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Staphylococcus aureus is one of the most commonly detected bacteria in diabetic skin and soft tissue infections. The incidence and severity of skin and soft tissue infections are higher in patients with diabetes, indicating a potentiating mechanism of hyperglycaemia and infection. The goal of this review is to explore the metabolic and virulence factor adaptations of S. aureus under hyperglycaemic conditions. Primary data from identified studies were included and summarised in this paper. Understanding the nexus of hyperglycaemia, metabolism, and virulence factors provides insights into the complexity of diabetic skin and soft tissue infections attributed to S. aureus., (© 2024 The Author(s). Wound Repair and Regeneration published by Wiley Periodicals LLC on behalf of The Wound Healing Society.)

Background: Recent studies suggest that gut microbiota composition, abundance and diversity can influence many chronic diseases such as type 2 diabetes. Modulating gut microbiota through targeted nutrition can provide beneficial effects leading to the concept of personalized nutrition for health improvement. In this prospective clinical trial, we evaluated the impact of a microbiome-based targeted personalized diet on hyperglycaemic and hyperlipidaemic individuals. Specifically, BugSpeaks ® -a microbiome profile test that profiles microbiota using next generation sequencing and provides personalized nutritional recommendation based on the individual microbiota profile was evaluated., Methods: A total of 30 participants with type 2 diabetes and hyperlipidaemia were recruited for this study. The microbiome profile of the 15 participants (test arm) was evaluated using whole genome shotgun metagenomics and personalized nutritional recommendations based on their microbiota profile were provided. The remaining 15 participants (control arm) were provided with diabetic nutritional guidance for 3 months. Clinical and anthropometric parameters such as HbA1c, systolic/diastolic pressure, c-reactive protein levels and microbiota composition were measured and compared during the study., Results: The test arm (microbiome-based nutrition) showed a statistically significant decrease in HbA1c level from 8.30 (95% confidence interval (CI), [7.74-8.85]) to 6.67 (95% CI [6.2-7.05]), p < 0.001 after 90 days. The test arm also showed a 5% decline in the systolic pressure whereas the control arm showed a 7% increase. Incidentally, a sub-cohort of the test arm of patients with >130 mm Hg systolic pressure showed a statistically significant decrease of systolic pressure by 14%. Interestingly, CRP level was also found to drop by 19.5%. Alpha diversity measures showed a significant increase in Shannon diversity measure ( p < 0.05), after the microbiome-based personalized dietary intervention. The intervention led to a minimum two-fold (Log2 fold change increase in species like Phascolarctobacterium succinatutens, Bifidobacterium angulatum, and Levilactobacillus brevis which might have a beneficial role in the current context and a similar decrease in species like Alistipes finegoldii, and Sutterella faecalis which have been earlier shown to have some negative effects in the host. Overall, the study indicated a net positive impact of the microbiota based personalized dietary regime on the gut microbiome and correlated clinical parameters., Competing Interests: Gopalakrishna Kallapura, Anthony Surya Prakash, Kumar Sankaran, Prabhath Manjappa and Debojyoti Dhar are employed by Leucine Rich Bio Pvt Ltd and Sanjay Ambhore by Shreya Clinic., (© 2024 Kallapura et al.)

Postprandial hyperglycaemia is associated with increased risk of cardiovascular disease. Recent studies highlight the role of the gut microbiome in influencing postprandial glycaemic (PPG) and lipidaemic (PPL) responses. The authors of this review sought to address the question: "To what extent does individual gut microbiome diversity and composition contribute to PPG and PPL responses?". CINAHL Plus, PubMed, Web of Science, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched from January 2010 to June 2020. Following screening, 22 studies were eligible to be included in the current review. All trials reported analysis of gut microbiome diversity and composition and PPG and/or PPL. Results were reported according to the 'Preferred Reporting Items for Systematic Reviews and Meta-Analysis' (PRISMA) statement. Individual microbiota structure was found to play a key role in determining postprandial metabolic responses in adults and is attributed to a complex interplay of diet, microbiota composition, and metagenomic activity, which may be predicted by metagenomic analysis. Alterations of gut microbiota, namely relative abundance of bacterial phylum Actinobacteria and Proteobacteria, along with Enterobacteriaceae, were associated with individual variation in postprandial glycaemic response in adults. The findings of the current review present new evidence to support a personalised approach to nutritional recommendations and guidance for optimal health, management, and treatment of common metabolic disorders. In conclusion, personalised nutrition approaches based on individual microbial composition may improve postprandial regulation of glucose and lipids, providing a potential strategy to ameliorate cardiometabolic health outcomes.

Existing evidence revealed grave prognosis for cryptococcal meningitis (CM), particularly its short-term mortality. However, its long-term survival and prognostic factors remained unknown. This study investigated 3-year mortality and analyzed its predictive factors in patients with CM. This retrospective cohort study with 83 cerebrospinal fluid culture-confirmed CM patients was conducted at China Medical University Hospital from 2003 to 2016. The 3-year mortality rate in patients with CM was 54% (45 deaths among 83 patients). Advanced age, human immunodeficiency virus (HIV) seronegative state, low Glasgow Coma Scale score on admission, decreased hemoglobin and hyperglycemia on diagnosis were associated with 3-year mortality. After multivariate adjustment in the Cox proportional hazard model, only severe hyperglycemia (serum glucose ≥200 mg/dL) on diagnosis could predict 3-year mortality., Competing Interests: The authors have declared that no competing interests exist.

Background: Our previous clinical research showed that the interaction between gut microbiota and bile acids (BAs) in patients with type 2 diabetes mellitus (T2DM) changed significantly. We hypothesized that T2DM could be improved by adjusting this interaction mediated by farnesoid X receptor (FXR). T2DM belongs to the category of "xiaoke" in traditional Chinese medicine. Radix scutellariae has the effects of clearing away heat and eliminating dampness, curing jaundice and quenching thirst and is widely used alone or in combination with other medicines for the treatment of T2DM in China and throughout Asia. Additionally, the interaction between Radix scutellariae and gut microbiota may influence its efficacy in the treatment of T2DM., Purpose: This study chose Radix scutellariae to validate that T2DM could improve by adjusting the interaction between gut microbiota and bile acid metabolism., Study Design and Methods: Radix scutellariae water extract (WESB) was administered to a T2DM rat model established by a high-fat diet combined with streptozotocin. The body weight and blood glucose and insulin levels were measured. The levels of serum lipids, creatinine, uric acid, albumin and total bile acid were also detected. Changes in the pathology and histology of the pancreas, liver and kidney were observed by haematoxylin-eosin staining. The 16S rRNAs of gut microbiota were sequenced, and the faecal and serum BAs were determined by liquid chromatography tandem mass spectrometry. The expression levels of BA metabolism-associated proteins in the liver and intestine were evaluated by immunoblot analysis., Results: The results showed that WESB improved hyperglycaemia, hyperlipaemia, and liver and kidney damage in T2DM rats. In addition, the abundances of key gut microbiota and the concentrations of certain secondary BAs in faeces and serum were restored. Moreover, there was a significant correlation between the restored gut microbiota and BAs, which might be related to the activation of liver cholesterol 7α-hydroxylase (CYP7A1) and the inhibition of FXR expression in the intestine rather than the liver., Conclusions: This study provided new ideas for the prevention or treatment of clinical diabetes and its complications by adjusting the interaction between gut microbiota and bile acid metabolism., (Copyright © 2021. Published by Elsevier GmbH.)

An array of chronic inflammatory diseases, including metabolic diseases such as obesity and diabetes, are thought to be promoted by disturbance of the intestinal microbiota. Such diseases disproportionately impact low-income communities, which are frequently afflicted by chronic stress and increased density housing. Hence, we hypothesized that overcrowded housing might promote stress, microbiota dysbiosis, inflammation, and, consequently, metabolic diseases. We tested this hypothesis in a tractable murine model of social overcrowding (SOC), in which mice were housed at twice normal density. SOC moderately impacted behavior in some widely used assays (Open Field, Elevated Plus Maze and Light/Dark tests) and resulted in a stark increase in corticosterone levels. Such indices of stress were associated with mild chronic gut inflammation, hyperglycemia, elevations in colonic cytokines, and alterations in gut microbiota composition. All of these consequences of SOC were eliminated by broad spectrum antibiotics, while some (inflammation and hyperglycemia) were transmitted by microbiota transplantation from SOC mice to germfree mice housed at normal density. Altogether, these results suggest a central role for intestinal microbiota in driving stress, inflammation, and chronic diseases that are promoted by overcrowded housing.

