Investigating the Interplay: Periodontal Disease and Type 1 Diabetes Mellitus-A Comprehensive Review of Clinical Studies.

Diabetes mellitus (DM) poses a significant challenge to global health, with its prevalence projected to rise dramatically by 2045. This narrative review explores the bidirectional relationship between periodontitis (PD) and type 1 diabetes mellitus (T1DM), focusing on cellular and molecular mechanisms derived from the interplay between oral microbiota and the host immune response. A comprehensive search of studies published between 2008 and 2023 was conducted to elucidate the association between these two diseases. Preclinical and clinical evidence suggests a bidirectional relationship, with individuals with T1DM exhibiting heightened susceptibility to periodontitis, and vice versa. The review includes recent findings from human clinical studies, revealing variations in oral microbiota composition in T1DM patients, including increases in certain pathogenic species such as Porphyromonas gingivalis, Prevotella intermedia, and Aggregatibacter actinomycetemcomitans, along with shifts in microbial diversity and abundance. Molecular mechanisms underlying this association involve oxidative stress and dysregulated host immune responses, mediated by inflammatory cytokines such as IL-6, IL-8, and MMPs. Furthermore, disruptions in bone turnover markers, such as RANKL and OPG, contribute to periodontal complications in T1DM patients. While preventive measures to manage periodontal complications in T1DM patients may improve overall health outcomes, further research is needed to understand the intricate interactions between oral microbiota, host response, periodontal disease, and systemic health in this population.

Beneficial In Vitro Effects of Polysaccharide and Non-Polysaccharide Components of Dendrobium huoshanense on Gut Microbiota of Rats with Type 1 Diabetes as Opposed to Metformin.

The extract of Dendrobium huoshanense, a traditional Chinese medicinal and food homologous plant belonging to the family Orchidaceae, was previously reported to have hypoglycemic and antioxidant effects. In this study, the direct effects of polysaccharide (DHP) and non-polysaccharide (NDHP) components of D. huoshanense, as well as its water extract (DHWE) were compared with that of metformin (an antidiabetic drug) on the gut microbiota (collected from fecal flora) of rats with streptozotocin-induced type 1 diabetes (T1D) using an in vitro fermentation method. The results showed that DHWE, DHP, and NDHP reduced pH and increased bacterial proliferation and short-chain fatty acid (SCFA) content in fermentation broth. DHWE, DHP, NDHP and metformin promoted the production of acetic and propionic acid, acetic acid, propionic acid and butyric acid, and propionic acid, respectively. DHWE, DHP, and NDHP reduced the abundance of Proteobacteria (subdominant pathogenic bacteria) and increased the abundance of Firmicutes (dominant beneficial gut bacteria). NDHP also reduced the abundance of Bacteroidetes (beneficial and conditional pathogenic). Metformin increased the abundance of Proteobacteria and reduced the abundance of Firmicutes and Bacteroidetes. At the genus level, NDHP promoted the proliferation of Megamonas and Megasphaera and decreased harmful bacteria (e.g., Klebsiella), and DHP increased the abundance of Prevotellaceae (opportunistic and usually harmless). By contrast, metformin increased the abundance of harmful bacteria (e.g., Citrobacter) and reduced the abundance of beneficial bacteria (e.g., Oscillospira). Our study indicates that DHWE, DHP, and NDHP are potentially more beneficial than metformin on the gut microbiota of T1D rats in vitro.

The Effect of Microbiome-Modulating Agents (MMAs) on Type 1 Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Gut microbiome-modulating agents (MMAs), including probiotics, prebiotics, postbiotics, and synbiotics, are shown to ameliorate type 1 diabetes (T1D) by restoring the microbiome from dysbiosis. The objective of this systematic review and meta-analysis was to assess the impact of MMAs on hemoglobin A1c (HbA1c) and biomarkers associated with (T1D). A comprehensive search was conducted in PubMed, Web of Science, Embase, Cochrane Library, National Knowledge Infrastructure, WeiPu, and WanFang Data up to 30 November 2023. Ten randomized controlled trials (n = 630) were included, with study quality evaluated using the Cochrane risk-of-bias tool. Random-effect models with standardized mean differences (SMDs) were utilized. MMA supplementation was associated with improvements in HbA1c (SMD = -0.52, 95% CI [-0.83, -0.20]), daily insulin usage (SMD = -0.41, 95% confidence interval (CI) [-0.76, -0.07]), and fasting C-peptide (SMD = 0.99, 95% CI [0.17, 1.81]) but had no effects on FBG, CRP, TNF-α, IL-10, LDL, HDL, and the Shannon index. Subgroup analysis of HbA1c indicated that a long-term intervention (>3 months) might exert a more substantial effect. These findings suggest an association between MMAs and glycemic control in T1D. Further large-scale clinical trials are necessary to confirm these findings with investigations on inflammation and gut microbiota composition while adjusting confounding factors such as diet, physical activity, and the dose and form of MMA intervention.

