Background
Diabetes and periodontitis are chronic non‐communicable diseases independently associated with mortality and have a bidirectional relationship.
Aims
To update the evidence for their ...epidemiological and mechanistic associations and re‐examine the impact of effective periodontal therapy upon metabolic control (glycated haemoglobin, HbA1C).
Epidemiology
There is strong evidence that people with periodontitis have elevated risk for dysglycaemia and insulin resistance. Cohort studies among people with diabetes demonstrate significantly higher HbA1C levels in patients with periodontitis (versus periodontally healthy patients), but there are insufficient data among people with type 1 diabetes. Periodontitis is also associated with an increased risk of incident type 2 diabetes.
Mechanisms
Mechanistic links between periodontitis and diabetes involve elevations in interleukin (IL)‐1‐β, tumour necrosis factor‐α, IL‐6, receptor activator of nuclear factor‐kappa B ligand/osteoprotegerin ratio, oxidative stress and Toll‐like receptor (TLR) 2/4 expression.
Interventions
Periodontal therapy is safe and effective in people with diabetes, and it is associated with reductions in HbA1C of 0.27–0.48% after 3 months, although studies involving longer‐term follow‐up are inconclusive.
Conclusions
The European Federation of Periodontology (EFP) and the International Diabetes Federation (IDF) report consensus guidelines for physicians, oral healthcare professionals and patients to improve early diagnosis, prevention and comanagement of diabetes and periodontitis.
Diabetes and periodontitis are chronic non-communicable diseases independently associated with mortality and have a bidirectional relationship.
To update the evidence for their epidemiological and ...mechanistic associations and re-examine the impact of effective periodontal therapy upon metabolic control (glycated haemoglobin, HbA1C).
There is strong evidence that people with periodontitis have elevated risk for dysglycaemia and insulin resistance. Cohort studies among people with diabetes demonstrate significantly higher HbA1C levels in patients with periodontitis (versus periodontally healthy patients), but there are insufficient data among people with type 1 diabetes. Periodontitis is also associated with an increased risk of incident type 2 diabetes.
Mechanistic links between periodontitis and diabetes involve elevations in interleukin (IL)-1-β, tumour necrosis factor-α, IL-6, receptor activator of nuclear factor-kappa B ligand/osteoprotegerin ratio, oxidative stress and Toll-like receptor (TLR) 2/4 expression.
Periodontal therapy is safe and effective in people with diabetes, and it is associated with reductions in HbA1C of 0.27–0.48% after 3 months, although studies involving longer-term follow-up are inconclusive.
The European Federation of Periodontology (EFP) and the International Diabetes Federation (IDF) report consensus guidelines for physicians, oral healthcare professionals and patients to improve early diagnosis, prevention and comanagement of diabetes and periodontitis.
Tissue-specific transcriptional regulation is central to human disease. To identify regulatory DNA active in human pancreatic islets, we profiled chromatin by formaldehyde-assisted isolation of ...regulatory elements coupled with high-throughput sequencing (FAIRE-seq). We identified ∼80,000 open chromatin sites. Comparison of FAIRE-seq data from islets to that from five non-islet cell lines revealed ∼3,300 physically linked clusters of islet-selective open chromatin sites, which typically encompassed single genes that have islet-specific expression. We mapped sequence variants to open chromatin sites and found that rs7903146, a TCF7L2 intronic variant strongly associated with type 2 diabetes, is located in islet-selective open chromatin. We found that human islet samples heterozygous for rs7903146 showed allelic imbalance in islet FAIRE signals and that the variant alters enhancer activity, indicating that genetic variation at this locus acts in cis with local chromatin and regulatory changes. These findings illuminate the tissue-specific organization of cis-regulatory elements and show that FAIRE-seq can guide the identification of regulatory variants underlying disease susceptibility.
