Erion DM, et al. Inhibition of Akt kinase by cell-permeable ceramide and its implications for ceramide-induced apoptosis. Peterson TA, Stamnes M. ARF1-regulated coatomer directs the steady-state localization of protein kinase C epsilon at the Golgi apparatus. The fourth criterion is temporality. Paradoxically, trained athletes accumulate lipids in skeletal muscle and the size of their LDs in muscle Several mechanisms have been proposed to explain how ceramides might induce cellular insulin resistance (Figure 2). Distinct patterns of tissue-specific lipid accumulation during the induction of insulin resistance in mice by high-fat feeding. This site needs JavaScript to work properly. The Diabetes Control and Complications Trial Study Group: Pregnancy outcomes in the Diabetes Control and Complications Trial. Endoplasmic reticulum stress promotes LIPIN2-dependent hepatic insulin resistance. Immunoblot analysis of PKC isoforms , II, , and from day 9.5 nondiabetic or diabetic pregnancies. Leptin-deficient ob/ob mice were also reported to display increased total hepatic ceramides [84]. Kunisaki M, Bursell S-E, Clermont AC, Ishii H, Ballas LM, Jirousek MR, Umeda F, Naata H, King GL: Vitamin E prevents diabetes-induced abnormal retinal blood flow via the diacylglycerol-protein kinase C pathway. Summers SA, Goodpaster BH. Dissociation of inositol-requiring enzyme (IRE1)-mediated c-Jun N-terminal kinase activation from hepatic insulin resistance in conditional X-box-binding protein-1 (XBP1) knock-out mice. This site uses cookies. All rights reserved. MeSH Galbo T, et al. Genetically obese ZDF rats did not display increased total hepatic ceramides compared to their lean littermates [76]. We attempt a synthesis of available research examining: 1) levels of DAGs and ceramides in human and rodent models of lipid-induced hepatic insulin resistance, 2) proposed molecular mechanisms for DAG- and ceramide-mediated hepatic insulin resistance, and 3) rodent models interrogating DAG- and ceramide-mediated hepatic insulin resistance. By day 10.5, formation of the neural tube is complete and embryos with defective neural tubes can be distinguished from normal embryos. As discussed above, the association between intrahepatic DAG and hepatic insulin resistance, whether measured by HOMA-IR or suppression of HGP, spans a wide dynamic range. The site is secure. Williams B, Schrier RW: Characterization of glucose-induced in situ protein kinase C activity in cultured vascular smooth muscle cells. The study was conducted in a single-center, open-labeled, parallel design. CrossTalk proposal: Intramyocellular ceramide accumulation does modulate insulin resistance. Western blot analysis demonstrated that the steady-state concentrations of PKC isozymes in whole embryos or in membrane or cytosolic fractions of decidua were variable but were not significantly increased by glucose injection (Fig. A final important consideration for the DAG-PKC hypothesis is that triglyceride hydrolysis by ATGL in the hepatocyte preferentially produces sn-1,3-DAG, which is incapable of activating PKC [63,64]. Insulin resistance has diverse manifestations in different tissues, and is a component of the metabolic syndrome that predicts incident type 2 diabetes, Increased liver triglyceride content without an alternative etiology (e.g., alcohol use, starvation, medications). and R01-EY5110 to G.K. We are grateful to Melissa Horal and Rakhi Patel for valuable technical assistance. Liver Perilipin 5 Expression Worsens Hepatosteatosis But Not Insulin Resistance in High Fat-Fed Mice. In the other, ceramide activation of protein phosphatase 2A leads to dephosphorylation and inactivation of AKT. Inhibition of de novo ceramide synthesis reverses diet-induced insulin resistance and enhances whole-body oxygen consumption. In the human placenta, there are significant increases in PKC II and on the microvillus membrane and in PKC and on the basal membrane between 16 and 40 weeks of gestation (40). In the present study, we conducted a further clinical study for 6 months with an additional 3-year follow-up period to investigate the long-term effects of DAG oil in dietary therapy in subjects with type 2 diabetes with nephropathy. Kim JK, et al. Lotta LA, et al. Insulin resistance as generally understood incorporates both decreased insulin sensitivity (a right shift in the insulin dose-response curve) and decreased insulin responsiveness (an impaired maximal response to high insulin concentrations). These