Gut microbiota from B-cell-specific TLR9-deficient NOD mice promote IL-10+ Breg cells and protect against T1D.

Introduction: Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing ß cells. Toll-like receptor 9 (TLR9) plays a role in autoimmune diseases, and B cell-specific TLR9 deficiency delays T1D development. Gut microbiota are implicated in T1D, although the relationship is complex. However, the impact of B cell-specific deficiency of TLR9 on intestinal microbiota and the impact of altered intestinal microbiota on the development of T1D are unclear. Objectives: This study investigated how gut microbiota and the intestinal barrier contribute to T1D development in B cell-specific TLR9-deficient NOD mice. Additionally, this study explored the role of microbiota in immune regulation and T1D onset. Methods: The study assessed gut permeability, gene expression related to gut barrier integrity, and gut microbiota composition. Antibiotics depleted gut microbiota, and fecal samples were transferred to germ-free mice. The study also examined IL-10 production, Breg cell differentiation, and their impact on T1D development. Results: B cell-specific TLR9-deficient NOD mice exhibited increased gut permeability and downregulated gut barrier-related gene expression. Antibiotics restored gut permeability, suggesting microbiota influence. Altered microbiota were enriched in Lachnospiraceae, known for mucin degradation. Transferring this microbiota to germ-free mice increased gut permeability and promoted IL-10-expressing Breg cells. Rag-/- mice transplanted with fecal samples from Tlr9 fl/fl Cd19-Cre+ mice showed delayed diabetes onset, indicating microbiota's impact. Conclusion: B cell-specific TLR9 deficiency alters gut microbiota, increasing gut permeability and promoting IL-10-expressing Breg cells, which delay T1D. This study uncovers a link between TLR9, gut microbiota, and immune regulation in T1D, with implications for microbiota-targeted T1D therapies.

Effects of gut microbiome on type 1 diabetes susceptibility and complications: A large-scale bidirectional Mendelian randomization and external validation study.

AIM: To assess and verify the effect of the gut microbiome on the susceptibility and complications of type 1 diabetes (T1D). MATERIALS AND METHODS: To achieve this aim, a two-sample and reverse Mendelian randomization (MR) analysis was conducted. In addition, an external validation study was performed using individual microbiome data of patients with T1D from the gutMEGA datasets and the National Clinical Research Center for Metabolic Diseases. The circulating metabolites facilitated two-sample MR analysis, mediation and multivariable MR analysis to evaluate the direct relationship between the gut microbiome and T1D complications. RESULTS: The MR analysis results from the discovery and validation phases confirmed that Veillonellaceae can potentially reduce the susceptibility of T1D. In the gutMEGA dataset, the average relative abundance of Veillonellaceae in patients with T1D was 0.66%, compared with 1.09% in the controls. Furthermore, the external validation, which included 60 patients with T1D and 30 matched healthy controls, found that the median relative abundance of Veillonellaceae was also lower than controls at 1.10% (95% CI 0.50%-1.80%). Specifically, the Eubacterium coprostanoligenes group, known for its ability to regulate cholesterol, was significantly associated with a lower risk of developing renal, neurological and ophthalmic complications in T1D. Moreover, high cholesterol in small high-density lipoprotein and cholesteryl esters in high-density lipoprotein were associated with a reduced risk of T1D renal and ophthalmic complications. The mediation and multivariable MR analysis combining cholesterol indicated that the E. coprostanoligenes group is the most dominant factor influencing T1D complications. CONCLUSIONS: Our findings supported the potential causal effect of gut microbiota on the susceptibility and complications of T1D.

Reversal of diabetes by an oral Salmonella-based vaccine in acute and progressive diabetes in NOD mice.

