lowering ceramides to overcome diabetes

Here are 13 science-backed ways to prevent diabetes. Most promising ASOs verified for in-vivo KD efficacy in healthy mice. In addition, measurements were made of a panel of plasma sphingolipids (SPL), including ceramides (Cer), sphingoid bases (SB), and sphingomyelins (SM), that have been linked to a variety of metabolic diseases and inflammatory conditions [15][16]. <>stream 0 1 TD Collectively, these data have two important implications. /T1_2 1 Tf Registration ID: ChiCTR-DDT-13003983 . Targeting a Ceramide Double Bond Improves Insulin Resistance and Hepatic Steatosis. Abstract. 2019-07-23T18:59:55Z C22:0, C20:0 and C18:0 ceramide correlated with decreased adiponectin concentrations, increased HOMA-IR, BMI Z-score, triglyceride and fasting blood glucose concentrations (p<0.05). (http://stm.sciencemag.org/content/scitransmed/10/468/eaat0344.full)Tj Type 2 Diabetes Risk Tied to Ceramide Levels HealthDay News — High ceramide levels may increase diabetes risk, while low levels could protect against the disease, according to findings from an experimental study published in Cell Metabolism. Here, we focus on the central issue of the insulin resistance triad. BT Serum ceramide changes were studied in 104 subjects consisting healthy adults, liver biopsy-proven patients with NAFLD and liver biopsy-proven patients with chronic hepatitis B (CHB). uuid:084660b6-1dd2-11b2-0a00-aa0000000000 There is considerable evidence that insulin resistance may arise from aberrant accumulation of intracellular lipids in insulin-responsive tissues due to lipotoxicity. Ceramides exert several biological activities that may contribute to the pathophysiology of cardiovascular disease and heart failure (HF). (on December 2, 2020)Tj In Cox regression analyses, all five plasma ratios of each ceramide with Cer(d18:1/24:0) were significantly associated with a greater risk of cardiovascular mortality (with unadjusted hazard ratios ranging from 1.23 to 1.59; P < 0.001 or less). At the same time, the clinical efficacy of lipid lowering drugs has resulted in improvement in the cardiovascular functions of chronic kidney disease (CKD) patients with or without diabetes, but no remarkable improvement has been observed in the kidney outcome. Introduction Sphingolipid accumulation has been linked to obesity, type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). Science Journals - Operations ET Lowering ceramides to overcome diabetes. (RELATED )Tj Aim To guide quality improvement strategies for type 2 diabetes by synthesising qualitative evidence on primary care physicians’ and nurses’ perceived influences on care. In diabetic subjects, the major insulin-resistant organs are liver, muscle, and adipose tissue. Mechanistic studies revealed that these metabolic effects were likely due to impaired β-oxidation resulting from inactivation of electron transport chain components. CerS6 deficiency increases lipid utilization in BAT and liver. “Our work shows that ceramides have an influential role in metabolic health,” says Summers. Lipid accumulation and autophagy markers in the HepG2 cells were analyzed. Objective 0 g Serum total ceramides and dihydroceramides (hepatic dihydroceramides 22:0 and 24:1) correlated negatively with whole-body but not with hepatic insulin sensitivity. For men, type 1 and type 2 diabetes can lead to an increased risk of erectile dysfunction, or ED for short. Patients with diabetes were treated for major cardiovascular diseases, ischemic heart disease, stroke, lower-extremity amputation and diabetic ketoacidosis. Biddinger et al. Operating at multiple levels of control, the adipocyte communicates with organ systems to adjust gene expression, glucoregulatory hormone exocytosis, enzymatic reactions, and nutrient flux to equilibrate the metabolic demands of a positive or negative energy balance. Thus, LDL-ceramide is elevated in type 2 diabetes and correlates with insulin resistance, supporting a pathogenic role of LDL-ceramide. CAS Article Google Scholar 22. 3.83501 1 Td When we applied a Bonferroni correction for multiple comparisons (using a P‐threshold 0.05/5 ceramide ratios = 0.01), none of the five plasma ratios of each ceramide with Cer(d18:1/24:0) remained statistically associated with the risk of cardiovascular mortality (with adjusted hazard ratios ranging from 1.10 to 1.23). ET 522 106 l Background: (Terms of Service)Tj /T1_0 1 Tf We measured baseline plasma concentrations of six previously identified high‐risk ceramide species [Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/20:0), Cer(d18:1/22:0), Cer(d18:1/24:0), and Cer(d18:1/24:1) and their individual plasma ratios with Cer(d18:1/24:0)]. However, these associations are weakened after adjustment for established cardiovascular risk factors, medication use, and plasma NT‐proBNP concentrations. S In this issue of Cell Metabolism, Xia et al. Introduction Sphingolipid accumulation has been linked to obesity, type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). BT To assess this possibility, we employed a lipidomic approach to quantify an array of serum nonglycosylated and glycosylated ceramides … More recently, distinct serum ceramides have shown to be elevated in diabetes (9, 10), and some specific ceramides may predict incident diabetes mellitus type 2 (DM2) even years before the onset of the disease . (Science, 1200 New York Avenue NW, Washington, DC 20005. In adipocytes from obese adults sphingosine, sphinganine, sphingosine-1-phosphate, C14-Cer, C16-Cer and C24-Cer were all increased. The presence of CKD remained significantly associated with higher levels of plasma ceramides (standardized beta coefficients ranging from 0.124 to 0.227, P<0.001) even after adjustment for body mass index, smoking, hypertension, diabetes, prior IHD, plasma LDL-cholesterol, hs-C-reactive protein levels and use of any lipid-lowering medications. endobj Clinical relevance of these ﬁndings is starting to emerge, as adipo-nectin levels inversely correlate with serum and tissue ceramides in insulin-resistant individuals (Blachnio-Zabielska et al., 2012; Lopez et al., 2013). 