Plasma sphingolipids are biomarkers of metabolic syndrome in non-human primates maintained on a Western-style diet

Abstract

BACKGROUND The intake of a Western diet enriched in animal fat has been shown to be a major risk factor for Type 2 diabetes and obesity. Previous rodent studies have indicated that these conditions may be triggered by the accumulation of the sphingolipid ceramide in insulin-sensitive tissues. However, data are lacking in this regard from both humans and non-human primates. OBJECTIVE Here we have investigated the relationship between plasma ceramides and metabolic syndrome in Rhesus macaques fed a high-fat and high-fructose (HFFD) ‘western’ diet. METHODS We investigated this relationship in cohorts of monkeys fed a HFFD for a period of 8 months to 5 years. Animals were classified as control, pre-diabetic or diabetic based on fasting plasma parameters and insulin sensitivity. RESULTS HFFD treatment produced significant increases in body weight and body fat and also resulted in a decline in insulin sensitivity. In parallel to the reduction in insulin sensitivity, significant increases in both plasma ceramide and dihydroceramide levels were observed, which further increased as animals progressed to the diabetic state. Plasma levels of the rare sphingolipid C18:0 deoxysphinganine, a marker of increased metabolic flux through serine palmitoyl transferase (SPT), were also elevated in both pre- and diabetic animals. Furthermore, plasma serine levels were significantly elevated in diabetic monkeys, which may indicate a shift in SPT substrate selectivity from serine to alanine or glycine. In contrast, branch chain amino acids were unchanged in pre-diabetic non-human primates, and only plasma valine levels were elevated in diabetic animals. CONCLUSION Together, these data indicate that HFFD induces de novo synthesis of ceramides in non-human primates, and that increased production of plasma ceramides is significantly correlated with the decline in insulin sensitivity.

Serum sphingolipids: relationships to insulin sensitivity and changes with exercise in humans

“…Discrete serum ceramide profiles are rendered across the spectrum of diabetes development, creating speculation that ceramides not only mark but contribute to the disease process (8,17). Nevertheless, a paucity of interventional studies in humans has made this speculation difficult to confirm.…”

“…Our data support the idea that serum ceramides, specifically the C16:0 and C18:0 species, promote insulin resistance via activation of inflammatory cascades in muscle. Total and C18:0 serum dihydroceramide and ceramide have been shown to be associated with prediabetes and diabetes (8,15,28) as well as able to predict progression to type 2 diabetes in epidemiological cohorts (26,28). Recent data indicate that dihydroceramide is more than an inactive precursor to ceramide formation and is an important intra-and extracellular signal influencing sterol regulatory element gene transcription, autophagy, and mitochondrial function (3,32,36,38).…”

“…Serum ceramides, a family of sphingolipids involved in diverse and relevant metabolic processes, have received considerable attention in relation to diabetes, making them prime candidates for further examination. Unlike other biomarkers, discrete serum ceramide profiles are rendered across the spectrum of diabetogenesis, creating speculation that ceramides not only mark but contribute to the disease process (8,17).…”

β-Hydroxypyruvate: A New Diabetogenic Factor?

“…Plasma b-hydroxypyruvate levels were positively correlated with plasma glucose levels in mice and b-hydroxypyruvate/D-serine ratios were higher in patients with T2DM compared with people with IGT in the study by Zhang et al (5). A previous study reported increased plasma serine (not necessarily D-serine) levels in diabetic nonhuman primates compared with nondiabetic control subjects (10). Thus, future studies should include the measurements of b-hydroxypyruvate, D-serine, and benzoate levels as well as b-hydroxypyruvate/D-serine ratio and DAO activity.…”

Dietary Sugars and Endogenous Formation of Advanced Glycation Endproducts: Emerging Mechanisms of Disease

“…Recently, alterations of the sphingolipid metabolism have been evidenced in obese and diabetic patients, with increased plasma levels of ceramide and sphingosine-1-phosphate, which are hypothesized to elicit an inflammatory condition [57,58]. In animal models of western diet, high in fats and fructose, the increased ceramide de novo synthesis has been reported, in relation with reduced insulin sensitivity [59,60]. In parallel, two very recent studies highlighted a possible role for diet-derived AGEs on this unbalance among sphingolipids intermediates through the action of the AGE-receptor RAGE [61,62].…”