Type 1 diabetes (T1D)-associated hyperglycemia develops, in part, from loss of insulin-secreting beta cells. The degree of glycemic dysregulation and the age at onset of disease can serve as indicators of the aggressiveness of the disease. Tracking blood glucose levels in prediabetic mice may demonstrate the onset of diabetes and, along with animal age, also presage disease severity. In this study, an analysis of blood glucose levels obtained from female NOD mice starting at 4 weeks until diabetes onset was undertaken. New onset diabetic mice were orally vaccinated with a Salmonella-based vaccine towards T1D-associated preproinsulin combined with TGFß and IL10 along with anti-CD3 antibody. Blood glucose levels were obtained before and after development of disease and vaccination. Animals were classified as acute disease if hyperglycemia was confirmed at a young age, while other animals were classified as progressive disease. The effectiveness of the oral T1D vaccine was greater in mice with progressive disease that had less glucose excursion compared to acute disease mice. Overall, the Salmonella-based vaccine reversed disease in 60% of the diabetic mice due, in part, to lessening of islet inflammation, improving residual beta cell health, and promoting tolerance. In summary, the age of disease onset and severity of glucose dysregulation in NOD mice predicted response to vaccine therapy. This suggests a similar disease categorization in the clinic may predict therapeutic response.

Can fecal microbiota transplantations modulate autoimmune responses in type 1 diabetes?

Type 1 diabetes (T1D) is a chronic autoimmune disease targeting insulin-producing pancreatic beta cells. T1D is a multifactorial disease incorporating genetic and environmental factors. In recent years, the advances in high-throughput sequencing have allowed researchers to elucidate the changes in the gut microbiota taxonomy and functional capacity that accompany T1D development. An increasing number of studies have shown a role of the gut microbiota in mediating immune responses in health and disease, including autoimmunity. Fecal microbiota transplantations (FMT) have been largely used in murine models to prove a causal role of the gut microbiome in disease progression and have been shown to be a safe and effective treatment in inflammatory human diseases. In this review, we summarize and discuss recent research regarding the gut microbiota-host interactions in T1D, the current advancement in therapies for T1D, and the usefulness of FMT studies to explore microbiota-host immunity encounters in murine models and to shape the course of human type 1 diabetes.

Accelerated onset of diabetes in non-obese diabetic mice fed a refined high-fat diet.

AIM: Type 1 diabetes results from autoimmune events influenced by environmental variables, including changes in diet. This study investigated how feeding refined versus unrefined (aka 'chow') diets affects the onset and progression of hyperglycaemia in non-obese diabetic (NOD) mice. METHODS: Female NOD mice were fed either unrefined diets or matched refined low- and high-fat diets. The onset of hyperglycaemia, glucose tolerance, food intake, energy expenditure, circulating insulin, liver gene expression and microbiome changes were measured for each dietary group. RESULTS: NOD mice consuming unrefined (chow) diets developed hyperglycaemia at similar frequencies. By contrast, mice consuming the defined high-fat diet had an accelerated onset of hyperglycaemia compared to the matched low-fat diet. There was no change in food intake, energy expenditure, or physical activity within each respective dietary group. Microbiome changes were driven by diet type, with chow diets clustering similarly, while refined low- and high-fat bacterial diversity also grouped closely. In the defined dietary cohort, liver gene expression changes in high-fat-fed mice were consistent with a greater frequency of hyperglycaemia and impaired glucose tolerance. CONCLUSION: Glucose intolerance is associated with an enhanced frequency of hyperglycaemia in female NOD mice fed a defined high-fat diet. Using an appropriate matched control diet is an essential experimental variable when studying changes in microbiome composition and diet as a modifier of disease risk.

Predicting the role of the human gut microbiome in type 1 diabetes using machine-learning methods.