0 1.00001 TD Here are some common home remedies for diabetes that keeps sugar it in control. BT Ceramides (Cer) are implicated in obesity-associated skeletal muscle and perhaps adipocyte insulin resistance. -1.668 0 Td © 2008-2020 ResearchGate GmbH. /T1_0 1 Tf <> 0 0 1 rg Fasting plasma ceramide subspecies were measured by quantitative tandem mass spectrometry. Sphingolipid species are not only increased in insulin-resistant humans with NASH but also correlate with hepatic oxidative stress and inflammation, suggesting that these lipids may play a role during progression of simple steatosis to NASH in humans. Furthermore, the research suggests that further studies are needed to understand what factors lead some people to develop more ceramides than is healthy. A recent study showed that depletion of dihydroceramide desaturase-1 (DES-1) in adipose and/or liver tissue decreases ceramide-to-dihydroceramide ratios (ceramide/dihydroceramide) in several tissues and improves the metabolic profile in mice. The American Diabetes Association reports that the average medical expenditure for people with diabetes was about $13,700 per year. 6 0 0 6 79 475 Tm Ceramides increase during obesity and promote insulin resistance. However, it remained unclear which distinct ceramide species in this organ contributes to instatement of systemic insulin resistance. Systolic blood pressure z-score and uric acid concentration were significantly lower after consuming milk compared to soda. Getting diagnosed with prediabetes is a serious wake-up call, but it doesn't have to mean you will definitely get diabetes.There is still time to turn things around. <>/ProcSet[/PDF/Text/ImageC]/XObject<>>>/Type/Page>> Ceramides have shown independent predictive value for negative cardiovascular outcomes as well as for the onset of type 2 diabetes. Lipid-induced hepatic insulin resistance is mediated by plasma membrane-bound sn-1,2-diacylglycerols, which promote PKCϵ translocation to the plasma membrane. The leading cause of […] These experiments highlight CerS6 inhibition as a specific approach for the treatment of obesity and type 2 diabetes mellitus, circumventing the side effects of global ceramide synthesis inhibition. Ceramide plays pathogenic roles in nonalcoholic fatty liver disease (NAFLD) via multiple mechanisms, and as such inhibition of ceramide de novo synthesis in the liver may be of therapeutically beneficial in patients with NAFLD. These significant associations were attenuated after adjustment for multiple established risk factors, New York Heart Association functional class, left ventricular ejection fraction, use of medications, plasma pentraxin‐3 levels, and, especially, plasma N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) levels. Illuminated Night Alters Behaviour and Negatively Affects Physiology and Metabolism in Diurnal Zebra Finches. The underlying cause of insulin resistance appears to be inflammation that can either be increased or decreased by the fatty acid composition of the diet. A ceramide-centric view of insulin resistance. HepG2 cells were incubated with fatty acid with or without myriocin treatment. Diabetes has become incredibly common, but there are several things you can do to avoid it. The cost of diabetes to our nation is a staggering $245 billion a year as of 2012. Among the sphingolipid species that we screened in lipidomic profiles, significantly increased ceramide was observed in NASH patients as compared to the controls and non-NASH patients, regardless of whether or not they have active CHB. Hyperinsulinemic-euglycemic clamps with d-[6,6-2H2]glucose were performed to quantify tissue-specific insulin sensitivity. Having higher than normal blood sugar levels is not a direct cause of blindness, but it does increase the risk of developing serious eye conditions such as diabetic retinopathy, which over time can lead to permanent loss of sight. 0 g Treatment with CerS6 ASO selectively reduced CerS6 expression by ∼90% predominantly in the liver and this CerS6 KD resulted in a significant reduction of C16:0 ceramide by about 50% in both liver and plasma. Thirty overweight and obese adolescent boys who were habitual consumers of sugar-sweetened beverages were randomly assigned to consume 24 oz/day of sugar-sweetened soda or an energy equivalent of reduced fat (2%) milk for 3 weeks with crossover to the alternate beverage after a ≥ 2 weeks washout. Diabetes Metab. Half of the 24 million people with diabetes don’t know they have it, and nearly all the 60 million people with pre-diabetes don’t know they have it. 10 0 0 10 72 624 Tm Ceramides vary in acyl-chain lengths from C14:0 to C30:0 and are synthesized by six ceramide synthase enzymes (CerS1-6). Collectively, these data suggest that FGF21 is a potent regulator of adiponectin secretion and that FGF21 critically depends on adiponectin to exert its glycemic and insulin sensitizing effects. Sprague Dawley rats were randomly divided into three groups: standard chow (n = 10), high-fat diet (HFD) (n = 10) or HFD combined with oral administration of myriocin (0.3 mg/kg on alternate days for 8 weeks) (n = 10). Conversely, CerS6-deficient (CerS6(Δ/Δ)) mice exhibit reduced C16:0 ceramides and are protected from high-fat-diet-induced obesity and glucose intolerance. <>/Filter/FlateDecode/Height 87/Length 19684/Name/X/Subtype/Image/Type/XObject/Width 350>>stream 69 0 obj a new therapeutic strategy for lowering ceramides and improving metabolic health—driving ceramide degradation. Experimental & Molecular Medicine, in press Zhao S, Kusminski CM and Scherer PE. Science Magazine Article 119 0 obj describe several disturbances of metabolism in the LIRKO mice. For men only there were significant (at least P < 0.05), positive correlations between adipocyte ceramides containing saturated FA and plasma IL-6 concentration. (ARTICLE TOOLS)Tj CerS6 should specifically be targeted for the reduction of C16:0 ceramides, that results in amelioration of insulin resistance, hyperglycemia and obesity. Blood was sampled for glucose, insulin (to calculate HOMA-IR) adiponectin and IL-6 concentrations. Milk consumption also significantly decreased plasma glucosyl ceramide (d18:1/C16:0) and lactosylceramides (d18:1/C16:0 and d18:1/C18:0). (Xia et al., 2015) identify a new therapeutic strategy for lowering ceramides and improving metabolic health—driving ceramide degradation. Hyperglycemia in the face of hyperinsulinemia is attributed to insulin resistance. We utilized ASO as therapeutic modality, CerS6 ASO molecules designed and synthesized were initially screened for in-vitro knock-down (KD) potency and cytotoxicity. Mechanistic studies revealed new ceramide actions that promoted lipid uptake and storage and impaired glucose utilization, none of which could be recapitulated by (dihydro)ceramides that lacked the critical double bond. In particular, prolonged periods of excess glucose intake can directly contribute to deterioration of insulin sensitivity. 