Listen to your heart when ceramide's calling for higher glucose.

An ounce of prevention is worth a pound of cure. Long-term and acute complications from diabetes can be reduced with patient education, support, and treatment [1]. In particular, early detection and identification of patients at high risk for diabetes onset facilitates favorable interventions via lifestyle, surgery or pharmacologic treatment [1]. Numerous clinical indicators such as LDL, BMI, Age, body fat, or triglycerides serve as indicators of risk for the development of diabetes. However, none of these are capable of predicting that a subject will develop diabetes 10-years before disease onset. Indeed, current diagnoses rely on glycosylated hemoglobin (A1C), plasma glucose readings, or glucose tolerance tests, which are only accurate in the later progression of the disease [1]. Recently, circulating lipids, specifically sphingolipids, have been gaining credibility as predictive biomarkers for cardiac and metabolic disorders. Of note, using unbiased lipidomics to profile a cohort of 250 patients, Bernard Thorens and colleagues determined that dihydroceramides can serve as strong predictors of type 2 diabetes. Astonishingly, relationships were observed up to 9-years prior to diagnosis. In this issue of EBioMedicine, Jensen et al. report findings from the largest study of its kind, profiling the Strong Heart Family Study to determine that several different circulating sphingolipids associate with fasting glucose levels [2].

Picture the glycerol backbone used for triglyceride synthesis and replace that glycerol with serine. You now have an image of the sphingolipid structure, which uses the amino acid to generate the sphingoid scaffold characteristic of sphingolipids. The ubiquitous biosynthetic pathway that produces sphingolipids from nutritional metabolites generates a structurally-diverse group of ceramides containing the sphingoid backbone linked to a variable-length acyl side chain. Six ceramide synthase enzymes (CerS1-CerS6) convey specificity for which acyl chain is incorporated. The tissue-specific distribution of the CerS enzymes are postulated to contribute to the diversity of serum sphingolipids in a tissue-representative way. For example, C18 ceramides (made with the 18 carbon-long unsaturated fatty acid stearate) are the most abundant species in muscle, and elevations in serum C18 ceramide likely indicate defects in muscle lipid metabolism. Consistent with this, Turpin-Nolan and colleagues recently demonstrated that CerS1-derived C18 ceramides are critical for insulin resistance induced by a high fat diet [3]. These data support our extensive work in preclinical models, where we established over 10-years ago that ceramides are causal mediators of insulin resistance [4]. Within a plethora of cell types, ceramides have been shown to inhibit the activation of insulin-stimulated Akt/PKB which is known to contribute to insulin resistance; they are also associated with mitochondrial dysfunction and increased oxidative stress [5]. Degrading ceramide appears to be the primary insulin-sensitizing mechanism driven by the adipocyte-derived hormone adiponectin [5].

It has since become clear to us that ceramides can be trafficked from tissue to tissue as poorly-understood lipid mediators of inter-organ crosstalk. Recently, the concept of using serum sphingolipids, particularly ceramides, as biomarkers of disease has gained traction, particularly in cardiovascular health where ratios of “bad” ceramides C16 and C18 to benign ceramides C24 and C24:1 correlate with adverse cardiac events in large clinical studies. Impressively, these studies have shown that plasma ceramides can predict major adverse cardiac events and cardiovascular death in patients with coronary artery disease better than LDL-cholesterol [6]. It has also been shown that elevated ceramides and the altered ratio of ceramide C16/C24 can predict adverse cardiovascular health in patients that have or have not been diagnosed with preexisting coronary artery disease [7]. The connection of plasma ceramides to diabetes, specifically in correlation to increased insulin resistance, has been shown in obese patients with type-2 diabetes [8]. The same has also been shown in mouse models [5,9]. A recent study utilizing plasma from the Strong Heart Family Study, the same pool of patient plasma used by Jensen et al., highlighted that, in the over 2000 patients not diagnosed with diabetes, elevated ceramides predicted higher baseline insulin and insulin resistance in their follow-up exams [10].

In EBioMedicine, Jensen et al. show that elevated 18:0 ceramide and sphingomyelin were seen in patients that were older, had higher BMIs, elevated body fat, exercised less, had elevated cholesterol and LDL, and had hypertension (Fig. 1). Increased concentrations of 18:0 ceramide also correlated with a decrease in HDL and were much more likely to be detected in former smokers. Both 18:0 and 22:0 ceramide species were elevated in patients with higher fasting glucose concentrations at the baseline measurement. This is the first time in a human screen that an association with ceramides and fasting glucose has been observed in non-diabetic patient populations. Interestingly, this study also shows that lactosylceramide (LC) 16:0 was associated with lower BMIs, reduced waist circumferences, lower triglyceride levels, and higher HDL and LDL. LC 16:0 also correlated with lower plasma glucose concentrations not only at baseline readings but also at the follow-up measurement five years later. These data indicate that circulating LC 16:0 is a novel biomarker for metabolic health and glucose regulation.

Fig. 1

The Strong Heart Family Study is a population-based cohort study comprised of 12 American Indian communities. From over 2000 samples of non-diabetic subjects, Jensen and colleagues show evidence in EBioMedicine that C18 Ceramides are a strong biomarker for elevations in fasting blood glucose. C18 ceramide also correlates with each of the metabolic risk factors above.

Jensen and colleagues present here that circulating sphingolipids could potentially be biomarkers indicating or foreshadowing the onset of the misregulation of glucose. Any advance in the ability to diagnose diabetes in an early state could be very advantageous to patient outcomes, as early interventions can delay the onset of frank diabetes. However, as dysregulation of sphingolipids may play a causal role in the initiation of diabetes, studies probing potential genetic causes of aberrant sphingolipid metabolism should be done in at-risk populations such as this. Targeting sphingolipid synthesis has been effective in animal models to reduce overall sphingolipid accumulation and prevent insulin resistance initiated by high concentrations of saturated-fats, glucocorticoids, or diet-induced obesity [4]. This study and the work of Lemaitre et al., when coupled with the large body of data showing causal roles for ceramides in insulin resistance, supports the need for future studies that target pharmaceutical intervention of sphingolipid accumulation.

Disclosure

Funding was provided by NIH R01DK108833 (to WLH), R01DK112826 (to WLH), 5T32DK091317 (JLW), R01DK115824 (to SAS) and SBIRDK116405 (to SAS). Scott Summers is a consultant and shareholder of Centaurus Therapeutics.