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

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.

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Long-term melatonin administration improves glucose homeostasis and insulin resistance state in high-fat-diet fed rats

Open Life Sciences ◽

10.2478/s11535-013-0211-z ◽

2013 ◽

Vol 8 (10) ◽

pp. 958-967

Author(s):

Xue-Dong Wan ◽

San-Qiang Li ◽

Shou-Min Xi ◽

Jian-Fei Wang ◽

Yan-Chun Guo ◽

...

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Reactive Oxygen Species ◽

Insulin Sensitivity ◽

Glucose Homeostasis ◽

Insulin Signaling ◽

High Fat Diet ◽

Metabolic Profiles ◽

Oxygen Species ◽

High Fat

AbstractEmerging evidence support an important role of reactive oxygen species in various forms of insulin resistance. It is identified that melatonin has antioxidant properties and prevents toxic effects of reactive oxygen species. In this study, we sought to assess the involvement of melatonin in the progression of insulin resistance in response to a high-fat diet (HFD) and to investigate the underlying mechanisms. Male rats were fed with a control diet, a high-fat diet, or a high-fat diet supplemented with melatonin (5 mg kg−1, i.p.) for 10 weeks. Glucose homeostasis, insulin sensitivity, antioxidative potency, and metabolic profiles in the rats were evaluated. Our results showed that a HFD led to increasing body mass, adipose tissue weight, plasma insulin, total cholesterol (TC), triglycerides (TG), free fatty acids (FFA), and decreased HDL-cholesterol (HDL-C) in rats. There was also a significant increase in the level of malondialdehyde (MDA) and decrease in superoxide dismutase (SOD) activity, oxidative stress markers both in the plasma and liver. An enhanced hepatic phosphoenolpyruvate carboxy-kinase (PEPCK) activity and RNA expression were observed. Impaired insulin signaling was evidenced by reducing insulin receptor substrate 2 (IRS2) tyrosine phosphorylation and protein kinase B (PKB) serine phosphorylation in response to insulin. Overactivation of stress-activated protein kinases JNK was also observed in the liver of HFD rats. However, simultaneous administration of melatonin to HFD rats significantly reduced oxidative stress in the system and liver, markedly improved impaired glucose homeostasis, insulin sensitivity, antioxidative potency, metabolic profiles and all the aforesaid adverse changes in HFD rats. Our results demonstrated that anti-oxidative property of melatonin is sufficient to ameliorate the insulin resistance condition, leading to the improvement of glucose homeostasis and the restoration of hepatic insulin signaling in a rat model of HFD-induced insulin resistance.

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Abstract 12189: Molecular Mechanisms Underlying Fasting Modulated Liver Insulin Sensitivity and Metabolism in Male Lipodystrophic Bscl2/Seipin-Deficient Mice

Circulation ◽

10.1161/circ.130.suppl_2.12189 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Weiqin Chen ◽

Hongyi Zhou ◽

Pradip Saha ◽

Luge Li ◽

Lawrence Chan

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Hepatic Steatosis ◽

Insulin Signaling ◽

Molecular Mechanisms ◽

De Novo ◽

Liver Lipid ◽

De Novo Lipogenesis ◽

Hepatic Insulin Signaling ◽

A Cell

Bscl2–/– mice recapitulate many of the major metabolic manifestations in Berardinelli-Seip Congenital Lipodystrophy type 2 (BSCL2) individuals, including lipodystrophy, hepatomegly, hepatic steatosis and insulin resistance. The mechanisms that underlie hepatic steatosis and insulin resistance in Bscl2–/– mice are poorly understood. To address this issue, we performed hyperinsulinemic-euglycemic clamp on Bscl2–/– and wild-type mice after an overnight (16-h) fast, and found that Bscl2–/– actually displayed increased hepatic insulin sensitivity. Interestingly, liver in Bscl2–/– mice after a short term (4-h) fast had impaired acute insulin signaling, a defect that disappeared after a 16-h fast. Notably, fasting dependent hepatic insulin signaling in Bscl2–/– mice was not associated with liver diacylglyceride and ceramide contents, but could be attributable in part to the expression of hepatic insulin signaling receptor and substrates. Meanwhile, increased de novo lipogenesis and decreased β-oxidation led to severe hepatic steatosis in fed or short fasted Bscl2–/– mice while liver lipid accumulation and metabolism in Bscl2–/– mice was markedly impacted by prolonged fasting. Furthermore, mice with liver-specific inactivation of Bscl2 manifested no hepatic steatosis even under high fat diet, suggesting Bscl2 does not play a cell autonomous role in regulating liver lipid homeostasis. Overall, our results offered new insights into the metabolic adaptations of liver in response to fasting and uncovered a novel fasting-dependent regulation of hepatic insulin signaling in a mouse model of human BSCL2.