2019 Jun 8. pii: S1262-3636(19)30091-6. doi: 10.1016/j.diabet.2019.05.008. In this article by Dr. Joel Fuhrman, learn how to eat to prevent diabetes and how to reverse diabetes. More and morenumber of people are living with diabetes and many others are prediabetes.About 90 to 95% of all diabetic people have type 2 diabetes. University of Texas Southwestern Medical Center, Relation between plasma ceramides and cardiovascular death in chronic heart failure: A subset analysis of the GISSI-HF trial: Plasma ceramides and chronic heart failure, DES1: A Key Driver of Lipotoxicity in Metabolic Disease, A Randomized Study of the Effect of Replacing Sugar-Sweetened Soda by Reduced Fat Milk on Cardiometabolic Health in Male Adolescent Soda Drinkers, Therapeutic effect and autophagy regulation of myriocin in nonalcoholic steatohepatitis, Targeting a ceramide double bond improves insulin resistance and hepatic steatosis, CerS1-Derived C 18:0 Ceramide in Skeletal Muscle Promotes Obesity-Induced Insulin Resistance, The Role of C16:0 Ceramide in the Development of Obesity and Type 2 Diabetes: CerS6 Inhibition as a Novel Therapeutic Approach, Inducible Overexpression of Adiponectin Receptors Highlight the Roles of Adiponectin-Induced Ceramidase Signaling in Lipid and Glucose Homeostasis, An FGF21-Adiponectin-Ceramide Axis Controls Energy Expenditure and Insulin Action in Mice, Specific Hepatic Sphingolipids Relate to Insulin Resistance, Oxidative Stress, and Inflammation in Nonalcoholic Steatohepatitis, Adiponectin, Leptin, and Fatty Acids in the Maintenance of Metabolic Homeostasis Through Adipose Tissue Crosstalk, CerS2 Haploinsufficiency Inhibits β-Oxidation and Confers Susceptibility to Diet-Induced Steatohepatitis and Insulin Resistance, Obesity-Induced CerS6-Dependent C-16:0 Ceramide Production Promotes Weight Gain and Glucose Intolerance, Plasma ceramides are elevated in female children and adolescents with type 2 diabetes, Sphingolipid Content of Human Adipose Tissue: Relationship to Adiponectin and Insulin Resistance, Inhibition of Ceramide Synthesis Ameliorates Glucocorticoid-, Saturated-Fat-, and Obesity-Induced Insulin Resistance, Selective versus Total Insulin Resistance: A Pathogenic Paradox, The plasma ceramides in patients with diabetes type II. People with diabetes typically have medical costs that are approximately 2.3 times higher than those without diabetes. ET Science Magazine Article Patients who died due to cardiovascular causes had significantly (P < 0.05 or less) higher levels of plasma Cer(d18:1/16:0) and Cer(d18:1/24:1), but lower levels of plasma Cer(d18:1/22:0) and Cer(d18:1/24:0) than had those who did not. White fat tissue is due to an accumulation of ceramides and has the opposite effect of increasing resistance to insulin. CerS6 KD resulted in lower body weight gain and accompanied by a significant reduction in whole body fat and fed/fasted blood glucose levels (1% reduction in HbA1c). WebMD tells you about seven types of foods to help control blood sugar, spare you from boredom, and stave off hunger. <>/MediaBox[0 0 594 758.834656]/Parent 119 0 R/Resources<>/Font<>/ProcSet[/PDF/Text]>>/TrimBox[0 0 594 758.834656]/Type/Page>> CerS6 mediated C16:0 ceramide reduction could be a potentially attractive target for the treatment of insulin resistance, obesity and type 2 diabetes. (PERMISSIONS)Tj -32.125 0 Td (http://stm.sciencemag.org/content/scitransmed/8/323/323rv1.full)Tj PKCϵ is both necessary and sufficient for mediating lipid-induced hepatic insulin resistance through phosphorylation of insulin receptor at Thr1160. Our investigations identified specific and selective therapeutic valid ASO for CerS6 ablation in in-vivo. ... More recently, studies conducted at the University of Utah and Merck Research Laboratories utilizing inducible whole-body and tissue-specific genetic ablation or knockdown of DEGS1 (the gene encoding DES1) in genetically defined or diet-induced obese mice have further advanced our understanding of ceramide-driven metabolic dysfunction (Chaurasia et al., 2019; ... Exploratory outcomes were insulin resistance as assessed by homeostatic model assessment of insulin resistance (HOMA-IR) and inflammation as assessed by C-reactive protein (CRP), as well as serum uric acid and serum transaminases. 0 0 1 rg 122 0 obj Results highlight potential diabetes drug target and role for ceramides in sensing nutrition. 8 0 0 8 187 378.99997 Tm CerS1DSkM mice exhibit improved insulin-stimulated suppression of hepatic glucose production, and lack of CerS1 in skeletal muscle improves systemic glucose homeostasis via increased release of Fgf21 from skeletal muscle. DALiM Software Applications Diabetes is an illness related to elevated blood sugar levels. BT A small chemical change — shifting the position of two hydrogen atoms — makes the difference between mice that are healthy and mice with insulin resistance and fatty liver, major risk factors for diabetes and heart disease. 