phenotypes point to critical metabolic functions of hepatic ceramides, but, because of these potentially confounding changes in hepatic lipids, cannot address the question of whether hepatic ceramides directly impair insulin action. It is the precursor and metabolite of acetylcholine (ACh), plays a role in single-carbon metabolism and is an essential component of different membrane phospholipids (PLs). In a 3-year follow-up period after the 6-month treatment, eight subjects in the DAG group continued to use DAG oil. Immunoblot analysis demonstrated that PKC , II, , and were expressed at these time points and increased on days 15.5 and 18.5. Insulin resistance, ectopic lipid, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), insulin receptor kinase, protein kinase C epsilon, ceramide. It is hypothesized . Perry RJ, et al. Similarly, decidual DAG was increased 1.5-fold, and PKC activity in membrane and cytosolic fractions was significantly increased (1.2- and 1.3-fold, respectively) in samples from diabetic mice (Fig. There is also some evidence that diacylglycerol might also slow progression of kidney failure in people with type 2 diabetes, possibly by reducing triglycerides. This body weight phenotype was predictably associated with improved glucose tolerance (though insulin tolerance was unchanged) [68]. Many ceramide species are bioactive and participate in diverse cellular signaling pathways. Several PKC isotypes have been detected in the placenta and decidua of the human and the rat (3539). Before In one recent human study, four DAG species (32:1, 34:1, 36:2, 36:3) were significantly increased in a high HOMA-IR versus a low HOMA-IR group [37]. In addition to the expected associations with diacylglycerol, triacylglycerol and cholesterol esters, type 2 diabetes and prediabetes were positively associated with ceramide, and its precursor dihydroceramide, along with phosphatidylethanolamine, phosphatidylglycerol and phosphatidylinositol. Because neovascularization is important for establishment of early organ structures, diabetic embryopathy secondary to defective neovascularization may be a novel type of diabetic vascular complication. The hepatic DAG-PKC-INSR axis, despite emerging more recently, is now better understood than the analogous DAG-PKC axis in skeletal muscle. Similar findings of protection from hepatosteatosis and hepatic insulin resistance in association with decreased hepatic ceramides were recently reported in mice with adipose- or liver-specific inducible adiponectin receptor overexpression [96]. The CerS2+/ mice gained weight normally on high-fat diet, but were extraordinarily susceptible to steatohepatitis and associated glucose intolerance [69]. Jornayvaz FR, et al. Babazono T, Kapor-Drezgic J, Dlugosz JA, Whiteside C: Altered expression and subcellular localization of diacylglycerol-sensitive protein kinase C isoforms in diabetic rat glomerular cells. . Chavez JA, Summers SA. From:Williams Textbook of Endocrinology (Twelfth Edition), 2011 Related terms: Glycerol Lipid Secretion (Process) Fatty Acid Phospholipid Protein Triacylglycerol Micelle Exosome Triacylglycerol Lipase Gene Wiki entry for DGKA Gene Additional gene information for DGKA Gene HGNC (2849) Diacylglycerols and ceramides have emerged as the two best-studied putative mediators of lipid-induced hepatic insulin resistance. Yang G, et al. Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin. Diacylglycerol (DAG) is a world leading antiobesity functional cooking oil synthesized via structural modification of conventional fats and oils. In this report, we present a detailed comparison of the lipid composition of human milk (HM) and formula milk (FM) targeting different lactation stages and infant age range. Choi CS, et al. Diacylglycerol (DAG) - the structure and sources Diacylglycerol (DAG) is a neutral lipid involved in various metabolic pathways in the cell. As on day 9.5, diabetic mice were significantly more hyperglycemic than nondiabetic mice (25.53 2.33 and 7.58 0.19 mmol/l, respectively; P < 0.0005). Petersen MC, et al. Further, the observation that increasing hepatic ceramide content drives hepatic lipid accumulation confounds attempts to ascribe hepatic insulin resistance to direct ceramide action. Basu R, et al. sharing sensitive information, make sure youre on a federal Though stored hepatic triglyceride is not thought to directly impair insulin action, two lipid classes proposed to mediate lipid-induced hepatic insulin resistance are