Shifts in the maternal gut microbiota have been implicated in the development of gestational diabetes mellitus (GDM). Understanding the interaction between gut microbiota and host glucose metabolism will provide a new target of prediction and treatment. In this nested case-control study, we aimed to investigate the causal effects of gut microbiota from GDM patients on the glucose metabolism of germ-free (GF) mice. Stool and peripheral blood samples, as well as clinical information, were collected from 45 GDM patients and 45 healthy controls (matched by age and prepregnancy body mass index (BMI)) in the first and second trimester. Gut microbiota profiles were explored by next-generation sequencing of the 16S rRNA gene, and inflammatory factors in peripheral blood were analyzed by enzyme-linked immunosorbent assay. Fecal samples from GDM and non-GDM donors were transferred to GF mice. The gut microbiota of women with GDM showed reduced richness, specifically decreased Bacteroides and Akkermansia, as well as increased Faecalibacterium. The relative abundance of Akkermansia was negatively associated with blood glucose levels, and the relative abundance of Faecalibacterium was positively related to inflammatory factor concentrations. The transfer of fecal microbiota from GDM and non-GDM donors to GF mice resulted in different gut microbiota colonization patterns, and hyperglycemia was induced in mice that received GDM donor microbiota. These results suggested that the shifting pattern of gut microbiota in GDM patients contributed to disease pathogenesis.

Blueberry dietary interventions have demonstrated remarkable potential against obesity and type 2 diabetes mellitus. However, the effects of fermented blueberry juice on metabolic syndrome, the gut microbiota, and insulin resistance have not yet been reported. This study aimed to investigate the potential of fermented blueberry juice against obesity, hyperglycemia, and gut microbiota dysbiosis in high fat diet (HFD)-fed mice. Our study findings revealed that supplementation with fresh blueberry juice (BBJ), and fermented blueberry juice with homemade probiotic starter (FBJ) or commercial starter (CFBJ) significantly decreased fat accumulation and low density lipoprotein cholesterol (LDL-C) levels in HFD-fed mice. FBJ showed relatively more potency to reduce body weight than BBJ and CFBJ. The percentage increase in the body weight of the FBJ group was almost the same as that in the normal chow diet (NCD) group, and was approximately 10% lower than the BBJ and CFBJ groups. Overall, all blueberry juices significantly ameliorated hyperlipidemia and insulin resistance in HFD-fed mice. Moreover, the dietary interventions with BBJ, FBJ, and CFBJ for 17 weeks significantly improved the community richness and diversity of the gut microflora along with an altered structure in the HFD-fed mice group. The FBJ treated mice group showed relatively low abundance of Firmicutes, obesity-related bacteria (Oscillibacter and Alistipes), and high abundance of lean bacteria (Akkermansia, Barnesiella, Olsenella, Bifidobacterium, and Lactobacillus) compared to the HFD-fed mice group. Furthermore, BBJ and FBJ treatments regulated the liver mRNA and protein expression levels involved in lipid and glucose metabolism. This study inferred that fermented blueberry juice could be used as a functional food to prevent the modern pandemics i.e., obesity and insulin resistance.

Diabetes Mellitus (DM) is an inflammatory clinical entity with different mechanisms involved in its physiopathology. Among these, the dysfunction of the gut microbiota stands out. Currently, it is understood that lipid products derived from the gut microbiota are capable of interacting with cells from the immune system and have an immunomodulatory effect. In the presence of dysbiosis, the concentration of lipopolysaccharides (LPS) increases, favoring damage to the intestinal barrier. Furthermore, a pro-inflammatory environment prevails, and a state of insulin resistance and hyperglycemia is present. Conversely, during eubiosis, the production of short-chain fatty acids (SCFA) is fundamental for the maintenance of the integrity of the intestinal barrier as well as for immunogenic tolerance and appetite/satiety perception, leading to a protective effect. Additionally, it has been demonstrated that alterations or dysregulation of the gut microbiota can be reversed by modifying the eating habits of the patients or with the administration of prebiotics, probiotics, and symbiotics. Similarly, different studies have demonstrated that drugs like Metformin are capable of modifying the composition of the gut microbiota, promoting changes in the biosynthesis of LPS, and the metabolism of SCFA., Competing Interests: Proopiomelanocortin

Aspergillus fumigatus is one of the most common fungal infections involved in the pulmonary diseases. Hypoxia-inducible factor-1α (HIF-1α) is important for antifungal immunity. Diabetes is a risk factor of pulmonary A. fumigatus infection and could affect the expression of HIF-1α. The aim of this investigation was to evaluate the role of HIF-1α in pulmonary A. fumigatus infection in diabetes. In murine model, we found diabetic mice had aggravated pulmonary A. fumigatus infection and declined expression of HIF-1α following pulmonary A. fumigatus infection. And these changes could be corrected by dimethyloxalylglycine (DMOG), the agonist of HIF-1α. In cell experiment, after A. fumigatus stimulation, hyperglycemic state was with a decreased HIF-1α expression and increased NLRP3/IL-1β signal pathway. The percentages of Th1 and Treg cells decreased, while percentages of Th2 and Th17 increased in hyperglycemic group. DMOG suppressed A. fumigatus-stimulated NLRP3 and IL-1β expressions in hyperglycemic group and corrected Th and Treg cells differentiation. These regulatory effects of DMOG could be dampened by activating of NLRP3. These data indicated that hyperglycemia suppressed the regulatory effect of HIF-1α in pulmonary A. fumigatus infection, which can affect Th and Treg cells differentiation by regulating the NLRP3/IL-1β signal pathway., (© FEMS 2020.)

Background: Recent studies suggest that there is a link between the gut microbiota and glucose metabolism. This study aimed to compare the gut microbiota during early pregnancy of women with hyperglycymia to those with normal blood glucose., Methods: Gut microbial composition was analysed in 22 women with hyperglycaemia and 28 age-matched healthy controls during their first prenatal visits (< 20 weeks) using high throughput sequencing of the V3-V4 region of the 16S ribosomal RNA gene. Hyperglycemia was diagnosed based on the criteria recommended by the International Association of Diabetes and Pregnancy Study Groups in 2010., Results: Women with hyperglycemia in pregnancy (HIP) had significantly lower microbial richness and diversity compared with healthy pregnant women. The proportions of the Firmicutes and Bacteroidetes phyla and the ratio of Firmicutes:Bacteroidetes were not different between the two groups. We observed that individuals with HIP had an increased abundance of Nocardiaceae, Fusobacteriaceae, etc., whereas healthy controls had significantly higher levels of Christensenellaceae, Clostridiales&#95;vadinBB60&#95;group, Coriobacteriaceae, etc. Similarly, levels of the members of the Ruminococcaceae family, including Ruminococcaceae&#95;UCG-014, Ruminococcaceae&#95;UCG-003, and Ruminococcaceae&#95;UCG-002, were significantly reduced in the HIP group and were negatively correlated with HbA1c. HbA1c levels were positively correlated with Bacteroidaceae and Enterobacteriaceae and negatively correlated with Christensenellaceae, etc. CRP was positively correlated with the Bacteroidaceae and Fusobacteriaceae families and the Fusobacterium genus., Conclusions: Our study revealed that individuals with HIP have gut microbial dysbiosis and that certain bacterial groups are associated with glucose metabolism during pregnancy. Further study is needed to provide new ideas to control glucose by modifying the gut microbiota.

Whole-grain dietary fiber intake is beneficial in the prevention of metabolic syndrome. Considering rich in bound phenolics being a special characteristic of whole-grain dietary fiber, the aim of this study was to evaluate the effects of the presence or absence of bound phenolics in rice bran dietary fiber (RBDF) on regulating glucose metabolism in diabetic db / db mice. In comparison to phenolics-removed RBDF (PR-RBDF) intervention without an antihyperglycemic effect, RBDF and formulated RBDF (F-RBDF, obtained by mixing PR-RBDF and hydrolyzed-bound phenolics) significantly reduced fasting blood glucose levels after 1 and 5 weeks of interventions, respectively. The presence of bound phenolics interventions could activate the IRS1/AKT/GLUT4 insulin signaling pathway in skeletal muscle and alter gut microbiota by modulating gut microbiota dysbiosis and enriching the butyric-acid-producing bacteria genera of the families Lachnospiraceae and Ruminococcaceae, thus leading to the reduction of blood glucose levels. These findings indicate that bound phenolics ensure the antihyperglycemic effect of RBDF.

