Inflammation in obesity, diabetes, and related disorders.

Obesity leads to chronic, systemic inflammation and can lead to insulin resistance (IR), ß-cell dysfunction, and ultimately type 2 diabetes (T2D). This chronic inflammatory state contributes to long-term complications of diabetes, including non-alcoholic fatty liver disease (NAFLD), retinopathy, cardiovascular disease, and nephropathy, and may underlie the association of type 2 diabetes with other conditions such as Alzheimer's disease, polycystic ovarian syndrome, gout, and rheumatoid arthritis. Here, we review the current understanding of the mechanisms underlying inflammation in obesity, T2D, and related disorders. We discuss how chronic tissue inflammation results in IR, impaired insulin secretion, glucose intolerance, and T2D and review the effect of inflammation on diabetic complications and on the relationship between T2D and other pathologies. In this context, we discuss current therapeutic options for the treatment of metabolic disease, advances in the clinic and the potential of immune-modulatory approaches.

Pleiotropic consequences of metabolic stress for the major histocompatibility complex class II molecule antigen processing and presentation machinery.

Hyperglycemia and hyperlipidemia are often observed in individuals with type II diabetes (T2D) and related mouse models. One dysmetabolic biochemical consequence is the non-enzymatic reaction between sugars, lipids, and proteins, favoring protein glycation, glycoxidation, and lipoxidation. Here, we identified oxidative alterations in key components of the major histocompatibility complex (MHC) class II molecule antigen processing and presentation machinery in vivo under conditions of hyperglycemia-induced metabolic stress. These modifications were linked to epitope-specific changes in endosomal processing efficiency, MHC class II-peptide binding, and DM editing activity. Moreover, we observed some quantitative and qualitative changes in the MHC class II immunopeptidome of Ob/Ob mice on a high-fat diet compared with controls, including changes in the presentation of an apolipoprotein B100 peptide associated previously with T2D and metabolic syndrome-related clinical complications. These findings highlight a link between glycation reactions and altered MHC class II antigen presentation that may contribute to T2D complications.

Postprandial macrophage-derived IL-1ß stimulates insulin, and both synergistically promote glucose disposal and inflammation.

The deleterious effect of chronic activation of the IL-1ß system on type 2 diabetes and other metabolic diseases is well documented. However, a possible physiological role for IL-1ß in glucose metabolism has remained unexplored. Here we found that feeding induced a physiological increase in the number of peritoneal macrophages that secreted IL-1ß, in a glucose-dependent manner. Subsequently, IL-1ß contributed to the postprandial stimulation of insulin secretion. Accordingly, lack of endogenous IL-1ß signaling in mice during refeeding and obesity diminished the concentration of insulin in plasma. IL-1ß and insulin increased the uptake of glucose into macrophages, and insulin reinforced a pro-inflammatory pattern via the insulin receptor, glucose metabolism, production of reactive oxygen species, and secretion of IL-1ß mediated by the NLRP3 inflammasome. Postprandial inflammation might be limited by normalization of glycemia, since it was prevented by inhibition of the sodium-glucose cotransporter SGLT2. Our findings identify a physiological role for IL-1ß and insulin in the regulation of both metabolism and immunity.

Immunometabolism of regulatory T cells.

The bidirectional interaction between the immune system and whole-body metabolism has been well recognized for many years. Via effects on adipocytes and hepatocytes, immune cells can modulate whole-body metabolism (in metabolic syndromes such as type 2 diabetes and obesity) and, reciprocally, host nutrition and commensal-microbiota-derived metabolites modulate immunological homeostasis. Studies demonstrating the metabolic similarities of proliferating immune cells and cancer cells have helped give birth to the new field of immunometabolism, which focuses on how the cell-intrinsic metabolic properties of lymphocytes and macrophages can themselves dictate the fate and function of the cells and eventually shape an immune response. We focus on this aspect here, particularly as it relates to regulatory T cells.

Helminth Infections and Diabetes: Mechanisms Accounting for Risk Amelioration.