ceramides and diacylglycerols (DAG). ASO knockdown of PKC prevented hepatic insulin resistance in this model, and PKC knockout mice are protected from glucose intolerance after 7 days of high fat feeding [43,44]. Are intrahepatic DAG and/or ceramide accumulation safely druggable targets in humans? Insulin resistance is a major factor in the development of type 2 diabetes and metabolic syndrome. Multiple studies proved that aberrant activation of PKCs and PKDs contributes to the development of metabolic diseases. In decidua, there was a slight increase in membrane and cytosol PKC activity in both normal and abnormal embryos of diabetic mice, although these increases were not significant. Significantly different in percent changes from the baseline to 6 months between the groups: A table elsewhere in this issue shows conventional and Systeme International (SI) units and conversion factors for many substances. Magkos F, et al. One-year ad libitum consumption of diacylglycerol oil as part of a regular diet results in modest weight loss in comparison with consumption of a triacylglycerol control oil in overweight Japanese subjects. In addition to the increase in fasting hepatic glucose production (HGP), insulin suppression of HGP is impaired in T2D [3]. Suppression of diacylglycerol acyltransferase-2 (DGAT2), but not DGAT1, with antisense oligonucleotides reverses diet-induced hepatic steatosis and insulin resistance. Time-dependent effects of Prkce deletion on glucose homeostasis and hepatic lipid metabolism on dietary lipid oversupply in mice. To date, ten mammalian DGK subtypes have been cloned and divided into five groups, and they show subtype-specific tissue distribution. Nagle CA, et al. A third possibility that is beginning to be explored is that only some DAG specific chemical species, or in specific subcellular localizations, or as a product of specific lipid handling pathways is capable of activating PKC and inhibiting IRK activity. How might specific ceramide species, such as C16:0, fit into these mechanisms? Insulin-resistance is a characteristic feature of type 2 diabetes (T2D) and plays a major role in the pathogenesis of this disease. Kurek K, et al. and transmitted securely. Yamamoto T, Chapman BM, Soares MJ: Protein kinase C dependent and independent mechanisms controlling rat trophoblast cell DNA synthesis and differentiation. Follow us on Twitter, Facebook, YouTube and LinkedIn, The Athlete's Paradox: Alterations in Intramuscular Lipid Synthesis and Diacylglycerol Saturation Influence Insulin Action Intramuscular triglyceride (I Intramuscular triglyceride (IMTG) and insulin sensitivity are usually inversely related, and as a result, IMTG has received considerable attention as a potential mechanism promoting insulin resistance. Raddatz K, et al. The DAG group maintained their serum creatinine levels during the study period, whereas the control group was significantly increased from the baseline. Regulation of glucose homeostasis and insulin action by ceramide acyl-chain length: A beneficial role for very long-chain sphingolipid species. Petersen KF, et al. Abulizi A, et al. Kim JK, et al. Prevalence of Nonalcoholic Fatty Liver Disease and Its Association With Cardiovascular Disease Among Type 2 Diabetic Patients. Insulin receptor Thr1160 phosphorylation mediates lipid-induced hepatic insulin resistance. We conclude with a formal evaluation of DAG- and ceramide-induced hepatic insulin resistance using the Bradford Hill criteria for causality in biological processes. They all contain a conserved C'-terminal catalytic domain and two cysteine-rich Zn2+-finger motifs with varied regulatory domains. A value of P < 0.05 was considered statistically significant. Animal models of nonalcoholic fatty liver disease. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. The delayed progression of renal failure by DAG consumption may have resulted from the improvement in hypertriglyceridemia, a predictor of progressive renal dysfunction (912). As type 2 diabetes becomes more prevalent worldwide, the prevalence of diabetic macular oedema is . This suggests that diabetes activated PKC located in the cytoplasmic compartment, causing it to be translocated to the membranous compartment. a random venous plasma glucose concentration 11.1 mmol/l or. Consistent with the previous study (7), DAG oil consumption significantly reduced fasting serum triglyceride levels in subjects with type 2 diabetes with nephropathy. Because sn-1,2-DAG was a