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Review

Impact of Nutraceuticals on Type 1 and Type 2 Diabetes Mellitus-Induced Micro- and Macrovasculopathies

by
Philanathi Mabena
1,2,*,
Thandi M. D. Fasemore
1 and
Pilani Nkomozepi
1
1
Department of Human Anatomy and Physiology, Faculty of Health Sciences, University of Johannesburg, Doornfontein Campus, Johannesburg 2028, South Africa
2
Human Biology and Integrated Pathology Department, Faculty of Health Sciences, Nelson Mandela University, Missionvale Campus, Gqeberha 6059, South Africa
*
Author to whom correspondence should be addressed.
Appl. Sci. 2024, 14(1), 64; https://doi.org/10.3390/app14010064
Submission received: 15 November 2023 / Revised: 15 December 2023 / Accepted: 19 December 2023 / Published: 20 December 2023
(This article belongs to the Special Issue Prevention and Treatments of Cardiovascular Diseases)
Versions Notes

Abstract

:
Diabetes mellitus (DM), one of the most serious non-communicable diseases, has long-term negative effects on the healthcare system due to its microvascular and macrovascular manifestations, which can be fatal if left untreated. Nutraceuticals, on the other hand, are alternative therapy choices of orally consumed natural food ingredients applicable in the management of several diseases, including diabetes mellitus. Through their antioxidant capabilities and bioactive components, nutraceuticals have been clinically demonstrated to be effective in preventing a number of ailments, including cancer, diabetes, heart disease, and kidney problems. Flavonoids, which are categorized as phytochemicals, are present in several of these nutraceuticals. Cocoa, one of the flavanols engaged in the treatment of diabetes mellitus, provides an additional non-pharmaceutical intervention in the management of diabetes mellitus, which, in part, is because of its high antioxidant capacity. Additionally, flavonoids improve insulin resistance and sensitivity, dyslipidemia, endothelial function, and blood pressure, as well as lower oxidative stress and inflammatory processes. As a result, they may be able to stop the progression of long-term vascular consequences of diabetes, such as cardiovascular disease, neuropathy, nephropathy, and retinopathy. Therefore, the effects of nutraceuticals (as an alternative treatment) on diabetic-related micro- and macrovascular problems are the main focus of this review.

1. Introduction

Diabetes mellitus is one of the most serious non-communicable diseases that has placed a significant burden on the healthcare system for many years, among many other important healthcare problems affecting the world. Diabetes mellitus affected roughly 425 million persons of reproductive age worldwide in 2017 [1]. More recently, this global prevalence increased to 536.6 million adults (20 to 79 years) in 2021, and it is predicted that by 2030, it will amount to a staggering 643 million, which by the year 2045, it would have reached 783.2 million [2]. This proves that the predicted estimates for diabetes mellitus continue to climb at an exponential rate globally. Following this, diabetes mellitus is becoming more common in low- to middle-income nations, as the majority of diabetes cases come from these regions (three in four adults) [2], with an estimated 39 million Africans suffering from it [1]. Furthermore, of those who were diagnosed with diabetes mellitus in 2021, approximately 6.7 million people died as a result [2]. Increasing age, male gender, family history of diabetes mellitus, low CD4 count, elevated body mass index (BMI), co-infections with the hepatitis C virus, and length of combination antiretroviral therapy (cART) use are among the prominent risk factors of diabetes mellitus [3]. Among the types of diabetes, type 2 diabetes mellitus is associated with an elevated risk of cardiovascular disease due to hypertension and dyslipidemia presentation and progression [4]. Notable, those with type 2 diabetes mellitus typically have two main symptoms: microvascular and macrovascular diseases, both of which have the potential to be life-threatening [5]. Diabetes microvascular consequences include retinopathy, neuropathy, nephropathy, and cardiomyopathy, while diabetes macrovascular complications include coronary artery disease, peripheral arterial disease, and cerebrovascular disease [5]. In this regard, vascular diabetes complications continue to be a primary cause of death and morbidity in people with type 2 diabetes mellitus [6]. Moreover, patients with diabetes have an increased risk of developing conditions like myocardial infarctions, strokes, and limb amputations associated with the advancement of macrovascular atherosclerosis. Nutraceuticals are components of natural foods that can be taken orally, have the ability to prevent certain diseases like type 1 and type 2 diabetes mellitus [7,8], and are alternate choices in the treatment and management of diseases. These health advantages include physical health improvement, slowing the aging process, preventing chronic diseases, improving life expectancy, and supporting the structure and function of the body [9]. Furthermore, they are pharmaceutically blended products with both nutritional and therapeutic benefits. These products consist of vitamins, minerals, antioxidants, and fatty acids, among others. As a result, accelerated research for better alternative interventions that will complement existing interventions and possibly provide much better bioactive properties that are effective in the fight against illnesses and diseases, while continuing to enjoy the beneficial effects provided by now-known nutraceuticals and appreciate their effectiveness in improving human well-being and health, may slow the accelerated rate of disease development and progression in the general populations across the world. Notably, nutraceuticals have shown remarkable success in lowering the need for traditional medications while also minimizing the possibility of negative side effects [10]. Consequently, the influence of nutraceuticals (as a supplemental treatment) on diabetic-induced microvascular and macrovascular issues is the main focus of this review.

2. Classifications of Microvascular and Macrovascular Complications of Diabetes Mellitus

2.1. Classifications of Microvascular Complications of Diabetes Mellitus

2.1.1. Diabetic Retinopathy (DR)

Diabetic retinopathy (DR) can result in irreversible blindness, particularly in those of reproductive age, when left untreated [11]. Oxidative stress, inflammation, neurodegeneration, and microvasculopathy are major contributors to the pathophysiology of DR [12]. However, when serum blood glucose levels are properly controlled, the onset and progression of DR can be slowed down, as well as the occurrence of oxidative stress (as a result of an imbalance between free radical oxygen species) [13] and resident inflammation. Indeed, chronic hyperglycemia causes microvascular endothelial dysfunction, which can contribute to retinal vascular ischemia and more vascular permeability [14]. Therefore, oxidative stress and other hyperglycemia-induced cellular damage underpin the fundamental mechanisms involved in the development and expression of diabetic vascular problems [15]. As a result, an effective therapeutic aimed at these pathways would be critical in fighting these disorders.

