Selective inhibition of 12-lipoxygenase protects islets and beta cells from inflammatory cytokine-mediated beta cell dysfunction

The primary function of pancreatic beta-cells is to produce and release insulin in response to increment in extracellular glucose concentrations, thus maintaining glucose homeostasis. Deficient beta-cell function can have profound metabolic consequences, leading to the development of hyperglycemia and, ultimately, diabetes mellitus. Therefore, strategies targeting the maintenance of the normal function and protecting pancreatic beta-cells from injury or death might be crucial in the treatment of diabetes. This narrative review will update evidence from the recently identified molecular regulators preserving beta-cell mass and function recovery in order to suggest potential therapeutic targets against diabetes. This review will also highlight the relevance for novel molecular pathways potentially improving beta-cell dysfunction.

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The Role of Vegan Diets in Lipotoxicity-Induced Beta-Cell Dysfunction in Type-2-Diabetes

Journal of Population Therapeutics and Clinical Pharmacology ◽

10.15586/jptcp.v27isp2.744 ◽

2020 ◽

Vol 27 (SP2) ◽

pp. e22-e38

Author(s):

Maximilian Andreas Storz

Keyword(s):

Type 2 Diabetes ◽

Fatty Acids ◽

Fatty Acid ◽

Beta Cell ◽

Beta Cells ◽

Beta Cell Function ◽

Cell Function ◽

Beta Cell Dysfunction ◽

Cell Dysfunction

Type-2-diabetes is considered the new plague of the current century and both, its incidence and prevalence are rapidly increasing. Chronic insulin resistance and a progressive decline in beta-cell function are discussed as the root causes of type-2-diabetes. Both were associated with obesity and pathologically elevated concentrations of circulating free fatty acids in the blood. The harmful effects of chronically elevated free fatty acid levels on glucose homeostasis and non-adipose tissues are referred to as lipotoxicity. Pancreatic beta-cells appear to be particularly vulnerable and both, dietary fat quantity and quality may impact beta-cell function. Diets high in saturated fats are especially harmful to beta-cells while (poly-)unsaturated fatty acids were associated with beta-cell protective effects. This review examined how a dietary modification towards a low-fat vegan diet, which is particularly low in saturated and trans-fats, could help to prevent or reduce lipotoxicity-induced beta cell dysfunction. Several potential mechanisms of action were identified including: (1) reduced total fat intake (fat quantity), (2) a more favorable polyunsaturated fatty acid to saturated fatty acid ratio (fat quality), (3) improved body weight and a reduction in adipose tissue mass, and finally (4) improved glycemic control. The latter appears of paramount importance in light of the accumulating evidence that lipotoxic events are tightly coupled to excess glucose levels. All four mechanisms are likely to contribute complementarily to improved beta-cell function in individuals with type-2-diabetes and may reduce the likelihood of lipotoxic events to occur. Physicians must consider these findings when counseling patients on lifestyle and nutrition.

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Inherent Beta Cell Dysfunction Contributes to Autoimmune Susceptibility

Biomolecules ◽

10.3390/biom11040512 ◽

2021 ◽

Vol 11 (4) ◽

pp. 512

Author(s):

Yong Kyung Kim ◽

Lori Sussel ◽

Howard W. Davidson

Keyword(s):

Insulin Secretion ◽

Beta Cell ◽

Beta Cells ◽

Pancreatic Beta Cell ◽

Cell Loss ◽

The Body ◽

Beta Cell Dysfunction ◽

Metabolic Characteristics ◽

Cell Dysfunction ◽

Glucose Stimulated Insulin Secretion

The pancreatic beta cell is a highly specialized cell type whose primary function is to secrete insulin in response to nutrients to maintain glucose homeostasis in the body. As such, the beta cell has developed unique metabolic characteristics to achieve functionality; in healthy beta cells, the majority of glucose-derived carbons are oxidized and enter the mitochondria in the form of pyruvate. The pyruvate is subsequently metabolized to induce mitochondrial ATP and trigger the downstream insulin secretion response. Thus, in beta cells, mitochondria play a pivotal role in regulating glucose stimulated insulin secretion (GSIS). In type 2 diabetes (T2D), mitochondrial impairment has been shown to play an important role in beta cell dysfunction and loss. In type 1 diabetes (T1D), autoimmunity is the primary trigger of beta cell loss; however, there is accumulating evidence that intrinsic mitochondrial defects could contribute to beta cell susceptibility during proinflammatory conditions. Furthermore, there is speculation that dysfunctional mitochondrial responses could contribute to the formation of autoantigens. In this review, we provide an overview of mitochondrial function in the beta cells, and discuss potential mechanisms by which mitochondrial dysfunction may contribute to T1D pathogenesis.