The global prevalence of type 2 diabetes mellitus (T2D) is increasing rapidly, with an anticipated 600 million cases by 2035. While infectious diseases such as helminth infections have decreased due to improved sanitation and health care, recent research suggests a link between helminth infections and T2D, with helminths such as Schistosoma, Nippostrongylus, Strongyloides, and Heligmosomoides potentially mitigating or slowing down T2D progression in human and animal models. Helminth infections enhance host immunity by promoting interactions between innate and adaptive immune systems. In T2D, type 1 immune responses are suppressed and type 2 responses are augmented, expanding regulatory T cells and innate immune cells, particularly type 2 immune cells and macrophages. This article reviews recent research shedding light on the favorable effects of helminth infections on T2D. The potential defense mechanisms identified include heightened insulin sensitivity and reduced inflammation. The synthesis of findings from studies investigating parasitic helminths and their derivatives underscores promising avenues for defense against T2D.

CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation.

Particulate ligands, including cholesterol crystals and amyloid fibrils, induce production of interleukin 1ß (IL-1ß) dependent on the cytoplasmic sensor NLRP3 in atherosclerosis, Alzheimer's disease and diabetes. Soluble endogenous ligands, including oxidized low-density lipoprotein (LDL), amyloid-ß and amylin peptides, accumulate in such diseases. Here we identify an endocytic pathway mediated by the pattern-recognition receptor CD36 that coordinated the intracellular conversion of those soluble ligands into crystals or fibrils, which resulted in lysosomal disruption and activation of the NLRP3 inflammasome. Consequently, macrophages that lacked CD36 failed to elicit IL-1ß production in response to those ligands, and targeting CD36 in atherosclerotic mice resulted in lower serum concentrations of IL-1ß and accumulation of cholesterol crystals in plaques. Collectively, our findings highlight the importance of CD36 in the accrual and nucleation of NLRP3 ligands from within the macrophage and position CD36 as a central regulator of inflammasome activation in sterile inflammation.

Molecular circadian clock disruption in the leukocytes of individuals with type 2 diabetes and overweight, and its relationship with leukocyte-endothelial interactions.

AIMS/HYPOTHESIS: Alterations in circadian rhythms increase the likelihood of developing type 2 diabetes and CVD. Circadian rhythms are controlled by several core clock genes, which are expressed in nearly every cell, including immune cells. Immune cells are key players in the pathophysiology of type 2 diabetes, and participate in the atherosclerotic process that underlies cardiovascular risk in these patients. The role of the core clock in the leukocytes of people with type 2 diabetes and the inflammatory process associated with it are unknown. We aimed to evaluate whether the molecular clock system is impaired in the leukocytes of type 2 diabetes patients and to explore the mechanism by which this alteration leads to an increased cardiovascular risk in this population. METHODS: This is an observational cross-sectional study performed in 25 participants with type 2 diabetes and 28 healthy control participants. Clinical and biochemical parameters were obtained. Peripheral blood leukocytes were isolated using magnetic bead technology. RNA and protein lysates were obtained to assess clock-related gene transcript and protein levels using real-time PCR and western blot, respectively. Luminex XMAP technology was used to assess levels of inflammatory markers. Leukocyte-endothelial interaction assays were performed by perfusing participants' leukocytes or THP-1 cells (with/without CLK8) over a HUVEC monolayer in a parallel flow chamber using a dynamic adhesion system. RESULTS: Participants with type 2 diabetes showed increased BMAL1 and NR1D1 mRNA levels and decreased protein levels of circadian locomotor output cycles kaput (CLOCK), cryptochrome 1 (CRY1), phosphorylated basic helix-loop-helix ARNT like 1 (p-BMAL1) and period circadian protein homologue 2 (PER2). Correlation studies revealed that these alterations in clock proteins were negatively associated with glucose, HbA1c, insulin and HOMA-IR levels and leukocyte cell counts. The leukocyte rolling velocity was reduced and rolling flux and adhesion were enhanced in individuals with type 2 diabetes compared with healthy participants. Interestingly, inhibition of CLOCK/BMAL1 activity in leukocytes using the CLOCK inhibitor CLK8 mimicked the effects of type 2 diabetes on leukocyte-endothelial interactions. CONCLUSIONS/INTERPRETATION: Our study demonstrates alterations in the molecular clock system in leukocytes of individuals with type 2 diabetes, manifested in increased mRNA levels and decreased protein levels of the core clock machinery. These alterations correlated with the impaired metabolic and proinflammatory profile of the participants with type 2 diabetes. Our findings support a causal role for decreased CLOCK/BMAL1 activity in the increased level of leukocyte-endothelial interactions. Overall, our data suggest that alterations in core clock proteins accelerate the inflammatory process, which may ultimately precipitate the onset of CVD in patients with type 2 diabetes.