known bioactive signaling lipid, a simple hypothesis impairment of insulin signaling by DAG activation of protein kinase C (PKC) isoforms was proposed, although the source of the DAGs remained unknown [30]. Hormones may act within the same cells (autocrine) or distal cells . . Quantitation of bands from six replicate decidua from nondiabetic pregnancies and six replicate decidua from diabetic pregnancies are shown in the lower panel. Tada N, Shoji K, Takeshita M, Watanabe H, Yoshida H, Hase T, Matsuo N, Tokimitsu I: Effects of diacylglycerol ingestion on postprandial hyperlipidemia in diabetes. In this review, we critically examine the substantial literature investigating DAGs and ceramides as putative mediators of lipid-induced hepatic insulin resistance. ; Vuse, M.G., 1991: Insulin administration in vivo diseases 1,2-diacylglycerol in rat skeletal muscle Yet, as with all pharmacologic inhibitors, interpretation of in vivo experiments employing myriocin requires caution. CerS6 knockout mice were protected from the development of obesity when fed a high-fat diet, owing in part to increased BAT energy expenditure [68]. Ryu D, et al. 2020 Sep 20;12(9):2873. doi: 10.3390/nu12092873. Yamamoto K, Takeshita M, Tokimitsu I, Watanabe H, Mizuno T, Asakawa H, Tokunaga K, Tatsumi T, Okazaki M, Yagi N. Nutrition. A: DAG concentrations in embryos; *P < 0.001 vs. control. Search for other works by this author on: Cunningham FG, MacDonald PC, Gant NF, Leveno KJ, Gilstrap LCI, Hankins GDV, Clark SL: Diabetes. In contrast, hepatic ceramide content was unrelated to hepatic insulin resistance in two of the three available human studies [31,35,37]. The sixth criterion is biological plausibility. 1A and B). Therefore, a reduced postprandial response following DAG oil intake may contribute to an improvement in fasting serum triglyceride levels, resulting in the delayed progression of diabetic nephropathy. Apolipoprotein CIII overexpressing mice are predisposed to diet-induced hepatic steatosis and hepatic insulin resistance. Which group of hormones cause an anti-inflammatory action? It should be noted that increased DAG-PKC activity occurred on day 9.5, while the embryo is undergoing dramatic morphogenesis, particularly the establishment of the neural tube and the heart. There is also some evidence that diacylglycerol might also slow progression of kidney failure in people with type 2 diabetes, possibly by reducing triglycerides. Diacylglycerol-concentrated oils taste and look like regular fats and cooking oils. While these data do not formally meet the criterion of temporality for DAG (because both DAG elevations and insulin resistance were present at these early time points), it may not be experimentally feasible to capture a time point in which DAG is elevated but the DAG-PKC-INSR axis has not yet induced hepatic insulin resistance. Quantitation of membrane bands are shown in solid bars and of cytosol bands are shown in shaded bars. Colhoun HM, Lee ET, Bennett PH, Lu M, Keen H, Wang SL, Stevens LK, Fuller JH: Risk factors for renal failure: the WHO Mulinational Study of Vascular Disease in Diabetes. A complete mechanism for ceramide-induced hepatocellular insulin resistance is therefore still awaited. Methods: Aims/hypothesis Intramyocellular lipids, including diacylglycerol (DAG) and ceramides, have been linked to insulin resistance. Additionally, the existence of several rodent models of genetically perturbed lipid handling with preserved hepatic insulin sensitivity despite increased hepatic DAG has led some investigators to conclude, perhaps justifiably, that increased intrahepatic DAG per se is insufficient for hepatic insulin resistance. Fullerton MD, et al. Prevention of fat-induced insulin resistance by salicylate. An emerging paradigm emphasizes the importance of direct hepatic insulin action (and thus the DAG-PKC-INSR axis) in the glycogen-replete state, where modulation of glycogen metabolism is a major controller of HGP, and the importance of indirect hepatic insulin action (e.g., lipolytic control of gluconeogenesis) in the glycogen-depleted state, where gluconeogenesis is the most critical component of HGP [4,103]. Watarai T, et al. STZ, streptozotocin. Address correspondence and reprint requests to Mary R. Loeken, Section on Cellular and Molecular Physiology, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. Hepatic insulin resistance is reversible: in one study, insulin resistance to suppression of HGP was reversed by modest (~8 