Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance.

By William L. Holland, J. Brozinick, Liping Wang, E. Hawkins, Katherine M Sargent, Yanqi Liu, Krishna Narra, Kyle L. Hoehn, Trina A. Knotts, Angela M. Siesky and 5 more. Cell Metabolism, 2007

1,231 citations recorded by the source corpus.

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. 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. Moreover, inhibition of ceramide synthesis markedly improves glucose tolerance and prevents the onset of frank diabetes in obese rodents. Collectively, these data have two important implications. First, they indicate that different fatty acids induce insulin resistance by distinct mechanisms discerned by their reliance on sphingolipid synthesis. Second, they identify enzymes required for ceramide synthesis as therapeutic targets for combating insulin resistance caused by nutrient excess or glucocorticoid therapy.

Subfields: Molecular Biology, Pharmacology, Surgery

View Paper: https://www.semanticscholar.org/paper/11f70c8ea5487f294047df67187bd268f10dc164

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

In Surgery

Citations in the corpus

Adiponectin, a Therapeutic Target for Obesity, Diabetes, and Endothelial Dysfunction (2017, background): “This effect appears to be dependent on activation of AdipoR1 or AdipoR2 [60].”
Integrating Mechanisms for Insulin Resistance: Common Threads and Missing Links (2012, neutral): “Myriocin prevents acute skeletal muscle insulin resistance following infusion of palmitate, but not oleate (Holland et al., 2007).”
Metabolic Syndrome and Insulin Resistance: Underlying Causes and Modification by Exercise Training (2013, neutral): “In line with findings for myriosin-treated rodents, tissues harvested from Des-1+/− mice accumulate less ceramide and these animals are refractory to insulin resistance (271).”
Inflammatory mechanisms linking obesity and metabolic disease (2017, background): “…inflammatory signaling by knockout of key pathways in obese mice, including components of NF-κ B (24) and JNK (25) pathways, as well as numerous other proinflammatory signaling molecules, scaffolding proteins, and cytokines, can disrupt the link between obesity and insulin resistance (15, 26–33).”
The PI3K/AKT pathway in obesity and type 2 diabetes (2018, background): “Ceramides disturb insulin signalling by AKT, leading to reduction of glucose utilization [54].”
An overview of sphingolipid metabolism: from synthesis to breakdown (2010, background): “Des1 −/− mice have highly elevated dihydroceramide, low levels of ceramide, multi-organ dysfunction, and failure to thrive [36].”
Central leptin regulates total ceramide content and sterol regulatory element binding protein-1C proteolytic maturation in rat white adipose tissue. (2009, background): “Central leptin infusion increases overall insulin sensitivity Recent evidence demonstrated that decreasing ceramide synthesis, using pharmacological and genetics approaches, improved insulin sensitivity in rodent models of insulin resistance (34).”
Sphingolipids, insulin resistance, and metabolic disease: new insights from in vivo manipulation of sphingolipid metabolism. (2008, background): “Specifically, pretreating rats with the SPT inhibitor myriocin completely prevented glucose intolerance resulting from the administration of the synthetic glucocorticoid dexamethasone (12).”
Cardiac remodeling in obesity. (2008, background): “The existence of mouse mutants with impaired ceramide biosynthesis and the availability of pharmacological inhibitors of ceramide biosynthesis that can be safely administered to animals (142) now provide the opportunity to clarify the role of ceramide accumulation in mediating lipoapoptosis that cha”
A ceramide-centric view of insulin resistance. (2012, background): “Hyperinsulinemic-euglycemic clamp studies confirm that myriocin improves insulin sensitivity in both muscle and the liver in these models (Holland et al., 2007a).”
Diabetes associated cell stress and dysfunction: role of mitochondrial and non‐mitochondrial ROS production and activity (2007, background): “…the cytosol, phosporylation and activation of Akt/PKB and promoting dephosphorylation (see Zierath, 2007 for comment) Indeed evidence for ceramide as a common intermediate linking nutrient excess to the induction of insulin resistance in rodents has recently been published (Holland et al. 2007).”