Amiloride lowers plasma TNF and interleukin-6 but not interleukin-17A in patients with hypertension and type 2 diabetes.

Interleukin (IL)-17A contributes to hypertension in preclinical models. T helper 17 and dendritic cells are activated by NaCl, which could involve the epithelial Na+ channel (ENaC). We hypothesized that the ENaC blocker amiloride reduces plasma IL-17A and related cytokines in patients with hypertension. Concentrations of IL-17A, IFN-γ, TNF, IL-6, IL-1ß, and IL-10 were determined by immunoassays in plasma from two patient cohorts before and after amiloride treatment: 1) patients with type 2 diabetes mellitus (T2DM) and treatment-resistant hypertension (n = 69, amiloride 5-10 mg/day for 8 wk) and 2) patients with hypertension and type 1 diabetes mellitus (T1DM) (n = 29) on standardized salt intake (amiloride 20-40 mg/day, 2 days). Plasma and tissue from ANG II-hypertensive mice with T1DM treated with amiloride (2 mg/kg/day, 4 days) were analyzed. The effect of amiloride and benzamil on macrophage cytokines was determined in vitro. Plasma cytokines showed higher concentrations (IL-17A ∼40-fold) in patients with T2DM compared with T1DM. In patients with T2DM, amiloride had no effect on IL-17A but lowered TNF and IL-6. In patients with T1DM, amiloride had no effect on IL-17A but increased TNF. In both cohorts, blood pressure decline and plasma K+ increase did not relate to plasma cytokine changes. In mice, amiloride exerted no effect on IL-17A in the plasma, kidney, aorta, or left cardiac ventricle but increased TNF in cardiac and kidney tissues. In lipopolysaccharide-stimulated human THP-1 macrophages, amiloride and benzamil (from 1 nmol/L) decreased TNF, IL-6, IL-10, and IL-1ß. In conclusion, inhibition of ENaC by amiloride reduces proinflammatory cytokines TNF and IL-6 but not IL-17A in patients with T2DM, potentially by a direct action on macrophages.NEW & NOTEWORTHY ENaC activity may contribute to macrophage-derived cytokine release, since amiloride exerts anti-inflammatory effects by suppression of TNF and IL-6 cytokines in patients with resistant hypertension and type 2 diabetes and in THP-1-derived macrophages in vitro.

Understanding how pre- and probiotics affect the gut microbiome and metabolic health.