Gut microbes is a crucial factor in the pathogenesis of type 1 diabetes (T1D). However, it is still unclear which gut microbiota are the key factors affecting T1D and their influence on the development and progression of the disease. To fill these knowledge gaps, we constructed a model to find biomarker from gut microbiota in patients with T1D. We first identified microbial markers using Linear discriminant analysis Effect Size (LEfSe) and random forest (RF) methods. Furthermore, by constructing co-occurrence networks for gut microbes in T1D, we aimed to reveal all gut microbial interactions as well as major beneficial and pathogenic bacteria in healthy populations and type 1 diabetic patients. Finally, PICRUST2 was used to predict Kyoto Encyclopedia of Genes and Genomes (KEGG) functional pathways and KO gene levels of microbial markers to investigate the biological role. Our study revealed that 21 identified microbial genera are important biomarker for T1D. Their AUC values are 0.962 and 0.745 on discovery set and validation set. Functional analysis showed that 10 microbial genera were significantly positively associated with D-arginine and D-ornithine metabolism, spliceosome in transcription, steroid hormone biosynthesis and glycosaminoglycan degradation. These genera were significantly negatively correlated with steroid biosynthesis, cyanoamino acid metabolism and drug metabolism. The other 11 genera displayed an inverse correlation. In summary, our research identified a comprehensive set of T1D gut biomarkers with universal applicability and have revealed the biological consequences of alterations in gut microbiota and their interplay. These findings offer significant prospects for individualized management and treatment of T1D.

Two putative glutamate decarboxylases of Streptococcus pneumoniae as possible antigens for the production of anti-GAD65 antibodies leading to type 1 diabetes mellitus / Dos supuestas glutamato descarboxilasas de Streptococcus pneumoniae como posibles antígenos para la producción de anticuerpos anti-GAD65 que conducen a la diabetes mellitus tipo 1

Type 1 diabetes mellitus (T1DM) has been increasing in prevalence in the last decades and has become a global burden. Autoantibodies against human glutamate decarboxylase (GAD65) are among the first to be detected at the onset of T1DM. Diverse viruses have been proposed to be involved in the triggering of T1DM because of molecular mimicry, i.e., similarity between parts of some viral proteins and one or more epitopes of GAD65. However, the possibility that bacterial proteins might also be responsible for GAD65 mimicry has been seldom investigated. To date, many genomes of Streptococcus pneumoniae (the pneumococcus), a prominent human pathogen particularly prevalent among children and the elderly, have been sequenced. A dataset of more than 9000 pneumococcal genomes was mined and two different (albeit related) genes (gadA and gadB), presumably encoding two glutamate decarboxylases similar to GAD65, were found. The various gadASpn alleles were present only in serotype 3 pneumococci belonging to the global lineage GPSC83, although some homologs have also been discovered in two subspecies of Streptococcus constellatus (pharyngis and viborgensis), an isolate of the group B streptococci, and several strains of Lactobacillus delbrueckii. Besides, gadBSpn alleles are present in > 10% of the isolates in our dataset and represent 16 GPSCs with 123 sequence types and 20 different serotypes. Sequence analyses indicated that gadA- and gadB-like genes have been mobilized among different bacteria either by prophage(s) or by integrative and conjugative element(s), respectively. Substantial similarities appear to exist between the putative pneumococcal glutamate decarboxylases and well-known epitopes of GAD65. In this sense, the use of broader pneumococcal conjugate vaccines such as PCV20 would prevent the majority of serotypes expressing those genes that might potentially contribute to T1DM.(AU)

Microbiological, lipid and immunological profiles in children with gingivitis and type 1 diabetes mellitus

Abstract Objective The aim of this study was to compare the prevalence of periodontal pathogens, systemic inflammatory mediators and lipid profiles in type 1 diabetes children (DM) with those observed in children without diabetes (NDM), both with gingivitis. Material and methods Twenty-four DM children and twenty-seven NDM controls were evaluated. The periodontal status, glycemic and lipid profiles were determined for both groups. Subgingival samples of periodontal sites were collected to determine the prevalence of periodontal microorganisms by PCR. Blood samples were collected for IL-1-β, TNF-α and IL-6 analysis using ELISA kits. Results Periodontal conditions of DM and NDM patients were similar, without statistical differences in periodontal indices. When considering patients with gingivitis, all lipid parameters evaluated were highest in the DM group; Capnocytophaga sputigena and Capnocytophaga ochracea were more prevalent in the periodontal sites of DM children. “Red complex” bacteria were detected in few sites of DM and NDM groups. Fusobacterium nucleatum and Campylobacter rectus were frequently found in both groups. Similar levels of IL-1-β, TNF-α and IL-6 were detected in DM and NDM children. Conclusion Clinical and immunological profiles are similar between DM and NDM children. The presence of Capnocytophaga sputigena and Capnocytophaga ochracea were associated with gingivitis in DM children.