Diabetic Retinopathy (DR) Classification

Clinically, diabetic retinopathy is categorized mainly into non-proliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR), where the sequence of progression in these categories is always from NPDR into PDR, with the latter eventually progressing into macular edema (a common cause for loss of vision and blindness amongst the diabetics) [16].
Non-proliferative DR (NPDR) and proliferative DR (PDR) are the two types of DR [14]. Patients progressing from NPDR to PDR typically present with a reduction in best-corrected visual acuity and a very high risk of suffering irreversible blindness due to retinal detachment, vitreous hemorrhage, and neovascular glaucoma. The prevention of this transitory change from NPDR to PDR is critical for relieving significant financial burden on the healthcare system since treatment and administration of PDR patients is four times more expensive (USD 1.207) than those with NPDR (USD 292).

Diabetic Retinopathy (DR) Prevalence

As previously stated, diabetic mellitus (DM) long-term complications include cataracts, retinopathy, neuropathy, and nephropathy, all of which are micro-complications of DM, with diabetic retinopathy being the most common cause of blindness globally in young working-class adults [17]. End-organ damage is unavoidable with diabetes mellitus microvascular problems [18]. As a result, for people who have had diabetes for more than two decades, it is practically certain that all patients with type 1 diabetes mellitus, and only 60% of those with type 2 diabetes, will develop DR [7]. In this regard, roughly 95 million people worldwide have diabetes and 1.5 billion have blindness, with 0.4 billion instances linked to diabetes [19]. In particular, 7.7 million persons in America have DR, with an estimated 11 million by 2030 [20]. Furthermore, a decade ago, the global prevalence of DR in people with diabetes was 34.6%, with 6.96% having proliferative diabetic retinopathy (PDR), 6.81% having diabetic macular edema (DME), and 10.2% having vision-threatening diabetic retinopathy (VTDR) [12].

Diabetic Retinopathy (DR) Pathogenesis

The loss of vascular integrity and morphological alterations is one of the symptoms of DR [18]. Furthermore, microaneurysms, hemorrhages, hard exudates, and cotton wool patches are all signs of DR [21]. Following these instances, fibrovascular growth and retinal detachment become unavoidable. Inflammation of the retina occurs in addition to the etiology of DR. This inflammatory process is seen in the retinal vasculature, which includes both choroidal and retinal vasculature. Furthermore, DR damages the blood–retinal barrier (BRB) by affecting retinal microvasculature [7]. As a result, it can be inferred that the combined effect of hyperglycemia and inflammation in DM patients is one of the major pathogenic mechanisms that underpins the elimination of endogenous antioxidants inside the retina, resulting in the retinal damages described above [22].

Diabetic Retinopathy (DR) Risk Factors

Non-modifiable risk factors for DR include diabetes duration, renal illness, puberty, and pregnancy, as well as modifiable risk factors such as obesity, smoking, hyperglycemia, hypertension, and dyslipidemia [7]. More crucially, the risk of acquiring DR increases as the duration of DM increases, as does the duration of hyperglycemia, arterial hypertension, low-density lipoprotein (LDL) cholesterol, and elevated creatinine levels [12]. As a result, good control of these parameters may be advantageous in overall DR control.

2.1.2. Diabetic Peripheral Neuropathy (DPN) and Its Prevalence

Diabetic peripheral neuropathy (DPN) is another type of diabetic microvascular consequence that affects around 50% of diabetes mellitus patients, with 26% experiencing distal painful neuropathy (another type of this issue) [23]. DPN is defined as the existence of nerve dysfunction signs and symptoms in patients with diabetes mellitus without considering other causes of the disease [24]. This consequence, however, is more common in people with type 1 diabetes (54–59%) than in people with type 2 diabetes (45%) [23]. Similarly, Wang [25] discovered that type 2 diabetes mellitus caused 52% of diabetic peripheral neuropathy.
Indeed, DPN has severe impacts on individuals with diabetes mellitus because the majority (50% of patients) have significantly deteriorated quality of life, making them unemployable and causing an increased economic burden in society. DPN typically appears as a consequence of a distal sensory neuron, which can result in sensory loss, ulceration, sluggish wound healing, pain, infections, and, ultimately, amputation of the affected foot [25,26]. In this sense, these difficulties may potentially impair a person’s walk and balance, placing them at risk of falling [27].
Approximately half (8–45%) of diabetics will acquire DPN [28,29]. Diabetes is an underlying risk factor for the development of DPN in this regard. Both hyperglycemia and dyslipidemia play a role in the development of DPN in diabetics. However, treating hyperglycemia, in particular, does not slow the progression of DPN in those with type 2 diabetes [29] because DPN is irreversible. Similar to DR pathogenesis, DPN pathogenesis involves oxidative stress and inflammatory mechanisms that have been shown to harm neural tissues [30].

2.1.3. Diabetic Nephropathy (DN)

Diabetes nephropathy (DN) has emerged as a new diabetic consequence as the frequency of diabetes mellitus has increased and diabetes has been diagnosed at a younger age. Approximately 20–40% of type 2 diabetic people will develop DN. As a result, persons with diabetes mellitus who develop DN face increased mortality risks [31].

Diabetic Nephropathy (DN) Prevalence

The likelihood of acquiring DN problems in patients who have DM continues to rise; as a result, around 25% of newly diagnosed DM cases will develop diabetic nephropathy, a known DM complication, within a decade. Diabetes mellitus has been established as one of the major causes of chronic kidney disease (CKD), with diabetic nephropathy being one of the leading causes of end-stage renal disease and mortality associated with cardiovascular events and only being detected after a long period of time [32]. Over a decade, around 40% of people with diabetes mellitus will develop DN [33], and finally, roughly 50% of diabetic people will have DN [34].
Regardless of the medicinal therapies currently available, patients with DN will eventually develop kidney failure [32]. Interestingly, the development and progression of DN are directly associated with poor glycemic management [35], which leads to persistent hyperglycemia, the creation of advanced glycation products (AGEs), and the secretion of inflammatory cytokines [32]. Diabetic nephropathy develops concurrently with other diabetes problems, notably diabetic retinopathy, due to the extended duration of diabetes.