137 0 obj /T1_1 1 Tf Chavez JA, Summers SA. 72 106 m -3.83501 0 Td 8 0 0 8 187 404.99988 Tm In another paradigm, lowering ceramides before putting the mice on a high-fat diet prevented weight gain and insulin resistance. American Association for the Advancement of Science Hence, blockade of ceramide signaling by myriocin may be of therapeutically beneficial in NASH. uuid:86618000-4745-73d5-a721-a6a1ffff39fc /Im0 Do ceramides. Summers SA. In rodents, numerous ceramide-lowering interventions have been shown to improve insulin sensitivity and ameliorate diabetes and cardiovascular pathologies . adipocytes lowers ceramides across many tissues involved in maintaining metabolic homeostasis. Collectively, these studies reveal that altering sphingolipid acylation patterns impacts hepatic steatosis and insulin sensitivity and identify CerS6 as a possible therapeutic target for treating metabolic diseases associated with obesity. ET All rights reserved. Myriocin treatment significantly attenuated liver pathology including steatosis, lobular inflammation and ballooning. But the approach they were using — which included inhibiting another enzyme — didn't work, Summers said. <> 0 0 1 rg /T1_0 1 Tf jѨ�\i-~��=��=�Op�(r�w]EQ��ڇ�MyƧ�H��4E�5�(HQ_�-*P1.�#*�kb"��f_+X�A¾�ՆK�$�Fx�UFJeF��q�� {vd��cg8Z��S#�3��_k��X `9��'�p� �(��3u�_�Od}�u�vn|TSI# !y� ��3�|�].�F��h�{U_�J�A�-��M0bD�22}[��-(��U�~[y�Tk��|�H m�L�;ƶc 0�X� ��?1�A�r��?oƀU�]C:/^��ّ,7(��a"��G�q��?b#Q�U��a�S�� L6��)��$�Hm�[AN��c�� t�PĎvU��Rl2!��VV�{^e(��^I, American Association for the Advancement of Science. ET 120 0 obj q We hypothesized that specific plasma ceramide subspecies are elevated in obese children and adolescents with type 2 diabetes (T2D), and that they inversely correlate with adiponectin and measures of insulin sensitivity. Six different ceramide synthases (CerS) that differ in tissue distribution and substrate specificity account for the diversity in acyl-chain composition of distinct ceramide species. True (Science)Tj In fact, Summers led a study, newly published in Science, that shows how targeting ceramides could reverse insulin resistance and fatty liver—major risk factors for diabetes and heart disease. /T1_1 1 Tf )Tj Serum ceramides have emerged as potential biomarkers of insulin resistance, diabetes, and heart disease. Importantly, metabolic improvements fail to occur in an adiponectin knockout background. 70 0 obj BT 1), the inhibitor is able to decrease ceramide synthesis without elevating intermediates such as sphinganine, which are upstream of ceramide formation and also have biological effects (9). We tested whether replacing soda with reduced fat milk would improve features of atherogenic dyslipidemia and other cardiometabolic risk factors. In particular, the sphingolipid ceramide has been implicated in this process. (http://science.sciencemag.org/content/sci/365/6451/386.full)Tj 0 0 1 rg Results 0 1.00001 TD Results ASOs with >85% inhibition of CerS6 mRNA were selected for further investigations. (2008) examine glucose and lipid metabolism in liver-specific insulin receptor knockout (LIRKO) mice (Michael et al., 2000). 0 0 1 rg The impetus for this -3.55701 0 Td Insulin resistance is a multi-faceted disruption of the communication between insulin and the interior of a target cell. ET Myriocin reversed the elevated body weight and serum transaminases and alleviated dyslipidemia in HFD fed rats. (Use of this article is subject to the )Tj %PDF-1.4 %�� Summers SA. But when you’re exhausted by “diabetes fatigue,” working out is easier said than done. Because of these data, a handful of companies have started to develop ceramide-reducing interventions in hopes … ( )Tj Mice lacking CerS1, either globally or specifically in skeletal muscle (CerS1DSkM), exhibit reduced muscle C18:0 ceramide content and significant improvements in systemic glucose homeostasis. Diabetes Shake Diet primarily occurs as a result of obesity and lack of exercise. Diabetes can be easily controlled by using simple home remedies available at home. -13.50598 0 Td 0 1.00001 TD CAS Article Google Scholar 21. dalim:psshoot:86618000-4745-73d5-a721-a6a1ffff39fc The scientists think this could mean that some people are more likely to convert calories into ceramides than others. The study focuses on ceramidase, an enzyme that removes an acyl-chain from ceramide, converting it to sphingosine, which does not oppose insulin signaling or induce apoptosis (Chavez et al., 2005; Lang et al., 2011). In type 1diabetes, people suffering from a do no Liver histology and autophagy function were measured. Hepatic total ceramides were higher by 50% and 33% in NASH compared with NAFL+ and NAFL-, respectively. (http://www.sciencemag.org/help/reprints-and-permissions)Tj “We’re thinking of ceramides as the next cholesterol.” This isn’t the first time that Summers’ group has found that lowering ceramides could reverse signs of diabetes and metabolic disease. Because of these data, a handful of companies have started to develop ceramide-reducing interventions in hopes … For women only, there was a negative correlation between C16-Cer ceramide and plasma adiponectin (r=−0.77, p= 0.003) and a positive correlation between total ceramide content and HOMA-IR (r=0.74, p= 0.006). 0 -8 8 0 576 329.87207 Tm CerS6 mediated C16:0 ceramide reduction could be a potentially attractive target for the treatment of insulin resistance, obesity and type 2 diabetes. (Science )Tj The identification of these mechanisms has great potential to identify novel targets for the treatment of diabetes and related metabolic disorders. endobj CerS6 expression were significantly elevated in the liver and brown adipose, this was correlated with significantly elevated C16:0 ceramide concentrations in plasma and liver. CerS6 ASO (AAGATGAGCCGCACC) was found most active with hepatic reduction of CerS6 mRNA expression. An increasing number of studies have shown a link between the development of diabetes and ceramide lipids (6–8). The implications of lipid lowering drugs in the treatment of diabetic nephropathy have been considered. While no effects of replacing soda with milk on lipid and lipoprotein measurements were observed in these normolipidemic weight-stable adolescent boys, decreases in systolic blood pressure, uric acid, and glycosphingolipids suggest that an