The gut microbiome, a complex assembly of microorganisms, significantly impacts human health by influencing nutrient absorption, the immune system, and disease response. These microorganisms form a dynamic ecosystem that is critical to maintaining overall well-being. Prebiotics and probiotics are pivotal in regulating gut microbiota composition. Prebiotics nourish beneficial bacteria and promote their growth, whereas probiotics help maintain balance within the microbiome. This intricate balance extends to several aspects of health, including maintaining the integrity of the gut barrier, regulating immune responses, and producing metabolites crucial for metabolic health. Dysbiosis, or an imbalance in the gut microbiota, has been linked to metabolic disorders such as type 2 diabetes, obesity, and cardiovascular disease. Impaired gut barrier function, endotoxemia, and low-grade inflammation are associated with toll-like receptors influencing proinflammatory pathways. Short-chain fatty acids derived from microbial fermentation modulate anti-inflammatory and immune system pathways. Prebiotics positively influence gut microbiota, whereas probiotics, especially Lactobacillus and Bifidobacterium strains, may improve metabolic outcomes, such as glycemic control in diabetes. It is important to consider strain-specific effects and study variability when interpreting these findings, highlighting the need for further research to optimize their therapeutic potential. The aim of this report is therefore to review the role of the gut microbiota in metabolic health and disease and the effects of prebiotics and probiotics on the gut microbiome and their therapeutic role, integrating a broad understanding of physiological mechanisms with a clinical perspective.

Serum immunoglobulin concentrations and risk of type 2 diabetes mellitus in adults: a prospective cohort study from the TCLSIH study.

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by hyperglycemia resulting from defects in insulin secretion and/or insulin action. Increasing evidence suggests that inflammation played an important role in the pathogenesis of T2DM. Prospective studies on the link between immunoglobulins concentrations and the risk of T2DM in adults are limited. We developed a cohort study including 7,093 adults without T2DM history. The incidence of T2DM was 16.45 per 1,000 person-years. Compared with the lowest quartiles, the hazard ratios (95% confidence intervals) of T2DM for the highest quartiles of IgG, IgE, IgM and IgA were 0.64 (0.48-0.85), 0.94 (0.72-1.23), 0.68 (0.50-0.92) and 1.62 (1.24-2.11) (P for trend was < 0.01, 0.84, 0.02 and < 0.0001), respectively, suggesting that serum IgG and IgM concentrations were inversely associated with the incidence of T2DM, and IgA levels were positively associated with the risk of T2DM in a general adult population.

Obesity differs from diabetes mellitus in antibody and T-cell responses post-COVID-19 recovery.

OBJECTIVE: Obesity and type 2 diabetes (DM) are risk factors for severe coronavirus disease 2019 (COVID-19) outcomes, which disproportionately affect South Asian populations. This study aims to investigate the humoral and cellular immune responses to SARS-CoV-2 in adult COVID-19 survivors with overweight/obesity (Ov/Ob, BMI ≥ 23 kg/m2) and DM in Bangladesh. METHODS: In this cross-sectional study, SARS-CoV-2-specific antibody and T-cell responses were investigated in 63 healthy and 75 PCR-confirmed COVID-19 recovered individuals in Bangladesh, during the pre-vaccination first wave of the COVID-19 pandemic in 2020. RESULTS: In COVID-19 survivors, SARS-CoV-2 infection induced robust antibody and T-cell responses, which correlated with disease severity. After adjusting for age, sex, DM status, disease severity, and time since onset of symptoms, Ov/Ob was associated with decreased neutralizing antibody titers, and increased SARS-CoV-2 spike-specific IFN-γ response along with increased proliferation and IL-2 production by CD8 + T cells. In contrast, DM was not associated with SARS-CoV-2-specific antibody and T-cell responses after adjustment for obesity and other confounders. CONCLUSION: Ov/Ob is associated with lower neutralizing antibody levels and higher T-cell responses to SARS-CoV-2 post-COVID-19 recovery, while antibody or T-cell responses remain unaltered in DM.

Islet autoantibody frequency in relatives of children with type 1 diabetes who have a type 2 diabetes diagnosis.

