The Role of Oleuropein in the Anti-Diabetic Action

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1		Leonardo A. Sechi	+ 1143 word(s)	1143	2021-12-28 02:42:41	\|
2	Format change	Jessie Wu	Meta information modification	1143	2022-01-10 02:54:33	\|

This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics14010040

Substantial consumption of extra-virgin olive oil (EVOO), vegetables, legumes, fruits, and whole grain cereals is the distinctive feature of the Mediterranean diet that replicates some of the traditional eating habits of the countries bordering the Mediterranean Sea.

oleuropein diabetes

1. Background

Type 2 diabetes currently accounts for more than 90% of all diabetic patients. Lifestyle interventions and notably dietary modifications are one of the mainstays for the prevention and treatment of type 2 diabetes. In this context, the Mediterranean diet with its elevated content of phytonutrients has been demonstrated to effectively improve glucose homeostasis. Oleuropein is the most abundant polyphenolic compound contained in extra-virgin olive oil and might account for some of the anti-diabetic actions of the Mediterranean diet.

2. Oleuropein and Diabetes: Clinical Evidence

As previously stated, the benefits of the regular consumption of extra-virgin olive oil (EVOO) in the management of diabetes have been repeatedly reported. Eleven obese patients with type 2 diabetes, who were treated with oral antidiabetic agents, ate refined oil polyphenol-free for four weeks. This was then replaced by polyphenol-rich EVOO for a further four weeks ^[1]. Polyphenol-rich EVOO significantly reduced body weight, fasting plasma glucose, and glycated hemoglobin and these changes were associated with a significant decrease in serum visfatin, a pro-inflammatory adipocytokine. Schwingshackl et al. conducted a meta-analysis in order to examine the association between EVOO consumption and the risk of type 2 diabetes, in addition to the effects of EVOO on its management ^[2]. The analysis included 15,784 subjects who were included in four cohort studies and 29 intervention trials. The results of this meta-analysis demonstrated that the highest EVOO intake category had a 16% lower risk of developing type 2 diabetes, as compared to the lowest. Additionally, in type 2 diabetics, EVOO supplementation resulted in a significantly greater reduction of fasting plasma glucose and glycated hemoglobin than in the control subjects. These studies provided solid evidence that the intake of EVOO could be beneficial for the prevention and management of type 2 diabetes, but did not provide any insight into the contribution of single components of EVOO.

With specific regard to oleuropein, the effects on glucose metabolism and diabetes have been examined in clinical studies and recent data provide initial evidence of the potential benefits (Table 1). In a randomized, double-blind, crossover trial conducted in New Zealand, 46 middle-aged, overweight men received oleuropein containing capsules (51 mg/day) or a placebo for 12 weeks ^[3]. As compared to the placebo, oleuropein supplementation was associated with a significant improvement in insulin sensitivity and pancreatic β-cells secretory capacity. Kerimi et al. conducted seven separate randomized, crossover, double-blind, placebo controlled, intervention trials on healthy volunteers to examine the effect of oleuropein on post-prandial blood glucose after the consumption of bread, glucose, or sucrose ^[4]. Oleuropein (35 to 200 mg/day) in solution attenuated the post-prandial blood glucose response after the consumption of sucrose, but did not affect post-prandial glucose after the ingestion of bread or glucose. Examination of the effects of oleuropein on enzymes involved in carbohydrate digestion showed the inhibition of sucrase and GLUT-2-mediated transport, but no significant effect on α-amylase, thus explaining the findings regarding the post-prandial blood glucose changes. Finally, in an open study of hypertensive patients, many of whom had obesity and/or diabetes, oral supplementation of oleuropein (100 mg/day) was administered for two months. In these patients, oleuropein decreased fasting blood glucose, together with other markers of a metabolic syndrome, such as waist circumference and serum triglycerides ^[5].

Table 1. Clinical trials that examined the effects of oleuropein on glucose homeostasis.

