The impact of zinc on the molecular signaling pathways in the diabetes disease

Zn is the second most common trace element in both human tissues and tissue fluids after iron [1]. Zn activates over 300 enzymes in the body and is vital in various metabolic pathways, including glucose metabolism [12]. Zn was shown to be a component of insulin crystals in 1934 [13]. Since then, a correlation between Zn, insulin, and diabetes has been hypothesized [14].

Till now, several experiments have attempted to determine the exact function of Zn and its NPs in the pathophysiology of diabetes mellitus [14]. Zn and its NPs have been shown to have anti-diabetic effects in both humans and rats [15]. Also, ZnNPs enhance glucose utilization by improving hepatic glycogenesis through changes in the insulin signaling pathway. ZnNPs also help to reduce blood glucose levels by inhibiting intestinal glucose absorption and increasing glucose uptake in skeletal muscle and adipose tissue [2], [16].

Zn has also been shown to reduce gluconeogenesis and glycogen breakdown through glucagon release suppression [2]. Zn is also known for maintaining the structure of insulin [17] and is needed for its biosynthesis, storage, and secretion [18]. Several Zn transporters in pancreatic cells, such as Zn transporter-8 (ZnT8), have been shown to play a significant role in insulin secretion [19], [20]. Zn could boost insulin signaling through various pathways, including increased phosphorylation of β subunit of the insulin receptor, increased phosphoinositide 3-kinase function, and inhibition of glycogen synthase kinase-3 [16].

The insulin molecule produces complexes and polymers with Zn in the β cell granules, according to previous research [14].

Zn deficiency has been attributed to diabetes, especially the development of Type 2 diabetes. Increasing lipogenesis and inhibiting the release of non-esterified fatty acids (NEFA) from adipocytes are all known insulin-mimetic effects of zinc [21].

Furthermore, given Zn’s antioxidant role, a lack of Zn can worsen diabetes’s oxidative stress-mediated complications [2]. Moreover, ZnO NPs have potent anti-diabetic activity through improved serum glucose and insulin levels and lipid parameters, as well as antioxidant impact, increased superoxide dismutase (SOD), and catalase (CAT) activities in Type 1 and 2 diabetic rats [2]. According to the presented data, there is a dynamic interrelationship between Zn, diabetes, and diabetic complications (Fig. 1). Therefore, developing a Zn-based medication for the treatment of Type 1 and Type 2 diabetes and their related risks becomes an appealing proposition [2].

Systemic hyperglycemia in DM causes several cardiovascular complications, including peripheral artery disease, hypertension, and cardiomyopathy, which is known as the leading cause of morbidity and mortality in people with diabetes [23]. 16.9% of diabetic patients meet diabetic cardiomyopathy requirements, and 54.4% of diabetic patients have diastolic dysfunction [24].

Diabetic cardiomyopathy can have an important role in the increased occurrence of heart failure in diabetic patients or streptozotocin (STZ)-induced diabetic animals [25]. Diabetic cardiomyopathy therapies are only in the early stages of development [25]. In recent years, Zn and some of its complexes have been suggested as treatment options for diabetic cardiomyopathy [26].

Susmita Barman and Krishnapura Srinivasan (2017) discovered that diabetic rats with Zn supplementation had substantially higher activities of cardiac antioxidant enzymes than the non-Zn treated group. Also, cardiac catalase (CAT) and Glutathione peroxidase (GPx) activity levels were higher in the diabetic control group than the regular control group, but this was reversed after Zn supplementation. It is thought that the elevated antioxidant activity in diabetes is the result of a compensatory process [27]. Ali Nazarizadeh, on the other hand, reported in 2015 that ZnO NPs therapy at the maximum dosage (10 mg/kg body weight B.W.) to both normal and diabetic rats increased malondialdehyde (MDA) levels [14]. Furthermore, intraperitoneal (IP) injection of streptozotocin (STZ) boosted MDA levels in the heart (nearly twofold) by inducing diabetes mellitus and hyperglycemia [14]. In a study, Siamak Asri-Rezaei discovered that administering ZnNPs at the dosage of 3 mg/kg B.W. to rats significantly decreases MDA levels, therefore preventing lipid peroxidation [28]. Despite this information, the maximum ZnNPs concentration (10 mg/kg B.W.) is related to increased lipid peroxidation [28]. So, it seems a dosage of 10 mg/kg of these NPs can have adverse and probably toxic effects in contrast to lower dosages.

