The Role of Inflammation in Diabetes: Current Concepts and Future Perspectives

Ridker P.M., Everett B.M., Pradhan A., MacFadyen J.G., Solomon D.H., Zaharris E., Mam V., Hasan A., Rosenberg Y., Iturriaga E., Gupta M., Tsigoulis M., Verma S., Clearfield M., Libby P., et. al.

Inflammation is causally related to atherothrombosis. Treatment with canakinumab, a monoclonal antibody that inhibits inflammation by neutralizing interleukin-1β, resulted in a lower rate of cardiovascular events than placebo in a previous randomized trial. We sought to determine whether an alternative approach to inflammation inhibition with low-dose methotrexate might provide similar benefit.We conducted a randomized, double-blind trial of low-dose methotrexate (at a target dose of 15 to 20 mg weekly) or matching placebo in 4786 patients with previous myocardial infarction or multivessel coronary disease who additionally had either type 2 diabetes or the metabolic syndrome. All participants received 1 mg of folate daily. The primary end point at the onset of the trial was a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Near the conclusion of the trial, but before unblinding, hospitalization for unstable angina that led to urgent revascularization was added to the primary end point.The trial was stopped after a median follow-up of 2.3 years. Methotrexate did not result in lower interleukin-1β, interleukin-6, or C-reactive protein levels than placebo. The final primary end point occurred in 201 patients in the methotrexate group and in 207 in the placebo group (incidence rate, 4.13 vs. 4.31 per 100 person-years; hazard ratio, 0.96; 95% confidence interval [CI], 0.79 to 1.16). The original primary end point occurred in 170 patients in the methotrexate group and in 167 in the placebo group (incidence rate, 3.46 vs. 3.43 per 100 person-years; hazard ratio, 1.01; 95% CI, 0.82 to 1.25). Methotrexate was associated with elevations in liver-enzyme levels, reductions in leukocyte counts and hematocrit levels, and a higher incidence of non-basal-cell skin cancers than placebo.Among patients with stable atherosclerosis, low-dose methotrexate did not reduce levels of interleukin-1β, interleukin-6, or C-reactive protein and did not result in fewer cardiovascular events than placebo. (Funded by the National Heart, Lung, and Blood Institute; CIRT ClinicalTrials.gov number, NCT01594333.).

Everett B.M., Donath M.Y., Pradhan A.D., Thuren T., Pais P., Nicolau J.C., Glynn R.J., Libby P., Ridker P.M.

Subclinical inflammation mediated in part by interleukin (IL)-1β participates in peripheral insulin resistance and impaired pancreatic insulin secretion. The authors tested the hypothesis that the IL-1β inhibitor canakinumab reduces incident diabetes. The authors randomized 10,061 patients with prior myocardial infarction and high-sensitivity C-reactive protein (hsCRP) ≥2 mg/l to placebo or canakinumab at doses of 50 mg, 150 mg, or 300 mg subcutaneously once every 3 months. The authors tested the effects of canakinumab on major cardiovascular events in patients with and without diabetes at baseline, and evaluated as a pre-specified analysis whether canakinumab would reduce the risk of adjudicated cases of new-onset type 2 diabetes among those with protocol-defined pre-diabetes at trial entry. The authors also evaluated the effect of canakinumab on fasting plasma glucose and glycosylated hemoglobin (HbA 1c ) in patients with and without established diabetes. Of the participants, 4,057 (40.3%) had baseline diabetes, 4,960 (49.3%) had pre-diabetes, and 1,044 (10.4%) had normal glucose levels. Among those without diabetes, increasing tertiles of hsCRP at baseline associated with an increased risk of developing diabetes during the median follow-up period of 3.7 years (incidence rates 3.2, 4.1, and 4.4 per 100 person-years; p = 0.003). Canakinumab 150 mg as compared with placebo had similar magnitude effects on major cardiovascular event rates among those with diabetes (hazard ratio [HR]: 0.85; 95% confidence interval [CI]: 0.70 to 1.03), pre-diabetes (HR: 0.86; 95% CI: 0.70 to 1.06), and normoglycemia (HR: 0.81; 95% CI: 0.49 to 1.35). Despite large reductions in hsCRP and IL-6, canakinumab did not reduce the incidence of new-onset diabetes, with rates per 100 person-years in the placebo, 50 mg, 150 mg, and 300 mg canakinumab groups of 4.2, 4.2, 4.4, and 4.1, respectively (log-rank p = 0.84). The HR comparing all canakinumab doses to placebo was 1.02 (95% CI: 0.87 to 1.19; p = 0.82). Canakinumab reduced HbA 1c during the first 6 to 9 months of treatment, but no consistent long-term benefits on HbA 1c or fasting plasma glucose were observed. Although IL-1β inhibition with canakinumab had similar effects on major cardiovascular events among those with and without diabetes, treatment over a median period of 3.7 years did not reduce incident diabetes. (Canakinumab Anti-inflammatory Thrombosis Outcomes Study [CANTOS]; NCT01327846 )

