Sphingosine kinase 2 promotes lipotoxicity in pancreatic β‐cells and the progression of diabetes

Song, Ziyu; Wang, Wei; Li, Ning; Yan, Sishan; Rong, Kuan; Lan, Tian; Xia, Pu

doi:10.1096/fj.201801496r

Cited by 25 publications

(52 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Only a few studies on the role of SphK2 in metabolic diseases have yet yielded inconsistent conclusions. We have recently reported that the global knockout of Sphk2 (Sphk2 −/− ) ameliorates the diabetic phenotype by protecting pancreatic β-cells against lipoapoptosis (15). Besides, the deletion of Sphk2 was recently shown to prevent aged mice from insulin resistance, at least in part, due to elevated adipose tissue lipolysis (16).…”

Section: Significancementioning

confidence: 99%

Regulation of hepatic insulin signaling and glucose homeostasis by sphingosine kinase 2

Aji

Huang

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Sphingolipid dysregulation is often associated with insulin resistance, while the enzymes controlling sphingolipid metabolism are emerging as therapeutic targets for improving insulin sensitivity. We report herein that sphingosine kinase 2 (SphK2), a key enzyme in sphingolipid catabolism, plays a critical role in the regulation of hepatic insulin signaling and glucose homeostasis both in vitro and in vivo. Hepatocyte-specific Sphk2 knockout mice exhibit pronounced insulin resistance and glucose intolerance. Likewise, SphK2-deficient hepatocytes are resistant to insulin-induced activation of the phosphoinositide 3-kinase (PI3K)-Akt-FoxO1 pathway and elevated hepatic glucose production. Mechanistically, SphK2 deficiency leads to the accumulation of sphingosine that, in turn, suppresses hepatic insulin signaling by inhibiting PI3K activation in hepatocytes. Either reexpressing functional SphK2 or pharmacologically inhibiting sphingosine production restores insulin sensitivity in SphK2-deficient hepatocytes. In conclusion, the current study provides both experimental findings and mechanistic data showing that SphK2 and sphingosine in the liver are critical regulators of insulin sensitivity and glucose homeostasis.

show abstract

Section: Significancementioning

confidence: 99%

Regulation of hepatic insulin signaling and glucose homeostasis by sphingosine kinase 2

Aji

Huang

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

show abstract

“…In contrast, a negative role of the SphK2/S1P axis was observed on β-cell fate. SphK2 expression KO reversed palmitate-induced cell death, whereas SphK2 overexpression promoted cell death under lipotoxic conditions in both INS-1 and MIN6 cells ( Figure 3 ) [ 94 ]. In fact, lipotoxicity induced the shuttling of SphK2 from the nucleus to the cytoplasm, where it led to mitochondrial apoptosis [ 94 ].…”

Section: S1p Metabolism and Pancreatic β Cell Fatementioning

confidence: 99%

“…SphK2 expression KO reversed palmitate-induced cell death, whereas SphK2 overexpression promoted cell death under lipotoxic conditions in both INS-1 and MIN6 cells ( Figure 3 ) [ 94 ]. In fact, lipotoxicity induced the shuttling of SphK2 from the nucleus to the cytoplasm, where it led to mitochondrial apoptosis [ 94 ]. SphK2 KO diabetic mice under HFD significantly improved their diabetic phenotypes [ 94 ], which suggests that, contrary to SphK1, SphK2 exerts a major role in promoting lipotoxicity-induced apoptosis of β cells [ 94 ].…”

