Reviews in Endocrine and Metabolic Disorders

, Volume 17, Issue 1, pp 111–116 | Cite as

Atherogenicity of postprandial hyperglycemia and lipotoxicity



Type 2 diabetes is characterized by a gradual decline in insulin secretion in response to nutrient loads; hence, it is primarily a disorder of postprandial glucose regulation. However, physicians continue to rely on fasting plasma glucose and glycated hemoglobin to guide management. There is a linear relationship between the risk of cardiovascular death and the 2-h oral glucose tolerance test, while a study confirms postprandial hyperglycemia as independent risk factor for cardiovascular disease in type 2 diabetes. At the same time, several studies show that postprandial hypertriglyceridemia may also be a cardiovascular risk factor. Interestingly, the simultaneous presence of postprandial hyperglycemia and postprandial hypertriglyceridemia has an additive effect in worsening endothelial function and inflammation. Evidence supports the hypothesis glucose postprandial hyperglycemia and hypertriglyceridemia may favor the appearance of the cardiovascular disease through the generation of an oxidative stress. Furthermore, clinical data suggest that postprandial hyperglycemia is a common phenomenon even in patients who may be considered in “good metabolic control”. Therefore, physicians should consider monitoring and targeting postprandial plasma glucose, as well as glycated hemoglobin and fasting plasma glucose, in patients with type 2 diabetes.


Postprandial hyperglycemia Postprandial hyperlipidemia Oxidative stress Endothelial dysfunction 

1 Introduction

Most of the risk factors for cardiovascular disease (CVD) make similar contributions to risk among patients with and without diabetes, and the relationship between fasting plasma glucose (FPG) or glycated hemoglobin (HbA1C) levels and macrovascular complications among diabetic patients is not strong [1]. Postprandial hyperglycemia (PPH), which captures “spikes” in blood glucose levels that are not captured by FBG or HbA1C levels, has historically been overlooked as a CV risk factor among diabetic patients, those with isolated PPH, and those in the general population [2]. However, postprandial state is a complex situation, and postprandial hyperlipidemia has been also involved in the pathogenesis of atherosclerosis [3].

The aim of this article is to review and update the evidence supporting a possible independent role of PPH and hyperlipidemia in the pathogenesis of CV complications of diabetes.

1.1 Epidemiological evidence

There is ample evidence from epidemiological studies to show that PPH is an independent risk factor for CVD, not only among diabetic patients, but also among subjects in the general population with mildly elevated postprandial or post-challenge levels [4]. In the Framingham Offspring Study, involving 3370 subjects with no history of diabetes or CVD, 2-h post-challenge (PC) glucose level at baseline significantly predicted CV events after 4 years (RR 1.1; 95 % CI 1.02-1.13), even after adjustment for FBG levels and non-glycemic risk factors, but the converse did not hold [5]. In the Diabetes Intervention Study, a prospective 11-year population-based study of 1139 newly diagnosed diabetic patients who were deemed to be well-controlled with diet alone, baseline postprandial glucose (PPG) levels predicted all-cause mortality, but FBG did not [6]. And a more recent naturalistic 5-year study of 529 patients attending a diabetes clinic in Turin, Italy, baseline post-lunch glucose levels, but not FBG or HbA1C, significantly predicted CV events, particularly in women, an effect which lasted even after a follow-up of 10 years [7, 8].

The strong relationship between serum triglyceride level and the mortality of ischemic coronary heart diseases was originally reported in the epidemiologic research carried out in 1985 as the Stockholm Prospective Study [9]. Then, several clinical studies have suggested that high postprandial triglycerides could become an independent risk factor for early development of atherosclerosis, and was correlated with other cardiovascular diseases [10, 11, 12, 13]. For example, high concentration of serum non-fasting triglyceride was shown to increase the risk for myocardial infarction, ischemic heart disease, and death [14].

1.2 Pathophysiological mechanisms

Acute increases in plasma glucose levels have significant hemodynamic effects even in normal subjects. In one study, maintenance of plasma glucose levels at 15 mmol/L for 2 hours in healthy subjects significantly increased mean heart rate (+9 bpm; p < 0.01), systolic (+20 mmHg; p < 0.01) and diastolic blood pressure (+14 mmHg, p < 0.001) and plasma catecholamine levels; these hemodynamic effects were abolished by infusion of glutathione, suggesting that these changes are mediated by an oxidative pathway [15]. If this is so, one would expect glucose levels to affect endothelial function as well; and indeed, a study of flow-mediated endothelium-dependent vasodilation (FMD) of the brachial artery among 52 subjects during an oral glucose tolerance test found significant decreases at 1 and 2 h among those with impaired glucose tolerance (IGT) or diabetes, but not control subjects. In fact, plasma glucose levels were negatively correlated with FMD. Endothelial function also normalized after 2 hours in the controls but remained impaired in the group with IGT, and especially the group with diabetes [16]. This evidence is consistent with the finding that modulating PPH with a variety of approaches (e.g. insulin aspart, acarbose), avoids its deleterious effects on endothelial function [17, 18].

