Abundant evidence supports a close association between vitamin D deficiency and T2DM [2,8], which is mediated by direct and indirect effects of vitamin D on insulin secretion, insulin sensitivity, insulin resistance and systemic inflammation [8].
In pancreatic β cells, vitamin D regulates calcium ion flow and intracellular calcium ion level, stimulating pancreatic β cells to promote insulin secretion through non-selective voltage channels [9]. Calcium-dependent endopeptidase is produced, and the activation of calcium-dependent endopeptidase promotes the conversion of proinsulin to insulin, so vitamin D and calcium ions are essential for insulin exocytosis [10].Cell experiments showed [11] that 1,25(OH)2 vitamin D combined with high glucose increased the insulin secretion of INS1E cells, and showed a difference with the increase of glucose concentration, and glucose stimulation of insulin secretion in INS1E β cells was associated with the type of vitamin D metabolite treatment.
In addition, vitamin D is an immune modulator that may affect inflammation, which can lead to diabetes. It can improve the absolute T-regulated cell number and phenotype in diabetic patients, and vitamin D supplementation is beneficial to reduce hS-CRP and IL-6 in type 2 diabetic subjects [15]. Vitamin D can also regulate the insulin resistance pathway associated with diabetes [16] and reduce the pathological conditions associated with insulin resistance, such as oxidative stress and inflammation. Diabetes is a process of chronic inflammation accumulation, and inflammation is a bridge connecting obesity and insulin resistance [17]. Inflammatory factors and adipocytokines produced by adipose tissue can affect the insulin action process by regulating inflammatory response.
This experiment showed that the level of vitamin D in the diabetic group was much lower than that in the non-diabetic group. Both the non-diabetic and diabetic patients with vitamin D deficiency had severe insulin resistance and increased inflammation level, especially in the diabetic vitamin D deficiency group. In the non-diabetic stage, vitamin D deficiency triggers the body to turn on the RAS system, producing more hormones that narrow blood vessels and raise blood pressure, such as AngII.AngII induces pancreatic β cell apoptosis and inhibits insulin signal transduction by regulating adipokines [18], and also inhibits GLUT4 expression and AMP kinase activity, leading to emerging diabetes and various diabetic complications. The overactivated two functional axes of RAS system, ACE/AngII and ACE2/Ang1-7, produce corresponding body effects.
In conclusion, vitamin D deficiency may change the improper regulation of ACE2 and ACE/AngII and the release of inflammatory factors, destroy the immune homeostasis of the body and participate in the occurrence and development of diabetes. ACE2 is expressed in different organs of human body, mainly in pancreatic islets and preferentially in insulin-producing β cells, and participates in activating RAS circulation in local tissues [19]. ACE2 can improve pancreatic microvascular endothelial function, regulate glucose homeostasis by regulating GAD67/GABA signal transduction in β cells, improve β cell function, and delay the development of diabetes [20].
Studies have shown that ACE2 deficiency in adipocytes increases the systolic blood pressure of obese female C57BL/6 mice [21], and TG regulates ACE2 expression by affecting the methylation level of ACE2 gene through Mthfd1 [22]. This experiment also showed that the blood pressure and blood lipid of diabetic patients were higher than that of normal group, and ACE2 expression was lower.
Study found that [23] vitamin D can increase the angiotensin-converting enzyme 2 (ACE2) and the ratio of the ACE, thereby increasing the hydrolysis angiotensin II and reduced subsequent inflammatory cytokine response to pathogens and lung injury.For DN patients, calcitriol combined with valsartan treatment [24] can effectively inhibit renal ACE expression, reduce AngII and renin levels, improve proteinuria symptoms, and improve renal function.Correlation analysis in this study showed that vitamin D in the non-diabetic group was negatively correlated with AngII and IL-6, and positively correlated with IL-10, indicating that vitamin D deficiency in the non-diabetic stage can cause stress response and release pro-inflammatory factors and inhibitory anti-inflammatory factors. Therefore, vitamin D supplementation in non-diabetic stage can delay the occurrence and development of diabetes. In the diabetic group, vitamin D was positively correlated with ACE2 and IL-10, and negatively correlated with ACE, AngII, IL-6, TNF-a, HOMA-IR and HbA1c, indicating that with the increase of vitamin D deficiency, the progressive decrease of ACE2 expression was caused. Loss of ACE2 can disrupt the balance of RAS in diabetes[25], resulting in impaired vascular function, direct β cell damage to local islets, deterioration of blood glucose control and enhancement of insulin resistance.
In conclusion, vitamin D deficiency can aggravate insulin resistance by mediating RAS system and inflammatory factors, and increase the potential pathogenic effect of diabetes.
Multiple linear regression analysis showed that IL-10 and AngII were the main influencing factors of vitamin D deficiency in the non-diabetic group, explaining 33.6% of the total variation of the regression equation, suggesting that the active function of pancreatic RAS and the reduction of anti-inflammatory factors affected the level of vitamin D in the non-diabetic group, which served as a warning.Vitamin D supplementation, especially at medium and high doses, can significantly reduce the risk of T2DM [26] and improve other metabolic parameters related to blood glucose control [27], such as glycated hemoglobin and insulin resistance.In the diabetes group, ACE2, IL-6, TNF-a, IL-10 and HOMA-IR were the main influencing factors of vitamin D deficiency, explaining 55.8% of the total variation of the regression equation. It suggests that with the aggravation of vitamin D deficiency and the loss of ACE2, the potential infection accelerates, and the body is in the stress state of high expression of inflammation, which is not enough to fight the invasion of inflammatory factors and the stress response of ACE/AngII to the organs of the whole body, and may cause the "inflammatory factor storm".
In conclusion, ACE2, ACE/AngII and inflammatory factors can be used as biomarkers of diabetes vitamin D deficiency.
There are shortcomings in this study: there are new patients and patients taking medicine in the diabetic population, which may cause the influence bias of drugs.