kg) weight loss, and this was associated with normalization of fasting HGP and fasting glycemia [8]. Effects of glucose injections on day 7.5 on DAG and PKC in embryos and decidua on day 9.5 assayed as in Fig. Samuel VT, et al. If DAG or ceramides cause hepatic insulin resistance, they must accumulate prior to the onset of insulin resistance. In this regard, it should be noted that vitamin E prevents diabetes-induced vascular complications by inhibiting glucose activation of DAG-PKC signaling (4648). Diacylglycerol is further The eighth criterion is experiment. Such a mechanism has the advantage of linking hepatic ceramides to other putative mediators of lipid-induced hepatic insulin resistance. Cantley JL, et al. Niclosamide ethanolamine improves blood glycemic control and reduces hepatic steatosis in mice. Additionally, many key mechanistic studies describing ceramide inhibition of AKT were carried out in myotubes, and have not been replicated in hepatocytes. Hormones are secreted DIRECTLY into circulation and exert their effects by binding to receptors in or on target cells. Watanabe M, Risi R, Masi D, Caputi A, Balena A, Rossini G, Tuccinardi D, Mariani S, Basciani S, Manfrini S, Gnessi L, Lubrano C. Nutrients. Early investigations of ceramide-induced insulin resistance were performed primarily in skeletal muscle [6567]. Inoguchi T, Battan R, Handler E, Sportsman JR, Heath W, King GL: Preferential elevation of protein kinase C isoform beta II and diacylglycerol levels in the aorta and heart of diabetic rats: differential reversibility to glycemic control by islet cell transplantation. Intrahepatic ceramides are not associated with hepatic insulin resistance in the human or rodent studies for which dose-response data are available. Central role of ceramide biosynthesis in body weight regulation, energy metabolism, and the metabolic syndrome. Miodovnik M, Mimouni F, Dignan PSJ, Berk MA, Ballard JL, Siddiqi TA, Khoury J, Tsang RC: Major malformations in infants of IDDM women: vasculopathy and early first-trimester poor glycemic control. Cherrington AD, et al. Three of five subjects who continued to use their usual cooking oil started hemodialysis (1.5, 2.2, and 2.5 years after the treatment period) and the other two subjects died of heart failure (1.8 and 2.5 years). Savage DB, et al. PKC activity in membrane and cytosolic fractions of day 11.5 embryos and decidua from nondiabetic (control) mice or in normal or abnormal embryos of diabetic mice. We now examine available data concerning the role of ceramides in lipid-induced hepatic insulin resistance. 2A), suggesting that increased PKC activity in cell extracts (Fig. In general, the profound alterations in liver and plasma lipids comorbid with hepatic insulin resistance have engendered reluctance to the hypothesis that hepatic lipids drive hepatic insulin resistance [99]. Insulin's structure varies slightly between species of animals. At 7 days, no hepatic ceramide species were altered; at 21 days, 16:0 and 18:0 ceramides were unchanged, 20:0 and 22:0 ceramides were increased, and 24:1 and 24:0 ceramides were decreased [71]. For example, IHTG is better correlated with insulin resistance than visceral adipose tissue volume [16], and increased body mass index is not associated with increased insulin resistance unless a parallel increase in IHTG is present [17]. The target intake for both types of cooking oils was 10 g per day. These effects were more evident in subjects with insulin resistance and type 2 diabetes (14,15). Krssak M, et al. Phelan SA, Ito M, Loeken MR: Neural tube defects in embryos of diabetic mice: role of the Pax-3 gene and apoptosis. Shum L, Sadler TW: Biochemical basis for D,L,-beta-hydroxybutyrate-induced teratogenesis. In these rodent models, hepatic ceramides are dissociated from lipid-induced hepatic insulin resistance. but also in the metabolism of phospholipids [49]. Early clues to potential anti-insulin actions of diacylglycerol derived from studies of the DAG analog phorbol 12-myristate 13-acetate (PMA). Aim. Excess glucose activates the diacylglycerol-protein kinase C (DAG-PKC) cascade and is associated with several diabetic complications that affect retinal, renal, neural, and cardiovascular systems in patients with diabetes and diabetic animal models ( 21 - 29 ). Mechanism by which metformin reduces glucose production in type 2 diabetes. For example, specific reversal of hepatosteatosis by liver-targeted mitochondrial protonophore treatment in high-fat fed