Carotenoids in the treatment of diabetes mellitus and its complications: A mechanistic review

doi:10.1016/j.biopha.2017.04.057

Biomedicine & Pharmacotherapy

Volume 91, July 2017, Pages 31-42

https://doi.org/10.1016/j.biopha.2017.04.057 Get rights and content

Abstract

Carotenoids are a large class of natural antioxidants that occur in many vegetables, foods and other natural sources. To date, a large number of biological properties have been reported from carotenoids, particularly protective effects against diabetes mellitus (DM), cancer, and neurodegenerative, metabolic and cardiovascular diseases. However, recent studies including clinical evidences, have shown that carotenoids play a role in the treatment of diabetes via enhancing insulin sensitivity. They are also able to protect the body from long-term consequences of diabetes including infectious diseases, nephropathy, neuronal and eye abnormalities. In this review, we try to discuss the mechanisms behind the biological effects of carotenoids for the prevention and treatment of DM and its complications. The authors believe that carotenoids will have a prominent place in the treatment of DM and its complications in the future.

Graphical abstract

Introduction

Carotenoids are a class of natural antioxidants that occur in fruits, vegetables and marine sources as colorful pigments. Most carotenoids such as β-carotene, lycopene, lutein, zeaxanthin, astaxanthin and bixin are lipophilic tetraterpenoids (40-carbon skeleton) having isoprene as their biogenetic precursor (Fig. 1). A body of scientific evidence suggests that carotenoids have beneficial effects in prevention of a large number of diseases, particularly cardiovascular diseases and cancer. Versatile biological activities of these carotenoids have been attributed to their scavenging free radicals, quenching ROS, augmentation of self-defense systems and photo-protection. Therefore, carotenoids prevent cancer, cardiovascular diseases, diabetes, osteoporosis, age-related eye diseases, Alzheimer's disease, etc.

Recent advances on biological properties of carotenoids have shown that carotenoids are able to not only prevent but also treat or ameliorate diabetes and its subsequent complications. Beneficial effects of carotenoids in diabetes and metabolic syndrome are more than those expected from natural antioxidants. It has been shown that dietary carotenoids and plasma β-carotene concentrations were inversely associated with fasting plasma glucose concentrations and insulin resistance, respectively [1]. An inverse relation was also observed between serum carotenoid (lycopene, lutein, β-carotene) concentrations and fasting serum insulin concentrations and metabolic syndrome [1], [2]. A large number of studies have revealed that carotenoids reduce type 2 diabetes risk in men and women [1], [3]. It has also been observed that carotenoid intake has an inverse relation with HbA_1c level [4]. In addition, recent findings have confirmed the protective roles of carotenoids including lycopene, lutein and zeaxanthin against diabetic retinopathy [5].

It should be noted, however, the role of carotenoids in the pathogenesis of diabetes remains unclear. The beneficial effects of carotenoids in diabetes cannot be simply associated with their antioxidant properties. It seems that other mechanisms (except antioxidant activity) play roles in the pharmacological effects of carotenoids. In this article, we review the preventive and therapeutic effects of carotenoids in diabetes and molecular mechanisms that are behind these pharmacological activities. In addition, we highlight the gaps in our knowledge about the association of carotenoid intake and diabetes, deserving future research.

Section snippets

Carotenoids intake and the incidence of diabetes mellitus

Previous studies revealed that dietary factors including antioxidants have important roles in the prevention of T2DM. Most of these studies show an inverse relation between dietary intake of vegetables and antioxidants and the risk of T2DM [6]. Considering the potent antioxidant effects of natural carotenoids, the role of carotenoids in the prevention and treatment of T2DM has been investigated in different studies. For example, Sugiura et al. in a recent study showed that in middle-aged and

Carotenoids intake and the insulin sensitivity

Insulin resistance is defined as insufficient response of tissues to the effects of circulating insulin. Most important results of insulin resistance are decreased insulin-mediated glucose uptake into the skeletal muscles, reduced insulin-stimulated inhibition of hepatic glucose production in the liver, and impaired ability of insulin to suppress lipolysis in adipose tissues. Indeed, insulin resistance has been recognized as a major predictor for the development of various metabolic diseases

The antioxidant role of carotenoids in DM

Fruits and vegetables are important natural sources of antioxidants that participate in the body’s defense against oxidative stress. The imbalance between free radicals and the antioxidant system(s) induces oxidative stress. The main antioxidant enzymes include SOD, CAT, GPx, and GR. Various studies have shown that DM affects both factors, increasing ROS and decreasing antioxidant defense capacity. Hyperglycemia, through glucose auto-oxidation, generates hydroxyl ( radical dot OH) radicals. Furthermore,

Carotenoids and the modulation of immune system in DM

High prevalence and the outcome of infectious diseases in diabetic patients indicate malfunction of the immune system during DM [64]. Immune dysfunction may be the result of the oxidative stress during hyperglycemia that was discussed previously. DM type 1 is an autoimmune and chronic inflammatory disease in which inflammatory mediators have a key role. They activate and amplify the immune response against β cells in the pancreatic islets. This may induce β cell destruction and suppression of

The protective effect of carotenoids in DM-induced nephropathy

The DM and its complications are the seventh leading cause of death in the United States [76]. Microvascular complications of DM include nephropathy, retinopathy, and neuropathy [77]. DM has been recognized as the leading cause of nephropathy. It is characterized by the glomerular basement membrane thickness, accumulation of extracellular matrix proteins, microaneurysm formation and mesangial nodule formation [77]. Moreover, accumulation of advanced glycation end products, systemic hypertension