The impairment of podocyte protein filtration function caused by excessive mitochondrial calcium intake is a critical feature of diabetic nephropathy (DN). Ca 2+ channel transient receptor potential cation channel subfamily V member 1 (TRPV1) has been reported to protect against ischemia-reperfusion induced acute renal injury, but there is no report about its role in DN. Here, we report that dietary capsaicin potently inhibits and reverses chronic renal structural and functional damages in db/db or streptozotocin (STZ)-induced diabetic mice in a TRPV1-dependent manner. Activation of TRPV1 by capsaicin alleviated hyperglycemia-induced mitochondrial dysfunction in podocytes, accompanied by reduced mitochondria-associated membranes (MAMs) formation and fewer Ca 2+ transport from endoplasmic reticulum (ER) to mitochondria. Mechanistically, TRPV1-mediated transient Ca 2+ influx activated 5' AMP-activated protein kinase (AMPK) that reduced the transcription of Fundc1, a key molecule participating in MAMs formation. Inhibition of AMPK or overexpression of Fundc1 obviously blocked the inhibitory effect of capsaicin on MAMs formation and functional decline in podocytes. These findings emphasize the critical role of mitochondrial Ca 2+ homeostasis in the maintenance of normal renal function and suggest an effective intervention method to counteract DN., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Oral microbes are a contributing factor to hyperglycemia by inducing an increase in insulin resistance resulting in uncontrolled blood glucose levels. However, the relationship between the distribution of oral flora and hyperglycemia is still controversial. Combining the power of MALDI-Biotyper with anaerobic bacterial culture, this study explores the correlation between anaerobic bacteria in the oral cavity and blood glucose levels. The results demonstrated that altered blood glucose levels contributed to a varied bacterial distribution in the oral cavity. Specifically, Veillonella spp. and Prevotella spp. were identified in a higher proportion in people with elevated blood glucose levels. Six bacterial species identified in this study (Prevotella melaninogenica, Campylobacter rectus, Streptococcus gordonii, Streptococcus mitis, Streptococcus salivarius, and Veillonella parvula) not only demonstrated a positive association with higher blood glucose levels, but also likely contribute to the development of the condition. The data demonstrated MALDI-TOF MS to be a simpler, faster, and more economical clinical identification tool that provides clarity and depth to the research on blood glucose and oral microbiota., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Resistance to therapy is one of the major factors that contribute to dismal survival statistics in pancreatic cancer. While there are many tumor intrinsic and tumor microenvironment driven factors that contribute to therapy resistance, whether pre-existing metabolic diseases like type 2 diabetes (T2D) contribute to this has remained understudied. It is well accepted that hyperglycemia associated with type 2 diabetes changes the gut microbiome. Further, hyperglycemia also enriches for a "stem-like" population within the tumor. In the current study, we observed that in a T2D mouse model, the microbiome changed significantly as the hyperglycemia developed in these animals. Our results further showed that, tumors implanted in the T2D mice responded poorly to gemcitabine/paclitaxel (Gem/Pac) standard of care compared to those in the control group. A metabolomic reconstruction of the WGS of the gut microbiota further revealed that an enrichment of bacterial population involved in drug metabolism in the T2D group. Additionally, we also observed an increase in the CD133+ tumor cells population in the T2D model. These observations indicated that in an animal model for T2D, microbial dysbiosis is associated with increased resistance to chemotherapeutic compounds.

Background: Diabetes mellitus (DM) is thought to affect tuberculosis (TB) clinical presentation and treatment response. Whether DM impacts radiological manifestations of pulmonary TB is still not clear. This study investigated the impact of glycemic status on radiological manifestations of pulmonary TB cases and its relationship with concentration of biochemical parameters in peripheral blood., Methods: A retrospective cross-sectional study used data from 132 microbiologically confirmed pulmonary TB patients from Lima, Peru, evaluated in a previous investigation performed between February and December 2017. Chest radiographs were analyzed by a radiologist and a pulmonologist. Radiographic lesions were identified as cavities, alveolar infiltrates and fibrous tracts. Hyperglycemia in TB patients was identified by use of fasting plasma glucose, HbA1c and oral glucose tolerance test. Clinical, biochemical and hematological parameters were also analyzed., Results: TB patients with hyperglycemia presented more frequently with cavities, alveolar infiltrates and fibrous tracts than those with normoglycemia. Hierarchical clustering analysis indicated that patients with more diverse and higher number of lung lesions exhibited a distinct laboratorial profile characterized by heightened white blood cell counts and circulating levels of total cholesterol, triglycerides and transaminases and simultaneously low levels of albumin and hemoglobin. Multivariable regression analyses adjusted for age, sex, prior TB, hemoglobin levels and acid-fast bacilli ≥2+ in sputum smears, demonstrated that presence of prediabetes or diabetes in TB patients was associated with increased odds of having 3 pulmonary lesion types (p = 0.003 and p < 0.01 respectively) or ≥ 4 lesions (p = 0.001 and p = 0.01 respectively)., Conclusion: Hyperglycemia (both DM and prediabetes) significantly affected the presentation of radiographic manifestations and the number of lesions in pulmonary TB patients as well as the biochemical profile in peripheral blood.

This study was aimed at investigating the hypoglycemic and hypolipidemic effects of a polysaccharide (RTFP) isolated from Rosa roxburghii Tratt fruit on type-2 diabetic db/db mice. The results indicated that the oral administration of RTFP could significantly decrease the body weight, fat, and liver hypertrophy and the levels of fasting blood glucose, serum insulin, and serum lipids of the db/db mice. Histopathological observation showed that RTFP could effectively protect the pancreas, liver, and epididymal fat against damage and dysfunction. Real-time quantitative polymerase chain reaction analysis confirmed that the gene expression levels of peroxisome proliferator-activated receptors-γ ( PPAR-γ ), sterol regulatory element-binding protein-1 ( SREBP-1c ), acetyl-CoA carboxylase-1 ( ACC-1 ), fatty acid synthase ( FAS ), and glucose-6-phosphatase ( G6 Pase ) were significantly down-regulated in the liver of db/db mice after treatment with RTFP. Moreover, RTFP treatment reversed gut dysbiosis by lowering the Firmicutes -to- Bacteroidetes ratio and enhancing the relative abundances of beneficial bacteria including Bacteroidaceae , Bacteroidaceae S24-7 group, and Lactobacillaceae . These findings suggest that RTFP can be used as a promising functional supplement for the prevention and treatment of type-2 diabetes mellitus.

Metformin beneficially impacts several aspects of metabolic syndrome including dysglycemia, obesity, and liver dysfunction, thus making it a widely used frontline treatment for early-stage type 2 diabetes, which is associated with these disorders. Several mechanisms of action for metformin have been proposed, including that it acts as an anti-inflammatory agent, possibly as a result of its impact on intestinal microbiota. In accord with this possibility, we observed herein that, in mice with diet-induced metabolic syndrome, metformin impacts the gut microbiota by preventing its encroachment upon the host, a feature of metabolic syndrome in mice and humans. However, the ability of metformin to beneficially impact metabolic syndrome in mice was not markedly altered by reduction or elimination of gut microbiota, achieved by the use of antibiotics or germfree mice. Although reducing or eliminating microbiota by itself suppressed diet-induced dysglycemia, other features of metabolic syndrome including obesity, hepatic steatosis, and low-grade inflammation remained suppressed by metformin in the presence or absence of gut microbiota. These results support a role for anti-inflammatory activity of metformin, irrespective of gut microbiota, in driving some of the beneficial impacts of this drug on metabolic syndrome.

Purpose: Accumulated evidence has indicated that the gut microbiome affected the pharmacology of anti-diabetic agents, and their metabolic products induced by the agents transformed the structure of gastrointestinal microbiota in return. However, the studies around heredity, ethnicity, or living condition, referring to human microbiome were mostly represented by an occidental pattern partial and rare studies that focused on the effect of several first-line hypoglycemic agents on the gut flora in a single medical center. Therefore, we aimed to explore the interaction between gut microbiome and type 2 diabetes (T2D) or hypoglycemics in Chinese population., Methods: A total of 130 T2D patients with a specific hypoglycemic treatment and 50 healthy volunteers were enrolled in this study. Gut microbiome compositons were analyzed by 16S ribosomal RNA gene-based sequencing protocol., Results: Hypoglycemic agents contributed to the alteration of specific species in gut bacteria rather than its total diversity. Metformin increased the abundance of Spirochaete, Turicibacter, and Fusobacterium. Insulin also increased Fusobacterium, and α-glucosidase inhibitors (α-GIs) contributed to the plentitude of Bifidobacterium and Lactobacillus. Both metformin and insulin improved taurine and hypotaurine metabolism, and α-GI promoted several amino acid pathways. Although the community of gut microbiota with metformin and insulin showed similarity, significant differences were available in each diabetic group with hypoglycemia., Conclusions: Gut microbiota is significantly associated with anti-diabetic agents. The gut microbiome and metabolism have shown respective characteristics in different T2D groups, which were also significantly different from the healthy group. This study provides some new insights for identification and exploration of the pathogenesis of T2D.