Reference	Study Design	Source, Main Content and Time of Exposure to Oleuropein	Effects on Glucose Metabolism
Kerimi et al. ^[6]	RCT, double-blind, crossover 24 healthy volunteers	Supplement vs. Placebo 35–200 mg—Single dose	Reduction of Post-prandial glucose Inhibition of GLUT2 and maltase
De Bock et al. ^[7]	RCT, double-blind, crossover 46 overweight volunteers	Olive Leaf vs. Placebo 51.1 mg vs. Placebo 12 weeks	Improvement in insulin sensitivity Improvement in pancreatic β-cell responsiveness
Hermans et al. ^[8]	Prospective, open observational 663 Hypertensive patients	Supplement 100 mg 8 weeks	Reduction of fasting glucose
Violi et al. ^[1]	RCT, double-blind, crossover 25 healthy volunteers	EVOO vs. Corn Oil 20 mg Single dose	Reduction of post-prandial glucose Inhibition of DPP-4 Improvement in GLP-1 mediated insulin secretion
Carnevale et al. ^[3]	RCT, double-blind 20 healthy volunteers	EVOO vs. Corn Oil 20 mg Single dose	Reduction of post-prandial glucose Inhibition of DPP-4 Improvement in GLP-1 mediated insulin secretion
Carnevale et al. ^[5]	RCT, double-blind 30 patients with IGT	EVOO vs. Corn Oil 20 mg Single dose	Reduction of post-prandial glucose Inhibition of DPP-4 activity Improvement in GLP-1 mediated insulin secretion
Del Ben et al. ^[9]	RCT, single-blind 25 patients with Type 2 Diabetes 20 healthy volunteers	EVOO Enriched vs. Standard Chocolate 40 mg Single dose	Reduction of post-prandial glucose Inhibition of DPP-4 activity Improvement in GLP-1 mediated insulin secretion

EVOO, Extra Virgin Olive Oil; IGT, Impaired Fasting Glucose; DPP-4, Dipeptidlpepdisase-4; GLP-1, Glucagon Like Peptide-1.

Clinical investigations have also tried to clarify some of the mechanisms that might mediate the effects of oleuropein on glucose metabolism. These investigations have brought the possibility that the incretin axis could be modulated by oleuropein to the forefront. The post-prandial glycemic profile was investigated in a crossover study of 25 healthy subjects that were randomly allocated to a Mediterranean diet with or without supplementation of oleuropein (20 mg). Two hours after the meal, subjects who ate oleuropein supplements had a significantly lower blood glucose and dipeptidyl-peptidase 4 (DPP-4) protein concentration and activity, and higher serum insulin and glucacon-like peptide-1 (GLP1) levels ^[9]. As an extension of this study, the same research group reported that the effects of oleuropein on blood glucose and DPP-4 were associated with a significant reduction in markers of oxidative stress, such as soluble NADPH oxidase-derived peptide activity and 8-iso-prostaglandin-2α ^[10]. The same protocol with a Mediterranean diet meal with or without oleuropein supplementation was later applied to 30 subjects with impaired fasting glucose ^[11]. In agreement with the findings obtained in healthy subject, the meal containing oleuropein was associated with a reduction of blood glucose and DPP-4 activity and an increase in insulin and GLP-1, as compared to the meal without oleuropein. Finally, similar experiments were conducted with a crossover design in 25 type 2 diabetic patients who were randomized to receive 40 g of oleuropein in the form of oleuropein-enriched chocolate or control chocolate ^[12]. In diabetic patients who received oleuropein-enriched (40 mg) chocolate, the increase in blood glucose following ingestion was smaller than in diabetic patients who received plain chocolate, and even in that case, the effect of oleuropein was associated with decreased DPP-4 activity.

In summary, initial clinical observations suggest that there is a potential for oleuropein use in the control of hyperglycemia. The findings suggest that oleuropein might decrease post-prandial blood glucose with a mechanism that counteracts oxidative stress-mediated incretin down-regulation. While more comprehensive evidence is required, the effects of oleuropein might provide both preventive and therapeutic benefits to patients with type 2 diabetes. Due to the significant variability in doses of refined oleuropein that were used in acute and chronic studies, and in the amount of oleuropein contained in EVOO, the current evidence does not allow us to establish suitable doses of this compound for clinical use.