The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes” includes ADA’s current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA’s clinical practice recommendations, please refer to the Standards of Care Introduction. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

Alhadj Ali M., Liu Y., Arif S., Tatovic D., Shariff H., Gibson V.B., Yusuf N., Baptista R., Eichmann M., Petrov N., Heck S., Yang J.H., Tree T.I., Pujol-Autonell I., Yeo L., et. al.

Immunotherapy using peptide from the self-antigen proinsulin is safe in type 1 diabetes and is associated with changes in immune regulation.

Antonopoulos A.S., Tousoulis D.

Clinical observations suggest a complex relationship between human obesity and cardiovascular disease. Whilst abdominal (visceral) adiposity leads to deleterious metabolic disturbances, subcutaneous fat accumulation has a benign effect on cardiometabolic risk. Notably, an accumulating body of evidence paradoxically links increased body mass index with a better prognosis in patients with established cardiovascular disease, a finding that has been termed the 'obesity paradox'. Whilst this is now acknowledged to be an epidemiological finding, a metabolically healthy obese group associated with low cardiovascular risk has also been identified. The current concept of adipose tissue (AT) biology suggests that AT expansion is feasible without accompanying adipocyte dysfunction. A metabolically healthy obese phenotype can be promoted by exercise, but is also linked with intrinsic AT molecular characteristics such as efficient fat storage and lipid droplet formation, high adipogenesis capacity, low extracellular matrix fibrosis, angiogenesis potential, adipocyte browning and low macrophages infiltration/activation. Such features are associated with a secretomic profile of human AT which is protective for the cardiovascular system. In the present review, we summarize the existing knowledge on the molecular mechanisms underlying the 'obesity paradox' and whether fatness can be healthy too.

Scheithauer T.P., Dallinga-Thie G.M., de Vos W.M., Nieuwdorp M., van Raalte D.H.

The twin pandemics of obesity and Type 2 diabetes (T2D) are a global challenge for health care systems. Changes in the environment, behavior, diet, and lifestyle during the last decades are considered the major causes. A Western diet, which is rich in saturated fat and simple sugars, may lead to changes in gut microbial composition and physiology, which have recently been linked to the development of metabolic diseases.We will discuss evidence that demonstrates the influence of the small and large intestinal microbiota on weight regulation and the development of insulin resistance, based on literature search.Altered large intestinal microbial composition may promote obesity by increasing energy harvest through specialized gut microbes. In both large and small intestine, microbial alterations may increase gut permeability that facilitates the translocation of whole bacteria or endotoxic bacterial components into metabolic active tissues. Moreover, changed microbial communities may affect the production of satiety-inducing signals. Finally, bacterial metabolic products, such as short chain fatty acids (SCFAs) and their relative ratios, may be causal in disturbed immune and metabolic signaling, notably in the small intestine where the surface is large. The function of these organs (adipose tissue, brain, liver, muscle, pancreas) may be disturbed by the induction of low-grade inflammation, contributing to insulin resistance.Interventions aimed to restoring gut microbial homeostasis, such as ingestion of specific fibers or therapeutic microbes, are promising strategies to reduce insulin resistance and the related metabolic abnormalities in obesity, metabolic syndrome, and type 2 diabetes. This article is part of a special issue on microbiota.

