3.2.2. Diabetic Cardiovascular Diseases

Cardiovascular complications, containing cardiomyopathy, atherosclerosis, coronary ischemia, and vascular disease, are associated with the high morbidity and mortality of diabetes mellitus [77,88], among which cardiomyopathy is responsible for 80% [17]. It was reported that tea could improve cardiovascular complications by decreasing hyperglycemia, adjusting lipid metabolism, activating signaling pathways, down-regulating the inflammatory factors, and so on.

Tea polyphenols could improve myocardial glycolipid energy metabolism and interfere with adiponectin mRNA and protein expression through AMPK activation, which was involved in insulin signaling [89]. Also, tea polyphenols could stimulate the activity of AMPK via the Ca<sup>2</sup>+/Ca-MKK/AMPK-mediated signaling pathway [90]. Additionally, tea polyphenols could regulate autophagy via mTOR and Akt signaling pathways, which was beneficial for the prevention and treatment of diabetic cardiomyopathy [91–93].

An in vivo study found that green tea could inhibit cardiac dyslipidemia, lipid peroxidation, and protein glycosylation through improving the activities of Ca2<sup>+</sup>-ATP and Na+/K<sup>+</sup>-ATP enzymes to regulate the content of Ca2+ and Na<sup>+</sup> [94]. Furthermore, EGCG could improve metabolic and cardiovascular pathophysiology by stimulating the production of nitric oxide (NO) from endothelium via phosphatidylinositol 3-hydroxykinase (PI3k)-dependent pathways [95]. Additionally, EGCG could inhibit inflammatory factors such as NF-κB and activator-1, which played an important role in vascular inflammation caused by insulin resistance [96,97]. In addition, it was found that green tea extract could reduce the progression of atherosclerosis by reversing endothelial dysfunction [98]. Also, MMP-9 played an important role in atherosclerosis, and green tea catechins could inhibit the mRNA expression and the activity of MMPs [83,99]. Further, green tea catechins increased plasma total antioxidant activity and prevented diabetic cardiovascular autonomic dysfunction by blocking changes in arterial pressure variability [77]. Moreover, the green tea extract inhibited the accumulation of aortic collagen, reduced the solubility of collagen, and decreased AGEs and collagen cross-linking, finally preventing diabetic cardiomyopathy in streptozotocin diabetic rats [98,100]. It was also reported that green tea flavonoids could alleviate the contraction of aortic strips, and green tea extract could protect against free radical and glucose-mediated protein damage [101].

Both black tea theaflavins and green tea catechins significantly attenuated high glucose-induced block of insulin signaling, reduced lipid accumulation, inhibited fatty acid synthesis, and stimulated fatty acid oxidation by activating the LKB1-AMPK pathway [54,102,103]. Furthermore, insulin deficiency and insulin resistance could induce exaggerated vasoconstriction [104], and black tea polyphenols could improve vasoconstriction through PI3K-Akt pathway and endothelial nitric oxide synthase (eNOS) phosphorylation [105,106].

White tea catechins could reduce the absorption of cholesterol in the intestines and increase the excretion of cholesterol and total fat in the feces [107]. Further, white tea could control the Krebs cycle by decreasing pyruvate through regulating lactic acid and the lactate dehydrogenase levels in the heart at the prediabetic state, thereby preventing diabetic cardiovascular disease [108–110]. In addition, white tea could regulate cardiac metabolic disorders by up-regulating the expression of cardiac GLUT1 and GLUT3 mRNA [87]. Quercetin, an important flavonoid found in write tea, could prevent diabetic vascular complications in both insulin deficiency and resistance by inhibiting inflammatory pathways, especially the NF-κB signaling [104].

Yellow tea "Junshan Yinzhen" could improve insulin resistance and the disorders of glucose and lipid metabolism in diabetic rats, which may be related to the high content of polyphenols, polysaccharides, and alkaloids in yellow tea [111]. Besides, yellow tea could control glucose e ffectively by maintaining normal expression of thioredoxin interacting protein, which played an important role in the synthesis and release of glucose in the liver [112].

Oolong tea contained less catechins than green tea, but more catechins than black tea [113]. Pu-erh tea extract could inhibit inflammation of visceral adipose tissue by down-regulating the inflammatory factors and inducing the expression of G-protein coupled receptor (Gpr120) [114].

Therefore, tea and its bioactive components, can be good protectors for cardiovascular complications of diabetes.