Diabetic Nephropathy (DN) Pathogenesis

Although the pathogenesis of DN is not fully and deeply understood, however, increased hyperglycemic states are currently believed to primarily be the culprit in the destruction of renal vasculature, subsequently leading to morphological alterations and, eventually, renal dysfunction [36]. The loss of morphological integrity in the DN includes increased thickness of the glomeruli basement membrane, building up of glomerular mesangial extracellular matrix together with increased collagen depositions, which eventually leads to glomerulosclerosis, inevitably leading to glomerular hyperfiltration and glomerular hypertrophy, elevated excretion of albumin and proteinuria, as well as decreased glomerular filtration rate [36]. Due to the lack of deeper insights into the disease development and progression of DN, as well as the vastness of its pathogenesis, appropriate therapeutic interventions are sorely lacking, and the latter affects patient outcomes [37].
Some mechanisms involved in the pathogenesis of DN include oxidative stress and inflammatory processes induced by hyperglycemia. In this regard, oxidative stress related to hyperglycemia is believed to play a role in inducing inflammation by facilitating the release of proinflammatory proteins and cytokines. Indeed, some of the inflammatory markers (interleukin-1, IL-6, IL-18, tumor necrosis factor-α) have been implicated in the development of DN [37]. Therefore, therapeutic approaches targeted at these factors would be more beneficial in the fight against diabetes mellitus, together with its devastating consequences.

Diabetic Nephropathy (DN) Risk Factors

The current understanding of DN risk factors concludes that there is an overlap between those involved in diabetic retinopathy (dyslipidemia, hypertension, poor blood glucose control, and sustained active tobacco smoking) and those of DN, and are all classified as modifiable risk factors [36,38]. However, the same cannot be said for their non-modifiable risk factors; DN non-modifiable risk factors include family history of DN, race (mostly affecting those of African ancestry, American populations with Mexican descent, and Pima people of Native Americans), increasing age, and sex (mainly males) [36,38].

2.1.4. Macrovascular Complications of Diabetes Mellitus

Diabetes mellitus (DM) macrovascular consequences include coronary artery disease, cerebrovascular disease, and peripheral vascular disease [39,40]. Macrovascular consequences of diabetes will inevitably emerge in patients with poorly managed glucose levels due to hyperglycemia. Even when treated, these consequences thrive in patients who have had the condition for a long time.
Over a decade ago, it was discovered that diabetic-associated macrovascular complications share a sped-up development and progression of atherosclerotic conditions, which contribute to the damage and clogging of coronary, carotid, and peripheral arteries, and thus an increased risk of cardiovascular events associated with these vascular conditions [41]. However, whether the aorta was involved in the macrovascular problems of diabetes mellitus and whether atherosclerosis development was linked to this vast central blood channel remain unknown. As a result, it would be quite interesting to investigate the effect and association of diabetes on the aorta and its integrity in order to gain a better understanding of the relationship between diabetes and macrovascular complications and how they are established (that is, what are the underlying mechanisms that occur in the aorta under diabetic conditions, and whether these mechanisms involve only atherosclerosis or whether other processes are occurring either concurrently or predominantly). Other pathways may be involved in vascular injury under these settings.
Indeed, high blood pressure influences the development of arteriosclerosis, a disorder that occurs in the arterial wall and is characterized by a loss of vascular compliance due to loss in elasticity. Hypertension and dyslipidemia are two processes connected to diabetes-related macrovascular problems [42]. The ability of diabetes to impact the number and integrity of elastin fibers would be extremely important because it would provide vital insights into the likelihood of additional processes being involved in the link between diabetes and aortic vascular integrity. Endothelial dysfunction has been found to play an important role in the development of diabetic vascular problems, including vasoconstriction [43]. Interestingly, both microvascular and macrovascular illnesses have been proven to co-exist and share comparable risk factors in people with diabetes. However, because it is not well-documented, this relationship of micro- and macrovascular needs further exploration.

Prevalence of Diabetes Mellitus Macrovascular Complications

Alarmingly, it has been estimated that by 2045, the global prevalence of diabetes mellitus will be 629–700 million, which undoubtedly warrants concurrent increases in cases of macrovascular complications of diabetes mellitus (especially in poorly controlled hyperglycemia), such as strokes, cardiovascular diseases, and myocardial infarctions, and that their occurrence may have socioeconomic implications in a given government [39]. Furthermore, the coexistence of the above-mentioned diabetes macrovascular diseases with increased development and progression of atherosclerosis, primarily in the carotid, coronary, and peripheral arteries, and thus strokes and myocardial infarctions [41], could be a possible association. In this regard, persons with diabetes mellitus are 2–4 times more likely than those without diabetes mellitus to suffer from cardiovascular events, and the former is more likely to die from these events than the latter [41].
Approximately 80% of people with diabetes mellitus have cardiovascular problems, and 65% die as a result of these complications [44]. However, it has been observed in the same group that glucose-lowering medications may improve cardiovascular events, hence improving patient outcomes in patients with diabetes mellitus [44]. Notably, the majority of recent data on diabetes complications and trends comes from industrialized countries, not underdeveloped countries [39]. Indeed, there are limited data on the trends and burden of diabetes complications in developing countries, particularly in Sub-Saharan Africa, and in studies that have been conducted, it has been reported that approximately 45% of people with diabetes have fasting lipids, with hypertension being the main complication in nearly 65% of individuals [45].
However, the estimated prevalence of 28 million people with diabetes in Africa by 2030 predicts a higher incidence of diabetes complications in Africa, particularly with increased urbanization (which is associated with increased consumption of processed and highly salted and fatty foods, sedentary lifestyle, and poor physical activities) [46]. Diabetes has a reported prevalence of 12.2% in the Middle East and North Africa and 12.7% in South Africa in people aged 20 to 79 years old [47].