Alvarez-Curto E., Milligan G.

There are significant numbers of nutrient sensing G protein-coupled receptors (GPCRs) that can be found in cells of the immune system and in tissues that are involved in metabolic function, such as the pancreas or the intestinal epithelium. The family of free fatty acid receptors (FFAR1-4, GPR84), plus a few other metabolite sensing receptors (GPR109A, GPR91, GPR35) have been for this reason the focus of studies linking the effects of nutrients with immunological responses. A number of the beneficial anti-inflammatory effects credited to dietary fats such as omega-3 fatty acids are attributed to their actions on FFAR4.This might play an important protective role in the development of obesity, insulin resistance or asthma. The role of the short-chain fatty acids resulting from fermentation of fibre by the intestinal microbiota in regulating acute inflammatory responses is also discussed. Finally we assess the therapeutic potential of this family of receptors to treat pathologies where inflammation is a major factor such as type 2 diabetes, whether by the use of novel synthetic molecules or by the modulation of the individual's diet.

Chow L.S., Odegaard A.O., Bosch T.A., Bantle A.E., Wang Q., Hughes J., Carnethon M., Ingram K.H., Durant N., Lewis C.E., Ryder J., Shay C.M., Kelly A.S., Schreiner P.J.

The prospective association between cardiorespiratory fitness (CRF) measured in young adulthood and middle age on development of prediabetes, defined as impaired fasting glucose and/or impaired glucose tolerance, or diabetes by middle age remains unknown. We hypothesised that higher fitness levels would be associated with reduced risk for developing incident prediabetes/diabetes by middle age. Participants were from the Coronary Artery Risk Development in Young Adults (CARDIA) study who were free from prediabetes/diabetes at baseline (year 0 [Y0]: 1985–1986). CRF was quantified by treadmill duration (converted to metabolic equivalents [METs]) at Y0, Y7 and Y20 and prediabetes/diabetes status was assessed at Y0, Y7, Y10, Y15, Y20 and Y25. We use an extended Cox model with CRF as the primary time-varying exposure. BMI was included as a time-varying covariate. The outcome was development of either prediabetes or diabetes after Y0. Model 1 included age, race, sex, field centre, CRF and BMI. Model 2 additionally included baseline (Y0) smoking, energy intake, alcohol intake, education, systolic BP, BP medication use and lipid profile. Higher fitness was associated with lower risk for developing incident prediabetes/diabetes (difference of 1 MET: HR 0.99898 [95% CI 0.99861, 0.99940], p < 0.01), which persisted (difference of 1 MET: HR 0.99872 [95% CI 0.99840, 0.99904], p < 0.01] when adjusting for covariates. Examining participants who had fitness measured from young adulthood to middle age, we found that fitness was associated with lower risk for developing prediabetes/diabetes, even when adjusting for BMI over this time period. These findings emphasise the importance of fitness in reducing the health burden of prediabetes and diabetes.

Guirguis-Blake J.M., Evans C.V., Senger C.A., O'Connor E.A., Whitlock E.P.