overall favorable effect on cardiometabolic risk can be achieved following a short-term dietary intervention. /T1_1 1 Tf (DOI: 10.1126/science.aax6594)Tj It remains unresolved whether obesity-associated alterations of specific CerSs and their defined acyl-chain length ceramides contribute to the manifestation of metabolic diseases. Avoiding body weight gain, or consuming diets low in saturated fatty acids or fructose from nonfruit sources are a likely means to increase hepatic fatty acid oxidation, inhibit ceramide synthesis, and lower circulating ceramide to improve metabolic health (Dubé et al. endobj (365)Tj Plasma lipids and lipoproteins and other laboratory measures were assessed after each beverage period. ET 1. Science Magazine (http://science.sciencemag.org/content/365/6451/319#BIBL)Tj BT U. scientists have been trying to find a way to lower ceramides for several years. These studies suggest that inhibition of DES1 may provide a means of treating hepatic steatosis and metabolic disorders. Today, I want to share with you more information about what you can do NOW to prevent and reverse diabetes and pre-diabetes. Accumulating experimental evidence has suggested that some ceramides, especially those with long and very-long chains, exhibit multiple biological activities that may influence the pathophysiology of both HF and atherosclerotic cardiovascular disease, including effects on cellular apoptosis, oxidative stress, endothelial dysfunction, inflammation, lipotoxicity, insulin resistance, and cardiomyopathy. /T1_1 1 Tf [Epub ahead of print] Association between specific plasma ceramides and high-sensitivity C-reactive protein levels in postmenopausal women with type 2 diabetes. Science. endobj Results: Metabolism research has made tremendous progress over the last several decades in establishing the adipocyte as a central rheostat in the regulation of systemic nutrient and energy homeostasis. BT -3.83501 0 Td CAS Article Google Scholar 22. Moreover, inhibition of ceramide synthesis markedly improves glucose tolerance and prevents the onset of frank diabetes in obese rodents. ( $6451$, 319-320. 121 0 obj The latest installment is found in this issue, where Biddinger et al. /T1_2 1 Tf 8 0 0 8 72 564.99997 Tm ET Abstract Accumulation of ceramides within tissues induces insulin resistance. True lowering ceramides, Resistance to insulin is a pathophysiological state related to the decreased response of peripheral tissues to the insulin action, hyperinsulinemia and raised blood glucose levels caused by increased hepatic glucose outflow. ET 8 0 0 8 187 351 Tm Type 2 diabetes makes up about 90% of cases of high protein drinks for diabetics, with the other 10% due primarily to type 1 diabetes and gestational diabetes. Moreover, studies in rodents reveal that inhibitors of ceramide synthesis prevent or reverse the pathogenic features of type 2 diabetes, nonalcoholic fatty liver disease, atherosclerosis, and cardiomyopathy. a new therapeutic strategy for lowering ceramides and improving metabolic health—driving ceramide degradation. /T1_0 1 Tf However, the therapeutic potential of CerS6 inhibition not been demonstrated. Compared to lean controls, total ceramide content (pg/adipocyte) was increased by 31 % (p<0.05) and 34 % (p<0.05) in obese females and males, respectively. BT -15.17299 0 Td Methods: Here, we have developed transgenic mice that overexpress AdipoR1 or AdipoR2 under the inducible control of a tetracycline response element. 5.50301 1 Td 0 g They are potent biomarkers of diabetes and heart disease and are now being measured clinically as predictors of major adverse cardiac events. Moreover, adiponectin exerts its beneficial metabolic effects at least partially through ceramide catabolism. Use of basic amino acids derivatives for lowering ceramide levels . Research design and methods: Herein, we review the central role of the adipocyte in the maintenance of metabolic homeostasis, highlighting three critical mediators: adiponectin, leptin, and fatty acids. Activation of these receptors promotes the deacylation of ceramide, a lipid metabolite that appears to play a causal role in impairing insulin signaling. (Right) Liver in mice in which ceramides were lowered by inactivating an enzyme, dihydroceramide desaturase 1, a target that could be used to develop new drugs against diabetes. They are potent biomarkers of diabetes and heart disease and are now being measured clinically as predictors of major adverse cardiac events. Humans with type 2 diabetes mellitus exhibit the classic triad of hyperinsulinemia, hyperglycemia, and hypertriglyceridemia. endobj 8 0 0 8 72 72 Tm The findings indicate that high ceramides levels may increase diabetes risk and low levels could protect against the disease. 1. Insulin is a key player in the disposal of carbohydrates from food. (REFERENCES)Tj Ceramide analogs have only marginal effects on glucose-stimulated insulin secretion, 17 and inhibitors of de novo ceramide synthesis do not overcome the secretory defects due to lipotoxicity. Further, myriocin also restored the impaired hepatic autophagy function in rats with HFD-induced NASH, and this has been verified in HepG2 cells. H��yTS��߽Ia "6p\P縠x�:�Z�.Su�k�:�8ud,E��ԺУ�:xt�S��Vk��9@��na��}/ �Ҟ6�G��y�@��{_r��cL�"��bFSg�j��z��"U�H�}�>�2��Z Ceramides contribute to the lipotoxicity that underlies diabetes, hepatic steatosis, and heart disease. application/pdf The precise contribution that each organ makes to hyperglycemia and hypertriglyceridemia is not known. (Downloaded from )Tj Trial registration: By genetically engineering mice, we deleted the enzyme dihydroceramide desaturase 1 (DES1), which normally inserts a conserved double bond into the backbone of ceramides … 87.5 0 0 21.75 72 664.25 cm (Christine M. Kusminski and Philipp E. Scherer)Tj Some people are more genetically at risk than others. A ceramide-centric view of insulin resistance. This was a cross-sectional study. Participants included 14 obese female subjects with T2D, ages 10-17, and 14 lean healthy controls of the same age and gender. In this study, we aimed to explore