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Joint Effects of Heat Stress and PM2.5 Exposure on Glucose Metabolism and Hepatic Insulin Signaling

10.21203/rs.3.rs-659151/v1 ◽

2021 ◽

Author(s):

Weijia Gu ◽

Ziwei Cai ◽

Mianhua Zhong ◽

Lung-Chi Chen ◽

Lu Zhang ◽

...

Keyword(s):

Heat Stress ◽

Particulate Matter ◽

Insulin Sensitivity ◽

Glucose Homeostasis ◽

Insulin Signaling ◽

Fine Particulate Matter ◽

Fine Particulate ◽

Hepatic Insulin Signaling ◽

Tnf Α ◽

Hsp72 Expression

Abstract Background: Heatwave events are occurring more frequently, accompanied by a significant increase in the ambient concentration of fine particulate matter (PM2.5). Epidemiological studies have suggested that heat stress or PM2.5 exposure would impair glucose homeostasis and insulin sensitivity, but the combined effect and the exact mechanisms are not well understood.Methods: C57BL/6 mice were randomly divided into filtered air (FA), fine particulate matter (PM) group, filtered air combined with heat stress (FH) group, and fine particulate matter combined with heat stress (PH) group for a 4-week PM2.5 exposure, followed by a 2-week heat stress exposure, via a whole-body exposure system. Systemic glucose homeostasis, insulin sensitivity, and circulating inflammatory cytokines were examined. HSP72 expression and insulin signaling in the liver were measured.Results: Glucose tolerance and insulin sensitivity were impaired in response to heat stress, accompanied by lessened hepatic GLUT2 expression and inhibited insulin signaling pathway. No synergistic effects of heat stress and PM2.5 exposure on glucose homeostasis were observed, while heat-upregulated HSP72 expression was attenuated with accumulated TNF-α induced by further PM2.5 exposure.Conclusions: Heat stress combined with PM2.5 exposure induced TNF-α, which could inhibit heat-elevated hepatic HSP72 expression. Elevated circulating TNF-α impaired hepatic insulin signaling and GLUT2 expression. Then, glucose homeostasis was perturbed, and insulin action was impaired.

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Molecular Mechanisms Underlying Fasting Modulated Liver Insulin Sensitivity and Metabolism in Male Lipodystrophic Bscl2/Seipin-Deficient Mice

Endocrinology ◽

10.1210/en.2014-1292 ◽

2014 ◽

Vol 155 (11) ◽

pp. 4215-4225 ◽

Cited By ~ 22

Author(s):

Weiqin Chen ◽

Hongyi Zhou ◽

Pradip Saha ◽

Luge Li ◽

Lawrence Chan

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Hepatic Steatosis ◽

Insulin Signaling ◽

Molecular Mechanisms ◽

De Novo ◽

Liver Lipid ◽

De Novo Lipogenesis ◽

Hepatic Insulin Signaling ◽

A Cell

Abstract Bscl2 −/− mice recapitulate many of the major metabolic manifestations in Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) individuals, including lipodystrophy, hepatomegly, hepatic steatosis, and insulin resistance. The mechanisms that underlie hepatic steatosis and insulin resistance in Bscl2−/− mice are poorly understood. To address this issue, we performed hyperinsulinemic-euglycemic clamp on Bscl2−/− and wild-type mice after an overnight (16-h) fast, and found that Bscl2−/− actually displayed increased hepatic insulin sensitivity. Interestingly, liver in Bscl2−/− mice after a short term (4-h) fast had impaired acute insulin signaling, a defect that disappeared after a 16-hour fast. Notably, fasting-dependent hepatic insulin signaling in Bscl2−/− mice was not associated with liver diacylglyceride and ceramide contents, but could be attributable in part to the expression of hepatic insulin signaling receptor and substrates. Meanwhile, increased de novo lipogenesis and decreased β-oxidation led to severe hepatic steatosis in fed or short-fasted Bscl2−/− mice whereas liver lipid accumulation and metabolism in Bscl2−/− mice was markedly affected by prolonged fasting. Furthermore, mice with liver-specific inactivation of Bscl2 manifested no hepatic steatosis even under high-fat diet, suggesting Bscl2 does not play a cell autonomous role in regulating liver lipid homeostasis. Overall, our results offered new insights into the metabolic adaptations of liver in response to fasting and uncovered a novel fasting-dependent regulation of hepatic insulin signaling in a mouse model of human BSCL2.