Summary Background Unlike most antihyperglycaemic drugs, glucagon-like peptide-1 (GLP-1) receptor agonists have a glucose-dependent action and promote weight loss. We compared the efficacy and safety ...of liraglutide, a human GLP-1 analogue, with exenatide, an exendin-based GLP-1 receptor agonist. Methods Adults with inadequately controlled type 2 diabetes on maximally tolerated doses of metformin, sulphonylurea, or both, were stratified by previous oral antidiabetic therapy and randomly assigned to receive additional liraglutide 1·8 mg once a day (n=233) or exenatide 10 μg twice a day (n=231) in a 26-week open-label, parallel-group, multinational (15 countries) study. The primary outcome was change in glycosylated haemoglobin (HbA1c ). Efficacy analyses were by intention to treat. The trial is registered with ClinicalTrials.gov , number NCT00518882. Findings Mean baseline HbA1c for the study population was 8·2%. Liraglutide reduced mean HbA1c significantly more than did exenatide (−1·12% SE 0·08 vs −0·79% 0·08; estimated treatment difference −0·33; 95% CI −0·47 to −0·18; p<0·0001) and more patients achieved a HbA1c value of less than 7% (54% vs 43%, respectively; odds ratio 2·02; 95% CI 1·31 to 3·11; p=0·0015). Liraglutide reduced mean fasting plasma glucose more than did exenatide (−1·61 mmol/L SE 0·20 vs −0·60 mmol/L 0·20; estimated treatment difference −1·01 mmol/L; 95% CI −1·37 to −0·65; p<0·0001) but postprandial glucose control was less effective after breakfast and dinner. Both drugs promoted similar weight losses (liraglutide −3·24 kg vs exenatide −2·87 kg). Both drugs were well tolerated, but nausea was less persistent (estimated treatment rate ratio 0·448, p<0·0001) and minor hypoglycaemia less frequent with liraglutide than with exenatide (1·93 vs 2·60 events per patient per year; rate ratio 0·55; 95% CI 0·34 to 0·88; p=0·0131; 25·5% vs 33·6% had minor hypoglycaemia). Two patients taking both exenatide and a sulphonylurea had a major hypoglycaemic episode. Interpretation Liraglutide once a day provided significantly greater improvements in glycaemic control than did exenatide twice a day, and was generally better tolerated. The results suggest that liraglutide might be a treatment option for type 2 diabetes, especially when weight loss and risk of hypoglycaemia are major considerations. Funding Novo Nordisk A/S.
Summary Background Agonists of the glucagon-like peptide-1 (GLP-1) receptor provide pharmacological levels of GLP-1 activity, whereas dipeptidyl peptidase-4 (DPP-4) inhibitors increase concentrations ...of endogenous GLP-1 and glucose-dependent insulinotropic polypeptide. We aimed to assess the efficacy and safety of the human GLP-1 analogue liraglutide versus the DPP-4 inhibitor sitagliptin, as adjunct treatments to metformin, in individuals with type 2 diabetes who did not achieve adequate glycaemic control with metformin alone. Methods In this parallel-group, open-label trial, participants (aged 18–80 years) with type 2 diabetes mellitus who had inadequate glycaemic control (glycosylated haemoglobin HbA1c 7·5–10·0%) on metformin (≥1500 mg daily for ≥3 months) were enrolled and treated at office-based sites in Europe, the USA, and Canada. Participants were randomly allocated to receive 26 weeks' treatment with 1·2 mg (n=225) or 1·8 mg (n=221) subcutaneous liraglutide once daily, or 100 mg oral sitagliptin once daily (n=219). The primary endpoint was change in HbA1c from baseline to week 26. The efficacy of liraglutide versus sitagliptin was assessed hierarchically by a non-inferiority comparison, with a margin of 0·4%, followed by a superiority comparison. Analyses were done on the full analysis set with missing values imputed by last observation carried forward; seven patients assigned to liraglutide did not receive treatment and thus did not meet criteria for inclusion in the full analysis set. This trial is registered with ClinicalTrials.gov , number NCT00700817. Findings Greater lowering of mean HbA1c (8·5% at baseline) was achieved with 1·8 mg liraglutide (−1·50%, 95% CI −1·63 to −1·37, n=218) and 1·2 mg liraglutide (−1·24%, −1·37 to −1·11, n=221) than with sitagliptin (−0·90%, −1·03 to −0·77, n=219). Estimated mean treatment differences for liraglutide versus sitagliptin were −0·60% (95% CI −0·77 to −0·43, p<0·0001) for 1·8 mg and −0·34% (−0·51 to −0·16, p<0·0001) for 1·2 mg liraglutide. Nausea was more common with liraglutide (59 27% patients on 1·8 mg; 46 21% on 1·2 mg) than with sitagliptin (10 5%). Minor hypoglycaemia was recorded in about 5% of participants in each treatment group. Interpretation Liraglutide was superior to sitagliptin for reduction of HbA1c , and was well tolerated with minimum risk of hypoglycaemia. These findings support the use of liraglutide as an effective GLP-1 agent to add to metformin. Funding Novo Nordisk.