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Integration of pro-inflammatory cytokines, 12-lipoxygenase and NOX-1 in pancreatic islet beta cell dysfunction

Molecular and Cellular Endocrinology ◽

10.1016/j.mce.2012.03.004 ◽

2012 ◽

Vol 358 (1) ◽

pp. 88-95 ◽

Cited By ~ 76

Author(s):

Jessica R. Weaver ◽

Theodore R. Holman ◽

Yumi Imai ◽

Ajit Jadhav ◽

Victor Kenyon ◽

...

Keyword(s):

Beta Cell ◽

Inflammatory Cytokines ◽

Pancreatic Islet ◽

Beta Cell Dysfunction ◽

Islet Beta Cell ◽

Cell Dysfunction ◽

12 Lipoxygenase ◽

Pancreatic Islet Beta Cell ◽

Pro Inflammatory Cytokines

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Absence of cannabinoid 1 receptor in beta cells protects against high-fat/high-sugar diet-induced beta cell dysfunction and inflammation in murine islets

Diabetologia ◽

10.1007/s00125-018-4576-4 ◽

2018 ◽

Vol 61 (6) ◽

pp. 1470-1483 ◽

Cited By ~ 22

Author(s):

Isabel González-Mariscal ◽

Rodrigo A. Montoro ◽

Máire E. Doyle ◽

Qing-Rong Liu ◽

Michael Rouse ◽

...

Keyword(s):

Beta Cell ◽

Beta Cells ◽

Beta Cell Dysfunction ◽

High Fat ◽

Cell Dysfunction ◽

High Sugar ◽

Cannabinoid 1 Receptor

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Butyrate Protects Pancreatic Beta Cells from Cytokine-Induced Dysfunction

International Journal of Molecular Sciences ◽

10.3390/ijms221910427 ◽

2021 ◽

Vol 22 (19) ◽

pp. 10427

Author(s):

Michala Prause ◽

Signe Schultz Pedersen ◽

Violeta Tsonkova ◽

Min Qiao ◽

Nils Billestrup

Keyword(s):

Beta Cell ◽

Beta Cells ◽

Beta Cell Function ◽

Pancreatic Beta Cells ◽

Cell Function ◽

Pancreatic Beta Cell ◽

Beta Cell Dysfunction ◽

Beta Cell Proliferation ◽

Cell Dysfunction ◽

Mouse Islets

Pancreatic beta cell dysfunction caused by metabolic and inflammatory stress contributes to the development of type 2 diabetes (T2D). Butyrate, produced by the gut microbiota, has shown beneficial effects on glucose metabolism in animals and humans and may directly affect beta cell function, but the mechanisms are poorly described. The aim of this study was to investigate the effect of butyrate on cytokine-induced beta cell dysfunction in vitro. Mouse islets, rat INS-1E, and human EndoC-βH1 beta cells were exposed long-term to non-cytotoxic concentrations of cytokines and/or butyrate to resemble the slow onset of inflammation in T2D. Beta cell function was assessed by glucose-stimulated insulin secretion (GSIS), gene expression by qPCR and RNA-sequencing, and proliferation by incorporation of EdU into newly synthesized DNA. Butyrate protected beta cells from cytokine-induced impairment of GSIS and insulin content in the three beta cell models. Beta cell proliferation was reduced by both cytokines and butyrate. Expressions of the beta cell specific genes Ins, MafA, and Ucn3 reduced by the cytokine IL-1β were not affected by butyrate. In contrast, butyrate upregulated the expression of secretion/transport-related genes and downregulated inflammatory genes induced by IL-1β in mouse islets. In summary, butyrate prevents pro-inflammatory cytokine-induced beta cell dysfunction.

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