A high-fiber diet is believed to reduce a person’s likelihood of developing type 2 diabetes, but it isn’t clear how. Since dietary fiber is not digested by human enzymes, Wang and colleagues hypothesized that fiber-eating gut microbes might be involved. To find out, the team examined diet data, fecal microbiomes, serum metabolites and markers of diabetes in thousands of participants. The analyses revealed, as expected, that eating more fiber was associated with a lower risk of diabetes, but the team also identified 24 microbial genera significantly associated with dietary fiber intake, nine of which were also linked to diabetes risk. For example, specific taxa associated with a lower diabetes risk included Butyrivibrio and Faecalibacterium and these were both boosted by increased fiber consumption. Furthermore, of 624 metabolites measured in participants’ blood, the team found 47 that were tied to both fiber intake and diabetes incidence, with the microbial metabolites indolepropionate and phenylpropionate both being inversely correlated with risk. By identifying specific fiber-induced microbes and metabolites linked to reduced diabetes risk, the results offer valuable information for the development of precision nutritional interventions, say the authors.

Many complications of diabetes, including neuropathy, retinopathy and cognitive impairment, are thought to involve vascular endothelial dysfunction. Because monocytes interact with the endothelium, contribute to vascular lesions and are ramped-up in diabetic mice, Zhao and colleagues reasoned these cells might be to blame. Comparing monocyte transcriptomes from patients and controls, they discovered the mRNA for protease Cathepsin D (CTSD) was strongly upregulated in patients, particularly those with microvascular complications. Moreover, mice whose monocytes were engineered to overexpress CTSD had both increased cerebrovascular permeability and cognitive impairment, akin to that seen in diabetic mice. The permeability was due to increased shuttling of vesicles across the endothelium (transcytosis), the team showed. Indeed, inhibiting endothelial caveolin—a factor necessary for transcytosis—prevented the increased permeability in the engineered mice. Further studies revealed CTSD itself (in a non-enzymatic form) boosted caveolin production and that CTSD inhibition in diabetic mice prevented transcytosis and cognitive impairment. Together the results suggest the CTSD-to-caveolin pathway as a clinical target for preventing vascular complications of diabetes.

Sorbs2 is an adaptor protein expressed within cardiomyocytes and is essential for heart function. Indeed, Sorbs2 mutations are linked to congenital heart disease, while mice lacking the protein develop cardiomyopathy and arrhythmia. Sorbs2 is also expressed in coronary arteries at higher levels to that seen in cardiomyocytes, yet far less is known about its vascular role. Sun and colleagues thus examined the role of Sorbs2 in coronary artery smooth muscle cells, showing that the protein interacts with both the protein and mRNA of a key potassium channel, called BK—important for vascular tone and cardiac blood flow. In mice lacking Sorbs2, arterial BK expression level and function were diminished—a phenomenon observed in diabetic vasculopathy. Given this similarity, the team looked at the possible role of Sorbs2 in diabetic mice. Sure enough, its expression was reduced by 60 percent in the coronary arteries of diabetic animals compared with those of controls. The team went on to show Sorbs2 expression is controlled by the transcription factor Nrf—also downregulated in diabetic mice. The results thus suggest reduced Nrf/Sorbs2/BK in diabetes ultimately leads coronary artery disease and that boosting this pathway might be a prevention strategy.

高纤维饮食被认为可以降低一个人患 2 型糖尿病的可能性，但具体如何降低尚不清楚。由于膳食纤维不被人体酶消化，王和同事推测可能与食用纤维的肠道微生物有关。为了找到答案，研究小组检查了数千名参与者的饮食数据、粪便微生物组、血清代谢物和糖尿病标志物。正如预期的那样，分析显示，吃更多的纤维与降低患糖尿病的风险相关，但研究小组还发现了 24 个与膳食纤维摄入量显着相关的微生物属，其中 9 个属也与糖尿病风险相关。例如，与较低糖尿病风险相关的特定分类群包括丁酸弧菌和粪杆菌，而这些分类群都因纤维消耗的增加而增加。此外，在参与者血液中测量的 624 种代谢物中，研究小组发现 47 种代谢物与纤维摄入量和糖尿病发病率有关，其中微生物代谢物吲哚丙酸和苯丙酸均与风险呈负相关。作者说，通过识别与降低糖尿病风险相关的特定纤维诱导微生物和代谢物，结果为制定精准营养干预措施提供了有价值的信息。

糖尿病的许多并发症，包括神经病变、视网膜病变和认知障碍，被认为与血管内皮功能障碍有关。由于单核细胞与内皮相互作用，导致血管病变，并且在糖尿病小鼠中单核细胞的数量增加，赵和同事推断这些细胞可能是罪魁祸首。通过比较患者和对照的单核细胞转录组，他们发现蛋白酶组织蛋白酶 D (CTSD) 的 mRNA 在患者中强烈上调，特别是那些患有微血管并发症的患者。此外，单核细胞被改造为过度表达 CTSD 的小鼠脑血管通透性增加，认知功能障碍，类似于糖尿病小鼠的情况。研究小组表明，渗透性是由于囊泡穿过内皮细胞的穿梭作用（转胞吞作用）增加所致。事实上，抑制内皮细胞小窝蛋白（转胞吞作用所必需的一个因子）可以防止工程小鼠通透性的增加。进一步的研究表明，CTSD 本身（以非酶促形式）可促进小窝蛋白的产生，并且糖尿病小鼠中的 CTSD 抑制可防止转胞吞作用和认知障碍。总之，这些结果表明 CTSD-to-caveolin 通路可作为预防糖尿病血管并发症的临床目标。

Sorbs2 是一种在心肌细胞内表达的衔接蛋白，对于心脏功能至关重要。事实上，Sorbs2 突变与先天性心脏病有关，而缺乏该蛋白的小鼠会患上心肌病和心律失常。 Sorbs2 在冠状动脉中的表达水平也高于心肌细胞中的表达水平，但对其血管作用的了解却少之又少。因此，Sun 及其同事研究了 Sorbs2 在冠状动脉平滑肌细胞中的作用，结果表明该蛋白质与关键钾通道（称为 BK）的蛋白质和 mRNA 相互作用，该钾通道对血管张力和心脏血流很重要。在缺乏 Sorbs2 的小鼠中，动脉 BK 表达水平和功能减弱——这是在糖尿病血管病变中观察到的现象。鉴于这种相似性，研究小组研究了 Sorbs2 在糖尿病小鼠中的可能作用。果然，与对照组相比，糖尿病动物的冠状动脉中其表达减少了 60%。研究小组继续表明，Sorbs2 的表达是由转录因子 Nrf 控制的，在糖尿病小鼠中也被下调。因此，结果表明糖尿病中 Nrf/Sorbs2/BK 的减少最终会导致冠状动脉疾病，而增强这一途径可能是一种预防策略。