Diabetes Mellitus Macrovascular Complications Pathogenesis

Cerebrovascular complications of diabetes mellitus arise from dysfunctional blood–brain barrier (BBB) (which could be through glucose transporter 1 and 3 destructions in the endothelium or GLUT 1, 2, 4 in astrocytes), which results in hyperglycemia, and this state induces an increase in the production of ROS and an imbalance in nitric oxide homeostasis [48]. Also, cerebrovascular complications involve dysfunctional endothelial lining, which is by far the major contributor to the development of atherosclerosis and arteriosclerosis (which both are to be blamed for macrovascular complications of DM, such as ischemic strokes) [48].
Diabetes mellitus has been reported to be the major risk factor for coronary artery diseases (CADs), which are classified as macrovascular complications of diabetes [49]. In this review, pathogenic processes like atherosclerosis (especially with the involvement of inflammation as it accelerates this process further) have been shown to contribute the most to the development of CAD. The presence of atherosclerotic plaques (which cause arterial narrowing) is very prominent in diabetic patients, partly because of the high levels of lipids in the blood, and these atheromatous plaques are highly likely to rupture and break off from these vessels to cause an even bigger and more significant occlusion of smaller vessels within the cardiac vasculature. The result of this can be myocardial infarction, which may be detrimental.
Similarly, peripheral artery disease development is intertwined with atherosclerotic plaques, which may either totally or partially occlude the peripheral vasculature [50].

Diabetes Mellitus Macrovascular Complications Risk Factors

Known risk factors for macrovascular complications seem to be similar across the subclasses (cerebrovascular diseases, coronary artery diseases, and peripheral artery diseases) and include aging, hypertension, dyslipidemia, diabetes and its extended duration, and obesity [49,50]. However, for peripheral artery diseases, smoking and diabetes account for a large part of risk factors.

3. Nutraceuticals

Nutraceuticals are food supplements that are biologically active and provide health advantages in addition to their nutritional value. Interestingly, the market for nutraceuticals has gained global momentum and niche, with an estimated value of USD 383 billion in 2016 and was projected to reach USD 561 billion in 2022; however, the scientific evidence that nutraceuticals have disease- and illness-alleviating effects, which sought to improve health and well-being of people suffering from a variety of illnesses, has proven to be vastly limited [51]. Nonetheless, nutraceuticals are classed according to dietary availability (traditional and non-traditional), their modes of action, and their chemical structures [9]. In this regard, Table 1 shows the classification of nutraceuticals as indicated above:

3.1. Nutraceuticals Classification and Their Potential Effects on Type 2 Diabetes Mellitus Treatment

3.1.1. Traditional Nutraceuticals

The following sections highlight foods and food items that have not been altered from their original condition and are used for both nutritional and health reasons [9].
(a) 
Functional Foods
When consumed, these foods add value to one’s health and contribute to the prevention of diseases such as type 2 diabetes mellitus due to their inherent antioxidant and anti-inflammatory properties [78], which are some of the major underlying mechanisms involved in the development of diabetes, and being able to combat them serves as an option for a better management strategy in the fight against diabetes mellitus. Furthermore, polyphenols, alkaloids, unsaturated fatty acids, vitamins A, B6, B12, C, D, and E, folate, and antioxidants (beta-carotene and lycopene) are among the most prevalent functional foods with noticeable health advantages [79].
One mechanism for postprandial hyperglycemia is the action of alpha-amylase and alpha-glycosidase enzymes in the human stomach, which work by turning food carbs into glucose after meals [52]. As a result, agents that target inhibition of these enzymes would contribute to hypoglycemic states, and phenolics possess this ability by inhibiting the enzymatic activity of alpha-glucosidase in the small intestine, as well as antioxidant and anti-inflammatory properties, which all contribute to mechanisms involved in the management and prevention of diabetes mellitus [52].
Millets and seeded grains have been used for decades for their nutritional benefits and subsequently possess active properties with health benefits, including micronutrients (zinc, magnesium, iron), which aid in insulin activity and metabolism. Phytochemicals (flavanols, phenolics), which have antioxidants, anti-diabetic and anti-inflammatory effects, and dietary fiber (soluble and insoluble fibers), delay carbohydrate digestion and absorption as a means of controlling glycemic levels [53]. L-carnitine is derived through dietary sources (such as meat and dairy products) as well as biosynthesis from lysine and methionine [80]. L-carnitine improves insulin sensitivity, decreases insulin resistance, and has lipid-lowering characteristics [54]. This is due to its effect on glucose metabolism in skeletal tissues (particularly in animal rat models), which increases insulin action in rats fed a fructose-rich diet [80].
Brown rice and its byproducts are another example of useful functional foods. Brown rice has a lower glycemic load and index than white rice, as well as a higher content of fiber, vitamins, minerals, phytic acids, polyphenols, tocopherols, tocotrienols, and other bioactive compounds; brown rice consumption has benefits on glycemic control, dyslipidemia, endothelial function, abdominal obesity, and liver function in type 2 diabetic patients. Its ability to manage blood glucose levels is attributable primarily to its high fiber content, which allows carbs in it to be slowly digested in the gastrointestinal tract [81]. As a result, eating fiber-rich meals is important in minimizing the risk of insulin resistance.
Vitamin D deficiency is risky since it has been linked to cardiovascular disease, hypertension, obesity, and inflammation. Vitamin D, on the other hand, boosts inflammatory cytokine production while decreasing pro-inflammatory cytokine release. Patients who are at high risk of developing diabetes may benefit from vitamin D supplementation. With vitamin D plus beta-glucan treatment, there is a significant improvement in entire patient health status, which may include mental health, physical health, lipid metabolism, leptin levels, and inflammatory state [55]. Patients who may have low risk or recent onset of type 1 diabetes mellitus may benefit from nicotinamide (vitamin B3), which has been shown to have protective effects and capabilities against the destruction of pancreatic beta cells [56]. This vitamin can also inhibit poly-ADP-ribose polymerase enzyme, which is a deoxyribonucleic acid (DNA) repair enzyme.
(b) 
Carotenoids
They are naturally occurring pigments in fruits and vegetables, with the most abundant types found in human diets being alpha-carotene, beta-carotene, and lutein zeaxanthin [82], and higher serum/plasma levels of α/β-carotene being associated with a lower incidence of diseases such as cardiovascular disease, obesity, and type 1 and type 2 diabetes mellitus [8,57,60]. They achieve this goal through their inherent ability to improve insulin sensitivity, preserve insulin receptors and reduce resistance, reduce adipocyte sizes (thus lowering an individual’s overall adipose tissue percentage), protect against inflammation by reducing proinflammatory cytokines, reduce low-density lipoprotein (LDL) while increasing high-density lipoprotein (HDL) [57], as well as being naturally occurring antioxidants [60]; all of which are required for combating oxidative stress and inflammation. Both oxidative stress and inflammation are important underlying factors in the progression of type 2 diabetes mellitus and other illnesses.
Furthermore, carotenoids such as lycopene have anti-diabetic properties as well as the ability to protect against endothelial dysfunction and the development of atheromatous plaques, thereby protecting against cardiovascular diseases and their complications [58]. Importantly, lycopene, together with lutein and zeaxanthin, are abundant in human ocular tissue and have an important role in visual function protection by discouraging the development of diabetic retinopathy [59]. Not only do carotenoids reduce the incidence of type 2 diabetes mellitus but also type 1 diabetes mellitus, where a study by Sanjeevi [8] reported lower risk of type 1 diabetes mellitus in the presence of dietary intake of fruits and vegetables, as well as higher serum levels of carotenoids, such as α-carotene, β-carotene, lutein, zeaxanthin, and β-cryptoxanthin [8]. Although the above-mentioned types of carotenoids have been demonstrated to be high in the serum of individuals with type 1 diabetes mellitus, however, poorly controlled glucose levels in blood will lead to a higher hyperglycemic state, which then causes oxidative stress; and indeed, the presence of hyperglycemic conditions have been strongly associated with reduced serum levels of these carotenoids. More interestingly, a carotenoid more superior in effectiveness over other carotenoids, such as lutein, β-carotene, and zeaxanthin, has been well studied in several studies. This carotenoid is known as astaxanthin and has been shown to possess the inherent ability to reduce glucose tolerance and blood glucose levels, promote enhanced serum levels of insulin, protect insulin-secreting beta cells, reduce blood levels of triglycerides, and improve high-density lipoproteins (HDL) blood levels [60]. All these properties are invaluable for the treatment and management of diabetes mellitus and its complications through quenching oxidative stress and chronic inflammation, which have been shown to be the major culprits underlying molecular mechanisms in disease development and progression of diabetes mellitus. It is worth noting that in the same mechanistic review by Roohbakhsh [60], astaxanthin was also shown to counteract and suppress the secretion of many inflammatory cytokines, such as nuclear factor kappa beta (NF-kβ), IL-6, IL-1β, and TNF-α, (expressed in several body tissues like retina, liver, brain, neuronal tissues), and suppress the production of superoxide, nitric oxide, and peroxynitrite, as included by hyperglycemic conditions. Thus, astaxanthin has been demonstrated to have an undoubted ability to attack hyperglycemic-induced oxidative stress and inflammation and, in so doing, reverse the degeneration of several tissues, including the retina, kidneys, nervous tissue, and liver, because these tissues become targets of destruction by diabetes mellitus.
(c) 
Dietary Fibers
Whole grains (WGs) (one of the main sources of dietary fibers) contain more non-digestible complex polysaccharides, such as soluble and insoluble fibers, inulin, beta-glucan, and resistant starches, as well as non-carbohydrate functional components, such as carotenoids, phytates and phytoesterogens, phenolic acids (ferulic acid, vanilic acid, caffeic acid, syringic acid, P-cumaric acid), and tocopherols [61]. Furthermore, wheat, barley, oatmeal, and rice (white and brown) are examples of whole grains that can be included in a diet.
All these bioactive chemicals are very useful in the management of cardiovascular diseases, obesity, diabetes mellitus, and hypertension through the following mechanisms: antioxidant and anti-inflammatory activities, facilitates secretion of glucagon-like peptide 1 (GLP-1) and leptin, and reduces ghrelin production by adjusting the gut microbiota in order to increase insulin secretion whilst facilitating cellular utilization of blood glucose [62]. Indeed, dietary fibers (including whole grains) have been shown to provide both short- and long-term health advantages for non-communicable diseases, such as cardiovascular disease and type 2 diabetes mellitus [63].
In this regard, foods like barley have a high concentration of β-glucan, which is the major component responsible for improved glucose tolerance and insulin resistance in diabetics. Thus, increased consumption of whole grains reduces the risk of developing these diseases, including diabetes and obesity, through mechanisms involving antioxidants, nutrients, and phytochemical action in combating oxidative stress (which is one of the main underlying processes involved in the development and progression of the mentioned diseases) [61]. Furthermore, eating of whole grains improves glycemic control in those with diabetes [64,66]. Thus, in the fight against type 2 diabetes mellitus, increasing and maintaining consumption of foods with effective management and prevention of heightened postprandial hyperglycemia is critical [65].
Consumption of oat products improves diabetic patients’ glycemic, insulinemic, and lipidemic responses and acts as an active element in lowering postprandial glycemia [9]. In other words, β-glucan is responsible for reducing fasting glucose and insulin levels, as well as insulin resistance, in persons with type 2 diabetes [67]. Furthermore, individuals with uncontrolled type 2 diabetes mellitus and significant insulin resistance are extremely difficult to treat; however, glycemic control and management improve with the use of these diet-based interventions [68].
(d) 
Fatty Acids
Sesame oil (or butter) contains unsaturated fatty acids, vitamins, minerals, and phytosterols and has been shown in animal and human studies to have invaluable properties that have been shown to improve several illnesses, such as diabetes mellitus, cancer, hypertension, tachycardia, and arteriosclerosis via its anti-diabetic, anti-hyperglycemic, anti-hyperlipidemia, anti-cancer, and antioxidative properties, and by enhancing immune function [69].