whether inhibition of ceramide signaling by myriocin is beneficial in animal model of NAFLD via regulating autophagy. However, the molecular basis for insulin resistance can be quite different in various organs. To answer this question, Kahn and associates have conducted systematic studies in mice in which they have ablated the insulin receptor gene in each of these suspect organs (Biddinger and Kahn, 2006). Regulation of Ceramides by Adipokines. Because of these data, a handful of companies have started to develop ceramide-reducing interventions in hopes … BT BT /T1_1 1 Tf As Chaurasia explains it, once ceramide synthesis is blocked, “Fat cells … Regular exercise is key to managing glycemic control and overall health in people with type 2 diabetes. Christine M. Kusminski's 12 research works with 160 citations and 1,575 reads, including: Dermal adipocytes contribute to the metabolic regulation of dermal fibroblasts 6 0 0 6 79 389 Tm Ceramide may play an important regulatory role in the autophagy function in the pathogenesis of NASH. ($print ISSN 0036-8075; online ISSN 1095-9203$ is published by the Amer\ ican Association for the Advancement of)Tj 134 0 obj Ectopic fat deposition is associated with increased tissue production of ceramides. Inhibition of ceramide synthesis prevents diabetes, steatosis, and cardiovascular disease in rodents. Aims Results: Overexpression of either adiponectin receptor isoform in the adipocyte or hepatocyte is sufficient to enhance ceramidase activity, whole body glucose metabolism, and hepatic insulin sensitivity, while opposing hepatic steatosis. Moreover, studies in rodents reveal that inhibitors of ceramide synthesis prevent or reverse the pathogenic features of type 2 diabetes, … These represent the first inducible genetic models that acutely manipulate adiponectin receptor signaling in adult mouse tissues, which allows us to directly assess AdipoR signaling on glucose and lipid metabolism. Methods The findings indicate that having high levels of ceramides may increase a person’s risk of developing type 2 diabetes, while low levels could prevent it. 8 0 0 8 72 611 Tm 8 0 0 8 193.38391 120 Tm No doubt, diabetes is one of the fastest spreading diseases in the world but the home remedies which are mentioned in this article will help you cure diabetes naturally in 30 days. Request PDF | On Jul 26, 2019, Christine M. Kusminski and others published Lowering ceramides to overcome diabetes | Find, read and cite all the research you need on ResearchGate In 2007, the Utah team found that mice who produced fewer ceramides were protected from diabetes and fatty liver disease. Based on abundant published data, risk score using the concentrations of circulating ceramides have been developed and adapted for routine clinical practice. 2019;365:319–20. 0 1 TD 2011; Dekker et al. Ceramides contribute to the lipotoxicity that underlies diabetes, hepatic steatosis, and heart disease. All plasma ratios of each ceramide with Cer(d18:1/24:0) were significantly higher in patients who died due to cardiovascular causes. endobj /T1_1 1 Tf Abdominal subcutaneous adipose biopsies were performed on 12 lean adults (males = 6), 12 obese adults (males =6) for measurement of sphingolipid content and activity of the main ceramide metabolism enzymes. /T1_0 1 Tf Chavez JA, Summers SA. The impetus for this ET BT An increasing number of studies have shown a link between the development of diabetes and ceramide lipids (6–8). Only in NASH were hepatic dihydroceramides (16:0, 22:0, and 24:1) and lactosylceramides increased. We examined whether the sphingolipid content of human subcutaneous adipose tissue and plasma varies by obesity and sex as well as the relationship between ceramide content and metabolic indices. The scientists think this could mean that some people are more likely to convert calories into ceramides than others. Ceramides have emerged as important regulators of tissue metabolism that play essential roles in cardiometabolic disease. CerS6 mediated C16:0 ceramide reduction could be a potentially attractive target for the treatment of insulin resistance, obesity and type 2 diabetes. All the above precede the onset of full-blown type 2 diabetes. By reducing the condensation of serine with palmitoyl-CoA to form 3-ketosphinganine (Fig. The Cause of Diabetes. /T1_1 1 Tf Methods and results BT ET Higher levels of specific plasma ceramides [especially when used in ratios with Cer(d18:1/24:0)] are associated with increased cardiovascular mortality in ambulatory patients with chronic HF. 0 0 m (CONTENT)Tj <> endstream lowering a1c in 3 months is partly due to a number of complications with which it is associated, including: two to four times the risk of cardiovascular disease, including ischemic heart disease and stroke; a 20-fold increase in lower limb amputations, and increased rates of hospitalizations. 124 0 obj 6 0 0 6 79 353 Tm /T1_1 1 Tf In a post hoc ancillary analysis of the Gruppo Italiano per lo Studio della Sopravvivenza nella Insufficienza Cardiaca‐Heart Failure (GISSI‐HF; NCT00336336) trial, we randomly selected a sample of 200 ambulatory patients with chronic HF who died due to cardiovascular causes and 200 patients who were alive at the end of the trial (after a median follow‐up period of 3.9 years). endstream (http://science.sciencemag.org/)Tj Since then, the researchers have been testing effects in human cells. Conclusions: Objective: Adiponectin and the signaling induced by its cognate receptors, AdipoR1 and AdipoR2, have garnered attention for their ability to promote insulin sensitivity and oppose steatosis. Data of registration: 13 May, 2013, retrospectively registered. Type 2 diabetes is typically a chronic disease associated with a ten-year-shorter life expectancy. ET Herein the authors discuss inhibition of dihydroceramide desaturase-1, the final enzyme in the ceramide biosynthesis pathway, as a potential therapeutic approach to lower ceramides and combat cardiometabolic disease. Insulin resistance and nonalcoholic fatty liver (NAFL) disease have been linked to several lipid metabolites in animals, but their role in humans remains unclear. (Lowering ceramides to overcome diabetes)Tj /T1_1 1 Tf [1][2][3][4][24][25]. In 2014, 7.2 million hospital discharges were reported with diabetes as a listed diagnosis. ET 2020-12-02T05:53-08:00 Recent genetic mouse studies suggest that specific sphingolipid C16:0 ceramide produced by ceramide synthase 6 (CerS6) plays an important role in the development of insulin resistance. Background Despite the availability of evidence-based guidance, many patients with type 2 diabetes do not achieve treatment goals. How are diabetes and erectile dysfunction related? 