Diabetes mellitus, a metabolic disease characterized by hyperglycemia and poor glucose control, is a risk factor for Mycobacterium tuberculosis ( M. tuberculosis ) infection and the development of active tuberculosis. To evaluate whether M. tuberculosis infection susceptibility is associated with an intrinsic factor in monocytes from type 2 diabetes (T2D) patients or it is associated with hyperglycemia per se , we analyzed TLR-2 and TLR-4 expression by flow cytometry and the cytokines IL-1 β , IL-6, IL-8, IL-10, and TNF- α by cytometric bead array assays, either stimulated with TLR-2 and TLR-4 ligands or infected with M. tuberculosis in the whole blood from T2D patients ( n = 43) and healthy subjects ( n = 26) or in CD14+ monocytes from healthy subjects cultured in high glucose (HG) (30 mM). The intracellular growth of M. tuberculosis was evaluated by CFU counts at 0, 1, and 3 days in both monocytes from T2D patients and monocytes from healthy subjects cultured in HG. We did not find significant differences in TLR expression, cytokine production, or growth of M. tuberculosis in monocytes from T2D patients compared with those in monocytes from healthy subjects. Despite these results, in vitro assays of monocytes cultured with 30 mM glucose led to significantly increased TLR-2 and TLR-4 basal expression compared to those of monocytes cultured with 11 mM glucose ( P < 0.05). Conversely, the production of IL-6 by TLR-2 ligand stimulation, of IL-1 β , IL-6, and IL-8 by TLR-4 ligand stimulation, and of IL-8 by M. tuberculosis infection significantly decreased in monocytes cultured in HG ( P < 0.05). Additionally, the intracellular survival of M. tuberculosis increased in monocytes in HG after day 3 of culture ( P < 0.05). In conclusion, HG decreased IL-8 production and the intracellular growth control of M. tuberculosis by monocytes, supporting the hypothesis that hyperglycemia plays an important role in the impaired immune responses to M. tuberculosis in patients with T2D., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this article., (Copyright © 2019 Martha Torres et al.)

Brown macroalgae are an important source of polyphenols with multiple health functions. In this work, polyphenol extracts from Lessonia trabeculate were purified and investigated for the antidiabetic activity in vitro and in vivo. The purified polyphenol extracts exhibited good antioxidant activities, α-glucosidase and lipase inhibition activities (IC 50 < 0.25 mg/mL). The HPLC-DAD-ESI-MS/MS analysis indicated that the compounds in polyphenol extracts were mainly phlorotannin derivatives, phenolic acid derivatives, and gallocatechin derivatives. In vivo, C57BL/6J rats treated with polyphenol extracts for 4 weeks had lower fasting blood glucose levels, insulin levels, as well as better serum lipid profiles and antioxidant stress parameters, compared with the diabetic control (DC) group. Histopathology revealed that polyphenol extracts preserved the architecture and function of the liver. Short-chain fatty acid contents in rats' fecal samples with polyphenols administration were significantly recovered as compared with the DC group. Furthermore, the gut microflora of rats was investigated with high-throughput 16S rRNA gene sequencing and results indicated that polyphenol extracts had a positive effect on regulating the dysbiosis of the microbial ecology in diabetic rats. All of the results from the study provided a scientific reference of the potentially beneficial effects of L. trabeculate polyphenols on diabetes management.

The polyphenols resveratrol (RSV) and curcumin (Cur) are phytoalexines and natural antibiotics with numerous pharmacological functions and metabolic impacts. Recent evidences show a broad control of gut microbiota by polyphenols which could influence glycemic regulation. The aim of this work is to estimate the respective effect of RSV and Cur alone or in association on the control of glycemia and on gut microbiota. A 5-week chronic treatment of hyperglycemic mice with RSV and/or Cur resulted in a differential effect on glucose tolerance test and modified gut microbiome. We precisely identified groups of bacteria representing a specific signature of the glycemic effect of RSV. Inferred metagenomic analysis and metabolic pathway prediction showed that the sulfur and branched-chain amino-acid (BCAA) metabolic activities are tightly correlated with the efficacy of RSV for the control of glycaemia. The impact on BCAA metabolism was further validated by serum metabolomics analysis. Altogether, we show that polyphenols specifically impact gut microbiota and corresponding metabolic functions which could be responsible for their therapeutic role., (Copyright © 2019. Published by Elsevier Inc.)

Background: The prevalence of obesity has raised global concerns. Environmental pollutants are one of the main causes of obesity. Many studies have demonstrated that dietary fiber could reduce obesity induced by high-fat diets, but whether environmental pollutant-induced obesity can be reversed is still unknown., Objectives: This study aimed to investigate the effects of pectin on obesity induced by a typical environmental pollutant p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) and explore the underlying mechanism by which pectin reversed p,p'-DDE-induced obesity., Methods: p,p'-DDE was used to induce obesity in C57BL/6J mice and pectin was supplied during and after cessation of p,p'-DDE exposure. Body and fat weight gain, plasma lipid profile and insulin resistance of mice were assessed. Gut microbiota composition and the levels of short-chain fatty acids (SCFAs) as well as the receptor proteins and hormones in the SCFAs-related signaling pathway were analyzed. Moreover, p,p'-DDE levels in various tissues of mice were detected., Results: Pectin supplementation reversed body and fat weight gain, dyslipidemia, hyperglycemia and insulin resistance in p,p'-DDE-exposed mice. Furthermore, pectin apparently altered the p,p'-DDE-induced microbial composition and then promoted the levels of SCFAs in colonic feces as well as the expression of G-protein coupled receptors and the concentration of hormone peptide YY (PYY) and glucagon like peptide-1 (GLP-1). Pectin treatment also significantly reduced p,p'-DDE accumulation in mice tissues during p,p'-DDE exposure but did not change p,p'-DDE metabolism after termination of p,p'-DDE exposure., Conclusions: Pectin had a good effect on reducing p,p'-DDE-induced obesity through regulating gut microbiota and provided a potential strategy for the treatment of environmental pollutant-caused health problems., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Ice plant (Mesembryanthemum crystallinum) extract (IPE) is a rich source of d-pinitol, which is widely known to have potential anti-diabetic effects. In the present study, response surface methodology (RSM) was used to optimize d-pinitol extraction conditions with the Box-Behnken design. We then evaluated the anti-diabetic effects properties of IPE that was extracted under optimized conditions (53 °C, 119 min extraction time, and 1 : 11 dilution) in type 2 diabetic Goto-Kakizaki (GK) rats. IPE (400 mg kg-1 day-1) effectively controlled the increased fasting blood glucose level (decreased by 45% vs. GK-control rats) and impaired glucose tolerance (decreased area under curve (AUC) of glucose values by 24%, p < 0.05 vs. GK-control rats) after eight weeks of treatment. Furthermore, IPE significantly improved pancreatic islet morphology, β-cell survival, and insulin secretion in diabetic rats, thus contributing to the antihyperglycemic effect. Finally, prebiotic effects of IPE on gut microbiota were observed and included increased abundance of the beneficial bacteria Bacteroidales&#95;S24-7 and Ruminococcaceae&#95;UCG-014 and decreased abundance of Treponema&#95;2 and Lactobacillus. Overall, IPE has a substantial effect on attenuating hyperglycemia and modulating gut microbiota composition in diabetic GK rats. Therefore, IPE might be a promising functional food for the prevention of diabetes.