Unsaturated fats, such as alpha-linolenic acid (omega 3), a precursor for eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and linoleic acid (omega 6), are essential for our diet because our bodies cannot produce them [70]. They, particularly EPA and DHA, contribute to the control of inflammatory and immunological responses. Furthermore, omega 3 fatty acids and glutamine are antioxidants that protect human tissues from oxidative stress (peroxidation and oxidation) in order to reduce or avoid cell harm [79].
Notably, a high-fat diet has been linked to the destruction of the islets of Langhans (cells (beta) responsible for the release of insulin, a hormone essential in the regulation of blood glucose levels) via disruption of fructose metabolism in the intestines [83]. As a result, not all fats are healthy and cannot be labelled as “good fats”, so it is critical to understand which fats are useful and how they improve our health and combat diseases like type 2 diabetes mellitus.
(e) 
Phytochemicals
People have benefited for many centuries from the use of medicinal plants (primary source of polyphenols, tannins, alkaloids, carbohydrates, terpenoids, steroids, and flavonoids), with phytochemicals capable of treating a variety of illnesses and diseases, owing to their presumed low adverse effects when compared to westernized medicine. Because medicinal plants offer anti-diabetic and hypoglycemic qualities, they are used as medication and targeted by pharmaceutical companies for their properties [84]. They are also affordable to the general public [85].
Flavonoids, one of the most frequent phytochemicals, are found in nearly all plants and occur in over 4000 different varieties. Given that nutraceuticals have been shown to improve diabetics’ insulin sensitivity, metabolism regulation, and hyperglycemic levels. Flavonoids and carotenoids (which account for 60% of all polyphenols and are found in higher concentrations in fruits and vegetables) have been shown to have antioxidant, antiviral, and anti-inflammatory properties [7]. They have been clinically proven to protect against numerous diseases, such as cancer, diabetes, heart disease, and kidney disorders, due to their antioxidant properties and bioactive components [9].
Cocoa, for example, is one of the flavanols used in the treatment of diabetes mellitus and, due to its strong antioxidant capacity, offers an alternative non-pharmaceutical intervention in the treatment of diabetes mellitus [71]. The following is a breakdown of its (cocoa) effects on diabetes mellitus vascular problems (as detailed in the preceding sections):
(i) 
Diabetic Retinopathy and Nutraceuticals (Cocoa) Treatment
Diabetes treatment consists of both pharmacological treatments and dietary adjustments. In this respect, whether diabetic retinopathy can be prevented or treated in diabetic patients through dietary changes has not been well examined; so, further research in this area is required [86]. Currently available DR treatment comprises of glycemic control, among other things, with active treatment starting only in advanced stages of the disease [12]. Nutrition, in addition to therapeutic intervention in diabetes therapy, plays an important role in both diabetes prevention and control. Carbohydrates, fatty acids, monounsaturated and polyunsaturated fatty acids, and vitamins are among the macronutrients involved in diabetes control [87].
Eating foods like fish, fruits, and vegetables may also protect against the onset and progression of DR. Cheese, for example, is estimated to have the capacity to slow DR progression by 40% [87]. Nutraceuticals such as carotenoids, xanthophyll, lutein, and zeaxanthin improve retinal health and function in retinal diseases while also protecting against hyperglycemia-induced vascular changes in diabetes [22]. Lutein supplementation, in particular, may be effective in preventing oxidative stress-induced retinal damage and slowing the progression of DR [21]. In addition to these nutraceuticals, flavonoids increase insulin sensitivity, carbohydrate and lipid metabolism, beta cell function, and hypoglycemia. Importantly, flavonoids have been shown to help lower the progression of diabetes and the development of diabetes complications, including DR [7].
Indeed, flavanols (found in a variety of fruits, vegetables, and cocoa products) offer a promising alternative treatment for diabetes mellitus due to their plentiful antioxidant capabilities (higher phenolic compounds) [71]. These nutraceuticals’ mechanisms for improving diabetes and retinal function include, but are not limited to, increasing insulin sensitivity, lowering blood pressure and inflammatory processes, and preventing platelet activation and aggregation [71,88]. It would be excellent to examine the preventive effects of cocoa (flavanol nutraceutical) against hyperglycemia-induced retinal dysfunctions in adult Sprague Dawley rats in order to better understand the mechanisms involved in the development and advanced state of diabetic retinopathy.
(ii) 
Diabetic Peripheral Neuropathy (DPN) and Cocoa Treatment
The inflammatory process and oxidative stress appear to be the primary processes involved in nerve injury and degeneration; therefore, treatment that targets these two fundamental factors in correcting this damage is critical. There is, in fact, an alternative medication with unique characteristics designed to cure these processes (oxidation and inflammation). Cocoa, which has healing properties, has been demonstrated to lower inflammation and oxidative stress through a number of mechanisms [89].
One of the most significant approaches is to reduce free radical oxygen species (ROS), which reduces nuclear factor kappa β (NFkβ), which reduces proinflammatory cytokines (IL-11, IL-6, TNF-α), thereby decreasing inflammation [89]). Notably, catechin polyphenols, anthocyanidins, and proanthocyanidins are the primary anti-inflammatory and anti-nociceptive properties of cocoa [90]. However, because flavanols (an active component of cocoa) contain antioxidant characteristics, cocoa can help fight oxidative stress (which happens when ROS exceed antioxidants) [89].
(iii) 
Diabetic Nephropathy (DN) and Cocoa Treatment
To mitigate the disease’s impact, blood glucose, blood pressure, and lipid levels should be carefully monitored. Indeed, Rabbani and Thornalley [91] proposed that these approaches to therapy are beneficial in the treatment of DN [91]. To prevent DN from progressing to end-stage renal disease, viable alternative therapy substitutes must be discovered quickly.
As a result, nutraceuticals, particularly flavanols, have been proven to protect against cardiovascular disease and diabetes by improving endothelial function, insulin sensitivity, and blood pressure control, among other things [92]. Cocoa, a dietary flavanol with significant antioxidant activity (especially procyanidin B2), has been shown to help diabetics retain kidney structural integrity and function [93].
(iv) 
Diabetic Macrovascular Complications and Cocoa Treatment
Endothelial vasodilation and blood flow have been demonstrated to rise with a daily intake of 200 mg of cocoa [94]. Cocoa is hypothesized to have this effect by boosting nitric oxide production, which is a potent endothelial-based vasodilator. Other effects of cocoa include improved antioxidant capacity and decreased lipid peroxidation, which explains how cocoa contributes to diabetes mellitus preventive mechanisms [71]. It also helps in preventing the development of hypertension (one of the risk factors for diabetes) by decreasing angiotensin-converting enzyme (which influences increased blood pressures via the renin–aldosterone–angiotensinogen system) [71]. Furthermore, cocoa possesses anti-inflammatory qualities that contribute to anti-diabetic effects by reducing platelet activation [95].
(f) 
Probiotics
Probiotics are mostly living bacteria and yeast that provide health advantages. They are usually found in fermented foods such as yoghurt and cheeses, functional foods such as cabbage and maize, and dietary supplements contained in tablets and capsules [96]. They are classified as nutraceuticals because they produce compounds that provide health benefits, such as essential vitamins, antioxidants, and fatty acids [79]. Streptococcus thermophilus and Lactobacillus bulgaricus are anti-diabetic probiotics found in yoghurts and fermented milk which work through lowering postprandial hyperglycemia, glycated hemoglobin (Hba1c), and fasting glucose levels [72].
(g) 
Prebiotics
Prebiotics, which are dietary fibers (even though not all fibers are prebiotics), have been shown to have the capacity to regulate the composition and growth of the gut microbiota, which is required to enhance health [74]. Prebiotic dietary fibers include Larch arabinogalactan-resistant starch, β-glucans, and xylooigosaccharides [73]. Fermented compounds having specialized roles in the maintenance of balanced composition and activity of gut microbiota include fructooligosaccharides, galactooligosacharides, lactulose, polydextrose, and inulin.
Indeed, the gut microbiota plays an important role in the synthesis of enzymes that are not encoded by the human genome, and they are crucial in the processing of various foods and compounds, such as the chemical digestion of polysaccharides, polyphenols, and some vitamins [74]. More importantly, an imbalance in the gut microbiota will undoubtedly contribute to the development of metabolic syndrome, such as type 2 diabetes mellitus [75], so it is critical to maintain proper gut microbiota balance in order to maintain health benefits and improve human well-being.
(h) 
Postbiotics
Postbiotics are bioactive molecules derived from probiotics and are secreted into the gastrointestinal microbial environment [97]. They possess the ability to directly or indirectly mediate biological activities and processes, with their manufacturing and storage conditions being far less stringent when compared to probiotics [97]. Gamma-aminobutyric acid (GABA), an organic acid, has been demonstrated to possess key functions (such as anti-hypertensive, antidepressant, and anti-diabetic) of postbiotics involved in the gut–brain axis and improvement of metabolic health in bodily systems [76].
(i) 
Synbiotics
The product of combining both probiotics and prebiotics is synbiotics, which are equipped with microorganisms needed by the gut microbiota for the maintenance of health advantages [77]. The most common health advantages involved include lowered oxidative stress and inflammatory process on the gastrointestinal cells, thereby aiding in the improvement of the lining of these cells [77].