AIM: This study aimed to evaluate characteristics of autoimmunity in individuals who have a type 2 diagnosis and are relatives of children with type 1 diabetes. METHODS: Pre-diagnosis samples (median 17 months before onset) from relatives who were later diagnosed with type 2 diabetes were measured for autoantibodies to glutamate decarboxylase 65 (GADA), islet antigen-2 (IA-2A), zinc transporter 8 (ZnT8A) and insulin (IAA) as well as the type 1 diabetes genetic risk score (GRS2). Associations between islet autoantibodies, insulin treatment and GRS2 were analysed using Fisher's exact and t-tests. RESULTS: Among 226 relatives (64% men; mean age at sampling 41 years; mean age 54 years at diagnosis), 32 (14%) were islet autoantibody-positive for at least one autoantibody more than a decade before diagnosis. Approximately half of these (n = 15) were treated with insulin. GADA-positivity was higher in insulin-treated relatives than in non-insulin-treated relatives (12/18 [67%] vs. 6/18 [33%], p < 0.001). IAA-positivity was observed in 13/32 (41%) of relatives with autoantibodies. GRS2 scores were increased in autoantibody-positive relatives (p = 0.032), but there was no clear evidence for a difference according to treatment (p = 0.072). CONCLUSION: This study highlights the importance of measuring islet autoantibodies, including IAA, in relatives of people with type 1 diabetes to avoid misdiagnosis.

Immunogenicity, efficacy, and safety of biosimilar insulin glargine (Gan & Lee glargine) compared with originator insulin glargine (Lantus®) in patients with type 2 diabetes after 26 weeks' treatment: A randomized open label study.

AIM: To evaluate the equivalence of immunogenicity, safety and efficacy of Gan & Lee (GL) Glargine (Basalin®; Gan & Lee Pharmaceutical) with that of the reference product (Lantus®) in adult participants with type 2 diabetes mellitus. METHODS: This was a phase 3, multicenter, open-label, equivalence trial conducted across 57 sites. In total, 567 participants with type 2 diabetes mellitus were randomized in a 1:1 ratio to undergo treatment with either GL Glargine or Lantus® for 26 weeks. The primary endpoint was the proportion of participants in each treatment arm who manifested treatment-induced anti-insulin antibodies (AIA). Secondary endpoints included efficacy and safety metrics, changes in glycated haemoglobin levels, and a comparative assessment of adverse events. Results were analysed using an equivalence test comparing the limits of the 90% confidence interval (CI) for treatment-induced AIA development to the prespecified margins. RESULTS: The percentages of participants positive for treatment-induced glycated haemoglobin by week 26 were similar between the GL Glargine (19.2%) and Lantus® (21.3%) treatment groups, with a treatment difference of -2.1 percentage points and a 90% CI (-7.6%, 3.5%) (predefined similarity margins: -10.7%, 10.7%). The difference in glycated haemoglobin was -0.08% (90% CI, -0.23, 0.06). The overall percentage of participants with any treatment-emergent adverse events was similar between the GL Glargine (80.1%) and Lantus® (81.6%) treatment groups. CONCLUSIONS: GL Glargine was similar to Lantus® in terms of immunogenicity, efficacy, and safety, based on the current study.

Quantitative analysis of Tr1 lymphocytes in patients with type 2 diabetes mellitus.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is usually accompanied by a low-grade inflammatory phenomenon, which participates in the pathogenesis of different complications of this condition. The inflammatory response is under the regulation of different mechanisms, including T regulatory (Treg) lymphocytes. However, the possible role of type 1 T regulatory (Tr1) cells in T2DM has not been explored so far. AIM: To carry out a quantitative analysis of Tr1 lymphocytes and other immune cell subsets in patients with T2DM and correlate these results with clinical findings and treatments. MATERIALS AND METHODS: Sixty patients with T2DM and twenty-three healthy controls were included in the study. Biochemical and anthropometric variables were evaluated, and Tr1 lymphocytes (CD4+CD49+LAG-3+IL-10+) and other cell subsets (Th17, Th22 and Foxp3 + Treg cells) were analyzed in peripheral blood samples by multiparametric flow cytometry. RESULTS: Significant increased levels of Tr1 cells were detected in patients with severe and mild disease, compared to healthy controls. In addition, CD4+IL-10+ lymphocytes were also increased in patients with T2DM. In contrast, similar levels of Foxp3+ Treg cells, Th17 and Th22 lymphocytes were observed in patients and controls. Likewise, no significant associations were detected between Tr1 cell levels and different clinical and laboratory parameters. However, those patients receiving glucagon-like peptide-1 receptor agonists (GLP-1-RA) showed similar levels of Tr1 cells than healthy controls, and significant lower numbers than untreated patients. CONCLUSION: We observed an increase in Tr1 and CD4+IL10+ lymphocyte levels in T2DM. Moreover, GLP1-RA treatment was significantly associated with normalization of the Tr1 levels. This highlights another potential immune dysfunction in patients with T2DM, which could participate in the pathogenesis of this condition.