Streptozotocin (STZ) is a cytotoxic glucose analogue that causes beta cell death and is widely used to induce experimental diabetes in rodents. The sensitivity of beta cells to STZ is ...species-specific and human beta cells are resistant to STZ. In experimental islet transplantation to rodents, STZ-diabetes must be induced before transplantation to avoid destruction of grafted islets by STZ. In human islet transplantation, injection of STZ before transplantation is inconvenient and costly, since human islet availability depends on organ donation and frail STZ-diabetic mice must be kept for unpredictable lapses of time until a human islet preparation is available. Based on the high resistance of human beta cells to STZ, we have tested a new model for STZ-diabetes induction in which STZ is injected after human islet transplantation. Human and mouse islets were transplanted under the kidney capsule of athymic nude mice, and 10–14 days after transplantation mice were intraperitoneally injected with five consecutive daily doses of STZ or vehicle. Beta-cell death increased and beta-cell mass was reduced in mouse islet grafts after STZ injection. In contrast, in human islet grafts beta cell death and mass did not change after STZ injection. Mice transplanted with rodent islets developed hyperglycemia after STZ-injection. Mice transplanted with human islets remained normoglycemic and developed hyperglycemia when the graft was harvested. STZ had no detectable toxic effects on beta cell death, mass and function of human transplanted islets. We provide a new, more convenient and cost-saving model for human islet transplantation to STZ-diabetic recipients in which STZ is injected after islet transplantation.
Abstract Background: Liraglutide, a human glucagon-like peptide 1 (GLP-1) analogue that has received marketing approval from the European Commission, is a treatment for type 2 diabetes mellitus (DM) ...that is administered as a once-daily subcutaneous injection. Objective: The aim of this review was to summarize the efficacy and safety data published about liraglutide, focusing on data from Phase III clinical trials. Methods: Relevant English-language publications were identified through a search of MEDLINE and EMBASE (from 1948 to October 2009). The search terms included the following: GLP-1, incretin effect, liraglutide, NN2211, exenatide, sitagliptin , and vildagliptin . Original research papers about liraglutide that were published in peer-reviewed journals were considered. Results: The literature search identified 39 relevant publications. The efficacy and tolerability of oncedaily liraglutide at doses of 0.6, 1.2, and 1.8 mg for type 2 DM, in combination with, and compared with, other type 2 DM treatments were investigated in the Liraglutide Effect and Action in Diabetes (LEAD) Phase III clinical trial program. In the LEAD studies, consistent reductions in glycosylated hemoglobin (HbA1c ) of up to 1.6% were seen with liraglutide, and up to 66% of patients achieved the HbA1c goal of <7%. Fasting and postprandial plasma glucose levels were also consistently reduced across the LEAD trials by up to 43 mg/dL (2.4 mmol/L) and 49 mg/dL (2.7 mmol/L), respectively. Hypoglycemia was reported at a rate of 0.03 to 1.9 events per patient annually. Liraglutide significantly improved β-cell function, as measured by homeostasis model assessment for β-cell function analysis (20%–44%) and by ratios of pro-insulin to insulin (−0.11 to 0.01). Consistent reductions in systolic blood pressure up to 6.7 mm Hg were also observed for liraglutide treatment. Liraglutide treatment, as monotherapy and in combination with oral antidiabetic drugs (OADs), was associated with weight loss of up to 3.24 kg. Overall, liraglutide was well tolerated. Nausea was the most common adverse event observed with liraglutide treatment, reported by 5% to 29% of patients; however, nausea was generally mild and transient. Conclusion: Once-daily liraglutide was effective and well tolerated when used as monotherapy or in combination with OADs in patients with type 2 DM, and is therefore a promising new treatment option for the management of type 2 DM.