3.1.2. Non-Traditional Nutraceuticals:

These are non-conventional foods with bioactive qualities that are manufactured through biotechnology engineering to improve people’s health and well-being, and they include fortified and recombinant nutraceuticals [98]. Rice supplemented with β-carotene and cereal enriched with vitamins and minerals are examples of such foods that, when ingested, can improve antioxidant capacity and, hence, provide health advantages [78].
(a) 
Fortified nutraceuticals
Orange juice enhanced with calcium (to make it more effective in the control of hyperglycemia by reducing it) and milk with cholecalciferol (which helps to improve human health and wellness) are examples of these nutraceuticals [78]. Furthermore, fortified nutraceuticals, such as cereals with nutrients and flour with folate, are important for human well-being [99].
(b) 
Recombinant nutraceuticals
These include genetically modified foods such as iron rice, golden rice, maize, golden mustard, multivitamin corn, and gold kiwifruit, all of which offer a health advantage as well as nutritional value [78]. Added to these are energy-producing bread, wine, yoghurt, cheese, vinegar, and fermented starch, which have been shown to provide nutritional benefits and whose production process cannot be completed without the use of biotechnology, so they are classified as nutraceuticals [99].

4. Conclusions

Nutraceuticals, in general, particularly phytochemical-rich foods, may be effective in the treatment of type 2 diabetes in addition to the standard diabetes medication. They improve dyslipidemia and insulin resistance while decreasing oxidative stress and inflammatory processes, potentially preventing the development of long-term diabetic vascular complications, such as cardiovascular disease, neuropathy, nephropathy, and retinopathy, with minimal side effects when compared to current standard diabetes treatment. As a result, more investments should be made in the investigation of more nutraceuticals and their undiscovered properties, which may provide even more effective and beneficial bioactive compounds that will not only aid in the fight against diabetes mellitus but also against numerous chronic diseases. So, this goal should be implemented sooner rather than later.

5. Future Studies/Recommendations

Extensive work has been conducted on the subject of nutraceutical research, particularly review studies, and a lot has been done in terms of classifying and identifying bioactive chemicals within these nutraceuticals. Furthermore, much research has been conducted to link the advantages of each bioactive molecule to the disorders they treat. However, there are still prospects for future investigation through genuine experimental efforts, either in vivo or in vitro models. Such models would provide a comprehensive knowledge of the underlying mechanisms involved in the development of a wide range of diseases, including type 2 diabetes and associated consequences (as detailed in the preceding sections). With this insight, better treatment and management of various conditions can be ensured, thereby boosting their health advantages and improving well-being.