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The Impact of Differentiation on Cytotoxicity and Insulin Sensitivity in Streptozotocin Treated SH-SY5Y Cells

Neurochemical Research ◽

10.1007/s11064-021-03269-2 ◽

2021 ◽

Vol 46 (6) ◽

pp. 1350-1358

Author(s):

Fruzsina Bagaméry ◽

Kamilla Varga ◽

Kitti Kecsmár ◽

István Vincze ◽

Éva Szökő ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Insulin Signaling ◽

Glycogen Synthase ◽

Insulin Metabolism ◽

Relative Significance ◽

Differentiated Cells ◽

Mature Neuron ◽

The Right ◽

The Impact

AbstractRecently neuronal insulin resistance was suggested playing a role in Alzheimer’s disease. Streptozotocin (STZ) is commonly used to induce impairment in insulin metabolism. In our previous work on undifferentiated SH-SY5Y cells the compound exerted cytotoxicity without altering insulin sensitivity. Nevertheless, differentiation of the cells to a more mature neuron-like phenotype may considerably affect the significance of insulin signaling and its sensitivity to STZ. We aimed at studying the influence of STZ treatment on insulin signaling in SH-SY5Y cells differentiated by retinoic acid (RA). Cytotoxicity of STZ or low serum (LS) condition and protective effect of insulin were compared in RA differentiated SH-SY5Y cells. The effect of insulin and an incretin analogue, exendin-4 on insulin signaling was also examined by assessing glycogen synthase kinase-3 (GSK-3) phosphorylation. STZ was found less cytotoxic in the differentiated cells compared to our previous results in undifferentiated SH-SY5Y cells. The cytoprotective concentration of insulin was similar in the STZ and LS groups. However, the right-shifted concentration–response curve of insulin induced GSK-3 phosphorylation in STZ-treated differentiated cells is suggestive of the development of insulin resistance that was further confirmed by the insulin potentiating effect of exendin-4. Differentiation reduced the sensitivity of SH-SY5Y cells for the non-specific cytotoxicity of STZ and enhanced the relative significance of development of insulin resistance. The differentiated cells thus serve as a better model for studying the role of insulin signaling in neuronal survival. However, direct cytotoxicity of STZ also contributes to the cell death.

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Susceptibility to oxidative stress, insulin resistance, and insulin secretory response in the development of diabetes from obesity

Vojnosanitetski pregled ◽

10.2298/vsp0706391k ◽

2007 ◽

Vol 64 (6) ◽

pp. 391-397 ◽

Cited By ~ 9

Author(s):