Cardiovascular disease (CVD) is the leading cause of death in the United States.To update a systematic review about the benefits of aspirin for the primary prevention of cardiovascular events in adults aged 40 years or older and to evaluate effect modification in subpopulations.MEDLINE, PubMed, Cochrane Central Register of Controlled Trials (January 2008 to January 2015), and Cochrane Database of Systematic Reviews.Two investigators independently reviewed 3396 abstracts and 65 articles according to prespecified criteria. All included trials evaluated aspirin for the primary prevention of cardiovascular events.Two investigators assessed study quality; data were abstracted by 1 reviewer and checked by a second.Two good-quality and 9 fair-quality randomized, controlled trials were identified. In analyses of all doses, aspirin reduced the risk for nonfatal myocardial infarction (MI) (relative risk [RR], 0.78 [95% CI, 0.71 to 0.87]) but not nonfatal stroke; aspirin showed little or no benefit for all-cause or cardiovascular mortality. Benefits began within the first 5 years. Older adults achieved greater relative MI reduction, but no other effect modifications were found in analyzed subpopulations. In trials with aspirin doses of 100 mg or less per day, the reduction in nonfatal MI benefit persisted (absolute risk reduction, 0.15 to 1.43 events per 1000 person-years) and a 14% reduction in nonfatal stroke benefit was noted, but no benefit was found for all-cause mortality (RR, 0.95 [CI, 0.89 to 1.01]) or cardiovascular mortality (RR, 0.97 [CI, 0.85 to 1.10]).Evidence for aspirin in primary prevention is heterogeneous and limited by rare events and few credible subgroup analyses.The beneficial effect of aspirin for the primary prevention of CVD is modest and occurs at doses of 100 mg or less per day. Older adults seem to achieve a greater relative MI benefit.Agency for Healthcare Research and Quality.

Derosa G., Maffioli P., Sahebkar A.

Aims To conduct a systematic review and meta-analysis of relevant randomized clinical trials (RCTs) to ascertain the effect size of orlistat in modulating plasma levels of adipokines, ghrelin and C-reactive protein (CRP). Methods Medline, SCOPUS, Web of Science and Google Scholar databases were searched. A random-effects model and the generic inverse variance method were used for quantitative data synthesis. Heterogeneity was quantitatively assessed using I2 index. Sensitivity analyses were conducted using the one-study remove approach. Random-effects meta-regression was performed using unrestricted maximum likelihood method to evaluate the impact of duration of treatment, percentage change in body mass index (BMI) and baseline BMI values as potential confounders of the estimated effect size. Results Meta-analysis suggested a significant increase in plasma levels of adiponectin [weighted mean difference (WMD): 19.18%, 95% confidence interval (CI): 5.80, 32.57, p = 0.005] and significant reductions in plasma levels of leptin (WMD: −13.24%, 95% CI: −20.69, −5.78, p = 0.001) and CRP (WMD: −11.52%, 95% CI: −16.55, −6.49, p < 0.001) following treatment with orlistat. In meta-regression, changes in plasma concentrations of adiponectin, leptin and CRP were associated with duration of treatment, but not with either change in BMI or baseline BMI values. Conclusion Orlistat is effective in increasing plasma concentrations of adiponectin and decreasing those of leptin and CRP.

Cabrera S.M., Wang X., Chen Y., Jia S., Kaldunski M.L., Greenbaum C.J., Mandrup-Poulsen T., Hessner M.J.

It was hypothesized that IL-1 antagonism would preserve β-cell function in new onset Type 1 diabetes (T1D). However, the Anti-Interleukin-1 in Diabetes Action (AIDA) and TrialNet Canakinumab (TN-14) trials failed to show efficacy of IL-1 receptor antagonist (IL-1Ra) or canakinumab, as measured by stimulated C-peptide response. Additional measures are needed to define immune state changes associated with therapeutic responses. Here, we studied these trial participants with plasma-induced transcriptional analysis. In blinded analyses, 70.2% of AIDA and 68.9% of TN-14 participants were correctly called to their treatment arm. While the transcriptional signatures from the two trials were distinct, both therapies achieved varying immunomodulation consistent with IL-1 inhibition. On average, IL-1 antagonism resulted in modest normalization relative to healthy controls. At endpoint, signatures were quantified using a gene ontology-based inflammatory index, and an inverse relationship was observed between measured inflammation and stimulated C-peptide response in IL-1Ra- and canakinumab-treated patients. Cytokine neutralization studies showed that IL-1α and IL-1β additively contribute to the T1D inflammatory state. Finally, analyses of baseline signatures were indicative of later therapeutic response. Despite the absence of clinical efficacy by IL-1 antagonist therapy, transcriptional analysis detected immunomodulation and may yield new insight when applied to other clinical trials.