The protective effect of carotenoids on neuronal abnormalities induced by DM

Accumulating evidence shows that DM affects brain function. A meta-analysis of 33 studies indicated that type 1 diabetic patients – lowered performance on intelligence, speed of information processing, psychomotor efficiency, visual and sustained attention, cognitive flexibility, and visual perception [84]. The authors concluded that cognitive deficits of these patients are associated with the presence of microvascular complications. It is worthwhile to mention that these complications of both

The effects of carotenoids on DM-induced eye abnormalities

Diabetic retinopathy is one of the important and common microvascular complications of DM. It is reported as one of the major causes of blindness and visual impairment in adults [101]. It is believed that hyperglycemia disrupts normal cellular metabolism and induces retinopathy. The important role of carotenoids in the eye and normal vision has been established well. The carotenoids have both functional role as pro-vitamin A in the visual pathway and structural role as macular pigments. The

Concluding remarks

Carotenoids are a class of natural lipophilic antioxidants with various biological activities. Over the past decades, most researches have been focused on the preventive/protective effects of carotenoids from various chronic diseases including diabetes (DM), metabolic syndrome, cancer and cardiovascular diseases. However, recent studies have indicated that carotenoids might play a role in the treatment of DM and its side effects. In spite of discrepancies concerning the correlation between the

Conflict of interest

The authors declare no conflict of interest.

Acknowledgment

This study was partially supported by the Mashhad University of Medical Sciences Research Council.

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ReviewCarotenoids in the treatment of diabetes mellitus and its complications: A mechanistic review

Abstract

Graphical abstract

Introduction

Section snippets

Carotenoids intake and the incidence of diabetes mellitus

Carotenoids intake and the insulin sensitivity

The antioxidant role of carotenoids in DM

Carotenoids and the modulation of immune system in DM

The protective effect of carotenoids in DM-induced nephropathy

The protective effect of carotenoids on neuronal abnormalities induced by DM

The effects of carotenoids on DM-induced eye abnormalities

Concluding remarks

Conflict of interest

Acknowledgment

Am. J. Clin. Nutr.

Nutr. Metab. Cardiovasc. Dis.

Biochim. Biophys. Acta

Cell Stress Chaperones

Life Sci.

Biochem. Pharmacol.

Biochem. Biophys. Res. Commun.

Am. J. Clin. Nutr.

Clin. Nutr.

Phytomedicine

Arch. Biochem. Biophys.

Am. J. Clin. Nutr.

Eur. J. Pharmacol.

Chem. Biol. Interact.

Lancet

Biochimie

Chem. Biol. Interact.

Int. Immunopharmacol.

J. Nutr. Biochem.

Clin. Chim. Acta

J. Diabetes Complicat.

Eur. J. Pharmacol.

J. Pain

Eur. J. Pain

Neuropharmacology

Life Sci.

Free Radic. Biol. Med.

Neuroscience

Metabolic syndrome and serum carotenoids: findings of a cross-sectional study in Queensland, Australia

Br. J. Nutr.

Relationship between serum carotenoids and hyperglycemia: a population-based cross-sectional study

J. Epidemiol.

Plasma carotenoids and diabetic retinopathy

Br. J. Nutr.

High-serum carotenoids associated with lower risk for developing type 2 diabetes among Japanese subjects: Mikkabi cohort study

BMJ Open Diabetes Res. Care

Associations of serum carotenoid concentrations with the development of diabetes and with insulin concentration: interaction with smoking: the Coronary Artery Risk Development in Young Adults (CARDIA) Study

Am. J. Epidemiol.

Plasma carotenoids and onset of dysglycemia in an elderly population: results of the Epidemiology of Vascular Ageing Study

Diabetes Care

The association between a biomarker score for fruit and vegetable intake and incident type 2 diabetes: the EPIC–Norfolk study

Eur. J. Clin. Nutr.

Plasma lycopene, other carotenoids, and the risk of type 2 diabetes in women

Am. J. Epidemiol.

Long-term beta-carotene supplementation and risk of type 2 diabetes mellitus: a randomized controlled trial

J. Am. Med. Assoc.

Effect of alpha-tocopherol and beta-carotene supplementation on the incidence of type 2 diabetes

Diabetologia

Astaxanthin inhibits expression of retinal oxidative stress and inflammatory mediators in streptozotocin-Induced diabetic rats

PLoS One

Safety of an astaxanthin-rich Haematococcus pluvialis algal extract: a randomized clinical trial

J. Med. Food

Astaxanthin protects beta-cells against glucose toxicity in diabetic db/db mice

Redox Rep.

Astaxanthin improves cognitive deficits from oxidative stress, nitric oxide synthase and inflammation through upregulation of PI3K/Akt in diabetes rat

Int. J. Clin. Exp. Pathol.

Astaxanthin from shrimp by-products ameliorates nephropathy in diabetic rats

Eur. J. Nutr.

Anticoagulatory and antiinflammatory effects of astaxanthin in diabetic rats

J. Food Sci.

Bixin and norbixin have opposite effects on glycemia, lipidemia, and oxidative stress in streptozotocin-induced diabetic rats

Int. J. Endocrinol.

Anti-hyperglycemic effects of saffron and its active constituents, crocin and safranal, in alloxan-induced diabetic rats

J. Med. Plants

Antihyperglycemic and antioxidant activity of crocin in streptozotocin-induced diabetic rats

Review
Carotenoids in the treatment of diabetes mellitus and its complications: A mechanistic review