scholarly journals Sulforaphane Prevents Hepatic Insulin Resistance by Blocking Serine Palmitoyltransferase 3-Mediated Ceramide Biosynthesis

Nutrients ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 1185 ◽  
Author(s):  
Wendi Teng ◽  
Yuan Li ◽  
Min Du ◽  
Xingen Lei ◽  
Siyu Xie ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Signaling Pathway ◽  
Glucose Homeostasis ◽  
Hepg2 Cells ◽  
Hepatic Insulin Resistance ◽  
Serine Palmitoyltransferase ◽  
Insulin Resistant ◽  
Ceramide Production

Sulforaphane (SFA), a naturally active isothiocyanate compound from cruciferous vegetables used in clinical trials for cancer treatment, was found to possess potency to alleviate insulin resistance. But its underlying molecular mechanisms are still incompletely understood. In this study, we assessed whether SFA could improve insulin sensitivity and glucose homeostasis both in vitro and in vivo by regulating ceramide production. The effects of SFA on glucose metabolism and expression levels of key proteins in the hepatic insulin signaling pathway were evaluated in insulin-resistant human hepatic carcinoma HepG2 cells. The results showed that SFA dose-dependently increased glucose uptake and intracellular glycogen content by regulating the insulin receptor substrate 1 (IRS-1)/protein kinase B (Akt) signaling pathway in insulin-resistant HepG2 cells. SFA also reduced ceramide contents and downregulated transcription of ceramide-related genes. In addition, knockdown of serine palmitoyltransferase 3 (SPTLC3) in HepG2 cells prevented ceramide accumulation and alleviated insulin resistance. Moreover, SFA treatment improved glucose tolerance and insulin sensitivity, inhibited SPTLC3 expression and hepatic ceramide production and reduced hepatic triglyceride content in vivo. We conclude that SFA recovers glucose homeostasis and improves insulin sensitivity by blocking ceramide biosynthesis through modulating SPTLC3, indicating that SFA may be a potential candidate for prevention and amelioration of hepatic insulin resistance via a ceramide-dependent mechanism.

scholarly journals Theaflavins Improve Insulin Sensitivity through Regulating Mitochondrial Biosynthesis in Palmitic Acid-Induced HepG2 Cells

2018 ◽  
Author(s):  
Tuantuan Tong ◽  
Ning Ren ◽  
Jiafan Wu ◽  
Na Guo ◽  
Xiaobo Liu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Palmitic Acid ◽  
Hepg2 Cells ◽  
Molecular Mechanisms ◽  
Glucose Transporter ◽  
Hepatic Insulin Resistance ◽  
Insulin Resistant ◽  
Mitochondrial Dna Copy Number ◽  
Increase Glucose Uptake

Theaflavins, the characteristic and bioactive polyphenols in black tea, possess the potential improvement effects on insulin resistance-associated metabolic abnormalities including obesity and type 2 diebetes. However, the molecular mechanisms of theaflavins improving insulin sensitivity are still not clear. In this study, we investigated the protective effects and mechanisms of theaflavins on palmitic acid-induced insulin resistance in HepG2 cells. Theaflavins could significantly increase glucose uptake of insulin-resistant cells at noncytotoxic doses. This activity was mediated by upregulating the glucose transporter 4 protein expression, increasing the phosphorylation of IRS-1 at Ser307, and reduced the phosphor-Akt (Ser473) level. Moreover, theaflavins were found to enhance mitochondrial DNA copy number through down-regulate the PGC-1β mRNA level and up-regulate PRC mRNA expression in insulin-resistant HepG2 cells. These results indicated that theaflavins could improve free fatty acid-induced hepatic insulin resistance by promoting mitochondrial biogenesis, and were promising functional food and medicines for insulin resistance-related disorders.

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

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 <i>in vivo </i>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 <i>Cask </i>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 <i>Cask</i> 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.

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

2015 ◽  
Vol 29 (4) ◽  
pp. 528-541 ◽  
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.

