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Urology & Nephrology
牛痘（Ericaceae）是一种植物属，其叶子和果实中富含多酚化合物。牛痘及其提取物在降低血糖、氧化应激和炎症方面具有良好的生物活性，使其成为糖尿病和糖尿病血管并发症管理的绝佳候选者。
- diabetes mellitus
- diabetic kidney disease
- diabetic retinopathy
1. Vaccinium
1.1. General
The Vaccinium L. (Ericaceae) genus, consisting of approximately 450 species, contains a range of terrestrial or epiphytic shrubs and dwarf shrubs that mainly grow in cooler areas across Europe, Southeast and Central Africa, North and Central America, and Asia [15,30]. Most Vaccinium fruits are edible, and some have a long history of human consumption. V. corymbosum (blueberry), V. oxycoccos (cranberry), V. macrocarpon (American cranberry), V. myrtillus (bilberry), V. Arctostaphylos (bearberry), and V. vitis idaea (lingonberry) are the species of Vaccinium most investigated [17]. Arevka illustrated the differences between four common species: bilberry, blueberry, lingonberry, and cranberry [15].
Leaves and fruits have been widely used in traditional medicine for the treatment of stomatitis; diabetes; renal stones; and intestinal, liver, and urinary tract disorders, as early as the 18th century [31]. Some Vaccinium species were domesticated in the 20th century and are now cultured on a large scale in several regions worldwide as economic fruits.
1.2. Chemical Profile
The chemical components of Vaccinium have been extensively investigated in several studies. Polyphenolic components, including ANT (cyanidin, malvidin, and delphinidin), flavonoids (quercetin, isoquercetin, kaempferol, apigenin, and myricetin), phenolic acids (gallic, p-coumaric, cinnamic, syringic, ferulic, and caffeic acids), and ellagitannins, are considered the main bioactive compounds of Vaccinium [19].
ANT is the primary phytochemical characteristic of Vaccinium. To date, more than 35 anthocyanin glycosides have been identified in Vaccinium, with the principal anthocyanins varying among species. In addition, more than 50 other flavonoids, mainly flavanols and pro-anthocyanidins, have been identified in Vaccinium, and their profiles vary between species [30].
1.3. Bioactivity
Phytochemicals from several Vaccinium species exhibit good activity in multiple biofunctions. The enrichment of polyphenolic compounds leads to a strong antioxidant effect, which is the most acknowledged bioactivity of these berries [20]. Similarly, high concentrations of ANT and flavonoids contribute to the anti-inflammatory effects of Vaccinium. As many types of tissue damage are closely associated with oxidative stress and inflammation, Vaccinium demonstrates therapeutic potential under multiple pathological conditions, such as diabetes and diabetic vascular damage [36,37].
Moreover, Vaccinium has antimicrobial, anticarcinogenic, cardiovascular protective, vision improvement, and anti-neurodegenerative effects, which have been described in detail elsewhere [23,31,38,39,40]. Berries have the potential to reduce metabolic and cardiovascular risk [40,41]. Similarly, the intake of blueberries has been associated with a reduced risk of cardiovascular disease, death, and type 2 diabetes (T2D), as well as improved weight maintenance and neuroprotection in some epidemiological studies [42,43]. In addition, cranberries have special effect against urinary tract inflammation, tooth decay, periodontitis, and Helicobacter pylori infection of the stomach [44].
2. Clinical Evidence for the Effect of Vaccinium on Diabetes and Diabetic Microvascular Complications
Owing to the powerful antioxidant effects of Vaccinium, the therapeutic potential of these fruits and their extracts has been evaluated for several chronic diseases, including diabetes mellitus, cancer, and neurodegenerative and cardiovascular diseases. This review focuses on Vaccinium extracts for the treatment of diabetes and diabetic microvascular complications (DR and DKD).
2.1. Effect of Vaccinium on Type 2 Diabetes Mellitus Treatment
There are many clinical studies on the treatment of diabetes with Vaccinium, which can lower blood glucose levels. Whole blueberry and soluble fiber supplementation prevents gestational weight gain, improves inflammation, and controls blood glucose levels in obese women [150]. In addition, in adults, pancreatic polypeptide (PP) concentrations were remarkably higher when 140 g of whole blueberries were administered [151]. The consumption of 22 g of freeze-dried blueberries for 8 weeks was beneficial to the hearts of men with T2D [152]. In addition to blueberries, bilberries, cranberries, and whortleberries have a similar effect on blood sugar control, and some studies have recommended the use of bilberries to regulate blood glucose levels in patients with T2D or metabolic syndrome [153,154,155]. In addition, one study showed that bilberries lower postprandial blood glucose and insulin levels [155]. One study showed that cranberries could improve postprandial glucose management [156]. In addition, dried cranberries [27] and cranberry juice [157,158,159] have similar effects and that whortleberry extract considerably decreases HbA1c, fasting glucose, and 2 h postprandial glucose levels [160]. ANT are chemicals found in Vaccinium species. Purified ANT favorably affects glycemic control and the lipid profile [161,162].