Radivoj Kocic ◽

Dusica Pavlovic ◽

Gordana Kocic ◽

Milica Pesic

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Lipid Peroxidation ◽

Insulin Sensitivity ◽

Healthy Subjects ◽

Critical Role ◽

Secretory Response ◽

Diabetic Patients ◽

Apparent Difference ◽

Insulin Secretory Response

Background/Aim. Oxidative stress plays a critical role in the pathogenesis of various diseases. Recent reports indicate that obesity may induce systemic oxidative stress. The aim of the study was to potentiate oxidative stress as a factor which may aggravate peripheral insulin sensitivity and insulinsecretory response in obesity in this way to potentiate development of diabetes. The aim of the study was also to establish whether insulin-secretory response after glucagonstimulated insulin secretion is susceptible to prooxidant/ antioxidant homeostasis status, as well as to determine the extent of these changes. Methods. A mathematical model of glucose/insulin interactions and C-peptide was used to indicate the degree of insulin resistance and to assess their possible relationship with altered antioxidant/prooxidant homeostasis. The study included 24 obese healthy and 16 obese newly diagnozed non-insulin dependent diabetic patients (NIDDM) as well as 20 control healthy subjects, matched in age. Results. Total plasma antioxidative capacity, erythrocyte and plasma reduced glutathione level were significantly decreased in obese diabetic patients, but also in obese healthy subjects, compared to the values in controls. The plasma lipid peroxidation products and protein carbonyl groups were significantly higher in obese diabetics, more than in obese healthy subjects, compared to the control healthy subjects. The increase of erythrocyte lipid peroxidation at basal state was shown to be more pronounced in obese daibetics, but the apparent difference was obtained in both the obese healthy subjects and obese diabetics, compared to the control values, after exposing of erythrocytes to oxidative stress induced by H2O2. Positive correlation was found between the malondialdehyde (MDA) level and index of insulin sensitivity (FIRI). Conclusion. Increased oxidative stress together with the decreased antioxidative defence seems to contribute to decreased insulin sensitivity and impaired insulin secretory response in obese diabetics, and may be hypothesized to favour the development of diabetes during obesity.

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EET Analog Treatment Improves Insulin Signaling in a Genetic Mouse Model of Insulin Resistance

10.2337/figshare.16811251.v1 ◽

2021 ◽

Author(s):

Kakali Ghoshal ◽

Xiyue Li ◽

Dungeng Peng ◽

John R. Falck ◽

Raghunath Reddy Anugu ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Signaling ◽

Genetic Model ◽

Water Soluble ◽

Hepatic Insulin Resistance ◽

Epoxyeicosatrienoic Acid ◽

Genetic Mouse Model ◽

Hepatic Insulin Signaling ◽

Underlying Mechanisms

We previously showed that global deletion of the cytochrome P450 epoxygenase Cyp2c44, a major epoxyeicosatrienoic acid (EET) producing enzyme in mice, leads to impaired hepatic insulin signaling resulting in insulin resistance. This finding led us to investigate whether administration of a water soluble EET analog restores insulin signaling in vivo in Cyp2c44(-/-) mice and investigated the underlying mechanisms by which this effect is exerted. Cyp2c44(-/-) mice treated with the analog EET-A for 4 weeks improved fasting glucose and glucose tolerance compared to Cyp2c44(-/-) mice treated with vehicle alone. This beneficial effect was accompanied by enhanced hepatic insulin signaling, decreased expression of gluconeogenic genes and increased expression of glycogenic genes. Mechanistically, we show that insulin-stimulated phosphorylation of insulin receptor β (IRβ) is impaired in primary Cyp2c44(-/-) hepatocytes and this can be restored by cotreatment with EET-A and insulin. Plasma membrane fractionations of livers indicated that EET-A enhances the retention of IRβ in membrane rich fractions, thus potentiating its activation. Altogether, EET analogs ameliorate insulin signaling in a genetic model of hepatic insulin resistance by stabilizing membrane-associated IRβ and potentiating insulin signaling.

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Specific Deletion of CASK in Pancreatic β Cells Affects Glucose Homeostasis and Improves Insulin Sensitivity in Obese Mice by Reducing Hyperinsulinemia Running Title: β Cell CASK Deletion Reduces Hyperinsulinemia

10.2337/figshare.16797871 ◽

2021 ◽

Author(s):

Xingjing Liu ◽

Peng Sun ◽

Qingzhao Yuan ◽

Jinyang Xie ◽

Ting Xiao ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Secretion ◽

Insulin Sensitivity ◽

Glucose Homeostasis ◽

Chow Diet ◽

Β Cells ◽

Pancreatic Β Cells ◽

Calcium Calmodulin Dependent ◽

Normal Chow

Calcium/calmodulin-dependent serine protein kinase (CASK) is involved in the secretion of insulin vesicles in pancreatic β-cells. The present study revealed a new in vivo role of CASK in glucose homeostasis during the progression of type 2 diabetes mellitus (T2DM). A Cre-loxP system was used to specifically delete the Cask gene in mouse β-cells (βCASKKO), and the glucose metabolism was evaluated in <a>βCASKKO</a> mice fed a normal chow diet (ND) or a high-fat diet (HFD). ND-fed mice exhibited impaired insulin secretion in response to glucose stimulation. Transmission electron microscopy showed significantly reduced numbers of insulin granules at or near the cell membrane in the islets of βCASKKO mice. By contrast, HFD-fed βCASKKO mice showed reduced blood glucose and a partial relief of hyperinsulinemia and insulin resistance when compared to HFD-fed wildtype mice. The IRS1/PI3K/AKT signaling pathway was upregulated in the adipose tissue of HFD-βCASKKO mice. These results indicated that knockout of the Cask gene in β cells had a diverse effect on glucose homeostasis: reduced insulin secretion in ND-fed mice, but improves insulin sensitivity in HFD-fed mice. Therefore, CASK appears to function in the insulin secretion and contributes to hyperinsulinemia and insulin resistance during the development of obesity-related T2DM.