According to a study by Hala (2015), diabetic rats had disrupted oxidative status in cardiac tissues compared to normal rats, as shown by a substantial increase in MDA and decreased levels of superoxide dismutase (SOD) function and glutathione (GSH). Administrating glibenclamide alone improved MDA and SOD levels. At the same time, the addition of Zn (30 mg/kg/day) also resulted in a substantial improvement in cardiac GSH levels compared to the non-Zn supplemented group. Furthermore, the addition of Zn (30 mg/kg/day) greatly reduced MDA levels in the cardiomyocytes [29].

In 2016, Ali Nazarizadeh reported that administration of higher doses of Zn (3 and 10 mg/kg B.W.) to both healthy and diabetic rats significantly decreased glutathione peroxidase (GSH-Px) function in the heart tissue compared to respective control groups in a time-relative manner. In comparison, a lower dose of the ZnNPs (1 mg/kg B.W.) improved enzyme activity in both healthy and diabetic groups; nevertheless, this rise was not stable, and a steady suppression was found during the research. The administration of Zn (50 mg/kg B.W.) to healthy rats did not affect GSH-Px activity [14]. Based on the mentioned articles, the effects of Zn NPs on cardiac oxidative stress are shown to be dose-dependent; thus, it could be demonstrated that low doses such as 3 mg/kg of NPs could decrease oxidative stress within cardiac tissue, whereas higher doses like 10 mg/kg could potentially increase cardiac oxidative stress.

Recent research has demonstrated that Zn supplementation can reduce the production of reactive oxygen species (ROS) in DM patients [30] and can prevent apoptosis in the heart caused by elevated glucose levels [28]. In 2017 Rezaei discovered that diabetes raises caspase-3 activity in the cardiomyocytes of rats in a time-dependent manner [28]. However, the administration of ZnNPs to diabetic rats at the middle dose (3 mg/kg B.W.) can effectively reverse this outcome [28]. In comparison, the maximum dose of Zn NPs (10 mg/kg B.W.) showed an adverse outcome by improving caspase-3 function in both healthy and diabetic rats compared to the respective control groups [28]. In a 2017 study, Rezaei found that diabetes increased the rate of apoptosis in myocardial cells [28].

Although ZnNPs (3 mg/kg B.W.) reduced diabetes-induced cardiomyocyte apoptosis, also, ZnNPs (10 mg/kg B.W.) greatly improved the apoptosis index [28]. It is also shown that caspase-3 cleavage products (ccCK-18) increase in the heart of diabetic rats in comparison with healthy rats (approximately four folds) [28]. It was discovered that administering 3 mg/kg Zn NPs to diabetic rats inhibited caspase-3 function in a time-relevant manner and decreased the content of caspase-cleaved cytokeratin-18 (ccCK-18) [28]. In comparison, a substantial increase in ccCK-18 concentration was observed in both healthy and diabetic rats given 10 mg/kg of Zn NPs [28]. It could be concluded that 3 mg/kg of Zn will lower the apoptosis of cardiac tissue while 10 mg/kg B.W. of Zn will raise apoptosis of cardiac tissue. While, as mentioned above, 10 mg/kg B.W. of ZnNP effectively decreased apoptosis in the heart.