Comparative assessment of immunogenicity of recombinant insulin Aspart from BioGenomics and its originator NovoRapid® in adult patients with type 2 diabetes mellitus.

OBJECTIVES: To assess and compare the immunogenicity of recombinant Insulin Aspart [manufactured by BioGenomics Limited (BGL-ASP)] with its originator NovoRapid® (manufactured by Novo Nordisk) in adult patients with type 2 diabetes mellitus. RESEARCH DESIGN AND METHODS: BGL-IA-CTP301 study was a randomized, open label, parallel group, multicenter phase-III clinical study to compare the efficacy and safety of recombinant Insulin Aspart 100 U/mL [manufactured by BioGenomics Limited (BGL-ASP)] with its reference medicinal product (RMP); NovoRapid® [manufactured by Novo Nordisk], in adult patients with Type 2 diabetes mellitus (T2DM). The primary objective of the study was to compare the immunogenicity of BGL-ASP and RMP; NovoRapid® in patient serum samples collected from phase-III clinical study. Immunogenicity was studied as the incidence of patients positive for anti-insulin Aspart (AIA) antibodies, developed against BGL-ASP/RMP at baseline, end of 12 week and end of 24 week of the treatment period. The changes in incidence of patients positive for AIA antibodies post-baseline were also studied to assess and compare the treatment-emergent antibody response (TEAR) between the treatment groups (BGL-ASP and RMP). Statistical evaluation was done by Fisher's exact test to compare the overall incidence of patients positive for AIA antibodies and the TEAR positives observed post-baseline in both the treated groups. An in-vitro neutralizing antibody assay (Nab assay) was also performed to study the effect of AIA antibodies in neutralizing the biological activity/metabolic function of the insulin. The neutralizing potential of AIA was studied by its effect on %glucose uptake. We also evaluated the association between AIA antibody levels and its impact on biological activity by studying the correlation between them. RESULTS: Analysis of immunogenicity data suggested that the percentage of patients positive for AIA antibodies until week 24 was similar and comparable in both the treatment groups, BGL-ASP and RMP; NovoRapid®. The changes in incidence of patients positive for AIA post-baseline in terms of TEAR positives were also similar and comparable between the treatment groups. The results of the Nab assay with confirmed positive AIA samples from BGL-ASP- and RMP-treated groups did not have any negative impact on %glucose uptake by the cells in Nab assay, confirming the absence of neutralizing antibodies in both the treatment groups. The correlation studies also showed absence of association between AIA antibody levels and percentage glucose uptake in both BGL-ASP and RMP-NovoRapid® treatment groups. CONCLUSIONS: The immunogenicity assessment based on the overall incidence of patients positive for AIA, changes in incidence of patients positive for AIA post-baseline, TEAR rates and absence of neutralizing antibodies, were found to be apparently similar and comparable in both the treatment groups (BGL-ASP and RMP). We conclude from our studies that the immunogenicity of BGL-ASP is similar and comparable to RMP and the observed immunogenicity in terms of anti-insulin Aspart antibody levels had no impact on the biological activity of insulin.

Diabetes and Infectious Diseases with a Focus on Melioidosis.