Sepsis-induced changes in in vivo insulin action in diabetic rats

1989 ◽  
Vol 257 (3) ◽  
pp. E301-E308 ◽  
Author(s):  
C. H. Lang ◽  
C. Dobrescu
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Insulin Action ◽  
Plasma Concentrations ◽  
Diabetic Rats ◽  
Hepatic Insulin Resistance ◽  
Blood Levels ◽  
Euglycemic Hyperinsulinemic Clamp ◽  
Glucose Output

The present study examined whether sepsis exacerbates the diabetes-induced peripheral and hepatic insulin resistance. Vascular catheters were placed in diabetic (70 mg/kg streptozotocin, 4-wk duration) and nondiabetic rats, and sepsis was produced by subcutaneous injections of live Escherichia coli. Basal glucose metabolism was determined with the use of [3-3H]glucose initiated 18 h after the first injection of bacteria. Thereafter, in vivo insulin action was assessed with the use of the euglycemic hyperinsulinemic clamp technique. Sepsis in nondiabetic rats produced a 57% reduction in the maximal responsiveness for the insulin-induced increase in total glucose utilization compared with nondiabetic nonseptic animals. Diabetes alone decreased both insulin sensitivity and responsiveness. When the septic insult was superimposed on the diabetic condition, the maximum responsiveness was unchanged compared with non-septic diabetic rats, but the 50% maximally efficient dose was reduced from 817 to 190 microU/ml, suggesting an improvement in insulin sensitivity. Sepsis did not alter the insulin-induced suppression of hepatic glucose output in either nondiabetic or diabetic animals. Sepsis increased the plasma concentrations of epinephrine, norepinephrine, glucagon, and corticosterone in both nondiabetic and diabetic rats; however, the elevation in catecholamines and glucagon was 65 to 250% greater in the diabetic animals. These results indicate that hypermetabolic sepsis produces peripheral insulin resistance in nondiabetic rats but does not worsen the preexisting insulin resistance in diabetic animals, despite the higher prevailing blood levels of glucagon and catecholamines.

scholarly journals ADP Induces Blood Glucose Through Direct and Indirect Mechanisms in Promotion of Hepatic Gluconeogenesis by Elevation of NADH

2021 ◽  
Vol 12 ◽  
Author(s):  
Xinyu Cao ◽  
Xiaotong Ye ◽  
Shuang Zhang ◽  
Li Wang ◽  
Yanhong Xu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Blood Glucose ◽  
Signaling Pathway ◽  
Liver Tissue ◽  
Hepatic Insulin Resistance ◽  
Indirect Pathway ◽  
Hepatic Gluconeogenesis ◽  
Insulin Tolerance ◽  
Elevated Expression

Extracellular ADP, a derivative of ATP, interacts with the purinergic receptors in the cell membrane to regulate cellular activities. This signaling pathway remains unknown in the regulation of blood glucose in vivo. We investigated the acute activity of ADP in mice through a peritoneal injection. In the lean mice, in response to the ADP treatment, the blood glucose was elevated, and pyruvate tolerance was impaired. Hepatic gluconeogenesis was enhanced with elevated expression of glucogenic genes (G6pase and Pck1) in the liver. An elevation was observed in NADH, cAMP, AMP, GMP and citrate in the liver tissue in the targeted metabolomics assay. In the primary hepatocytes, ADP activated the cAMP/PKA/CREB signaling pathway, which was blocked by the antagonist (2211) of the ADP receptor P2Y13. In the circulation, gluconeogenic hormones including glucagon and corticosterone were elevated by ADP. Insulin and thyroid hormones (T3 and T4) were not altered in the blood. In the diet-induced obese (DIO) mice, NADH was elevated in the liver tissue to match the hepatic insulin resistance. Insulin resistance was intensified by ADP for further impairment in insulin tolerance. These data suggest that ADP induced the blood glucose through direct and indirect actions in liver. One of the potential pathways involves activation of the P2Y13/cAMP/PKA/CREB signaling pathway in hepatocytes and the indirect pathway may involve induction of the gluconeogenic hormones. NADH is a signal for gluconeogenesis in the liver of both DIO mice and lean mice.

