Recent Insights Into Mechanisms of β-Cell Lipo- and Glucolipotoxicity in Type 2 Diabetes

Lytrivi, Maria; Castell, Anne-Laure; Poitout, Vincent; Cnop, Miriam

doi:10.1016/j.jmb.2019.09.016

Cited by 290 publications

(260 citation statements)

References 199 publications

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“…Therefore, impaired autophagy caused by aging and obesity with lipid overload can lead to β-cell dysfunction [ 55 ]. Impaired autophagic flux was also found to be closely associated with lipotoxicity-induced β-cell dysfunction, endoplasmic reticulum stress, oxidative stress, inflammation, and mitochondrial dysfunction [ 10 ]. Herein, we demonstrated that the 3-MA- or PA-induced autophagic inhibition was alleviated by MKP-5 overexpression.…”

Section: Discussionmentioning

confidence: 99%

“…Autophagy is an intracellular process wherein cellular metabolic homeostasis is maintained via the recycling of specific proteins and organelles. Autophagic flux can be blocked by PA owing to its ability to impair the conversion of lysosomes to autophagosomes, resulting in the apoptotic death of islet β cell lines and human pancreatic islets [ 9 , 10 ]. In contrast, other studies suggest that FFAs can induce autophagy [ 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

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MKP-5 Relieves Lipotoxicity-Induced Islet β-Cell Dysfunction and Apoptosis via Regulation of Autophagy

Zhao

et al. 2020

IJMS

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Mitogen-activated protein kinase phosphatase-5 (MKP-5) is a regulator of extracellular signaling that is known to regulate lipid metabolism. In this study, we found that obesity caused by a high-fat diet (HFD) decreased the expression of MKP-5 in the pancreas and primary islet cells derived from mice. Then, we further investigated the role of MKP-5 in the protection of islet cells from lipotoxicity by modulating MKP-5 expression. As a critical inducer of lipotoxicity, palmitic acid (PA) was used to treat islet β-cells. We found that MKP-5 overexpression restored PA-mediated autophagy inhibition in Rin-m5f cells and protected these cells from PA-induced apoptosis and dysfunction. Consistently, a lack of MKP-5 aggravated the adverse effects of lipotoxicity. Islet cells from HFD-fed mice were infected using recombinant adenovirus expressing MKP-5 (Ad-MKP-5), and we found that Ad-MKP-5 was able to alleviate HFD-induced apoptotic protein activation and relieve the HFD-mediated inhibition of functional proteins. Notably, HFD-mediated impairments in autophagic flux were restored by Ad-MKP-5 transduction. Furthermore, the autophagy inhibitor 3-methyladenine (3-MA) was used to treat Rin-m5f cells, confirming that the MKP-5 overexpression suppressed apoptosis, dysfunction, inflammatory response, and oxidative stress induced by PA via improving autophagic signaling. Lastly, employing c-Jun amino-terminal kinas (JNK), P38, or extracellular-regulated kinase (ERK) inhibitors, we established that the JNK and P38 MAPK pathways were involved in the MKP-5-mediated apoptosis, dysfunction, and autophagic inhibition observed in islet β cells in response to lipotoxicity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

MKP-5 Relieves Lipotoxicity-Induced Islet β-Cell Dysfunction and Apoptosis via Regulation of Autophagy

Zhao

et al. 2020

IJMS

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“…These mechanistic insights into the action of phlorizin reinvigorated interest in developing SGLT-inhibiting agents to lower blood glucose in diabetes. Glucose toxicity on the b-cell -that is, damage to the insulin-producing cells in the pancreas as a consequence of chronically high circulating glucose, which often occurs concordantly with lipotoxicity resulting from increased circulating lipids -has been identified as a key driver of the transition from insulin resistance to diabetes (24,25). In support of this hypothesis, Rossetti and colleagues demonstrated that lowering the glucose load presented to the body, and thereby reducing systemic glucose toxicity, improved b-cell function and reversed insulin resistance in partially pancreatectomized, streptozotocin-treated diabetic rats (26,27).…”

Section: History and Mechanism Of Sglt2 Inhibitorsmentioning

confidence: 99%

Sodium-glucose cotransporter-2 inhibitors: Understanding the mechanisms for therapeutic promise and persisting risks