Exposure to air particulate matter has been linked with hypertension and blood pressure levels. The metabolic risks of air pollution could vary according to the specific characteristics of each area, ...and has not been sufficiently evaluated in Spain. We analyzed 1103 individuals, participants in a Spanish nationwide population based cohort study (di@bet.es), who were free of hypertension at baseline (2008-2010) and completed a follow-up exam of the cohort (2016-2017). Cohort participants were assigned air pollution concentrations for particulate matter < 10 μm (PM
) and < 2.5 μm (PM
) during follow-up (2008-2016) obtained through modeling combined with measurements taken at air quality stations (CHIMERE chemistry-transport model). Mean and SD concentrations of PM
and PM
were 20.17 ± 3.91 μg/m
and 10.83 ± 2.08 μg/m
respectively. During follow-up 282 cases of incident hypertension were recorded. In the fully adjusted model, compared with the lowest quartile of PM
the multivariate weighted ORs (95% CIs) for developing hypertension with increasing PM
exposures were 0.82 (0.59-1.14), 1.28 (0.93-1.78) and 1.45 (1.05-2.01) in quartile 2, 3 and 4 respectively (p for a trend of 0.003). The corresponding weighted ORs according to PM
exposures were 0.80 (0.57-1.13), 1.11 (0.80-1.53) and 1.48 (1.09-2.00) (p for trend 0.004). For each 5-μg/m
increment in PM
and PM
concentrations, the odds for incident hypertension increased 1.22 (1.06-1.41) p = 0.007 and 1.39 (1.07-1.81) p = 0.02 respectively. In conclusion, our study contributes to assessing the impact of particulate pollution on the incidence of hypertension in Spain, reinforcing the need for improving air quality as much as possible in order to decrease the risk of cardiometabolic disease in the population.
β-cells undergo an epithelial to mesenchymal transition (EMT) when expanded in monolayer culture and give rise to highly proliferative mesenchymal cells that retain the potential to re-differentiate ...into insulin-producing cells.
To investigate whether EMT takes place in the endocrine non-β cells of human islets.
Human islets isolated from 12 multiorgan donors were dissociated into single cells, purified by magnetic cell sorting, and cultured in monolayer.
Co-expression of insulin and the mesenchymal marker vimentin was identified within the first passage (p1) and increased subsequently (insulin+vimentin+ 7.2±6% at p1; 43±15% at p4). The endocrine non-β-cells did also co-express vimentin (glucagon+vimentin+ 59±1.5% and 93±6%, somatostatin+vimentin+ 16±9.4% and 90±10% at p1 and p4 respectively; PP+vimentin+ 74±14% at p1; 88±12% at p2). The percentage of cells expressing only endocrine markers was progressively reduced (0.6±0.2% insulin+, 0.2±0.1% glucagon+, and 0.3±0.2% somatostatin+ cells at p4, and 0.7±0.3% PP+ cells at p2. Changes in gene expression were also indicated of EMT, with reduced expression of endocrine markers and the epithelial marker CDH-1 (p<0.01), and increased expression of mesenchymal markers (CDH-2, SNAI2, ZEB1, ZEB2, VIM, NT5E and ACTA2; p<0.05). Treatment with the EMT inhibitor A83-01 significantly reduced the percentage of co-expressing cells and preserved the expression of endocrine markers.
In adult human islets, all four endocrine islet cell types undergo EMT when islet cells are expanded in monolayer conditions. The presence of EMT in all islet endocrine cells could be relevant to design of strategies aiming to re-differentiate the expanded islet cells towards a β-cell phenotype.
Background and Objective
Use of self‐reported questionnaires in Dentistry may be useful to estimate the prevalence of periodontitis in epidemiological studies. This study aims to assess the accuracy ...of self‐reporting for predicting the prevalence of periodontitis in a Spanish population participating in a diabetes incidence study.
Materials and Methods
Data were collected from 231 patients participating in the Di@bet.es study. Eight questions about periodontal health were included in a health patient‐reported questionnaire. The outcomes from self‐reporting were validated against a full‐mouth periodontal examination. Multivariable logistic regression predictive modeling was used to determine the sensitivity, specificity, and area under the receiver operator characteristic curve (AUROCC).
Results
Self‐reported gum health, loose teeth, tooth appearance, and use of dental floss were associated with different definitions of severe periodontitis. Correlations between responses to the questions were weak. The question “Do you think you might have gum disease?” combined with demographic and well‐established risk factors resulted in an AUC value of 0.75, sensitivity of 75.2%, and specificity of 60.6% for severe periodontitis. The answer to 4 questions combined with age, educational level, smoking status, and tooth loss was 76.4% sensitive and 63.5% specific, with an AUC of 0.75 in predicting prevalence of ≥25% of teeth with probing pocket depth (PPD) ≥6 mm.
Conclusion
Predictive models, combining self‐reporting on oral health status with demographic and risk factors, were useful for estimating the prevalence of severe periodontitis in the Spanish population.
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