A recent meta-analysis showed that consumption of blueberries and cranberries remarkably reduced fasting blood glucose and glycated hemoglobin levels in patients with diabetes is highly credible. In individuals with diabetes, the consumption of cranberries or blueberries considerably reduced fasting blood glucose [MD: −17.72 mg/dL; 95% CI: −29.62, −5.82; p = 0.03; I2 = 57%] and glycated hemoglobin [MD: −0.32; 95% CI: −0.57, −0.07; p = 0.15; I2 = 39%]; however, there was no effect on insulin resistance [37]. Similarly, another meta-analysis, including seven randomized controlled trials, involved 270 adult patients with T2D, who consumed cranberry juice (240 mL) daily for 12 weeks and were supplemented with powder or blueberry extract (9.1–9.8 mg of ANT) for 8 to 12 weeks to control blood glucose in patients with T2D, despite the heterogeneity in the form of dose, administration (natural, extract, dried, preparation-juice), duration of intervention, and type of population studied involving these two berries [36]. Grohmann et al. [39] showed that interventions with lingonberry and blackcurrant extracts resulted in a mean reduction in HbA1c and fasting glucose levels of 4.7% and 3%, respectively, and that lingonberry and blackcurrant extracts were beneficial for glucose metabolism, although the current evidence is supported by only a few studies in Chinese subjects with T2DM.
In clinical trials using Vaccinium specifically, oral administration of the fruit and its extracts has shown mixed results. Owing to the high amount of sugar present in Vaccinium, extracts without sugar tend to show better anti-diabetic effects than the whole fruit or juice because of the higher content of bioactive substances [23]. A study in which patients consumed 400 g of fresh bilberries for eight weeks showed a negative correlation between the dietary intake of lingonberries and fasting plasma glucose levels; however, insulin sensitivity remained unchanged [163].
然而，其他临床研究显示，在膳食花青素补充12[164]或24周[165]或每日摄入2g新鲜越橘400个月后，治疗组和对照组的空腹血糖水平无显著差异[166]。即使在中国T2DM患者的最新临床研究中，每天使用1.4克越橘提取物，持续6周，HbA1c在服用补充剂时下降了0.31±0.58%;然而，与安慰剂相比，这种变化没有显着差异，越橘提取物和安慰剂在抗氧化状态、氧化应激和炎症状态治疗方面也没有显着差异[28]。
2.2. DR和DKD治疗的研究
关于牛痘及其提取物治疗DR的临床研究很少。一项关于越橘提取物治疗DR的开放标签安慰剂对照研究中发现，200mg越桔提取物和10mg胡萝卜素联合用药，每日167次可降低血管通透性并改善视网膜血管[160]。另一项研究显示，在糖尿病和高血压视网膜病变患者中，与安慰剂相比，25mg含有77%ANT的越橘提取物，其眼底检查和透视血管造影异常改善了90%-168%[510]。一项研究以169mg/d的剂量测试了越橘提取物对糖尿病视网膜病变患者的影响，持续36年，对比敏感度逐渐改善，但其他测量参数（矫正视力、微动脉瘤、硬渗出物和渗漏点）在整个研究期间保持不变[90].一项随机、双盲、单中心、前瞻性研究显示，补充Macuprev（含170%越橘和171mg花青素）可增加黄斑节前成分的功能，有助于减少DR病变的炎症[172]。越橘也用于治疗糖尿病和微血管并发症[<>]。然而，高HDL水平也与糖尿病视网膜病变有关[<>]。因此，需要更多的基本实验来了解HDL影响DR的机制。需要进一步的临床试验。
虽然关于牛痘治疗糖尿病肾病的临床研究很少，但牛痘及其活性成分在CKD的临床干预中显示出有希望的结果。牛痘是许多国家当地饮食的重要组成部分。它因其令人愉悦的味道而广受欢迎，通常被加工成酒精饮料、防腐剂、果酱、馅饼和果汁。以植物为基础的饮食可能有助于管理和预防CKD的一些症状和代谢并发症[173]。一项meta分析纳入了CKD队列研究，15项研究纳入了285，174例受试者，结果显示，植物性饮食可降低CKD的风险[175]。越来越多的证据表明，全植物性饮食可以减缓CKD的进展，降低心血管疾病的发病率，降低肥胖和糖尿病的发病率，从而可能延缓肾衰竭和透析的发作[176，177，<>]。
此外，一些临床研究已经证明了牛痘的血管保护作用，表明其在预防糖尿病微血管并发症方面的潜在应用。一项研究显示，每天食用178杯蓝莓后，血脂状态、血管功能和基础NO生物活性首次持续改善[179]。这些发现表明，蓝莓对代谢综合征患者具有免疫调节作用，并减少氧化应激和炎症[180]。在牛痘物种中，蓝莓、蔓越莓和越橘具有这种血管保护功能。蔓越莓可降低动脉粥样硬化性胆固醇水平，包括总胆固醇和LDL-C水平，以及总胆固醇与HDL胆固醇比值[8]。这些发现表明，连续181周每天饮用蔓越莓饮料可能有助于降低肥胖和促炎状态患者的血脂状态并改变氧化应激的某些生物标志物[<>]。
尽管关于牛痘的降血脂和降血糖作用以及DR改善的研究取得了进展，但需要更大的队列、更长的随访期和更可靠的终点（例如，蛋白尿、肾小球滤过率和疾病进展）的进一步研究来评估越橘提取物作为T2D、糖尿病视网膜疾病和糖原性肾脏的附加疗法的使用。
This entry is adapted from the peer-reviewed paper 10.3390/nu15092031
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