Hersoug L.-., Møller P., Loft S.

The composition of the gut microbiota and excessive ingestion of high-fat diets (HFD) are considered to be important factors for development of obesity. In this review we describe a coherent mechanism of action for the development of obesity, which involves the composition of gut microbiota, HFD, low-grade inflammation, expression of fat translocase and scavenger receptor CD36, and the scavenger receptor class B type 1 (SR-BI). SR-BI binds to both lipids and lipopolysaccharide (LPS) from Gram-negative bacteria, which may promote incorporation of LPS in chylomicrons (CMs). These CMs are transported via lymph to the circulation, where LPS is transferred to other lipoproteins by translocases, preferentially to HDL. LPS increases the SR-BI binding, transcytosis of lipoproteins over the endothelial barrier,and endocytosis in adipocytes. Especially large size adipocytes with high metabolic activity absorb LPS-rich lipoproteins. In addition, macrophages in adipose tissue internalize LPS-lipoproteins. This may contribute to the polarization from M2 to M1 phenotype, which is a consequence of increased LPS delivery into the tissue during hypertrophy. In conclusion, evidence suggests that LPS is involved in the development of obesity as a direct targeting molecule for lipid delivery and storage in adipose tissue.

Nastasi C., Candela M., Bonefeld C.M., Geisler C., Hansen M., Krejsgaard T., Biagi E., Andersen M.H., Brigidi P., Ødum N., Litman T., Woetmann A.

The gut microbiota is essential for human health and plays an important role in the pathogenesis of several diseases. Short-chain fatty acids (SCFA), such as acetate, butyrate and propionate, are end-products of microbial fermentation of macronutrients that distribute systemically via the blood. The aim of this study was to investigate the transcriptional response of immature and LPS-matured human monocyte-derived DC to SCFA. Our data revealed distinct effects exerted by each individual SCFA on gene expression in human monocyte-derived DC, especially in the mature ones. Acetate only exerted negligible effects, while both butyrate and propionate strongly modulated gene expression in both immature and mature human monocyte-derived DC. An Ingenuity pathway analysis based on the differentially expressed genes suggested that propionate and butyrate modulate leukocyte trafficking, as SCFA strongly reduced the release of several pro-inflammatory chemokines including CCL3, CCL4, CCL5, CXCL9, CXCL10 and CXCL11. Additionally, butyrate and propionate inhibited the expression of lipopolysaccharide (LPS)-induced cytokines such as IL-6 and IL-12p40 showing a strong anti-inflammatory effect. This work illustrates that bacterial metabolites far from the site of their production can differentially modulate the inflammatory response and generally provides new insights into host-microbiome interactions.

van Asseldonk E.J., van Poppel P.C., Ballak D.B., Stienstra R., Netea M.G., Tack C.J.

Inflammation associated with obesity is involved in the development of insulin resistance. We hypothesized that anti-inflammatory treatment with the Interleukin-1 receptor antagonist anakinra would improve insulin sensitivity. In an open label proof-of-concept study, we included overweight patients diagnosed with type 1 diabetes with an HbA1c level over 7.5%. Selecting insulin resistant patients with longstanding type 1 diabetes allowed us to study the effects of anakinra on insulin sensitivity. Patients were treated with 100mg anakinra daily for one week. Insulin sensitivity, insulin need and blood glucose profiles were measured before, after one week and after four weeks of follow-up. Fourteen patients completed the study. One week of anakinra treatment led to an improvement of insulin sensitivity, an effect that was sustained for four weeks. Similarly, glucose profiles, HbA1c levels and insulin needs improved. In conclusion, one week of treatment with anakinra improves insulin sensitivity in patients with type 1 diabetes.

Sidossis L., Kajimura S.