Diabetes mellitus (DM) leads to impaired innate and adaptive immune responses. This renders individuals with DM highly susceptible to microbial infections such as COVID-19, tuberculosis and melioidosis. Melioidosis is a tropical disease caused by the bacterial pathogen Burkholderia pseudomallei, where diabetes is consistently reported as the most significant risk factor associated with the disease. Type-2 diabetes is observed in 39% of melioidosis patients where the risk of infection is 13-fold higher than non-diabetic individuals. B. pseudomallei is found in the environment and is an opportunistic pathogen in humans, often exhibiting severe clinical manifestations in immunocompromised patients. The pathophysiology of diabetes significantly affects the host immune responses that play a critical role in fighting the infection, such as leukocyte and neutrophil impairment, macrophage and monocyte inhibition and natural killer cell dysfunction. These defects result in delayed recruitment as well as activation of immune cells to target the invading B. pseudomallei. This provides an advantage for the pathogen to survive and adapt within the immunocompromised diabetic patients. Nevertheless, knowledge gaps on diabetes-infectious disease comorbidity, in particular, melioidosis-diabetes comorbidity, need to be filled to fully understand the dysfunctional host immune responses and adaptation of the pathogen under diabetic conditions to guide therapeutic options.

Reduced Immunogenicity of COVID-19 Vaccine in Obese Patients with Type 2 Diabetes: A Cross-Sectional Study.

The global pandemic of coronavirus infection 2019 (COVID-19) was an unprecedented public health emergency. Several clinical studies reported that heart disease, lung disease, diabetes, hypertension, dyslipidemia, and obesity are critical risk factors for increased severity of and hospitalization for COVID-19. This is largely because patients with these underlying medical conditions can show poor immune responses to the COVID-19 vaccinations. Diabetes is one of the underlying conditions most highly associated with COVID-19 susceptibility and is considered a predictor of poor prognosis of COVID-19. We therefore investigated factors that influence the anti-SARS-CoV-2 spike IgG antibody titer after three doses of vaccination in patients with type 2 diabetes. We found that obesity was associated with low anti-SARS-CoV-2 spike IgG antibody titers following three-dose vaccination in type 2 diabetics. Obese patients with type 2 diabetes may have attenuated vaccine efficacy and require additional vaccination; continuous infection control should be considered in such patients.

Effect of metformin on gut microbiota imbalance in patients with T2DM, and the value of probiotic supplementation.

PURPOSE: To investigate the effect of metformin on gut microbiota imbalance in patients with type 2 diabetes mellitus (T2DM), and the value of probiotic supplementation. METHODS: A total of 84 newly diagnosed T2DM patients were randomly divided into probiotics group, metformin group, and control group, with 28 patients in each group. The blood glucose control, islet function, gut microbiota, and inflammatory factors were compared between three groups. RESULTS: After 3 months of treatment, fasting plasma glucose (FPG), 2-h postprandial plasma glucose (2-h PG), and glycosylated hemoglobin A1c (HbA1c) were evidently decreased in both probiotics and metformin groups (P < 0.05) and were lower than that in the control group prior to treatment. Besides, FPG, 2-h PG, and HbA1c were lower in the metformin group than that in the control group. FPG, 2-h PG, and HbA1c were further lower in the probiotic group than in the metformin group (P < 0.05). Fasting insulin (FINS) and islet ß cell (HOMA-ß) -function were dramatically increased in the same group (P < 0.05), while insulin-resistant islet ß cells (HOMA-IR) were significantly lower in the same group (P < 0.05); FINS and HOMA-ß were significantly higher, while HOMA-IR was significantly lower (P < 0.05) in both groups than in the control group prior to treatment. HOMA-IR was also lower in the probiotic group than in the metformin group after treatment (P < 0.05); the number of lactobacilli and bifidobacteria increased (P < 0.05) in both probiotic and metformin groups than in the control group prior to treatment, and the number of Enterobacteriaceae and Enterococcus was lower in the control group prior to treatment (P < 0.05). In addition, the number of lactobacilli and bifidobacteria was higher and the number of enterobacteria and enterococci was lower in the probiotic group than that in the metformin group after treatment, and the differences were statistically significant (P < 0.05). Lipopolysaccharide (LPS), interleukin 6 (IL-6), and C-reactive protein (CRP) levels were lower in both probiotic and metformin groups (P < 0.05). The serum LPS, IL-6, and CRP levels were lower in both probiotic and metformin groups, compared to the control group prior to the treatment (P < 0.05). CONCLUSION: Metformin while treating T2DM assists in improving the imbalance of gut microbiota.