Hyperglycemia caused by excessive intake of sucrose leads to lifestyle-related diseases such as diabetes. Administration of a lactic acid bacterial strain to mice suppresses sucrose-induced hyperglycemia, but evidence for a similar effect in humans is lacking. Here we show that Enterococcus faecalis YM0831, identified using an in vivo screening system with silkworms, suppressed sucrose-induced hyperglycemia in humans. E. faecalis YM0831 also suppressed glucose-induced hyperglycemia in silkworms. E. faecalis YM0831 inhibited glucose uptake by the human intestinal epithelial cell line Caco-2. A transposon insertion mutant of E. faecalis YM0831, which showed decreased inhibitory activity against glucose uptake by Caco-2 cells, also exhibited decreased inhibitory activity against both sucrose-induced and glucose-induced hyperglycemia in silkworms. In human clinical trials, oral ingestion of E. faecalis YM0831 suppressed the increase in blood glucose in a sucrose tolerance test. These findings suggest that E. faecalis YM0831 inhibits intestinal glucose transport and suppresses sucrose-induced hyperglycemia in humans., Competing Interests: Y.M. and K.S. are inventors on patent PCT/JP2016/79218, which has been filed as a method using the silkworm system for identifying lactic acid bacteria that may suppress sucrose-induced hyperglycemia. S.H. is representative director of Pharmaspur Inc. (Tokyo, Japan). K.S. has an advisory role in Genome Pharmaceuticals Institute Co., Ltd (Tokyo, Japan). M.I. declares no competing interests.

Background: Type 2 diabetes mellitus (T2DM) is related to the gut microbiota with numerous molecular mechanisms. Modulating the gut microbiota by probiotics could be effective in management of T2DM. The aim of the present trial was to evaluate the effect of Lactobacillus casei on glycemic control and serum sirtuin1 (SIRT1) and fetuin-A in patients with T2DM., Methods: Forty patients with T2DM (n = 20 for each group) were divided into intervention (probiotic) and placebo groups. The intervention group received a daily capsule containing 108 cfu of L. casei for eight weeks. The patients in placebo group took capsules containing maltodextrin for the same time duration. Anthropometric measurements, dietary intake questionnaires, and blood samples were collected, and the patients were assessed by an endocrinologist at the beginning and at the end of the trial., Results: Fasting blood sugar, insulin concentration, and insulin resistance significantly decreased in probiotic group compared with placebo group (-28.32 [-50.23 to -6.41], 0.013; -3.12 [-5.90 to -0.35], 0.028; -32.31 [-55.09 to -9.54], 0.007, respectively). Moreover, HbA1c reduced after intervention, but the reduction was not significant (-0.45 [-0.96 to 0.05], 0.077). In comparison with placebo, the L. casei supplementation significantly increased SIRT1 and decreased fetuin-A levels at the end of the trial (0.52 [0.026 to 1.02], 0.040; -17.56 [-32.54 to -2.58], 0.023, respectively)., Conclusion: L. casei supplementation affected SIRT1 and fetuin-A levels in a way that improved glycemic response in subjects with T2DM. Affecting the SIRT1 and fetuin-A levels introduces a new known mechanism of probiotic action in diabetes management.

The anti-hyperglycemic effect of metformin is believed to be caused by its direct action on signaling processes in hepatocytes, leading to lower hepatic gluconeogenesis. Recently, metformin was reported to alter the gut microbiota community in humans, suggesting that the hyperglycemia-lowering action of the drug could be the result of modulating the population of gut microbiota. However, the critical microbial signaling metabolites and the host targets associated with the metabolic benefits of metformin remained elusive. Here, we performed metagenomic and metabolomic analysis of samples from individuals with newly diagnosed type 2 diabetes (T2D) naively treated with metformin for 3 d, which revealed that Bacteroides fragilis was decreased and the bile acid glycoursodeoxycholic acid (GUDCA) was increased in the gut. These changes were accompanied by inhibition of intestinal farnesoid X receptor (FXR) signaling. We further found that high-fat-diet (HFD)-fed mice colonized with B. fragilis were predisposed to more severe glucose intolerance, and the metabolic benefits of metformin treatment on glucose intolerance were abrogated. GUDCA was further identified as an intestinal FXR antagonist that improved various metabolic endpoints in mice with established obesity. Thus, we conclude that metformin acts in part through a B. fragilis-GUDCA-intestinal FXR axis to improve metabolic dysfunction, including hyperglycemia.

Microbial contamination along with over expressions of matrix metalloproteinases 2 and 9 impairs wound healing in diabetic patients. Silver-based antimicrobial agents have been successfully used for treating non-healing chronic wounds associated with infection. However, topical application of silver-ion compounds impairs wound healing process. Thus, usage of biogenic silver nanoparticles appears as a new means to reduce the toxicity of silver compounds in the wound care system. Here, following our previous method, AgNPs was synthesized using the culture filtrate of Brevibacillus brevis KN8(2) then characterized by UV-visible spectrophotometry, TEM, SAED, XRD and DLS measurements. The antibacterial activity of AgNPs was evaluated against the most common wound infecting pathogens Pseudomonas aeruginosa and Staphylococcus aureus by well diffusion assay. Further, the wound healing efficacy of biogenic AgNPs was examined in streptozotocin-induced diabetic mice by measuring wound area closure, histopathology, mRNA and protein expressions of MMP-2, MMP-9. Our results demonstrates that besides antimicrobial activity, biogenic AgNPs decreased the mRNA and protein expression of MMP-2 and MMP-9 in wounded granulation tissues leads to early wound healing in diabetic mice. These findings revealed that biogenic AgNPs synthesized from B. brevis KN8(2) could be an effective therapeutic agent in the management of diabetic foot ulcer with/without infection., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Aims: To describe the incidence of and risk factors for postoperative infections and the correlation between postoperative hyperglycemia despite tight blood glucose control with infectious and other complications after contemporary cardiac surgery., Material and Methods: The study comprised 1356 consecutive adult patients who underwent cardiac surgery between January 2013 and December 2014 and were followed up for 6 months. Patients surviving the first 2 days were included in the analysis. Preoperative demographic information, medical history, procedural details, and the postoperative course were recorded. The target range for blood glucose levels was 4-7 mmol/L and repeated arterial blood samples were obtained during the intensive care unit stay. The associations of blood glucose levels during the first postoperative day and the occurrence of postoperative infections and other significant complications were analyzed., Results: Of the study cohort, 9.8% developed infectious complications which were classified as major surgical site infections in 2.2%, minor surgical site infections in 1.1%, lung infections in 2.0%, unclear fever or bacteremia in 0.3%, cannula or catheter related in 2.6%, multiple in 1.5%, and other in 0.2%. The incidence of deep sternal wound infection was 2.0%. Repeated hyperglycemia occurred in 39.7% of patients and was associated with increased rates of postoperative infections, 12.1% versus 8.2%, p = 0.019; stroke, 4.9% versus 1.5%, p < 0.001; and mortality, 6.1% versus 2.1%, p < 0.001, when compared to patients with single or no hyperglycemia., Conclusion: Every 10th patient develops infectious complications after cardiac surgery. Repeated hyperglycemia is associated with increased rates of infectious complications, stroke, and mortality.

Objective: To investigate the possible relationship between the gut microbiota and hyperlipidemia,hyperglycemia in middle-aged and elderly people in Chengdu., Methods: 51 of middle-aged and elderly people participated in this study. The concentration of blood glucose and lipid,and the other physiological parameters of the subjects were analyzed,and their fecal microbiota was also profiled by Illumina high-throughput sequencing technique., Results: The fecal microbiota in the middle-aged and elderly were mainly Firmicutes,Bacteroidetes,Proteobacteria,Fusobacteria,Actinobacteria,Verrucomicrobia. The diversity offecalmicrobiota was significantly lower in the subjects with higher blood glucose ( P <0.05),while it did not exhibited relationship with changes in blood lipids. At the bacterial phyla: Proteobacteria and Bacteroidetes were respectively significantly higher in middle-aged and elderly women with higher blood glucose ( P <0.05). At the bacterial genus: Faecalibacterium was significantly lower in the hyperglycemic subjects ( P <0.05),its abundance and blood glucose levels were negatively correlated ( r =⁻0.278, P =0.048); Prevotella and Paraprevotella were significantly lower in the high blood lipids group ( P <0.05),and both of them were negatively correlated with blood lipid levels ( r =⁻0.357, P =0.10; r =⁻0.365, P =0.008)., Conclusion: The fecal microbiota in the tested middle-aged and elderly subjects varied with blood glucose and blood lipid concentration. Intestinal microbes might posses close relationship with blood glucose and lipid metabolism in middle-aged and elderly people., (Copyright© by Editorial Board of Journal of Sichuan University (Medical Science Edition).)