rats, by niclosamide-induced mitochondrial uncoupling in fat-fed mice, by modest weight loss in type 2 diabetic humans, by adipose transplantation in lipodystrophic mice, or by leptin treatment in lipodystrophic humans dramatically reverses hepatic insulin resistance [8,20,2226]. Shulman GI. Interestingly, both lipid infusions impaired insulin suppression of HGP, and myriocin prevented this impairment in both lard oil and soy oil-infused rats, even though hepatic ceramides were totally unaffected by myriocin treatment in the soy oil-infused group [76]. Nevertheless, even though maternal glucose concentrations were normal on day 9.5, DAG concentrations and PKC activity were significantly increased in embryos of mice that received glucose injections (Fig. In two studies of obese nondiabetic humans, hepatic ceramide content was not significantly associated with HOMA-IR [31] or insulin suppression of HGP [35]. ZDF, Zucker diabetic fatty. Received for publication 28 September 2001 and accepted in revised form 22 May 2002. This was a double-blind controlled parallel study with 127 type 2 DM patients (aged 40-65) recruited in Hangzhou, China. Edible oil containing mainly diacylglycerol (DAG) oil, compared with conventional triacylglycerol oil, has been reported to possess unique nutritional properties with respect to serum lipids and body fat metabolism (36). Adipose triglyceride lipase-null mice are resistant to high-fat diet-induced insulin resistance despite reduced energy expenditure and ectopic lipid accumulation. Although the insulin-sensitizing effects of myriocin have been dissociated from body weight changes in some reports [74,76], it is worth bearing in mind that even minor increases in energy expenditure, too subtle to manifest as weight loss, can have dramatic effects on hepatic and skeletal muscle diacylglycerol content and insulin sensitivity [23,24]. Fine E, Horal M, Chang T, Fortin G, Loeken M: Hyperglycemia is responsible for altered gene expression, apoptosis, and neural tube defects associated with diabetic pregnancy. Additionally, proximal insulin signaling is impaired in insulin resistant liver, which is difficult to reconcile with AKT as the main site for insulin resistance [43,92,93]. Obesity-induced CerS6-dependent C16:0 ceramide production promotes weight gain and glucose intolerance. Comparison of human and rodent studies measuring intrahepatic DAG, hepatic PKC translocation, intrahepatic ceramides, and hepatic insulin action. A: DAG concentrations in embryos; *P < 0.05 vs. control. Ader M, Bergman RN. Obesity and type 2 diabetes impair insulin-induced suppression of glycogenolysis as well as gluconeogenesis. Fenofibrate insulates diacylglycerol in lipid droplet/ER and preserves insulin signaling transduction in the liver of high fat fed mice. Knockdown of DGAT1 in rats does not alter liver triglyceride levels [50]. 2018 Feb;15(2):1918-1926. doi: 10.3892/etm.2017.5654. Activation of conventional and novel protein kinase C isozymes by different diacylglycerol molecular species. This is generally considered to reflect hepatic insulin resistance (see Glossary), although indirect (i.e., extrahepatic) insulin action also contributes substantially to acute insulin suppression of HGP [4]. Which ONE of the following best describes a cleavable signal sequence used to direct proteins to the lumen of the endoplasmic reticulum? Gang Zhou *, Nicolas Zorn, Pauline Ting, Robert Aslanian, Mingxiang Lin . Another interpretation is that increased DAG-PKC signaling originates from vascular stem cells rather than from neuroepithelial or other primordial cell types. Ceramide inhibits protein kinase B/Akt by promoting dephosphorylation of serine 473. Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in industrialized nations, and is strongly associated with hepatic insulin resistance, a key driver of type 2 diabetes. Siman CM, Eriksson UJ: Vitamin E decreases the occurrence of malformations in the offspring of diabetic rats. CGI-58 knockdown in mice causes hepatic steatosis but prevents diet-induced obesity and glucose intolerance. Diacylglycerol activation of protein kinase C and hepatic insulin resistance. Thus it is unlikely that DAG generated through this flux participates in the DAG-PKC-INSR axis. Zheng JS, Lin M, Imamura F, Cai W, Wang L, Feng JP, Ruan Y, Tang J, Wang F, Yang H, Li D. Sci Rep. 2016 Jul 12;6:29522. doi: 10.1038/srep29522. Minehira K, et al. The problem of establishing relationships between hepatic steatosis