Introduction
Postprandial glucose excursions are a detrimental factor in diabetic complications [
1]. An important mechanism for postprandial glucose peaks contributing to increased risk of diabetic complications may be the formation of α-dicarbonyls, which have been linked to a range of detrimental effects on cellular function [
2].
We recently showed that individuals with type 2 diabetes had higher plasma levels of the α-dicarbonyls methylglyoxal (MGO), glyoxal (GO) and 3-deoxyglucosone (3-DG), after a glucose load [
3]. These highly reactive α-dicarbonyls are mainly formed as glycolytic intermediates during glucose metabolism and rapidly interact with protein residues [
2]. Importantly, α-dicarbonyl stress has been linked to diabetic complications [
2]. However, whether type 2 diabetes is associated with higher plasma α-dicarbonyls after a meal is unknown.
Weight loss interventions, particularly energy restriction and bariatric surgery, have been linked to improved glucose metabolism and reduction of diabetic complications [
4]. Interestingly, beneficial effects of energy restriction and bariatric surgery on insulin resistance seem to occur rapidly [
5]. Thus, it is likely that α-dicarbonyls will be rapidly reduced by these interventions.
Therefore, we investigated whether type 2 diabetes is associated with higher fasting and postprandial plasma α-dicarbonyl levels compared with lean and obese women with normal glucose tolerance (NGT) and whether a diet very low in energy or Roux-en-Y gastric bypass (RYGB) reduces plasma α-dicarbonyl levels in obese women with type 2 diabetes.
Discussion
This study shows that obese individuals with type 2 diabetes have higher fasting and particularly higher postprandial plasma α-dicarbonyl levels than individuals without diabetes. Moreover, VLCD and RYGB reduced plasma α-dicarbonyl stress in obese type 2 diabetic individuals, mainly through reduction of fasting plasma α-dicarbonyls.
In obese NGT individuals, we found higher fasting plasma MGO levels compared with lean individuals, but we observed no further postprandial increase. Interestingly, these increased fasting MGO levels were reduced by RYGB. The elevated fasting MGO levels in obese individuals compared with healthy individuals remained significant after adjustment for glucose. Therefore, other pathways may contribute to increased MGO formation in obese NGT individuals. In contrast, fasting and postprandial plasma levels of the other α-dicarbonyls were not affected by the presence of obesity.
Our current findings on increased postprandial α-dicarbonyl stress in type 2 diabetes, together with similar findings in type 1 diabetes [
7], are in line with our previous work, in which we demonstrated increased α-dicarbonyl stress in type 2 diabetic individuals after an oral glucose load [
3]. Therefore, it is likely that the increased α-dicarbonyl levels after a meal result from increased postprandial glucose levels. Furthermore, the possible role of other substrates for α-dicarbonyl formation, such as reduced lipid oxidation and reactive oxygen species (ROS) cannot be excluded. ROS are known to increase postprandially in type 2 diabetes [
8] and, therefore, reduction of ROS by weight loss could also be responsible for lower postprandial MGO stress, but this phenomenon deserves further investigation. Additionally, a VLCD may reduce MGO via induction of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), an inducer of the MGO-detoxifying enzyme glyoxalase-1 [
9].
Our current findings are of potential clinical importance, since α-dicarbonyls have been identified as potential key mediators of diabetic complications. Of the three major α-dicarbonyls, MGO is the most potent glycating agent [
2]. MGO seems to play a crucial role in the development of diabetic complications, particularly via induction of endothelial dysfunction. Therefore, excursions in MGO at the fasting and postprandial level in type 2 diabetic individuals are a potential target for prevention and treatment of diabetic complications. For example, quenching α-dicarbonyls may be possible with the vitamin B
6 analogue, pyridoxamine [
10]. Furthermore, MGO may be reduced via induction of glyoxalase-1, using inducers of Nrf2 [
9].
This is the first study that describes increased postprandial α-dicarbonyl stress in obese type 2 diabetic individuals, and its reduction by weight loss. Future work should investigate whether a VLCD and RYBG achieve health improvements and lower cardiovascular risk through reduced α-dicarbonyl stress. A limitation of this study was that we could not include a control group that remained weight-stable. Nevertheless, we report on two distinct interventions that aimed to induce weight loss, showing comparable results. Another limitation was that we lacked statistical power to investigate mediating factors through which α-dicarbonyl levels were improved by VLCD and RYGB. Additionally, we investigated women only in the current study, but we have no basis to assume that our results would be different in men. Furthermore, our study does not reveal which tissues contribute to the plasma pool of α-dicarbonyls. Although we hypothesise that plasma α-dicarbonyls are derived from insulin-independent cells which are in close contact with blood, such as endothelial cells and erythrocytes, animal studies are needed to fully address this issue.
In conclusion, we demonstrated increased postprandial α-dicarbonyl stress in obese individuals with type 2 diabetes, which can be reduced by a VLCD or RYGB. These data highlight the potential to reduce α-dicarbonyls as a target to prevent or delay development of complications in obese type 2 diabetic individuals.
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