Background: Non-digestible carbohydrates present in cereals such as fructans and arabinoxylans represent promising prebiotic nutrients to prevent the development of obesity and related metabolic disorders., Objective and Design: The aim of this study was to determine the corrective effects of wheat bran-derived arabinoxylan oligosaccharides in obese mice fed a western diet (WD). WD was given for 4 weeks before wheat bran extract (WBE) supplementation (5%) for an additional 4 weeks, whereas a control group received the standard diet., Results: Bifidogenic effect of WBE was evidenced by an induction of both Bifidobacterium animalis and Bifidobacterium pseudolongum in the caecal content. WBE supplementation normalised WD-induced fat-mass expansion, steatosis, hypercholesterolemia, hyperleptinemia, hyperglycemia and hyperinsulinemia reaching the values of control mice. The reduced glucose-dependent insulinotropic polypeptide (GIP) release observed in WD + WBE mice may be a protective mechanism in terms of reducing adipose tissue storage, hepatic steatosis and glucose homoeostasis., Conclusion: We found that WBE completely abolished WD-induced metabolic disorders. Those results might be useful to take into account nutritional advices to treat obesity and related metabolic disorders such as type 2 diabetes, hypercholesterolaemia and fatty liver diseases when obesity was already established.

Objective: To identify a causal mechanism responsible for the enhancement of insulin resistance and hyperglycaemia following periodontitis in mice fed a fat-enriched diet., Design: We set-up a unique animal model of periodontitis in C57Bl/6 female mice by infecting the periodontal tissue with specific and alive pathogens like Porphyromonas gingivalis ( Pg ), Fusobacterium nucleatum and Prevotella intermedia . The mice were then fed with a diabetogenic/non-obesogenic fat-enriched diet for up to 3 months. Alveolar bone loss, periodontal microbiota dysbiosis and features of glucose metabolism were quantified. Eventually, adoptive transfer of cervical (regional) and systemic immune cells was performed to demonstrate the causal role of the cervical immune system., Results: Periodontitis induced a periodontal microbiota dysbiosis without mainly affecting gut microbiota. The disease concomitantly impacted on the regional and systemic immune response impairing glucose metabolism. The transfer of cervical lymph-node cells from infected mice to naive recipients guarded against periodontitis-aggravated metabolic disease. A treatment with inactivated Pg prior to the periodontal infection induced specific antibodies against Pg and protected the mouse from periodontitis-induced dysmetabolism. Finally, a 1-month subcutaneous chronic infusion of low rates of lipopolysaccharides from Pg mimicked the impact of periodontitis on immune and metabolic parameters., Conclusions: We identified that insulin resistance in the high-fat fed mouse is enhanced by pathogen-induced periodontitis. This is caused by an adaptive immune response specifically directed against pathogens and associated with a periodontal dysbiosis., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Diabetic patients have higher risk of urinary tract infection (UTI). In the present study, we investigated the impact of glycemic control in diabetic patients on UTI prevalence, type of strains, and their antimicrobial drugs susceptibility. This study was conducted on urine samples from 722 adult diabetic patients from which 252 (35%) samples were positive for uropathogens. Most UTI cases occurred in the uncontrolled glycemic group (197 patients) versus 55 patients with controlled glycemia. Higher glycemic levels were measured in uncontrolled glycemia group (HbA1c = 8.3 ± 1.5 and 5.4 ± 0.4, resp., P < 0.0001). Females showed much higher prevalence of UTI than males in both glycemic groups (88.5% and 11.5%, resp., P < 0.0001). In the uncontrolled glycemia group 90.9% of the UTI cases happened at ages above 40 years and a clear correlation was obtained between patient age ranges and number of UTI cases (r = 0.94; P = 0.017), whereas in the group with controlled glycemia no trend was observed. Escherichia coli was the predominant uropathogen followed by Klebsiella pneumoniae and they were together involved in 76.2% of UTI cases. Those species were similarly present in both diabetic groups and displayed comparable antibiotic resistance pattern. These results highlight the importance of controlling glycemia in diabetic patients to reduce the UTI regardless of age and gender.

Glucose toxicity may play a crucial role in evoking neurologic complications of critical illness. We studied whether the neuropathological alterations in fatal human critical illness observed under hyperglycemia are present and can be attenuated by maintaining normoglycemia in a mouse model of prolonged sepsis induced by cecal ligation and puncture. Mice were randomized to moderate hyperglycemia (>8.3 mmol/L, n = 8) or normoglycemia (4.4-6.7 mmol/L, n = 8). After 5 days, hippocampus and frontal cortex from septic mice were compared with those from healthy controls (n = 8). Blood glucose was 7.8 ± 1.3 mmol/L in hyperglycemic and 6.1 ± 0.7 mmol/L in normoglycemic critically ill mice (P = 0.007). The percentage of damaged neurons was twofold higher in frontal cortex (P = 0.01) and hippocampus (P = 0.06) of hyperglycemic ill mice than that of healthy mice. In frontal cortex, neuronal damage was attenuated under normoglycemia (P = 0.04). Critical illness reduced astrocyte density and activation status fourfold in hippocampus (P ≤ 0.02), but not in frontal cortex, irrespective of glycemic control. Microglia were twofold to fourfold more abundant in both brain areas of hyperglycemic critically ill mice (P ≤ 0.002), but only in frontal cortex were they reduced in number with normoglycemia (P = 0.0008). The density of apoptotic cells and abundance of carbonylated proteins were significantly higher than normal in frontal cortex of hyperglycemic ill mice only (P = 0.05). In a mouse model of prolonged polymicrobial sepsis, remarkable neuropathological changes develop with neuronal damage, impaired astrocyte activation, increased microglia, apoptosis, and accumulation of carbonylated proteins. These changes were partially prevented or attenuated when hyperglycemia was prevented with insulin. Frontal cortex appeared more vulnerable to hyperglycemic insults than hippocampus.

Compared with other cancers, diabetes mellitus is more closely associated with hepatocellular carcinoma (HCC). However, whether hyperglycemia is associated with hepatic carcinogenesis remains uncertain. In this study, we investigate the effect of hyperglycemia on HCC development. Mice pretreated with 7,12-dimethylbenz (a) anthracene were divided into three feeding groups: normal diet (Control), high-starch diet (Starch), and high-fat diet (HFD) groups. In addition, an STZ group containing mice that were fed a normal diet and injected with streptozotosin to induce hyperglycemia was included. The STZ group demonstrated severe hyperglycemia, whereas the Starch group demonstrated mild hyperglycemia and insulin resistance. The HFD group demonstrated mild hyperglycemia and severe insulin resistance. Multiple HCC were macroscopically and histologically observed only in the HFD group. Hepatic steatosis was observed in the Starch and HFD groups, but levels of inflammatory cytokines, interleukin (IL)-6, tumor necrosis factor-α, and IL-1β, were elevated only in the HFD group. The composition of gut microbiota was similar between the Control and STZ groups. A significantly higher number of Clostridium cluster XI was detected in the feces of the HFD group than that of all other groups; it was not detectable in the Starch group. These data suggested that hyperglycemia had no effect on hepatic carcinogenesis. Different incidences of HCC between the Starch and HFD groups may be attributable to degree of insulin resistance, but diet-induced changes in gut microbiota including Clostridium cluster XI may have influenced hepatic carcinogenesis. In conclusion, in addition to the normalization of blood glucose levels, diabetics may need to control insulin resistance and diet contents to prevent HCC development., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Type 2 diabetes mellitus is an established risk factor for tuberculosis but the underlying mechanisms are largely unknown. We examined the effects of hyperglycaemia, a hallmark of diabetes, on the cytokine response to and macrophage infection with Mycobacterium tuberculosis. Increasing in vitro glucose concentrations from 5 to 25 mmol/L had marginal effects on cytokine production following stimulation of peripheral blood mononuclear cells (PBMCs) with M. tuberculosis lysate, LPS or Candida albicans, while 40 mmol/L glucose increased production of TNF-α, IL-1β, IL-6 and IL-10, but not of IFN-γ, IL-17A and IL-22. Macrophage differentiation under hyperglycaemic conditions of 25 mmol/L glucose was also associated with increased cytokine production upon stimulation with M. tuberculosis lysate and LPS but in infection experiments no differences in M. tuberculosis killing or outgrowth was observed. The phagocytic capacity of these hyperglycaemic macrophages also remained unaltered. The fact that only very high glucose concentrations were able to significantly influence cytokine production by macrophages suggests that hyperglycaemia alone cannot fully explain the increased susceptibility of diabetes mellitus patients to tuberculosis.

