Microcirculation and Type 2 Diabetes
The elephant in the room
The incidence of type 2 diabetes mellitus (T2DM) continues to increase globally.1 An important driver of this condition are changes in microcirculation, which precede diabetic microangiopathy and play a significant role in the secondary complications of T2DM.2 Vascular-rich tissues, such as the eyes, kidneys and extremities are particularly vulnerable to pro-inflammatory changes that occur in the endothelium as a result of chronic hyperglycaemia, increasing the risk of retinopathy, nephropathy and neuropathy.3 As such, supporting the microcirculation is a noteworthy strategy in reducing secondary complications and in improving overall health outcomes in these patients.
Microcirculation: bringing life to the tissues
The microcirculation represents the endpoint of the vascular network and is comprised of the smallest blood vessels (BV), the arterioles, venules and capillaries.4 Supplying essential blood, oxygen and nutrients to all of the cells and organs in the body, while facilitating the removal of metabolic waste products, 4,5 microcirculation ensures the health and vitality of all tissues.
BVs are almost exclusively lined by endothelial cells that work in conjunction with smooth muscle cells to regulate blood flow and vascular tone.4 This is achieved via the release of various vasoconstrictive and vasodilating factors, including endothelial nitric oxide synthase (eNOS), a primary vasodilator that has a regulatory effect on BV tone and helps to maintain endothelial homeostasis.6,7 Without the ability to produce nitric oxide (NO), vascular tone is compromised, leading to BV constriction and stiffness.5 This reduces the ability of oxygen and nutrients to reach target tissues and limits the removal of waste by-products, which then precipitates the accumulation of reactive oxidative species (ROS).8 Because of the damage caused by a number of inflammatory mediators and ROS, cells in the area become hypoxic, compromising the tissue or organ involved and accelerating disease progression.8 As such, microcirculation is intimately connected with endothelial function and vice versa.
Endothelium maintains a delicate balance
Endothelial cell dysfunction occurs early in insulin resistance states and diabetes and represents a key consideration in supporting these patients.9 The pathogenesis of endothelial dysfunction in diabetes is complex and involves several pathways. Primarily, endothelial dysfunction is, simply put, the inability of the BVs to maintain the balance between vasoconstrictive and vasodilatory activity. This is initially due to the effects of insulin resistance and subsequent increased oxidative stress on the ‘uncoupling’ of eNOS activity.
Uncoupling is the process by which eNOS is oxidised producing superoxide and peroxynitrate, instead of NO.10 This triggers a perpetual cycle of vascular oxidative stress through the transfer of electrons to molecular oxygen, forming reactive oxygen species (ROS), which further consumes NO and increases oxidative stress.10 This prolonged inflammatory and oxidative stress state results in impaired endothelial, cellular and mitochondrial function as the redox balance cannot be maintained. Consequently, reduced production of NO in vascular endothelial cells, and decreased sensitivity of vascular smooth muscle to NO, results in vasoconstriction and ischemia as well as a shift towards a pro-inflammatory, pro-thrombotic and vasoconstrictive state in the endothelium.8
Supporting microcirculation, dampening the inflammatory response and clearing ROS are therefore important considerations in reducing the onset, or slowing the progression of serious secondary complications in these patients.
Plant polyphenols: a bridge to vascular health
Plant compounds possess a variety of anti-inflammatory and antioxidant properties that directly stimulate NO production and vasodilation, supporting tissue microcirculation. Phenolic compounds (polyphenols) possess strong antioxidant and anti-inflammatory activity, with a demonstrated ability to support endothelial health and microcirculation.3 Some of the specific therapeutics that have been shown to improve microcirculation include:
Amaranthus hybridus (Red amaranth) – rich in polyphenols, flavonoids and tannins, the leaves have been used throughout Asia and Africa as a dietary green leafy vegetable.11 A. hybridis is naturally rich in nitrates,12 which are absorbed orally and converted to nitrite and then to nitric oxide via the nitrate-nitrite-nitric oxide pathway.13 Although this plant does naturally contain some oxalates, the amount in this extract is much lower than other nitrate-rich leafy greens, making it a suitable option for those with sensitivities.14
Theobroma cacao (Cocoa) – contains large amounts of polyphenol compounds including flavonoids, epicatechin, catechin, and polymeric proanthocyanidins.15,16 The flavonols within cocoa increase NO levels in endothelial cells as they activate eNOS.16 Cocoa also contains the methylxanthines theobromine and caffeine, which are considered nitrogenous compounds that help to relax smooth muscle.16 The antioxidant activity of cacao also reduces inactivation of NO by ROS through the inhibition of NADPH oxidase.16
Camellia sinensis (Green tea) – contains catechins, such as epigallocatechin-3-gallate (EGCG), as well as quercetin, theanine, caffeine, chlorogenic acid, and gallic acid.17 Epidemiological studies show a positive relationship between green tea consumption and reduced risk for T2DM.18 In a case-control study in patients with diabetic retinopathy (DR), it was found that drinking green tea for at least one year, on a weekly basis, reduced the likelihood of developing DR by approximately 50%.19
In the vascular system, ECGC has demonstrated the ability to stimulate NO production resulting in vasodilation and microvascular recruitment while inhibiting vasoconstriction.20 Ultimately, these positive actions may contribute to the correction of insulin resistance by improving the microvascular delivery of hormones as well as nutrients to relevant target tissues regulating glucose homeostasis.20
Vaccinium myrtillus (Bilberry) – is considered one of the richest sources of polyphenol anthocyanins, which are believed to be responsible for their health benefits.21 Studies on the use of V. myrtillus in diabetic retinopathy have shown marked improvements in patients, reducing retinoic haemorrhages, improving ophthalmoscopic and angiographic patterns.22 Further, animal studies have demonstrated that anthocyanins from V. myrtillus improve vascular tone, blood flow and vasoprotection.23
Let It Flow
Encouraging healthy microcirculation and endothelial function is an important treatment aim when supporting patients with diabetes. Many plants contain compounds that directly or indirectly contribute to NO production, improving endothelial health and microcirculation to tissues. They also contain a wide variety of antioxidant compounds, including polyphenols, that reduce inflammation and oxidative stress in the endothelium. These therapeutics may therefore constitute an effective intervention in order to slow the progression of the deleterious secondary complications associated with diabetes.
DISCLAIMER: The information contained within is intended to be used as an educational tool and it is not intended to be used to diagnose, treat, cure or prevent any disease, nor should it be used for therapeutic purposes or as a substitute for your own health professional's advice.
References
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