Dyspeptic symptoms in patients with type 1 diabetes: endoscopic findings, Helicobacter pylori infection, and associations with metabolic control, mood disorders and nutritional factors

Objectives To evaluate, in a group of patients with long-standing type 1 diabetes (DM1), an association of dyspepsia symptoms with: changes in the gastroduodenal mucosa, infection by Helicobacter pylori, glycemic control, and psychological and nutritional factors. Subjects and methods A total of 32 patient with DM1 were studied (age: 38 ± 9 years; females: 25; diabetes duration: 22 ± 5 years). All patients answered a standardized questionnaire for the evaluation of gastrointestinal symptoms and underwent upper gastrointestinal endoscopy, with gastric biopsies for the evaluation of Helicobacter pylori infection. The presence of anxiety and depression was evaluated by the HAD scale. Nutritional parameters were BMI, arm and waist circumference, skinfold measurement, and body fat percentage. Results Upper endoscopy detected lesions in the gastric mucosa in 34.4% of the patients, with similar frequency in those with (n = 21) and without dyspepsia (n = 11). The patients with dyspepsia complaints showed greater frequency of depression (60% vs. 0%; p = 0.001), higher values for HbA1c (9.6 ± 1.7 vs. 8.2 ± 1.3%; p = 0.01) and lower values for BMI (24.3 ± 4.1 vs. 27.2 ± 2.6 kg/m2; p = 0.02), body fat percentage (26.6 ± 6.2 vs. 30.8 ± 7.7%; p = 0.04), and waist circumference (78.7 ± 8 vs. 85.8 ± 8.1 cm; p = 0.02). No association was found between the symptoms and the presence of Helicobacter pylori. Conclusions Dyspepsia symptoms in patients with long-standing DM1 were associated with glycemic control and depression, and they seem to negatively influence the nutritional status of these patients. .

Estudo da micobiota em conjuntiva sadia de diabéticos, residentes na área urbana da cidade de São Paulo - Brasil / Study of mycobiota in the healthy conjunctiva of diabetics who reside in the urban area of the city of São Paulo, Brazil

OBJETIVOS: Determinar a micobiota de conjuntiva sadia em indivíduos diabéticos, segundo tipo de diabetes, idade, sexo, tempo de doenca, tipo de tratamento e estádio da retinopatia. Estabelecer a micobiota anemófila nas salas de colheita. MÉTODOS: Estudo transversal de 803 diabéticos residentes na zona urbana de São Paulo - SP/Brasil. Foi usado para primo-isolamento o meio de cultivo ágar Sabouraud dextrose com cloranfenicol e para identificacão dos fungos filamentosos a chave de De Hoog. RESULTADOS: Dos diabéticos avaliados, 6,6 por cento (53/803) apresentavam diabetes tipo 1 e 93,4 por cento (750/803) tipo 2. Os cultivos positivos para fungos em conjuntiva de diabéticos foi 4,2 por cento (34/803), sendo 1,9 por cento (1/53) nos diabéticos tipo 1 e 4,4 por cento (33/740) nos diabetes tipo 2 (p=0,720). Não foi verificada associacão estatisticamente significante quanto à presenca ou não de isolamentos de fungos em relacão idade (p=0,575), sexo (p=0,517), tempo de doenca (p=0,633), tipo de tratamento (p=0,422) e estádio de retinopatia diabética (p=0,655) desses indivíduos. Todos os fungos identificados foram filamentosos: Aspergillus spp. representou 59,5 por cento (25/42) dos isolamentos sendo 47,6 por cento (20/42) Aspergillus niger. Ocorreu crescimento de fungos anemófilos do ar ambiente da sala, observando-se coincidências entre as espécies isoladas no ar e na conjuntiva. CCONCLUSÕES: Foi identificada presenca de micobiota em conjuntiva sadia de diabéticos, não havendo associacão entre a maior positividade de isolamentos fúngicos e o tipo de diabetes, idade, sexo, tempo de doenca, tipo de tratamento e estádio da retinopatia diabética. Nas salas de colheita foi identificada micobiota anemófila.