Section: S1p Metabolism and Pancreatic β Cell Fatementioning

confidence: 99%

Sphingosine-1-Phosphate Metabolism in the Regulation of Obesity/Type 2 Diabetes

Guitton

Bandet

Mariko

et al. 2020

Cells

View full text Add to dashboard Cite

Obesity is a pathophysiological condition where excess free fatty acids (FFA) target and promote the dysfunctioning of insulin sensitive tissues and of pancreatic β cells. This leads to the dysregulation of glucose homeostasis, which culminates in the onset of type 2 diabetes (T2D). FFA, which accumulate in these tissues, are metabolized as lipid derivatives such as ceramide, and the ectopic accumulation of the latter has been shown to lead to lipotoxicity. Ceramide is an active lipid that inhibits the insulin signaling pathway as well as inducing pancreatic β cell death. In mammals, ceramide is a key lipid intermediate for sphingolipid metabolism as is sphingosine-1-phosphate (S1P). S1P levels have also been associated with the development of obesity and T2D. In this review, the current knowledge on S1P metabolism in regulating insulin signaling in pancreatic β cell fate and in the regulation of feeding by the hypothalamus in the context of obesity and T2D is summarized. It demonstrates that S1P can display opposite effects on insulin sensitive tissues and pancreatic β cells, which depends on its origin or its degradation pathway.

show abstract

“…Furthermore, both apoptotic and necrotic cell deaths of beta-cells have been reported [51]. Song et al (2020) found that STZ (35 mg/kg)-injected mice showed near 50% TUNEL-positive cells, served as a hallmark of apoptosis, followed by additional 12-week HFD feeding [52]. The past studies have also demonstrated that a low dose of STZ can acutely induce beta-cell apoptosis as a prediabetic mouse model for the following reasons: (i) mild hyperglycemia; (ii) mild pancreatic islet damage; (iii) apoptosis of beta-cells at <60% [33].…”

Section: Discussionmentioning

confidence: 99%

Flavonoids Identification and Pancreatic Beta-Cell Protective Effect of Lotus Seedpod

et al. 2020

View full text Add to dashboard Cite

Oxidative stress is highly associated with the development of diabetes mellitus (DM), especially pancreatic beta-cell injury. Flavonoids derived from plants have caused important attention in the prevention or treatment of DM. Lotus seedpod belongs to a traditional Chinese herbal medicine and has been indicated to possess antioxidant, anti-age, anti-glycative, and hepatoprotective activities. The purpose of this study was to demonstrate the pancreatic beta-cell protective effects of lotus seedpod aqueous extracts (LSE) against oxidative injury. According to HPLC/ESI-MS-MS method, LSE was confirmed to have flavonoids derivatives, especially quercetin-3-glucuronide (Q3G). In vitro, LSE dose-dependently improved the survival and function of rat pancreatic beta-cells (RIN-m5F) from hydrogen peroxide (H2O2)-mediated loss of cell viability, impairment of insulin secretion, and promotion of oxidative stress. LSE showed potential in decreasing the H2O2-induced occurrence of apoptosis. In addition, H2O2-triggered acidic vesicular organelle formation and microtubule-associated protein light chain 3 (LC3)-II upregulation, markers of autophagy, were increased by LSE. Molecular data explored that antiapoptotic and autophagic effects of LSE, comparable to that of Q3G, might receptively be mediated via phospho-Bcl-2-associated death promoter (p-Bad)/B-cell lymphoma 2 (Bcl-2) and class III phosphatidylinositol-3 kinase (PI3K)/LC3-II signal pathway. In vivo, LSE improved the DM symptoms and pancreatic cell injury better than metformin, a drug that is routinely prescribed to treat DM. These data implied that LSE induces the autophagic signaling, leading to protect beta-cells from oxidative stress-related apoptosis and injury.

show abstract

Sphingosine kinase 2 promotes lipotoxicity in pancreatic β‐cells and the progression of diabetes

Cited by 25 publications

References 31 publications

Regulation of hepatic insulin signaling and glucose homeostasis by sphingosine kinase 2

Regulation of hepatic insulin signaling and glucose homeostasis by sphingosine kinase 2

Sphingosine-1-Phosphate Metabolism in the Regulation of Obesity/Type 2 Diabetes

Flavonoids Identification and Pancreatic Beta-Cell Protective Effect of Lotus Seedpod

Contact Info

Product

Resources

About