PPH has also been seen to cause myocardial perfusion defects. In prospective study, 20 patients with well-controlled diabetes and 20 healthy controls were given a standard mixed meal, and myocardial contrast echography was used to assess myocardial perfusion [19]. Before the meal, the two groups had similar myocardial flow velocity, blood volume and blood flow. In the PC state, all these parameters increased significantly in the normal controls, but flow velocity increased slightly and blood volume and flow decreased significantly among the patients with diabetes [19]. There was a significant correlation between changes in blood volume and the degree of PPH in the diabetic patients. These data suggest that postprandial myocardial perfusion defects are related to impaired coronary microvascular circulation and represent an early marker of diabetic CV damage. A follow-up study showed that treatment with rapid insulin analog (but not regular human insulin) significantly decreased PPH and partly reversed the postprandial myocardial perfusion defects seen among diabetic patients [20]. Since PPG levels ≤6.7 mmol/L were achieved by 60 % of the diabetic patients receiving insulin analog but only 30 % of those receiving human insulin, the differing effects of the two regimens on myocardial perfusion were directly related to their differing effects on PPG [20].

In type 2 diabetic patients, the effects of two different standard meals, designed to produce different levels of PPH, on the plasma oxidative status and LDL oxidation were evaluated [21]. LDL was more susceptible to oxidation after the meal that produced a significantly higher degree of hyperglycemia [21].

Postprandial hypertriglyceridemia is now established as an important risk factor for CVD [22]. Because hypertriglyceridemia is reported to decrease the serum level of high-density lipoprotein (HDL) while it increases the remnant lipoproteins and small dense LDL, these effects would induce thrombogenesis, intimal proliferation and promote atherosclerosis [23]. One of the pathophysiological backgrounds for the increased risk for atherosclerosis and these diseases may be an endothelial inflammation and dysfunction [24]. In fact, it has been reported that the postprandial rapid rise in serum triglyceride levels after a high-fat meal was associated with transient endothelial dysfunction, as evaluated by the impairment in FMD [25, 26], and the endothelial dysfunction has been demonstrated to precede the formation of atherosclerotic lesion [27].

It is worthy of interest the evidence that PPH and postprandial hypertriglyceridemia have a cumulative effects on endothelial dysfunction, inflammation and oxidative stress generation [28, 29], and that the combination of a statin plus an angiotensin II receptor blocker has a protective effect on this phenomenon [30].

1.2.1 The central role of oxidative stress

Reactive oxygen and nitrogen species have a wide range of actions; now it is known that this reactive species either initiate or intermediate several gene and enzymatic-dependant reactions in different normal or pathological reactions, They act as signaling molecules between mitochondria and other compartments of the cell which are required to promote health and longevity [31, 32, 33]. On the other hand, the alterations of redox balance lead to a common pathway for many diseases including hypertension, atherosclerosis, heart failure, ischemia reperfusion injury [34].

It has been suggested that four key biochemical changes induced by hyperglycemia —(a) increased flux through the polyol pathway (in which glucose is reduced to sorbitol, reducing levels of both NADPH and reduced glutathione), (b) increased formation of advanced glycation end products (AGEs), (c) activation of protein kinase C (with effects ranging from vascular occlusion to expression of pro-inflammatory genes), and (d) increased shunting of excess glucose through the hexosamine pathway (mediating increased transcription of genes for inflammatory cytokines and PAI-1)—are all activated by a common mechanism: overproduction of superoxide radicals [35]. Excess plasma glucose drives excess production of electron donors (mainly NADH/H+) from the tricarboxylic acid cycle; in turn, this surfeit results in the transfer of single electrons (instead of the usual electron pairs) to oxygen, producing superoxide radicals and other reactive oxygen species (instead of the usual H2O end product). The superoxide anion itself inhibits the key glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase, and in consequence, glucose and glycolytic intermediates spill into the polyol and hexosamine pathways, as well as additional pathways that culminate in protein kinase C activation and intracellular AGE formation [35]. (Fig. 1).
Fig. 1

In the cells, hyperglycaemia and hyperlipemia induce overproduction of superoxide at the mitochondrial level and nitric oxide overproduction through both iNOS and eNOS. Whereas PKC and NF-κB are also activated and favor an overexpression of the enzyme NADPH. NADPH generates a great amount of superoxide. Superoxide overproduction, accompanied by increased nitric oxide generation, favors the formation of the strong oxidant peroxynitrite, which in turn damages DNA. DNA damage is an obligatory stimulus for the activation of the nuclear enzyme PARP. PARP activation in turn reduces the GAPDH activity. This process results in endothelial dysfunction, which, in turn, contributes to the development of diabetic complications. Abbreviations: eNOS = endothelial nitric oxide synthase, GAPDH = glyceraldehyde-3-phosphate dehydrogenase, H pathway = hexosamine pathway, iNOS = inducible nitric oxide synthase, NF-κB = nuclear factor kappa B, NADPH = nicotinamide adenine dinucleotide phosphate, PARP = poly(ADP-ribose) polymerase, PKC = protein kinase C

Very recently, it has been confirmed that 1 h acute glucose is enough to induce superoxide generation in both endothelial cells and animals [36].