References

Santangelo, C.; Filesi, C.; Vari, R.; Scazzocchio, B.; Filardi, T.; Fogliano, V.; D’Archivio, M.; Giovannini, C.; Lenzi, A.; Morano, S.; et al. Consumption of extra-virgin oil rich in phenolic compounds improves metabolic control in patients with type 2 diabetes mellitus: A possible involvement of reduced levels of circulating visfatin. J. Endocrinol. Invest. 2016, 39, 1295–1301.
Schwingshackl, L.; Lampousi, A.M.; Portillo, M.P.; Romaguera, D.; Hoffmann, G.; Boeing, H. Olive oil in the prevention and management of type 2 diabetes mellitus: A systematic review and meta-analysis of cohort studies and intervention trials. Nutr. Diabetes 2017, 7, e262.
de Bock, M.; Derraik, J.G.; Brennan, C.M.; Biggs, J.B.; Morgan, P.E.; Hodgkinson, S.C.; Hofman, P.L.; Cutfield, W.S. Olive (Olea europaea L.) leaf polyphenols improve insulin sensitivity in middle-aged overweight men: A randomized, placebo-controlled, crossover trial. PLoS ONE 2013, 8, e57622.
Kerimi, A.; Nyambe-Silavwe, H.; Pyner, A.; Oladele, E.; Gauer, J.S.; Stevens, Y.; Williamson, G. Nutritional implications of olives and sugar: Attenuation of post-prandial glucose spikes in healthy volunteers by inhibition of sucrose hydrolysis and glucose transport by oleuropein. Eur. J. Nutr. 2019, 58, 1315–1330.
Hermans, M.P.; Lempereur, P.; Salembier, J.P.; Maes, N.; Albert, A.; Jansen, O.; Pincemail, J. Supplementation effect of a combination of olive (Olea europea L.) leaf and fruit extracts in the clinical management of hypertension and metabolic syndrome. Antioxidants 2020, 9, 872.
Fki, I.; Sayadi, S.; Mahmoudi, A.; Daoued, I.; Marrekchi, R.; Ghorbel, H. Comparative study on beneficial effects of hydroxytyrosol and oleuropein rich olive leaf extracts on high-fat diet induced lipid metabolism disturbance and liver injuries in rats. Biomed. Res. Int. 2020, 2020, 1315202.
Zheng, S.; Wang, Y.; Fang, J.; Geng, R.; Li, M.; Zhao, Y.; Kang, S.G.; Huang, K.; Tong, T. Oleuropein ameliorates advanced stage of type 2 diabetes in db/db mice by regulating gut microbiota. Nutrients 2021, 13, 2131.
Marcelino, G.; Hiane, P.A.; de Cassia Freitas, K.; Figueiredo Santana, L.; Pott, A.; Rodrigues Donadon, J.; de Cassia Avellaneda Guimares, R. Effects of olive oil and its minor components on cardiovascular diseases, inflammation, and gut microbiota. Nutrients 2019, 11, 1826.
Violi, F.; Loffredo, L.; Pignatelli, P.; Angelico, F.; Bartimoccia, S.; Nocella, C.; Cangemi, R.; Petruccioli, A.; Monticolo, R.; Pastori, D.; et al. Extra virgin olive oil use is associated with improved post-prandial blood glucose and LDL cholesterol in healthy subjects. Nutr. Diabetes. 2015, 5, e172.
Carnevale, R.; Silvestri, R.; Loffredo, L.; Novo, M.; Cammisotto, V.; Castellani, V.; Bartimoccia, S.; Nocella, C.; Violi, F. Oleuropein, a component of extra virgin olive oil, lowers postprandial glycaemia in healthy subjects. Br. J. Clin. Pharmacol. 2018, 84, 1566–1574.
Carnevale, R.; Loffredo, L.; Del Ben, M.; Angelico, F.; Nocella, C.; Petruccioli, A.; Bartimoccia, S.; Monticolo, R.; Cava, E.; Violi, F. Extra virgin olive oil improves post-prandial glycemic and lipid profile in patients with impaired fasting glucose. Clin. Nutr. 2017, 36, 782–787.
Del Ben, M.; Nocella, C.; Loffredo, L.; Bartimoccia, S.; Cammisotto, V.; Mancinella, M.; Angelico, F.; Valenti, V.; Cavarretta, E.; Carnevale, R.; et al. Oleuropein-enriched chocolate by extra virgin olive oil blunts hyperglycaemia in diabetic patients: Results from a one-time 2-hour post-prandial cross over study. Clin. Nutr. 2020, 39, 2187–2191.

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1. Background

2. Oleuropein and Diabetes: Clinical Evidence

References