Brown adipose tissue (BAT), a specialized fat that dissipates energy to produce heat, plays an important role in the regulation of energy balance. Two types of thermogenic adipocytes with distinct developmental and anatomical features exist in rodents and humans: classical brown adipocytes and beige (also referred to as brite) adipocytes. While classical brown adipocytes are located mainly in dedicated BAT depots of rodents and infants, beige adipocytes sporadically reside with white adipocytes and emerge in response to certain environmental cues, such as chronic cold exposure, a process often referred to as "browning" of white adipose tissue. Recent studies indicate the existence of beige adipocytes in adult humans, making this cell type an attractive therapeutic target for obesity and obesity-related diseases, including type 2 diabetes. This Review aims to cover recent progress in our understanding of the anatomical, developmental, and functional characteristics of brown and beige adipocytes and discuss emerging questions, with a special emphasis on adult human BAT.

Rehman G., Sher A., Rauf A., Shah Z.A., Alsanie W.F., Alamri A.S., Alhomrani M., Ribaudo G.

Baltramonaityte V., Karhunen V., Felix J.F., Penninx B.W., Cecil C.A., Fairchild G., Milaneschi Y.

Wang Z., Wang G., Zhao D., Fu Q.

Singh A.K., Rana H.K., Sharma R., Pandey A.K.

Luong T., Yang S., Kim J.

Monahan R.C., Li-Gao R., Noordam R., van der Velde J.H., Willems van Dijk K., de Koning E., Mook-Kanamori D.O., le Cessie S., Rosendaal F.R., de Mutsert R.

Deng Y., Zhong G., Jin T., Wang J., Peng X., Zhou K., Chen X., Cao X.

Soremekun C., Jjingo D., Kateete D., Nash O., Nitsch D., Nyirenda M., Gill D., Zeggini E., Grallert H., Peters A., Chikowore T., Batini C., Soremekun O., Fatumo S.

IntroductionObservational studies have identified associations between hematological traits and type-2 diabetes mellitus (T2D). However, it is difficult to infer causal effects due to the potential of confounding. Our study utilizes the Mendelian randomization (MR) approach to address the above limitation and investigate the causal effect of hematological traits such as white blood cell (WBC), platelets (PLT), and red blood cell (RBC) on T2D in individuals of African ancestry.MethodsThe participating cohorts included participants of African ancestry in the Blood Cell consortium and the Million Veteran Program dataset. Using GWAS summary statistics, we applied a univariable and multivariable Two-sample MR to estimate the causal relationship between hematological traits and T2D.ResultsIn the main IVW MR estimates, genetically predicted levels of mean corpuscular hemoglobin concentration (MCHC), mean corpuscular hemoglobin (MCH), and mean corpuscular volume (MCV) were associated with decreased risk of T2D. We also observed a decreased risk of T2D with genetically predicted total WBC count and neutrophil count (NEU), for the WBC traits. The multivariable analysis further supported the direct associations of genetically predicted MCH, MCHC, and MCV levels with a decreased risk of T2D. For the European ancestry, a similar pattern of association was observed for MCH and MCV.DiscussionThese findings indicate that hematological traits may differentially play a role in the development of T2D and be affected by T2D. However, further research is needed to validate and explore the biological pathways and mechanisms involved in these associations.

Tenore G., Mohsen A., Ricciotti A., Piombarolo G., Podda G.M., Di Gioia C.R., Romeo U.