Investigation of insulin resistance through a multiorgan microfluidic organ-on-chip

2021 ◽  
Author(s):  
Nida Tanataweethum ◽  
Allyson Trang ◽  
Chaeeun Lee ◽  
Jhalak Mehta ◽  
Neha Patel ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Lipid Synthesis ◽  
Hepatic Insulin Resistance ◽  
Insulin Resistant ◽  
Brown Adipose ◽  
Hepatic Glucose ◽  
On Chip ◽  
Adipose Organ

Abstract The development of hepatic insulin resistance (IR) is a critical factor in developing type 2 diabetes (T2D), where insulin fails to inhibit hepatic glucose production but retains its capacity to promote hepatic lipogenesis. Improving insulin sensitivity can be effective in preventing and treating T2D. However, selective control of glucose and lipid synthesis has been difficult. It is known that excess white adipose tissue is detrimental to insulin sensitivity, whereas brown adipose tissue transplantation can restore it in diabetic mice. However, challenges remain in our understanding of liver-adipose communication because the confounding effects of hypothalamic regulation of metabolic function cannot be ruled out in previous studies. There is a lack of in vitro models that use primary cells to study cellular-crosstalk under insulin resistant conditions. Building upon our previous work on the microfluidic primary liver and adipose organ-on-chips, we report for the first time the development of integrated insulin resistant liver-adipose (white and brown) organ-on-chip. The design of the microfluidic device was carried out using computational fluid dynamics; the experimental studies were conducted by carrying out detailed biochemical analysis RNA-seq analysis on both cell types. Further, we tested the hypothesis that brown adipocytes regulated both hepatic insulin sensitivity and lipogenesis. Our results show effective co-modulation of hepatic glucose and lipid synthesis through a platform for identifying potential therapeutics for IR and diabetes.

scholarly journals New insight into the mechanisms of ectopic fat deposition improvement after bariatric surgery

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Giulia Angelini ◽  
Lidia Castagneto Gissey ◽  
Giulia Del Corpo ◽  
Carla Giordano ◽  
Bruna Cerbelli ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Bariatric Surgery ◽  
Insulin Sensitivity ◽  
Hepatic Insulin Resistance ◽  
Alcoholic Fatty Liver ◽  
Fat Accumulation ◽  
Impaired Liver ◽  
Ectopic Fat Deposition

AbstractNon-alcoholic fatty-liver disease (NAFLD) is frequent in obese patients and represents a major risk factor for the development of diabetes and its complications. Bariatric surgery reverses the hepatic features of NAFLD. However, its mechanism of action remains elusive. We performed a comprehensive analysis of the mechanism leading to the improvement of NAFLD and insulin resistance in both obese rodents and humans following sleeve-gastrectomy (SG). SG improved insulin sensitivity and reduced hepatic and monocyte fat accumulation. Importantly, fat accumulation in monocytes was well comparable to that in hepatocytes, suggesting that Plin2 levels in monocytes might be a non-invasive marker for the diagnosis of NAFLD. Both in vitro and in vivo studies demonstrated an effective metabolic regeneration of liver function and insulin sensitivity. Specifically, SG improved NAFLD significantly by enhancing AMP-activated protein kinase (AMPK) phosphorylation and chaperone-mediated autophagy (CMA) that translate into the removal of Plin2 coating lipid droplets. This led to an increase in lipolysis and specific amelioration of hepatic insulin resistance. Elucidating the mechanism of impaired liver metabolism in obese subjects will help to design new strategies for the prevention and treatment of NAFLD.

scholarly journals Rat amylin-(8—37) enhances insulin action and alters lipid metabolism in normal and insulin-resistant rats

1997 ◽  
Vol 273 (5) ◽  
pp. E859-E867 ◽  
Author(s):  
M. Hettiarachchi ◽  
S. Chalkley ◽  
S. M. Furler ◽  
Y.-S. Choong ◽  
M. Heller ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Lipid Metabolism ◽  
Insulin Sensitivity ◽  
Insulin Action ◽  
Glycogen Synthesis ◽  
Human Growth ◽  
Whole Body ◽  
Nonesterified Fatty Acids ◽  
Insulin Resistant