There is ample evidence from in vitro and animal studies that marked fluctuations in glucose levels, as seen in diabetic patients, have consequences that are even more deleterious than those of continuous high glucose levels. For example, in cultures of human umbilical vein endothelial cells, levels of nitrotyrosine (a marker of oxidative stress), intercellular adhesion molecule-1, vascular cellular adhesion molecule-1, E-selectin, interleukin-6, endoglin and 8-hydroxydeoxyguanosine (a marker of oxidative damage of DNA) were all increased after incubation in a medium containing 20 mM glucose compared with a 5 mM glucose medium, but alternating the two media caused even greater increases [37, 38, 39, 40, 41]. In addition, intermittent hyperglycemic conditions increased rates of cellular apoptosis and stimulated the expression of caspase-3 (a pro-apoptotic protein) but decreased bcl-2 (an anti-apoptotic protein); these effects were abolished by adding superoxide dismutase (which scavenges free radicals) or inhibitors of the mitochondrial electron transport chain, suggesting that overproduction of free radicals in the mitochondria mediates the apoptotic effects of increased glucose concentrations [40].

The Goto-Kakizaki (GK) rat is a widely-used animal model of diabetes without obesity. One study found that a single bolus injection of glucose (causing an acute spike in glucose concentrations) was sufficient to cause a reversible increase in the number of monocytes adhering to endothelial cells in the thoracic aorta; monocytes adhesion is considered an early event in the pathogenesis of atherosclerosis [42]. The effect was not inhibited by octreotide and was therefore independent of increases in insulin levels, but was not seen in rats with streptozocin-induced diabetes and chronic hyperglycemia [42]. Similarly, GK rats fed twice daily to induce spikes of PPH had greater degrees of monocytes adhesion than did diabetic rats fed ad libitum, despite significantly higher mean HbA1C levels in the latter group; the effect was often accompanied by intimal thickening of the aorta [43]. Insulin and nateglinide both reduce PPH; at doses that reduced PPH without significantly affecting HbA1C levels, these compounds reduced both monocytes adhesion and intimal thickness [44], as did a 12-week course of acarbose [45].

Since dietary fatty acids are a good source of oxidised/oxidisable lipids and can lead to activation of mitochondrial metabolism and to the formation of reactive oxygen species, it has been proposed that oxidative stress could link postprandial hypertriacylglycerolaemia to vascular damage [46].

The majority of the experiments highlighted a significant impairment of postprandial endothelial function following a high fat meal [47, 48, 49, 50]. Notably, Vogel et al. [49] and Plotnick et al. [50] showed a correlation between the magnitude of postprandial hypertriacylglycerolaemia and the degree of endothelial function impairment. Others evaluated the impact of high fat meal-induced hypertriacylglycerolaemia on markers of oxidative stress. The majority of these investigations observed increased postprandial oxidative stress or impaired plasma antioxidant capacity through multiple different markers [51, 52]. These data allow one to conclude that a high fat meal induces transient but significant hypertriacylglycerolaemia that impairs endothelial function and increases oxidative stress and/or lowers antioxidant defences [46].

2 Conclusion

Many clinicians caring for diabetic patients have a “fasting glucocentric” outlook: they focus on FBG and HbA1C levels as the main measures of glycemic status when evaluating a diabetic patient’s CV risk. However, there is ample epidemiological evidence that PPH predicts CV disease and mortality not only among patients already identified as diabetic, but also among subjects in the general population. Mounting mechanistic evidence suggests that hyperglycemia has myriad adverse effects that are mediated through oxidative stress (e.g. production of superoxide anion). Moreover, the available interventional studies suggest that strategies directed toward decreasing PPH should decrease CVD risks and improve clinical outcomes. Similarly, avoiding an acute increase of triglycerides during the meal may significantly impact in reducing the cardiovascular risk of diabetic patients.


Compliance with ethical standards

Conflicts of interest

The authors do not have conflicts of interest to declare.


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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)BarcelonaSpain
  2. 2.Centro de Investigacion Biomèdica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM)BarcelonaSpain
  3. 3.Department of Cardiovascular and Metabolic DiseasesIRCCS MultimedicaMilanItaly

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