Pathophysiology of mitochondrial lipid oxidation: Role of 4-hydroxynonenal (4-HNE) and other bioactive lipids in mitochondria

Free Radical Biology and Medicine, Journal Year: 2017, Volume and Issue: 111, P. 316 - 327

Published: April 27, 2017

Language: Английский

---

Mitochondrial protein interactome elucidated by chemical cross-linking mass spectrometry

Proceedings of the National Academy of Sciences, Journal Year: 2017, Volume and Issue: 114(7), P. 1732 - 1737

Published: Jan. 27, 2017

Mitochondrial protein interactions and complexes facilitate mitochondrial function. These range from simple dimers to the respirasome supercomplex consisting of oxidative phosphorylation I, III, IV. To improve understanding function, we used chemical cross-linking mass spectrometry identify 2,427 cross-linked peptide pairs 327 proteins in whole, respiring murine mitochondria. In situ were observed throughout electron transport chain membrane complexes, ATP synthase, contact site cristae organizing system (MICOS) complex. Cross-linked sites showed excellent agreement with empirical structures delivered complementary constraints for silico docking. data established direct physical evidence assembly complex I-III enabled prediction interfacial regions complexes. Finally, a database tools harness as molecular probes, allowing quantification conformation-dependent interfaces dynamic assembly.

Language: Английский

---

Interorgan Metabolic Crosstalk in Human Insulin Resistance

Physiological Reviews, Journal Year: 2018, Volume and Issue: 98(3), P. 1371 - 1415

Published: May 16, 2018

Excessive energy intake and reduced expenditure drive the development of insulin resistance metabolic diseases such as obesity type 2 diabetes mellitus. Metabolic signals derived from dietary or secreted adipose tissue, gut, liver contribute to homeostasis. Recent metabolomic studies identified novel metabolites enlarged our knowledge on classic metabolites. This review summarizes evidence their roles mediators interorgan crosstalk regulators sensitivity metabolism. Circulating lipids free fatty acids, acetate, palmitoleate tissue short-chain acids gut effectively act skeletal muscle. Intracellular diacylglycerols sphingolipids can serve lipotoxins by directly inhibiting action in muscle liver. In contrast, acid esters hydroxy have been recently shown exert a series beneficial effects. Also, ketoacids are gaining interest potent modulators mitochondrial function. Finally, branched-chain amino not only predict diseases, but also inhibit signaling. Here, we focus humans, which regulates homeostasis main insulin-sensitive tissues, muscle, liver, tissue.

Language: Английский

---

Disruption of Mitochondria-Associated Endoplasmic Reticulum Membrane (MAM) Integrity Contributes to Muscle Insulin Resistance in Mice and Humans

Diabetes, Journal Year: 2018, Volume and Issue: 67(4), P. 636 - 650

Published: Jan. 11, 2018

Modifications of the interactions between endoplasmic reticulum (ER) and mitochondria, defined as mitochondria-associated membranes (MAMs), were recently shown to be involved in control hepatic insulin action glucose homeostasis, but with conflicting results. Whereas skeletal muscle is primary site insulin-mediated uptake main target for alterations insulin-resistant states, relevance MAM integrity resistance unknown. Deciphering importance MAMs on signaling could help clarify this controversy. Here, we show different mice models obesity type 2 diabetes (T2D) a marked disruption ER-mitochondria an early event preceding mitochondrial dysfunction resistance. Furthermore, human myotubes, palmitate-induced associated reduction structural functional interactions. Importantly, experimental increase contacts myotubes prevents action, whereas alters hormone. Lastly, found association altered from obese subjects or without T2D compared healthy lean subjects. Collectively, our data reveal new role highlight essential subcellular alteration humans. Therefore, reduced coupling common several insulin-sensitive tissues playing key homeostasis context T2D.

Language: Английский

---