IntroductionThe association between diabetes mellitus (DM) and oral lichen planus (OLP) has been widely reported. However, most of the studies focused on epidemiological aspects and shared inflammatory pathways, with few exploring the consequences of this association on the clinical course of OLP. The study aims to retrospectively observe the impact of DM on the clinical presentation and management strategy of OLP.MethodsA total of 97 OLP patients were retrieved from the Department database. The patients were distributed into two groups: OLP patients with DM “test group” (n = 47) and OLP patients without DM “control group” (n = 50). The descriptive and statistical analyses were performed on the variables related to the clinical presentation of OLP, the management of OLP, and the general and demographic information.ResultsRegarding primary outcomes related to the clinical presentation variables, DM patients were symptomatic and more susceptible to present atrophic lesions at the first visit, compared to those without DM with a statistical significance (p = 0.0017 and p = 0.0016 respectively). Buccal mucosa was generally the most affected site in both groups and was notably higher in patients with DM (p = 0.0286). Regarding the management variables, DM patients were subjected to a higher number of follow-ups per year (p = 0.0420), a higher number of prescribed general treatments per year (p = 0.0006), and a higher number of prescribed non-cortisone-based treatments per year (p = 0.0001). In regard to the secondary outcomes related to the general and demographic variables, a statistically significant difference was observed with concomitant diseases, where patients with DM were more susceptible to concomitant diseases (p = 0.0321), particularly cardiopathy (p = 0.0422), arterial hypertension (p = 0.0418), dyslipidemia (p = 0.0411), and coagulopathy (p = 0.0411).DiscussionDM patients were highly presented with symptomatic OLP and showed a difference in the management strategy where more follow-ups and treatment prescriptions were needed. It seems that the clinician should consider DM as an essential co-factor that may influence the management procedures of OLP. Considering interdisciplinary management and involving endocrinologists may add significant value to the OLP management process.

Kumar M., Wasnik A., Sagar V., Priya N., Kujur A., Kumar D.

Abstract Diabetes is undeniably one of the most prevalent global health problems with a high risk burden. The present forms of management, insulin administration and lifestyle changes, may address the origins and consequences of the disease to some extent, but the answers are still far from being complete. This phenomenon is bringing in a rising number of people who seek for new therapies and immunization. Through the years, vaccine usage for prevention of infectious diseases has been researched for its potential use in the delay, prevention, or reversal of diabetes. These vaccines, which aim at different processes, including autoimmunity, inflammation, and insulin resistance, play a role in both Type 1 and Type 2 diabetes. Among the candidates for vaccine types are the IA-2 peptide vaccines, glucose-regulating vaccines, incretin-based vaccines, and protein-based vaccines. In this review, we offer a snapshot of the current efforts in diabetes vaccine development, describing the target molecules on the antigens, their mechanisms of action, and the research progress status. It highlights the imperativeness of importance of ongoing investigations for the invention of vaccines as well as the provision of new therapeutic options for diabetic persons.

Wang H., Gu L., Ma Y., Xing X., Qu Y., Shi X., Liu X., Wan H., Zhu Q., Shen Y., Chen C., Su L., Wang Y., Liu K.

Nanjundamoorthi D., Soni M.

Background and Aims: Large unstained cells (LUCs) are peroxidase negative mononuclear cells which include large lymphocytes in healthy individuals, peroxidase negative blasts, plasma cells and atypical lymphoid cells. This study aims to assess the causes for elevated LUC% in ADVIA 2120i by rapid peripheral smear review. Materials and Methods: All consecutive anticoagulated blood samples with LUC% >4%, from June 2022 to March 2024, were processed in ADVIA 2120i, and demographic factors, LUC parameters and peripheral smear observations were documented under six diagnostic disease categories. Statistical analysis was performed using SPSS software (IBM, 28.0). Results: The median LUC count of 0.5 × 10 3 cells/µL with an inter-quartile range of 0.2–2.3 × 10 3 cells/µL of blood was observed in haematolymphoid neoplasms. There was a significant overlap of %LUC values among different categories. The majority (69.6%) had % LUC between 4.1% and 9.9%. Marked elevations were observed in AML, CML, ALL and infections. Conclusion: Absolute LUC count could be used as a cost-effective and readily available marker to identify a case of clinically suspicious haematolymphoid neoplasm with LUC count more than or equal to 0.5 × 10 3 cells/µL of blood in conjunction with other complete blood count parameters. However, reflex peripheral smear testing is mandatory in the current setting for confirmation.

Julius A., Malakondaiah S., Pothireddy R.B.

She Y., Wang C., Fu L., Luo L., Li Y.

Alzaabi A.A., Alzaabi F.M., Al Tarawneh D.J., Al Tarawneh Y.J., Khan A., Khan M.A., Siddiqui T.W., Siddiqui R.W., Nishat S.M., Siddiqui S.W.