2012;15:585–94. Tissue Immune Cells Fuel Obesity-Associated Inflammation in Adipose Tissue and Beyond. default 2012;15:585–94. endobj The title )Tj BT Ceramides have emerged as important regulators of tissue metabolism that play essential roles in cardiometabolic disease. 2020. (http://science.sciencemag.org/content/365/6451/319)Tj There ceramides proved to decrease metabolic activity of fat tissue. ... Ceramides are critical components of sphingolipids with multiple biological functions [18]. Front Endocrinol, in press Kim M, Lee C, Seo DY, Horton JD, Park JY, Scherer PE. Recent evidence suggests that ceramides can play an important pathophysiological role in the development of diabetes. In contrast, muscle-specific deficiency of C16:0 ceramide-producing CerS5 and CerS6 failed to protect mice from obesity- induced insulin resistance. C18:1-Cer was increased in obese males and C24:1-Cer in obese females. More recently, distinct serum ceramides have shown to be elevated in diabetes (9, 10), and some specific ceramides may predict incident diabetes mellitus type 2 (DM2) even years before the onset of the disease . (http://stm.sciencemag.org/content/scitransmed/10/467/eaat4271.full)Tj A recent study showed that depletion of dihydroceramide desaturase-1 (DES-1) in adipose and/or liver tissue decreases ceramide-to-dihydroceramide ratios (ceramide/dihydroceramide) in several tissues and improves the metabolic profile in mice. /T1_1 1 Tf Cell Metab. 2020-12-02T05:53-08:00 Therefore, we pharmacologically investigated the selective ablation of CerS6 using antisense oligonucleotides (ASO) in obese insulin resistance animal models. 2019;365:319–20. Since 2007, scientists have known that lowering ceramides could prevent diabetes. 0 g This may be a reflection of tissue insulin resistance and could be a result of low adiponectin levels. First, they indicate that different fatty acids induce insulin resistance by distinct mechanisms discerned by their reliance on sphingolipid synthesis. BT Here we reveal that CERS6 mRNA expression and C16:0 ceramides are elevated in adipose tissue of obese humans, and increased CERS6 expression correlates with insulin resistance. Moreover, FGF21 lowers blood glucose levels and enhances insulin sensitivity in diabetic Lep(ob/ob) mice and diet-induced obese (DIO) mice only when adiponectin is functionally present. Q 5�f @a,uWP2�4 Conclusions: ( is a registered trademark of AAAS. 8 0 0 8 357.45605 85.99997 Tm CerS6 should specifically be targeted for the reduction of C16:0 ceramides, that results in amelioration of insulin resistance, hyperglycemia and obesity. In rodents, numerous ceramide-lowering interventions have been shown to improve insulin sensitivity and ameliorate diabetes and cardiovascular pathologies . Importantly, adiponectin-knockout mice are refractory to changes in energy expenditure and ceramide-lowering effects evoked by FGF21 administration. ET Liver lipid peroxides (total ceramides, sphingomyelin 22:0) and the pJNK-to-tJNK ratio (ceramide 24:0; hexosylceramides 22:0, 24:0, and 24:1) all positively correlated with the respective hepatic sphingolipids. [138 0 R 139 0 R 140 0 R 141 0 R 142 0 R 143 0 R 144 0 R 145 0 R 146 0 R 147 0 R] 8 0 0 8 187 473 Tm Aberrant ceramide signaling has been linked to obesity, insulin resistance and metabolic disorders [19, Access scientific knowledge from anywhere. (http://stm.sciencemag.org/content/scitransmed/11/489/eaav0120.full)Tj 2013). Using genetic engineering, researchers had deleted the gene that converts saturated fats into ceramides. The findings mark a milestone in diabetes research. 2020 Discover the best and worst foods for fighting diabetes. When challenged with a leptin-deficient genetic model of type 2 diabetes, AdipoR2 expression in adipose or liver is sufficient to reverse hyperglycemia and glucose intolerance. 6 0 0 6 79 432.99997 Tm endobj Objective: /T1_1 1 Tf -8.11398 0 Td CerS6 should specifically be targeted for the reduction of C16:0 ceramides, that results in amelioration of insulin resistance, hyperglycemia and obesity. You can request the full-text of this article directly from the authors on ResearchGate. This study examined the relationship of sphingolipids with hepatic and peripheral metabolism in 21 insulin-resistant obese patients without (NAFL-) or with (NAFL+) and nonalcoholic steatohepatitis (NASH), and 7 healthy lean individuals undergoing tissue biopsies during bariatric or elective abdominal surgery. FGF21, a member of the fibroblast growth factor (FGF) superfamily, has recently emerged as a regulator of metabolism and energy utilization. The association between plasma levels of distinct ceramides (that have been previously associated with increased cardiovascular risk) and cardiovascular mortality in patients with chronic HF has received little attention. (1) report the largest longitudinal study to date correlating sphingolipids with insulin resistance, profiling a cohort of 2,086 American Indians at high risk for diabetes. We conclude that the sexual dimorphism in adipose tissue behavior in humans extends to adipose tissue sphingolipid content its association with adiponectin, IL-6 and insulin resistance. Thus, CerS6 appear to play an important role in the development of obesity and insulin resistance. Targeting the body’s ceramide chemistry in a subtle way could lead to the development of safe new treatments for type 2 diabetes, heart disease, and other metabolic conditions. Here, we show that FGF21 rapidly and robustly stimulates adiponectin secretion in rodents while diminishing accumulation of ceramides in obese animals. 