Dermatophytes are fungi responsible for causing superficial infections. In patients with diabetes mellitus (DM), dermatophytosis is usually more severe and recurrent. In the present study, we aimed to investigate the influence of short and long term hypoinsulinemia-hyperglycemia (HH) during experimental infection by Trichophyton mentagrophytes as well as alterations in the mononuclear phagocytes. Our results showed two distinct profiles of fungal outcome and immune response. Short term HH induced a discrete impaired proinflammatory response by peritoneal adherent cells (PAC) and a delayed fungal clearance. Moreover, long term HH mice showed low and persistent fungal load and a marked reduction in the production of TNF-α by PAC. Furthermore, while the inoculation of TM in non-HH mice triggered high influx of Gr1(+) monocytes into the peripheral blood, long term HH mice showed low percentage of these cells. Thus, our results demonstrate that the time of exposure of HH interferes with the TM infection outcome as well as the immunobiology of mononuclear phagocytes, including fresh monocyte recruitment from bone marrow and PAC activity.

In an experimental model of obesity and hyperglycemia in Drosophila melanogaster we studied the effect of diet modification and administration of metformin on systemic infection with Rhizopus, a common cause of mucormycosis in diabetic patients. Female Wt-type Drosophila flies were fed regular (RF) or high-fat diet (HFD; 30% coconut oil) food with or without metformin for 48 h and then injected with R. oryzae. Survival rates, glucose and triglyceride levels were compared between 1) normal-weight flies (RF), 2) obese flies (HFD), 3) obese flies fed with RF, 4) flies continuously fed on HFD + metformin, 5) flies fed on HFD + metformin, then transferred to RF, and 6) obese flies administered metformin after infection [corrected].Glucose levels were compared across groups of non-infected flies and across groups of infected flies. Survival was significantly decreased (P = 0.003) in obese flies, while post-infection glucose levels were significantly increased (P = 0.0001), compared to normal-weight flies. Diet and administration of metformin led to weight loss, normalized glucose levels during infection, and were associated with decreased mortality and tissue fungal burden. In conclusion, diet and metformin help control infection-associated hyperglycemia and improve survival in Drosophila flies with mucormycosis. Fly models of obesity bear intriguing similarities to the pathophysiology of insulin resistance and diabetes in humans, and can provide new insights into the pathogenesis and treatment of infections in obese and diabetic patients.

Background: Serum C-reactive protein (CRP) is elevated in both periodontitis and type 2 diabetes mellitus through inflammation. Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis have been found in periodontal pockets in patients with diabetes. This study examines effect modification by examining the extent to which the associations between periodontitis and hyperglycemia were different by levels of serum CRP and periodontal pathogens., Methods: Blood samples with plasma were evaluated for immunoglobulin G antibodies, CRP, and fasting glucose from 5,731 participants ≥ 20 years old receiving oral examinations and providing other health-related data from the National Health and Nutrition Examination Survey III. The study participants were classified into quartiles of probing depth (PD) and clinical attachment level (CAL). The first quartile was the reference. Logistic regression models with survey procedures were used to explore the roles of inflammation levels from serum CRP and periodontal pathogens on the relations with periodontitis, including PD, CAL, and hyperglycemia, and their joint associations with interaction terms., Results: Stronger associations between PD and diabetes existed in people having elevated CRP and titers for P. gingivalis; odds ratios comparing extreme quartiles of PD were 1.31 and 3.40 in the groups with low and high CRP, respectively, and 1.28 and 2.96 in groups with low and high titers for P. gingivalis, respectively. The joint association patterns were similar for CAL and diabetes., Conclusions: The strengths of association between periodontitis and diabetes were stronger in people having elevated serum CRP and P. gingivalis titers. This may suggest that chronic inflammatory conditions could increase the impact of periodontitis on hyperglycemic status.

The effects of increased colonic fermentation of dietary fibres (DF) on the net portal flux (NPF) of carbohydrate-derived metabolites (glucose, SCFA and, especially, butyrate), hormones (insulin, C-peptide, glucagon-like peptide 1 and glucose-dependent insulinotropic peptide) and NEFA were studied in a healthy catheterised pig model. A total of six pigs weighing 59 (SEM 1·6) kg were fitted with catheters in the mesenteric artery and in the portal and hepatic veins, and a flow probe around the portal vein, and included in a double 3 × 3 cross-over design with three daily feedings (at 09.00, 14.00 and 19.00 hours). Fasting and 5 h postprandial blood samples were collected after 7 d adaptation to each diet. The pigs were fed a low-DF Western-style control diet (WSD) and two high-DF diets (an arabinoxylan-enriched diet (AXD) and a resistant starch-enriched diet (RSD)). The NPF of insulin was lower (P= 0·04) in AXD-fed pigs (4·6 nmol/h) than in RSD-fed pigs (10·5 nmol/h), despite the lowest NPF of glucose being observed in RSD-fed pigs (203 mmol/h, P= 0·02). The NPF of total SCFA, acetate, propionate and butyrate were high, intermediate and low (P< 0·01) in AXD-, RSD- and WSD-fed pigs, respectively, with the largest relative increase being observed for butyrate in response to arabinoxylan supplementation. In conclusion, the RSD and AXD had different effects on the NPF of insulin and glucose, suggesting different impacts of arabinoxylan and resistant starch on human health.

Cystic fibrosis-related diabetes (CFRD) is the most common comorbidity associated with cystic fibrosis (CF), impacting more than half of patients over age 30. CFRD is clinically significant, portending accelerated decline in lung function, more frequent pulmonary exacerbations, and increased mortality. Despite the profound morbidity associated with CFRD, little is known about the underlying CFRD-related pulmonary pathology. Our aim was to develop a murine model of CFRD to explore the hypothesis that elevated glucose in CFRD is associated with reduced lung bacterial clearance. A diabetic phenotype was induced in gut-corrected CF transmembrane conductance regulator (CFTR) knockout mice (CFKO) and their CFTR-expressing wild-type littermates (WT) utilizing streptozotocin. Mice were subsequently challenged with an intratracheal inoculation of Pseudomonas aeruginosa (PAO1) (75 μl of 1-5 × 10(6) cfu/ml) for 18 h. Bronchoalveolar lavage fluid was collected for glucose concentration and cell counts. A portion of the lung was homogenized and cultured as a measure of the remaining viable PAO1 inoculum. Diabetic mice had increased airway glucose compared with nondiabetic mice. The ability to clear bacteria from the lung was significantly reduced in diabetic WT mice and control CFKO mice. Critically, bacterial clearance by diabetic CFKO mice was significantly more diminished compared with nondiabetic CFKO mice, despite an even more robust recruitment of neutrophils to the airways. This finding that CFRD mice boast an exaggerated, but less effective, inflammatory cell response to intratracheal PAO1 challenge presents a novel and useful murine model to help identify therapeutic strategies that promote bacterial clearance in CFRD.

Aim: Evidences from several studies suggest that probiotics affect glucose homeostasis. This paper reviews the results of animal and human studies on the role of probiotics in modulating glucose homeostasis., Method: A systematic literature search using multiple databases was conducted without time limitation. Primary outcomes evaluated were parameters related to glucose homeostasis. Secondary outcomes were inflammatory markers, lipid profile, body weight, and energy intake., Results: A total of 17 animal studies and four human studies were identified. Among these, 16 animal studies and three human studies had documented significant improvements in at least one glucose homeostasis related parameter. Inflammatory markers and lipid profile were significantly improved in the animal model, while data from human studies were controversial. Changes in body weight and energy intake that could be due to probiotics supplementation were also inconclusive., Conclusion: Well-designed placebo-controlled clinical trials with validated outcome variables are needed to determine the effect of probiotics on glucose homeostasis.