Zn is believed to have anti-ulcer and anti-inflammatory effects [31]. According to Prasad and colleagues (2004), Zn decreases the production of inflammatory cytokines such as tumor necrosis factor- α (TNF-α) and interleukin-1 (IL-1) in humans [32]. In 2017, Rezaei observed that administering ZnNPs at the middle dose (3 mg/kg B.W.) greatly decreased TNF- α levels in the heart tissue of diabetic rats (close to normal range) in a time-relevant manner [28]. The maximum dose of Zn NPs (10 mg/kg B.W.) was also shown to inhibit TNF- α levels in diabetic rats but wasn’t as compelling as the middle dose [28]. Furthermore, in healthy animals, the administration of the maximum dosage increased TNF -α levels [28]. The current results are partly consistent with Baky and colleagues’ research. In their study, oral administration of Zn NPs at doses of 600 and 1000 mg/kg was found to elevate levels of inflammatory factors such as TNF-α, IL-6, and C-reactive protein (CRP), therefore causing inflammation in the rat’s heart [33]. TNF- α has a well-established role in the pathophysiology of heart failure [33]. The combination of lipoic acid or vitamin E with Zn NPs effectively decreased the release of inflammatory biomarkers such as TNF-α, IL-6, and CRP in the diabetes condition [33]. The mixture of Zn and glibenclamide resulted in a highly substantial decrease in TNF- α levels in the heart tissue of rats, according to Hala Attia (2015) [29]. The addition of Zn to glibenclamide resulted in a substantial reduction in cardiac TNF- α levels compared to glibenclamide alone [29]. TNF- α production inhibition can be mediated by cyclic nucleotide signaling, which is indirectly activated by Zn, according to von Bülow et al., 2005 [34]. According to Table 1, it can be concluded that lower levels of Zn NPs (3–10 mg/kg) could potentially decrease the inflammation in cardiac tissue; the maximum level (600–1000 mg/kg) administered orally will increase inflammation rate in the heart.

The study of autophagy control has become increasingly important because autophagy is now viewed as a potential therapeutic target due to its correlation with aging, neural degeneration disorders, diabetes, and fatty liver [35], [36], [37], [38], [39], [40], [41], [42]. Zn has long been believed to play a part in apoptosis and cell cycle control [43], [44]. Nonetheless, research into the function of Zn in autophagy is just getting started. The idea that Zn is a positive regulator of autophagy is gaining traction [37]. Zn is required for both basal activity of autophagy and induced autophagy, according to in vitro studies [37], [45], [46], [47].

Angiogenesis is a broad term that refers to the physiological mechanism of new blood vessel formation, also known as neovascularization [48]. It has been shown that the rate of angiogenesis in the myocardial tissue of diabetic rats is lower compared to healthy rats [49]. It was discovered that the cardiac expression of VEGF-A and its receptors decreased in diabetic rats and diabetic human’s myocardium [50]. VEGF-A is the primary signaling pathway that governs endothelial cell growth and migration; thus, it is the foundation of many vessels and their receptors [50]. Diabetes disrupts vascular homeostasis by altering neovascularization pathways. It is shown that hyperglycemia in diabetes triggers endothelial dysfunction and reduces angiogenesis in diabetic cardiac tissue through various glyco-oxidative compounds. As a result, angiogenesis and capillary density is shown to be less in diabetic rats’ heart [51], [52]. Human umbilical vein endothelial cells (HUVECs) migration and early tube development are aided by NPs such as ZnO. These NPs can enable kinases like AKT [53]. In a recent study, Barui discovered that Zn nanoflowers could facilitate the proliferation and migration of HUVECs and stimulate angiogenesis (5–20 µg/mL) [54]. Vascular endothelial zinc finger-1 (VEZF-1) has been thought to be associated with the regulation of angiogenesis [55]. Zn has also been reported to be critical for endothelial cell proliferation and migration during venous angiogenesis in zebrafish [56]. According to table1, 15–20 µg/mL of Zn can raise angiogenesis inside heart tissue.