Perry

Shulman

2020

Journal of Biological Chemistry

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In a healthy person, the kidney filters nearly 200 g of glucose per day, almost all of which is reabsorbed. The primary transporter responsible for renal glucose reabsorption is sodium-glucose cotransporter-2 (SGLT2). Based on the impact of SGLT2 to prevent renal glucose wasting, SGLT2 inhibitors have been developed to treat diabetes and are the newest class of glucose-lowering agents approved in the U.S. By inhibiting glucose reabsorption in the proximal tubule, these agents promote glycosuria, thereby reducing blood glucose concentrations and often resulting in modest weight loss. Recent work in humans and rodents has demonstrated that the clinical utility of these agents may not be limited to diabetes management: SGLT2 inhibitors have also shown therapeutic promise in improving outcomes in heart failure, atrial fibrillation, and, in preclinical studies, certain cancers. Unfortunately, these benefits are not without risk: SGLT2 inhibitors predispose to euglycemic ketoacidosis in those with type 2 diabetes, and largely for this reason, are not approved to treat type 1 diabetes. The mechanism for each of the beneficial and the harmful effects of SGLT2 inhibitors – with the exception of their effect to lower plasma glucose concentrations – is an area of active investigation. In this review, we discuss the mechanisms by which these drugs cause euglycemic ketoacidosis, hyperglucagonemia and stimulate hepatic gluconeogenesis as well as their beneficial effects in cardiovascular disease and cancer. In so doing, we aim to highlight the crucial role for selecting patients for SGLT2 inhibitor therapy and highlight several crucial questions that remain unanswered.

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“…Other studies revealed that long-term high free fatty acid content was related to prolonged exposure of TG in pancreatic islets, which may impair pancreatic β-cell function [40][41][42]. Furthermore, glycotoxicity and lipotoxicity were interactive rather than independent adverse effects on pancreatic β-cell [43][44][45]. Long term exposure of pancreatic beta cells to high fatty acids concentrations could result in impaired glucose-induced insulin secretion [46,47] and increased β-cell death [48].…”

Section: Discussionmentioning

confidence: 99%

Association between triglyceride-glucose index and risk of incident diabetes: a secondary analysis based on a Chinese cohort study

Tien

et al. 2020

Preprint

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Background: Recent studies have suggested the triglyceride-glucose index (TyG index) may serve as a suitable substitute for insulin resistance. However, evidence for the relationship between TyG index and risk of diabetes remains limited. This study sought to explore the association of baseline TyG index with risk of developing diabetes in Chinese adults.Methods: This retrospective cohort study was conducted using data from the health screening program in China. A total of 201,298 non-diabetic individuals were included. TyG index was calculated as Ln [fasting plasma glucose (mg/dl) × fasting triglyceride level (mg/dl)/2]. Diabetes was defined as fasting plasma glucose ≥126 mg/dl and/or self-reported diabetes. Cox proportion-hazard model was employed to evaluate the independent impact of baseline TyG index on future diabetes risk. Sensitivity and subgroup analyses were implemented to verify the reliability of results. Notably, data were downloaded from the DATADRYAD website, and used only for secondary analyses.Results: During an average follow-up of 3.12 years, among 201,298 individuals aged ≥20 years, 3,389 subjects developed diabetes. After adjusting for potential confounders, elevated TyG index were independently correlated with greater risk of incident diabetes (hazard ratio (HR), 3.34; 95% confidence interval (CI), 3.11–3.60). Compared with the lowest quartile (Q1), increasing TyG index (Q2, Q3, and Q4) was related to increased HR estimates of incident diabetes [HR (95% CI), 1.83 (1.49–2.26); 3.29 ( 2.70–4.01), and 6.26 (5.15–7.60), respectively]. Moreover, a nonlinear relationship was observed between TyG index and risk of diabetes and the slope of the curve increased accompanying the rise of TyG index. Subgroup analysis revealed the positive association was stronger among subjects with age < 40 years, body mass index ≥18.5 kg/m2 and < 24 kg/m2, or systolic blood pressure <140 mmHg, or in females.Conclusions: Elevated TyG index is independently correlated with increased risk of incident diabetes in Chinese adults, indicating it may represent a reliable predictor of diabetes in high-risk populations.

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Recent Insights Into Mechanisms of β-Cell Lipo- and Glucolipotoxicity in Type 2 Diabetes

Cited by 290 publications

References 199 publications

MKP-5 Relieves Lipotoxicity-Induced Islet β-Cell Dysfunction and Apoptosis via Regulation of Autophagy

MKP-5 Relieves Lipotoxicity-Induced Islet β-Cell Dysfunction and Apoptosis via Regulation of Autophagy

Sodium-glucose cotransporter-2 inhibitors: Understanding the mechanisms for therapeutic promise and persisting risks

Association between triglyceride-glucose index and risk of incident diabetes: a secondary analysis based on a Chinese cohort study

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