Aims/hypothesis: Patients with diabetes are more prone to bacterial infections mostly due to hyperglycemia-induced suppression of immune cells function. B lymphocytes by secreting antibodies inhibit microbial replication, but the impact of high glucose concentration on humoral immune response is not fully resolved. The aim of this work was to investigate the effect of high glucose concentration on B cells response to stimulation with a bacterial antigen and autocrine regulation., Methods: Purified human peripheral blood B cells were cultured at different glucose concentrations and stimulated in vitro with Staphylococcus aureus Cowan I (SAC) plus IL-2. B cells proliferation, differentiation and IgM expression were analyzed by flow cytometry. B cell ATP release and involvement of P2 purinergic receptors in regulation of IgM secretion was assessed., Results: B cells cultured at 25 mM glucose in response to SAC stimulation released significantly less (≈ 55%) IgM comparing to cells maintained in 5mM glucose. Under resting and stimulatory conditions B cells released significant quantities of ATP to the culture media, but ATP level decreased when B cells were maintain in high glucose. SAC-induced B cell IgM release was totally blocked by highly selective antagonist (Az11645373) of P2X7 receptor. IgM secretion increased in the presence of potent P2X7 receptor agonist (BzATP), but this effect was abolished by high glucose concentration., Conclusions/interpretation: High glucose concentration impairs B cell function by suppression of P2X7 receptor-dependent IgM release in response to in vitro bacterial antigen stimulation. This alteration may greatly contribute to the impaired humoral immune response in diabetics., (Copyright © 2012 Elsevier GmbH. All rights reserved.)

The vicious cycle is that hyperglycemia (≥11.1 mmol/l) or other diabetes-associated factors facilitate or worsen the development of infections and vice versa, the infections deteriorate the glycemic control of the patients. Diabetic patients are prone to some infections, infection recurrences and poor outcomes. Immunocompromised state and frequent antibiotic use are associated with antibiotic resistance of the bacterial pathogens, such as Mycobacterium tuberculosis (in some studies), methicillin-resistant Staphylococcus aureus, Streptococcus pneumoniae, Gram-negative bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii, bacteria in diabetic foot infections and different opportunistic and rare pathogens or multidrug-resistant strains. Prompt diagnostics and susceptibility testing, early and aggressive surgical and/or antibiotic therapy, and, importantly, good glycemic control are of utmost importance for treatment of antibiotic-resistant infections in diabetic patients.

Objective: To investigate the positive rate, infection rate and bearing rate of salivary candida in patients with type 2 diabetes mellitus (DM), individuals with impaired glucose regulation (IGR) and individuals with normal glucose tolerance (NGT) and their predisposing factors., Methods: Questionnaire was given to 145 patients with DM, 142 individuals with IGR and 149 NGT individuals. Oral examination was carried out, and fasting plasma glucose (FPG) level and plasma glucose level of 2 hours post glucose-load (PG2h), resting salivary flow, salivary pH value were tested. Salivary candida was cultured., Results: In DM, IGR and NGT groups, the positive rates of salivary candida were 21.4% (31/145), 7.0% (10/142), 4.7% (7/149) respectively, the infection rates were 7.6% (11/145), 1.4% (2/142), 1.3% (2/149) respectively, and the bearing rates of salivary candida were 13.8% (20/145), 5.6% (8/142), 3.4% (5/149) respectively. The candida positive rate, candida infection rate in DM group were higher than those of IGR and NGT groups respectively (P < 0.05). There were no significant differences in the candida positive rate, infection rate and bearing rate between IGR and NGT groups (P > 0.05). Resting salivary flow in DM [(1.30 ± 1.20) ml/10 min] and IGR [(1.40 ± 1.17) ml/10 min]groups were lower than that in NGT group [(1.93 ± 1.66) ml/10 min], salivary pH values in DM (7.11 ± 0.56) and IGR (7.05 ± 0.48) groups were lower than that in NGT group (7.38 ± 0.48) (P < 0.05), while FPG value in DM [(7.68 ± 2.75) mmol/L] and IGR [(5.67 ± 0.73) mmol/L] groups were respectively higher tham that in NGT group [(4.99 ± 0.44) mmol/L], P < 0.05. The infection rate of salivary candida was influenced to some degree by age, FPG level and bearing denture (OR value = 1.106, 1.258, 3.166)., Conclusions: The patients with DM were more subjected to bearing or infection of candida than individuals with IGR and NGT. To control the plasma glucose level will help to decrease the positive rate and infection rate of oral candida.

Background: Diabetic patients are at increased risk for bacterial infections; these studies provide new insight into the role of the host defense complement system in controlling bacterial pathogens in hyperglycemic environments., Methods: The interactions of complement C3 with bacteria in elevated glucose were assayed for complement activation to opsonic forms, phagocytosis and bacterial killing. C3 was analyzed in euglycemic and hyperglycemic conditions by mass spectrometry to measure glycation and structural differences., Results: Elevated glucose inhibited S. aureus activation of C3 and deposition of C3b and iC3b on the bacterial surface. S. aureus-generated C5a and serum-mediated phagocytosis by neutrophils were both decreased in elevated glucose conditions. Interestingly, elevated glucose increased the binding of unactivated C3 to S. aureus, which was reversible on return to normal glucose concentrations. In a model of polymicrobial infection, S. aureus in elevated glucose conditions depleted C3 from serum resulting in decreased complement-mediated killing of E. coli. To investigate the effect of differing glucose concentration on C3 structure and glycation, purified C3 incubated with varying glucose concentrations was analyzed by mass spectrometry. Glycation was limited to the same three lysine residues in both euglycemic and hyperglycemic conditions over one hour, thus glycation could not account for observed changes between glucose conditions. However, surface labeling of C3 with sulfo-NHS-biotin showed significant changes in the surface availability of seven lysine residues in response to increasing glucose concentrations. These results suggest that the tertiary structure of C3 changes in response to hyperglycemic conditions leading to an altered interaction of C3 with bacterial pathogens., Conclusions: These results demonstrate that hyperglycemic conditions inhibit C3-mediated complement effectors important in the immunological control of S. aureus. Mass spectrometric analysis reveals that the glycation state of C3 is the same regardless of glucose concentration over a one-hour time period. However, in conditions of elevated glucose C3 appears to undergo structural changes.

Diabetes is considered to be a genetically and environmentally based chronic metabolic and vascular syndrome caused by a partial or total insulin deficiency with alteration in the metabolism of lipids, carbohydrates and proteins culminating with different manifestations in different organisms. In humans hyperglycemia is the main consequence of defects in the secretion and/or action of insulin, and its deregulation can produce secondary lesions in various organs, especially kidneys, eyes, nerves, blood vessels and immune systems. Periodontal disease is an entity of localized infection that involves tooth-supporting tissues. The first clinical manifestation of periodontal disease is the appearance of periodontal pockets, which offer a favorable niche for bacterial colonization. The etiology of periodontal disease is multifactorial, being caused by interactions between multiple micro-organisms (necessary but not sufficient primary etiologic factors), a host with some degree of susceptibility and environmental factors. According to current scientific evidence, there is a symbiotic relationship between diabetes and periodontitis, such that diabetes is associated with an increased incidence and progression of periodontitis, and periodontal infection is associated with poor glycaemic control in diabetes due to poor immune systems. Hence, for a good periodontal control it is necessary to treat both periodontal disease and glycaemic control.

Background: The bacterial genus Shigella is the leading cause of dysentery. There have been significant increases in the proportion of Shigella isolated that demonstrate resistance to nalidixic acid. While nalidixic acid is no longer considered as a therapeutic agent for shigellosis, the fluoroquinolone ciprofloxacin is the current recommendation of the World Health Organization. Resistance to nalidixic acid is a marker of reduced susceptibility to older generation fluoroquinolones, such as ciprofloxacin. We aimed to assess the efficacy of gatifloxacin versus ciprofloxacin in the treatment of uncomplicated shigellosis in children., Methodology/principal Findings: We conducted a randomized, open-label, controlled trial with two parallel arms at two hospitals in southern Vietnam. The study was designed as a superiority trial and children with dysentery meeting the inclusion criteria were invited to participate. Participants received either gatifloxacin (10 mg/kg/day) in a single daily dose for 3 days or ciprofloxacin (30 mg/kg/day) in two divided doses for 3 days. The primary outcome measure was treatment failure; secondary outcome measures were time to the cessation of individual symptoms. Four hundred and ninety four patients were randomized to receive either gatifloxacin (n=249) or ciprofloxacin (n=245), of which 107 had a positive Shigella stool culture. We could not demonstrate superiority of gatifloxacin and observed similar clinical failure rate in both groups (gatifloxacin; 12.0% and ciprofloxacin; 11.0%, p=0.72). The median (inter-quartile range) time from illness onset to cessation of all symptoms was 95 (66-126) hours for gatifloxacin recipients and 93 (68-120) hours for the ciprofloxacin recipients (Hazard Ratio [95%CI]=0.98 [0.82-1.17], p=0.83)., Conclusions: We conclude that in Vietnam, where nalidixic acid resistant Shigellae are highly prevalent, ciprofloxacin and gatifloxacin are similarly effective for the treatment of acute shigellosis.