To clarify roles of amylin, we investigated metabolic responses to rat amylin-(8—37), a specific amylin antagonist, in normal and insulin-resistant, human growth hormone (hGH)-infused rats. Fasting conscious rats were infused with saline or hGH, each with and without amylin-(8—37) (0.125 μmol/h), over 5.75 h. At 3.75 h, a hyperinsulinemic (100 mU/l) clamp with bolus 2-deoxy-d-[3H]glucose and [14C]glucose was started. hGH infusion led to prompt (2- to 3-fold) basal hyperamylinemia ( P < 0.02) and hyperinsulinemia. Amylin-(8—37) reduced plasma insulin ( P < 0.001) and enhanced several measures of whole body and muscle insulin sensitivity ( P < 0.05) in both saline- and hGH-infused rats. Amylin-(8—37) corrected hGH-induced liver insulin resistance, increased basal plasma triglycerides and lowered plasma nonesterified fatty acids in both groups, and reduced muscle triglyceride and total long-chain acyl-CoA content in saline-treated rats ( P < 0.05). In isolated soleus muscle, amylin-(8—37) blocked amylin-induced inhibition of glycogen synthesis but had no effect in the absence of amylin. Thus 1) hyperamylinemia accompanies insulin resistance induced by hGH infusion; 2) amylin-(8—37) increases whole body and muscle insulin sensitivity and consistently reduces basal insulin levels in normal and hGH-induced insulin-resistant rats; and 3) amylin-(8—37) elicits a significant alteration of in vivo lipid metabolism. These findings support a role of amylin in modulating insulin action and suggest that this could be mediated by effects on lipid metabolism.

scholarly journals Quantification of adipose tissue insulin sensitivity

2016 ◽  
Vol 64 (5) ◽  
pp. 989-991 ◽  
Author(s):  
Esben Søndergaard ◽  
Michael D Jensen
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Insulin Resistant ◽  
Healthy Humans ◽  
Metabolic Defects ◽  
Tissue Resistance

In metabolically healthy humans, adipose tissue is exquisitely sensitive to insulin. Similar to muscle and liver, adipose tissue lipolysis is insulin resistant in adults with central obesity and type 2 diabetes. Perhaps uniquely, however, insulin resistance in adipose tissue may directly contribute to development of insulin resistance in muscle and liver because of the increased delivery of free fatty acids to those tissues. It has been hypothesized that insulin adipose tissue resistance may precede other metabolic defects in obesity and type 2 diabetes. Therefore, precise and reproducible quantification of adipose tissue insulin sensitivity, in vivo, in humans, is an important measure. Unfortunately, no consensus exists on how to determine adipose tissue insulin sensitivity. We review the methods available to quantitate adipose tissue insulin sensitivity and will discuss their strengths and weaknesses.

scholarly journals Four sesquiterpene glycosides from loquat (Eriobotrya japonica) leaf ameliorates palmitic acid-induced insulin resistance and lipid accumulation in HepG2 Cells via AMPK signaling pathway

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e10413
Author(s):  
Jiawei Li ◽  
Xiaoqin Ding ◽  
Tunyu Jian ◽  
Han Lü ◽  
Lei Zhao ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Palmitic Acid ◽  
Signaling Pathway ◽  
Lipid Accumulation ◽  
Hepg2 Cells ◽  
Eriobotrya Japonica ◽  
Expression Levels ◽  
Ampk Signaling ◽  
Insulin Resistant ◽  
Compound C

Insulin resistance (IR), caused by impaired insulin signal and decreased insulin sensitivity, is generally responsible for the pathophysiology of type 2 diabetes mellitus (T2DM). Sesquiterpene glycosides (SGs), the exclusive natural products from loquat leaf, have been regarded as potential lead compounds owing to their high efficacy in hypoglycemia and hypolipidemia. Here, we evaluated the beneficial effects of four single SGs isolated from loquat leaf, including SG1, SG2, SG3 and one novel compound SG4 against palmitic acid-induced insulin resistance in HepG2 cells. SG1, SG3 and SG4 could significantly enhance glucose uptake of insulin-resistant HepG2 cells at non-cytotoxic concentration. Meanwhile, Oil Red O staining showed the decrease of both total cholesterol and triglyceride content, suggesting the amelioration of lipid accumulation by SGs in insulin-resistant HepG2 cells. Further investigations found that the expression levels of phosphorylated AMPK, ACC, IRS-1, and Akt were significantly up-regulated after SGs treatment, on the contrary, the expression levels of SREBP-1 and FAS were significantly down-regulated. Notably, AMPK inhibitor Compound C (CC) blocked the regulative effects, while AMPK activator AICAR mimicked the effects of SGs in PA-treated insulin-resistant HepG2 cells. In conclusion, SGs (SG4>SG1≈SG3>SG2) improved lipid accumulation in insulin-resistant HepG2 cells through the AMPK signaling pathway.

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