Estudo comparativo sobre a colonização por leveduras no sulco gengival de diabéticos tipo 1 / Comparative study of yeast colonization in the gingival crevice of diabetes mellitus type 1 patients

Comparou-se pacientes diabéticos tipo 1 com pacientes controles saudáveis, para avaliar as condições periodontais e da mucosa, identificar, qualificar e inter-relacionar, com o nível glicêmico do diabético, a presença de leveduras na gengiva e na saliva, através de: teste de hemoglobina glicosilada, índice de placa, índice gengival, índice de sangramento gengival, o nível de inserção, a profundidade de sondagem, exame radiográfico, inspeção da mucosa, teste de fluxo salivar e exame microbiológico. As diferenças não foram significantes quanto às condições periodontais e de mucosa, entre os pacientes, nem quanto à prevalência de leveduras entre os locais amostrados, exceto que os pacientes diabéticos mais velhos apresentaram nível de inserção clínica 77% maior que os mais jovens e o dobro de leveduras que os demais grupos. A C. albicans foi a levedura mais freqüente. Concluiu-se que houve uma leve tendência dos pacientes diabéticos apresentarem uma susceptibilidade aumentada à doença periodontal e maior frequência de leveduras, não podendo generalizar e estender os resultados de uma população tão pequena, sugerindo que se avalie uma população maior.(AU)

This work assessed (a) the differences of periodontal and soft tissue conditions, between diabetics type 1 patients, (b) the prevalence and comparison of yeast in gingival and saliva, (c) possible association between yeast with glycaemic conditions of the diabetic patients. Twenty-four patients were subdivided in 3 groups: diabetic subjects aging from 13 to 19 years (A) and aging from 20 or more years (B) and healthy controls (C) with periodontal diseases, aging from 20 or more years. There were performed the hemoglobin glycated test, radiological examination, anamnestic information, periodontal and soft tissues condition, salivary flow and microbiological analysis of the gingival and saliva; the plaque index, gingival index, bleeding sulcular index, clinical attachment level and probing depth were recorded. There were no significant differences in relation to the periodontal and mucosa conditions between diabetic patients, exception was to group B that showed 77% more attachment loss than group A. The results showed no significant differences in the prevalence of yeast, however there were twice more numbers of yeast in group B. C. albicans was the most frequent detected yeast. Although data from this study were not significant, a slightly tendency to a high prevalence of yeast and an increased susceptibility to periodontal diseases in diabetic population were shown. So, it would be prudent to elucidate in a greater population.(AU)

Actinobacillus actinomycetemcomitans in Brazilian insulin-dependent individuals with diabetes mellitus

The prevalence of Actinobacillus Actinomycetemcomitans (Aa) in subgingival plaque specimens from 26 insulin-dependent diabetes mellitus patients, 11-25 years of age, was determined between January 1987 and December 1989. One hundred and thirty subgingival plaque samples were collected with sterile periodontal curettes. The specimens were weighed, diluted, inoculated on trypticase-soy-serum-bacitracin-vancomycin agar medium (TSBV) and incubated under microaerophilic conditions. Aa was isolated from 2.3//of healthy periodontal areas in these patients, while the microorganism was found in 12.5//of the sites with gingivitis and in 2.6//of the periodontal pockets examined. Although biochemical tests used for the characterization of Aa strains showed homogeneous results, different biotypes were isolated from one or more periodontal sites in the same patient

Estado de portador de Staphylococcus aureus en pacientes diabéticos

Estudio bacteriológico realizado en pacientes diabéticos insulino dependientes y no insulino dependientes que asisten al Patronato contra la Diabetes, en el período comprendido de Junio a Julio de 1987. Las infecciones causadas por Staphylococcus aureus han constitutido una muy seria preocupación para médicos y epidemiologos, por la gravedad que representan especialmente para diabéticos; en quiens se ha demostrado que el estado del portador es fuente de infección frecuente representado riesgo de diseminación para ellos y otros pacientes. (1) En este trabajo se investigaron 120 pacientes diabéticos, pudiéndose establecer que la frecuencia del estado portador varía significativamente en relación a los datos que se tienen de la población en general, que la presencia de Staphylococcus a nivel nasal es mayor en frecuencia los pacientes diabéticos insulinos dependientes (Tipo I) que en no dependientes, además que el patrón de susceptibilidad a los antimicrobianos varió notablemente entre un grupo y otro, la resistencia a las penicilinas G y a la oxacilina es dos veces mayor en cepas aisladas en pacientes insulino dependientes