Author Contributions

Conceptualization, P.M. and P.N.; methodology, P.M. and P.N.; software, P.M.; validation, P.M., P.N. and T.M.D.F.; formal analysis, P.M. and P.N.; investigation, P.M. and P.N.; resources, P.M. and P.N.; data curation, P.M. and P.N.; writing—original draft preparation, P.M., P.N. and T.M.D.F.; writing—review and editing, P.M., P.N. and T.M.D.F.; visualization, P.M. and P.N.; supervision, P.N.; project administration, P.M. and P.N.; funding acquisition, P.N. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding, and the APC was funded by the University of Johannesburg, Faculty of Health Sciences.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

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Table 1. Description of nutraceuticals classification based on type of nutraceuticals, source, active chemicals, and mechanisms of action, as well as type of disease targeted.
Table 1. Description of nutraceuticals classification based on type of nutraceuticals, source, active chemicals, and mechanisms of action, as well as type of disease targeted.
Classification of Nutraceuticals
Type of NutraceuticalSourceActive ChemicalMechanism of ActionDisease/IllnessReference
Traditional Nutraceuticals
Functional Foods
PolyphenolsFruits, vegetables, berries, grains, spicesPhenolic acidsAlpha-glucosidase inhibition, antioxidant, anti-inflammatoryDiabetes mellitus[52]
MilletsGrainsSoluble and insoluble fibers, zinc, magnesium, iron, flavanols, phenolicsDelays carbohydrate metabolism, glycemic control, antioxidants, anti-diabetic, anti-inflammation Diabetes mellitus[53]
L-carnitineDietary sources (meat, dairy products), biosynthesis from lysine and methionine Antioxidants, lipid-lowering propertiesEnhances insulin sensitivity, lowering insulin resistanceDiabetes mellitus, atherosclerosis[54]
Vitamin DDiet Increases production of inflammatory cytokines, suppressing release of pro-inflammatory cytokinesCardiovascular diseases, hypertension, obesity, inflammation, diabetes mellitus[55]
Nicotinamide (vitamin B3)Dietary sources (fish, legumes, eggs, nuts)NicotinamideInhibition of DNA repair enzyme (poly-ADP-ribose polymerase), protects against beta cell destructionType 1 diabetes mellitus[56]
CarotenoidsFruits and vegetablesβ-carotene, α-carotene, lutein zeaxanthin, β-cryptoxanthinAnti-diabetic and anti-inflammatory properties Type 1 and type 2 diabetes mellitus, cardiovascular diseases, obesity[8,57]
LycopeneAnti-diabetic and antioxidants propertiesCardiovascular disease, diabetes mellitus, diabetic retinopathy[58,59]
AstaxanthinAntioxidant properties, anti-inflammatory properties, anti-hyperglycemicDiabetes mellitus and its complications[60]
Dietary Fibers
Whole grainsWheat, barley, oatmeal, riceNon-digestible polysaccharides (NDPs), soluble/insoluble fibers, β-glucans, inulin, resistant starchAntioxidant, anti-inflammatory activities, secretion of glucagon-like peptide 1 (GLP-1) and leptin, reduces ghrelin synthesis, prevents postprandial hyperglycemia, improves insulin resistanceCardiovascular diseases, obesity, and diabetes mellitus[61,62,63,64,65,66,67,68]
Fatty Acids
Sesame oil Unsaturated fatty acids, vitamins, minerals, phytosterols, lignansAnti-diabetic, anti-hyperglycemic, anti-hyperlipidemia, anti-cancer, antioxidative properties, and enhances immune functionDiabetes mellitus, cancer, hypertension, tachycardia, arteriosclerosis,[69]
Flaxseed, fish oil, sunflower seed, nuts Omega 3 and omega 6Modulation of inflammation and immune responseDiabetes mellitus[70]
Phytochemicals
FlavanolsFruits, vegetables, chocolatesCocoaAntioxidants, anti-inflammationCancer, diabetes mellitus, heart disease, renal problems[71]
Probiotics
Yogurt, fermented milkStreptococcus thermophilus, Lactobacillus bulgaricusHypoglycemic activitiesDiabetes mellitus[72]
Prebiotics
Dietary fibers, fermented foodsLarch arabinogalactan-resistant starch, beta-glucans, xylooigosaccharides, fructooligosaccharides, galactooligosacharides, lactulose, polydextrose, inulinRegulate composition and activity of gut microbiotaType 2 diabetes mellitus[73,74,75]
PostbioticsPrebiotic microorganismsGABAAnti-hypertensive, antidepressant, anti-diabeticNeurological disorders, diabetes complications[76]
SynbioticsProducts of pre-probiotics Reduction in oxidative stress, inflammatory process, gastrointestinal barrier maintenance [77]
Non-Traditional Nutraceuticals
Fortified
Orange juice enriched with calcium,
milk with cholecalciferol 		Calcium, ascorbic acidAnti-hyperglycaemia, enhance insulin sensitivityDiabetes mellitus[78]
RecombinantIron rice, golden rice, maize, golden mustard, multivitamin corn, gold kiwifruitAscorbic acid, carotenoidsEnhance immune response [78]
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Mabena, P.; Fasemore, T.M.D.; Nkomozepi, P. Impact of Nutraceuticals on Type 1 and Type 2 Diabetes Mellitus-Induced Micro- and Macrovasculopathies. Appl. Sci. 2024, 14, 64. https://doi.org/10.3390/app14010064

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Mabena P, Fasemore TMD, Nkomozepi P. Impact of Nutraceuticals on Type 1 and Type 2 Diabetes Mellitus-Induced Micro- and Macrovasculopathies. Applied Sciences. 2024; 14(1):64. https://doi.org/10.3390/app14010064

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Mabena, Philanathi, Thandi M. D. Fasemore, and Pilani Nkomozepi. 2024. "Impact of Nutraceuticals on Type 1 and Type 2 Diabetes Mellitus-Induced Micro- and Macrovasculopathies" Applied Sciences 14, no. 1: 64. https://doi.org/10.3390/app14010064

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