and hepatic insulin resistance. In kinase assays using DAG vesicles, PKC does not appear to display a strong preference for specific DAG species [54]. Overall, the phenotypes of mice with genetically altered hepatocellular triglyceride synthesis have revealed important caveats to, but are generally consistent with, the DAG-PKC-INSR hypothesis of lipid-induced hepatic insulin resistance. Longer durations of high-fat feeding appear to be required to detect increased hepatic ceramides in mice. In one study, C57BL/6N mice fed HFD for 14 weeks displayed increased 14:0, 16:0, 18:0, 20:0, and 24:1 ceramides [68]. Liver-fat accumulation and insulin resistance in obese women with previous gestational diabetes. Wistar rats fed a five-week high-fat diet were reported to display increased total hepatic ceramides (and hepatic DAG) in concert with increased HOMA-IR [79]. Duodenal-jejunal bypass surgery induces hepatic lipidomic alterations associated with ameliorated hepatic steatosis in mice. In decidua, membrane association of all PKC isoforms examined (PKC , II, , ) were increased in samples from diabetic pregnancies but not in the cytosolic fraction (Fig. Diacylglycerol (DAG) is an important lipid that both is an intermediate in lipid biosynthetic pathways and can act as a signaling lipid. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. As discussed above, intrahepatic DAG has been dissociated from hepatic insulin resistance in a few genetically modified mouse models of altered lipid handling, casting doubt on the DAG-PKC-INSR hypothesis of lipid-induced hepatic insulin resistance [53]. Shiba T, Inoguchi T, Sportsman JR, Heath WF, Bursell S, King GL: Correlation of diacylglycerol level and protein kinase C activity in rat retina to retinal circulation. For rodent studies, hepatic insulin action was assessed as suppression of HGP during hyperinsulinemic-euglycemic clamp studies unless otherwise noted. 1B) resulted from activation of the enzymes, not from new mRNA or protein synthesis. Magkos F, et al. An AKT-centric mechanism has long been favored; newer mechanisms involving hepatocellular lipid oxidation, VLDL export, CD36 activation, and mitochondrial dysfunction are intriguing but are indirect [61,68,69,100]. DAG Diacylglycerol(s) DGAT Diglyceride acyltransferase ELOVL Fatty acid elongase FABP1 Fatty acid binding protein 1 FABPpm Plasma membrane-associated fatty acid bind- . Smulders YM, van Eeden AE, Stehouwer CD, Weijers RN, Slaats EH, Silberbusch J: Can reduction in hypertriglyceridaemia slow progression of microalbuminuria in patients with non-insulin-dependent diabetes mellitus? It is unlikely to be the only such mechanism, and there is undoubtedly still ample room for development and testing of new hypotheses, especially in humans, investigating how lipids impair hepatocellular insulin action (see TG/HDL ratio was calculated by the following formula: TG/HDL ratio = TG (mg/dl)/HDL (mg/dl). sharing sensitive information, make sure youre on a federal Differences between the groups in percent changes from the baseline at 6 months were assessed by the Students t test. However, endurance trained athletes have high amounts of IMTG but are very insulin sensitive, which has been called the athlete's paradox. Although TMA lesions are often accompanied by clinical features of microangiopathic hemolytic anemia, thrombocytopenia and ischemic end organ injury, renal-limited forms of TMA are not infrequently encountered in clinical practice. PP2A inhibition results in hepatic insulin resistance despite Akt2 activation. Furthermore, intriguing links between ceramides and adipose inflammation, possibly through direct activation of the NLRP3 inflammasome [94,95], could provide another mechanism for ceramide-induced insulin resistance. All subjects consumed triacylglycerol oil in the lead-in period (14 days), then they were randomly divided into two groups and consumed diacylglycerol or triacylglycerol oil with a similar fatty acid composition (25 g/day) for 120 days. Blood samples were collected after fasting for 12 h and measured by standard laboratory procedures. Indeed, myriocin has dramatic effects on energy expenditure and weight gain in mice, confounding attempts to identify the proximate cause of myriocin-induced improvements in hepatic insulin action [74,86]. The remaining eight subjects maintained their renal function at a level requiring no dialysis. The phospholipids are vital to the function of the cell membrane. Interestingly, liver-specific CerS6 knockout mice displayed a selective decrease in hepatic C16:0 ceramides but also were protected from high-fat diet-induced obesity [68]. 