Elucidating the causal nexus and immune mediation between frailty and chronic kidney disease: integrative multi-omics analysis.

BACKGROUND: Empirical research has consistently documented the concurrent manifestation of frailty and chronic kidney disease (CKD). However, the existence of a reverse causal association or the influence of confounding variables on these correlations remains ambiguous. METHODS: Our analysis of 7,078 participants from National Health and Nutrition Examination Survey(NHANES) (1999-2018) applied weighted logistic regression and Mendelian Randomization (MR) to investigate the correlation between the frailty index (FI) and renal function. The multivariate MR analysis was specifically adjusted for type 2 diabetes and hypertension. Further analysis explored 3282 plasma proteins to link FI to CKD. A two-step network MR highlighted immune cells' mediating roles in the FI-CKD relationship. RESULT: Genetically inferred FI and various renal function markers are significantly correlated, as supported by NHANES analyses. Multivariate MR analysis revealed a direct causal association between the FI and CKD. Additionally, our investigation into plasma proteins identified Tmprss11D and MICB correlated with FI and CKD, respectively. A two-step network MR to reveal 15 immune cell types, notably Central Memory CD4+ T cells and Lymphocytes, as crucial mediators between FI and CKD. CONCLUSION: Our work establishes a causal connection between frailty and CKD, mediated by specific immune cell profiles. These findings highlight the importance of immune mechanisms in the frailty-CKD interplay and suggest that targeting shared risk factors and immune pathways could improve management strategies for these conditions. Our research contributes to a more nuanced understanding of frailty and CKD, offering new avenues for intervention and patient care in an aging population.

Evidence for a Pro-Inflammatory State of Macrophages from Non-Obese Type-2 Diabetic Goto-Kakizaki Rats.

Obesity causes insulin resistance (IR) through systemic low-grade inflammation and can lead to type 2 diabetes mellitus (T2DM). However, the mechanisms that cause IR and T2DM in non-obese individuals are unclear. The Goto-Kakizaki (GK) rat develops IR spontaneously and is a model of non-obese T2DM. These rats exhibit hyperglycemia beginning at weaning and exhibit lower body mass than control Wistar rats. Herein, we tested the hypothesis that macrophages of GK rats are permanently in a pro-inflammatory state, which may be associated with a systemic inflammation condition that mimics the pathogenesis of obesity-induced T2DM. Using eighteen-week-old GK and control Wistar rats, we investigated the proportions of M1 (pro-inflammatory) and M2 (anti-inflammatory) macrophages isolated from the peritoneal cavity. Additionally, the production of inflammatory cytokines and reactive oxygen species (ROS) in cultured macrophages under basal and stimulated conditions was assessed. It was found that phorbol myristate acetate (PMA) stimulation increased GK rat macrophage ROS production 90-fold compared to basal levels. This response was also three times more pronounced than in control cells (36-fold). The production of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), tended to be upregulated in cultured macrophages from GK rats under basal conditions. Macrophages from GK rats produced 1.6 times more granulocyte-macrophage colony-stimulating factor (GM-CSF), 1.5 times more monocyte chemoattractant protein-1 (MCP-1) and 3.3 times more TNF-α than control cells when stimulated with lipopolysaccharide (LPS) (p = 0.0033; p = 0.049; p = 0.002, respectively). Moreover, compared to control cells, GK rats had 60% more M1 (p = 0.0008) and 23% less M2 (p = 0.038) macrophages. This study is the first to report macrophage inflammatory reprogramming towards a pro-inflammatory state in GK rats.