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PGRN Induces Impaired Insulin Sensitivity and Defective Autophagy in Hepatic Insulin Resistance

Molecular Endocrinology ◽

10.1210/me.2014-1266 ◽

2015 ◽

Vol 29 (4) ◽

pp. 528-541 ◽

Cited By ~ 21

Author(s):

Jiali Liu ◽

Huixia Li ◽

Bo Zhou ◽

Lin Xu ◽

Xiaomin Kang ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Insulin Signaling ◽

Nuclear Factor Κb ◽

Hepatic Insulin Resistance ◽

Causative Role ◽

Dependent Manner ◽

Nuclear Factor ◽

Impaired Insulin

Abstract Progranulin (PGRN) has recently emerged as an important regulator for glucose metabolism and insulin sensitivity. However, the underlying mechanisms of PGRN in the regulation of insulin sensitivity and autophagy remain elusive. In this study, we aimed to address the direct effects of PGRN in vivo and to evaluate the potential interaction of impaired insulin sensitivity and autophagic disorders in hepatic insulin resistance. We found that mice treated with PGRN for 21 days exhibited the impaired glucose tolerance and insulin tolerance and hepatic autophagy imbalance as well as defective insulin signaling. Furthermore, treatment of mice with TNF receptor (TNFR)-1 blocking peptide-Fc, a TNFR1 blocking peptide-Fc fusion protein to competitively block the interaction of PGRN and TNFR1, resulted in the restoration of systemic insulin sensitivity and the recovery of autophagy and insulin signaling in liver. Consistent with these findings in vivo, we also observed that PGRN treatment induced defective autophagy and impaired insulin signaling in hepatocytes, with such effects being drastically nullified by the addition of TNFR1 blocking peptide -Fc or TNFR1-small interference RNA via the TNFR1-nuclear factor-κB-dependent manner, indicating the causative role of PGRN in hepatic insulin resistance. In conclusion, our findings supported the notion that PGRN is a key regulator of hepatic insulin resistance and that PGRN may mediate its effects, at least in part, by inducing defective autophagy via TNFR1/nuclear factor-κB.

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The tumor suppressor TMEM127 regulates insulin sensitivity in a tissue-specific manner

Nature Communications ◽

10.1038/s41467-019-12661-0 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 4

Author(s):

Subramanya Srikantan ◽

Yilun Deng ◽

Zi-Ming Cheng ◽

Anqi Luo ◽

Yuejuan Qin ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Tumor Suppressor ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Suppressor Gene ◽

Nutrient Sensing ◽

Whole Body ◽

Insulin Sensitizer

Abstract Understanding the molecular components of insulin signaling is relevant to effectively manage insulin resistance. We investigated the phenotype of the TMEM127 tumor suppressor gene deficiency in vivo. Whole-body Tmem127 knockout mice have decreased adiposity and maintain insulin sensitivity, low hepatic fat deposition and peripheral glucose clearance after a high-fat diet. Liver-specific and adipose-specific Tmem127 deletion partially overlap global Tmem127 loss: liver Tmem127 promotes hepatic gluconeogenesis and inhibits peripheral glucose uptake, while adipose Tmem127 downregulates adipogenesis and hepatic glucose production. mTORC2 is activated in TMEM127-deficient hepatocytes suggesting that it interacts with TMEM127 to control insulin sensitivity. Murine hepatic Tmem127 expression is increased in insulin-resistant states and is reversed by diet or the insulin sensitizer pioglitazone. Importantly, human liver TMEM127 expression correlates with steatohepatitis and insulin resistance. Our results suggest that besides tumor suppression activities, TMEM127 is a nutrient-sensing component of glucose/lipid homeostasis and may be a target in insulin resistance.

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