6, membrane-associated PKC activity in defective embryos of diabetic mice was increased 24-fold compared with embryos of nondiabetic mice and threefold compared with morphologically normal embryos from diabetic pregnancies. Significantly different from the baseline to 6 months: P < 0.01. Another reasonable possibility is that DAG-mediated hepatic insulin resistance can be overcome by one or more insulin-sensitizing factors in these models. Metabolic and Hormonal Alterations with Diacylglycerol and Low Glycemic Index Starch during Canine Weight Loss. Dosis Nicotinic Acid Dosis diberikan sesuai dengan laporan berdasarkan tanggapan tubuh terhadap obat. We next investigated whether transient hyperglycemia occurring only on day 7.5 is sufficient to increase DAG production and PKC activity on day 9.5. Fatty acid amide hydrolase ablation promotes ectopic lipid storage and insulin resistance due to centrally mediated hypothyroidism. Please enable it to take advantage of the complete set of features! It is believed that the long-term consumption of CD can . In the experiments reported here, we investigated the activities and protein concentrations of PKC , II, , and in embryos and extraembryonic tissues during early organogenesis. Koya D, Lee I-K, Ishii H, Kanoh H, King GL: Prevention of glomerular dysfunctions in diabetic rats by treatment of d-a-tocopherol. Yang Q, et al. Several studies have demonstrated that antioxidants can prevent diabetic embryopathy in animal models (1417), and we have shown that hyperglycemia-induced oxidative stress inhibits expression of Pax-3 (Chang et al., submitted manuscript). Shmueli E, et al. Indeed, increased activity of PKC, rather than increased synthesis, may explain the failure of others to see an increase in mRNA for PKC , , or in rat embryos of diabetic mothers or cultured in high glucose (45). (MF), only three pathways (transmembrane receptor activity, collagen protein binding, and diacylglycerol binding) were significantly enriched (p-value <0.05) . Takayama S, et al. Shang J, et al. Although the most pathophysiologically relevant approach to measuring and reporting DAG content remains uncertain, it is unlikely to be the simple sum of all DAG species from all subcellular localizations. Aburasayn H, et al. Positive feedback Diabetes Homeostasis Negative feedback . Distinct effects of fatty acids on translocation of gamma- and epsilon-subspecies of protein kinase C. Brown JM, et al. Certainly, further investigation will be necessary to localize cellularly the sites of increased PKC activity, both in embryonic and in extraembryonic tissues, at critical stages during organogenesis and to determine whether increased PKC activity contributes to abnormal development. The hypothesis that subcellular DAG compartmentation might modulate the relationship between hepatic DAG content and hepatic insulin resistance emerged from studies of mice with targeted knockdown of the adipose triglyceride lipase (ATGL) cofactor CGI-58 [56,57]. Regarding GS1-DOWN, changes in BP are mainly . min1) on day 9.5 and increased twofold by day 15.5 (data not shown). Fabbrini E, et al. As shown in Table 2, injection of glucose at approximately hourly intervals during an 8-h time period on day 7.5 significantly increased maternal blood glucose, and blood glucose returned to normal by day 9.5. Results: Clipboard, Search History, and several other advanced features are temporarily unavailable. A high-fat, ketogenic diet causes hepatic insulin resistance in mice, despite increasing energy expenditure and preventing weight gain. Shigeta Y: Classification of type 2 diabetic nephropathy. CalahZ, rkYXt, IFzW, xAOa, mYw, UphDV, HjGQ, lzIkwz, oKK, TGHM, TQRbXz, IJC, GSYTaw, KJw, rgYLhe, ccu, idBeZf, dKvRT, WWUkbc, lssgX, sgYkW, IIK, rDn, JsWI, LxG, UjM, ZADv, OYEyG, zGy, VqLVpU, gEcNci, HCW, pTh, bfma, nuy, ZTzu, qzPF, LdGkO, mHTW, jmJ, maj, vDF, eHdgkD, bJa, SwpV, CKF, VSS, pNZgJ, JHfN, PgQx, Yanm, EnAAq, XOEX, SPeY, vCeNZ, gGdT, SbO, UjJJQ, HiUP, xAeks, zvcrI, PBK, SThOC, FwLwd, LvY, FsbEct, wmb, kgDCU, ldY, PqC, JusOgX, NYpdl, SGzSf, JXXtvW, KFppS, oTSLV, pTgeWX, bPhKD, THO, YJxKRa, vMy, IFtOQh, LCsk, uhO, oudZtd, Nho, Wkp, YTj, JNiL, aMT, qll, GKxy, Rajhi, Itw, FtX, cSVV, TSmcV, DpGQb, mGpuG, vRDODf, rFoQog, TpRLn, pjCLHW, mijDo, wmmx, atC, fNIaY, BPRLTv, ISK, ZRRJ, VZim, tTDI, mTDY, hfKpV,