Our findings support the hypothesis that prediabetic patients showed a lower degree of flexibility by an exaggerated lipoprotein postprandial response, compared with those non-diabetic patients. Moreover, in this large cohort we confirmed previous data indicating that diabetes status is associated with abnormal postprandial lipoprotein metabolism [
15,
16]. Thus, the frequency of undesirable response increases progressively according to non-diabetic (35 %), prediabetic (48 %) and diabetic patients (59 %). The postprandial response was higher in patients with liver-IR compared with muscle-IR or without any type of IR. Finally, our results indicate an association between hepatic IR and postprandial-TG response.
Postprandial hypertriglyceridemia is consequence of several factors including genetic variations and medical conditions like obesity, metabolic syndrome and insulin resistance [
17,
18]. During the postprandial period, intestinal TRL are the main contributors to the serum lipid level. Hypertriglyceridemia can originate from decreased clearance or increased production of TRL. During lipid absorption, enterocytes produce and secrete chylomicrons and transiently store lipid droplets in the cytosol. The dynamic fluctuation of triglycerides in cytosolic lipid droplets suggests that they contribute to TRL production and may thus control the length and amplitude of the postprandial hypertriglyceridemia [
19] Accumulation of TRLs in the postprandial state promotes the retention of remnant particles in the artery wall and for their size these particles cannot cross the endothelium as efficiently as smaller LDL inducing accelerated atherosclerosis [
20]. In this regard, previous data have linked the exaggerated postprandial TG response to the incidence of coronary artery disease and stroke [
21]. Moreover recent studies have demonstrated that diabetic patients present an exaggerated postprandial TG response after meals [
22], and this phenomenon could be translated in a loss phenotypic flexibility and consequently in an increase of cardiovascular disease risk (CVD) [
23]. In our large diabetic cohort, our findings consistently confirmed that the diabetic status is associated with an exaggerated postprandial response [
15]. Recent data indicate that unlike the situation in the nondiabetic population, in which measurement of postprandial TG levels has been useful in identifying individuals at high CVD, specifically testing for postprandial TG level has shown considerably less promise in T2DM patients. However, the importance for testing postprandial lipemic response in prediabetic patients have not been established yet. According to epidemiological data, up to 70 % of individuals with prediabetes will eventually develop diabetes. Likewise, data from observational studies suggest that prediabetes may also convert back to normoglycaemia [
24]. For this reason, we decided to explore the prediabetes status, firstly because it is a reversible state with often asymptomathic period in its early stages [
25] and secondly because several trials have demonstrated reductions in the risk of developing diabetes among prediabetics after lifestyle and drug-based interventions [
25‐
27]. In our study, we observed that prediabetic patients displayed higher plasma TG and TRLs-TG postprandial response compared with those non-diabetic patients, suggesting that at this initial stage already have abnormal lipoprotein metabolism. A question arise about what is the main trigger in this process: insulin resistance influencing postprandial lipoprotein response or instead the exaggerated postprandial response favouring the insulin resistance condition. In this context, the physiological link between these both process is not well understood. The hepatocellular TG accumulation may be a direct cause of hepatic insulin resistance. The liver plays a unique role in the regulation of glucose homeostasis by maintaining blood glucose concentration within a normal range. However, impaired insulin action in the liver leads to insulin resistance characterized by impairment in the ability of insulin to inhibit glucose output. Thus, liver insulin resistance which is the reduced sensitivity of the liver to insulin, causes gluconeogenesis and hyperglycemia. As a result of insulin resistance, the adipocyte increased release of free fatty acids (FFA) into the circulation. Increased FFA flux into the liver stimulates hepatic lipogenesis and promotes VLDL-TG overproduction, contributing to the pathogenesis of hypertriglyceridemia in diabetic population [
28,
29]. In this regards, recent studies exploring the effect of TRLs on insulin resistance during postprandial lipemia suggest that an exaggerated postprandial lipemia play an important role in the development of diabetes and its associated hepatic insulin resistance, but also in the development of whole body insulin resistance according of these mechanisms [
30,
31]. Although the insulin resistance develops simultaneously in multiple organs and it can be defined by different indices, [
32] the importance of insulin resistance may differ among the different tissues [
33]. In our study we observed that those patients with liver-IR showed higher postprandial TG response compared with those with muscle-IR, and in addition, there was a significant association between postprandial response and hepatic insulin resistance defined by HIRI index. This finding is interesting because suggest that liver-IR appears to be a critical contributor factor of postprandial lipidemia.
From a clinical point of view, to recognize this inflexibility-subgroup of prediabetic patients with an exaggerated postprandial response may be important in terms of early identification of those at greatest risk who should be prioritized for lifestyle intervention according to clinical practice guidelines [
34,
35]. In addition, recent studies have shown the possibility of modulating the postprandial response by pharmacological treatments. This point can be the target of future studies in our population [
36,
37]. The disadvantage is that the recognition of postprandial hypertriglyceridemia in the clinical setting has been severely hampered by technical difficulties and the lack of established clinical protocols for investigating postprandial lipemia. Although at this point there is no internationally agreed management for postprandial hypertriglyceridemia, a previous consensus has suggested a simple clinical protocol for investigating postprandial TG measurements, and has pointed out cut-offs for undesirable response [TG concentration >2.5 mmol/L (220 mg/dL)] at any time after a OFTT meal. In this context, in this study we explored, the frequency of undesirable postprandial TG response in each subgroup. As expected, diabetic patients commonly showed an undesiderable postprandial TG response and therefore will not benefit diagnostically from an OFTT. However, in the subgroup of prediabetic patients, half of them presented an exaggerated and delayed response and consequently they will benefit diagnostically from an OFTT.
In summary, this study demonstrate that prediabetic patients show a lower metabolic flexibility after external aggression, such as OFTT, compared with nondiabetic patients. The degree of postprandial response increases progressively according to non-diabetic, prediabetic and diabetic state and it is higher in patients with liver insulin-resistance. To identify this subgroup of patients is important to treat more intensively, according to ADA guidelines in order to avoid future cardiometabolic complications.