0 g The study focuses on ceramidase, an enzyme that removes an acyl-chain from ceramide, converting it to sphingosine, which does not oppose insulin signaling or induce apoptosis ( Chavez et al., 2005 , Lang … … ET <> However, the exact mechanism(s) whereby FGF21 mediates its actions have not been elucidated. (This article cites 14 articles, 2 of which you can access for free)Tj Inhibiting global ceramide synthesis negated the effects of CerS2 haploinsufficiency in vivo, and increasing C16-ceramides by overexpressing CerS6 recapitulated the phenotype in isolated, primary hepatocytes. (Science\240)Tj United States Patent 6350782 . )Tj This was also observed for components of the ceramide catabolism pathway, such as cell type–specific overexpression of acid ceramidase, in addition to overexpression … <>stream Skeletal muscle accumulates ceramides in obesity, which contribute to the development of obesity-associated insulin resistance. ET The Role of Ceramides in Diabetes and Cardiovascular Disease. Hepatic oxidative capacity, lipid peroxidation, and the phosphorylated-to-total c-Jun N-terminal kinase (pJNK-to-tJNK) ratio was measured to assess mitochondrial function, oxidative stress, and inflammatory activity. Lipid and lipoprotein measurements, C-reactive protein, and serum transaminases did not differ significantly between the soda and milk phases of the study. Conclusions Insulin resistance is a key feature of type 2 diabetes, and the strong association between fat oversupply and defective insulin action in target tissues, especially skeletal muscle and liver, has motivated the search for intracellular lipid mediators that can interfere with insulin signaling and glucose homeostasis. By qPCR analysis, it was revealed that myriocin corrected the expression pattern of fatty acid metabolism associated genes including Fabp1, Pparα, Cpt-1α and Acox-2. Change your diet Plasma levels of C18:0, C20:0 and C22:0 ceramide, as well as C24:1 dihydroceramide, were elevated in obese female children and adolescents with T2D. In rodents, numerous ceramide-lowering interventions have been shown to improve insulin sensitivity and ameliorate diabetes and cardiovascular pathologies . Next, we utilized leptin deficiency ob/ob and high fat diet (HFD) induced obese mouse models for pharmacological efficacy study. Hepatic maximal respiration related positively to serum lactosylceramides subspecies, hepatic sphinganine, and lactosylceramide 14:0. CAS Article Google Scholar 21. Subjects with T2D had higher concentrations of C22:0 and C20:0 ceramides, with a 2-fold increase in C18:0 ceramide and C24:1 dihydroceramide (p<0.05). BT Second, they identify enzymes required for ceramide synthesis as therapeutic targets for combating insulin resistance caused by nutrient excess or glucocorticoid therapy. Blindness is one of the many, albeit rarer, complications of uncontrolled diabetes. A healthy diet can help you keep your type 2 diabetes in check. Results: Type 2 diabetes can be reversed — and even type 1 diabetics can improve their life and health. BT Lowering ceramides to overcome diabetes - NASA/ADS Excess nutrient intake leads to a disruption in metabolic homeostasis. Collectively, these results reveal the tissue-specific function of distinct ceramide species during the development of obesity-associated insulin resistance. Science. By genetically engineering mice, we deleted the enzyme dihydroceramide desaturase-1 (DES1) which normally inserts a conserved double bond into the backbone of ceramides and other predominant sphingolipids. 133 0 obj Here, ceramide profiling of high-fat diet (HFD)-fed animals revealed increased skeletal muscle C18:0 ceramide content, concomitant with increased expression of ceramide synthase (CerS)1. Cell Metab. Prior to longitudinal metabolic studies, we performed a dose titration target engagement analysis with CerS6 ASO in healthy mice to select the optimal dose. /T1_2 1 Tf Soda consumption in adolescents has been linked to poorer metabolic outcomes. Moreover, ASO-mediated CerS6 KD significantly improved oral glucose tolerance (during oGTT) and mice displayed improved insulin sensitivity. Conclusion: These observations reveal that adiponectin is critical for AdipoR-induced ceramidase activation which enhances hepatic glucose and lipid metabolism via rapidly acting “cross-talk” between liver and adipose tissue sphingolipids. endobj Herein, we demonstrate that the sphingolipid ceramide is a common molecular intermediate linking several different pathological metabolic stresses (i.e., glucocorticoids and saturated fats, but not unsaturated fats) to the induction of insulin resistance. Insulin resistance occurs in 20%-25% of the human population, and the condition is a chief component of type 2 diabetes mellitus and a risk factor for cardiovascular disease and certain forms of cancer. Conclusions Methods: 0 1 TD /T1_0 1 Tf Lowering Ceramides to Overcome Diabetes. Jul 04, 2019 12:00 PM. -0.278 0 Td Haploinsufficiency for ceramide synthase 2 (CerS2), the dominant isoform in the liver that preferentially makes very-long-chain (C22/C24/C24:1) ceramides, led to compensatory increases in long-chain C16-ceramides and conferred susceptibility to diet-induced steatohepatitis and insulin resistance. The study focuses on ceramidase, an enzyme that removes an acyl-chain from ceramide, converting it to sphingosine, which does not oppose insulin signaling or induce apoptosis (Chavez et al., 2005; Lang et al., 2011). CerS6 deletion increases energy expenditure and improves glucose tolerance, not only in CerS6(Δ/Δ) mice, but also in brown adipose tissue- (CerS6(ΔBAT)) and liver-specific (CerS6(ΔLIVER)) CerS6 knockout mice. Δ/Δ ) ) mice exhibit reduced C16:0 ceramides and improving metabolic health—driving ceramide degradation common, but there are things... The soda and milk phases of the insulin resistance well as for the onset of frank in... 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