Altered brain spontaneous and synchronization activity in latent autoimmune diabetes in adults: A resting-state functional MRI study.

AIMS: This study aimed to explore the clinical features and spontaneous brain activity among patients with latent autoimmune diabetes in adults (LADA) and to investigate the relationship among these characteristics. METHODS: We conducted a cross-sectional study using cognitive assessments and resting-state functional magnetic resonance imaging (rs-fMRI) to evaluate the cognitive function and brain activities of healthy controls (HCs) and patients with LADA. Functional connectivity (FC) analysis was performed on the brain regions that showed significantly different activation in regional homogeneity (ReHo) analysis between the two groups. Furthermore, a linear regression model was conducted for the association between metabolism and cognition. RESULTS: This study enrolled patients with LADA (and age-, sex-, and education-matched HCs). Patients with LADA had worse cognitive status at the general level and poorer memory than controls. Rs-fMRI analysis among patients with LADA showed decreased ReHo values in the right occipital lobe and temporal lobe and decreased seed-based FC in the right parietal lobe compared to those of controls. The seed-based FC values in the right parietal lobe were positively associated with word fluency and processing speed in patients with LADA. Furthermore, low-density lipoprotein cholesterol was negatively correlated with Montreal Cognitive Assessment scores in patients with LADA. CONCLUSIONS: Patients with LADA had worse cognitive function and decreased spontaneous brain activity in the temporal lobe and occipital lobe compared to controls. Moreover, glycolipid metabolism was closely related to brain structure and function in patients with LADA.

Th1 bias of liver mucosal-associated invariant T cells promotes hepatic gluconeogenesis in type 2 diabetes mellitus.

AIMS: It is acknowledged that aberrant liver immunity contributes to the development of type 2 diabetes mellitus (T2DM). Mucosal-associated invariant T (MAIT) cells, an innate-like T-cell subset, are enriched in the human liver. Nevertheless, the characterisation and potential role of hepatic MAIT cells in T2DM remain unclear. MATERIALS AND METHODS: Fourteen newly diagnosed T2DM subjects and 15 controls received liver biopsy. The frequency and cytokine production of MAIT cells were analysed by flow cytometry. The expression of genes involved in glucose metabolism was determined in HepG2 cells co-cultured with hepatic MAIT cells. RESULTS: Compared with controls, hepatic MAIT cell frequency was significantly increased in T2DM patients (24.66% vs. 14.61%, p = 0.001). There were more MAIT cells producing interferon-γ (IFN-γ, 60.49% vs. 33.33%, p = 0.021) and tumour necrosis factor-α (TNF-α, 46.84% vs. 5.91%, p = 0.021) in T2DM than in controls, whereas their production of interleukin 17 (IL-17) was comparable (15.25% vs. 4.55%, p = 0.054). Notably, an IFN-γ+ TNF-α+ IL-17+/- producing MAIT cell subset was focussed, which showed an elevated proportion in T2DM (42.66% vs. 5.85%, p = 0.021) and positively correlated with plasma glucose levels. A co-culture experiment further indicated that hepatic MAIT cells from T2DM upregulated the gene expression of pyruvate carboxylase, a key molecule involved in gluconeogenesis, in HepG2 cells, and this response was blocked with neutralising antibodies against IFN-γ and TNF-α. CONCLUSIONS: Our data implicate an increased Th1-like MAIT cell subset in the liver of newly diagnosed T2DM subjects, which induces hyperglycaemia by promoting hepatic gluconeogenesis. It provides novel insights into the immune regulation of metabolic homoeostasis. CLINICAL TRIAL REGISTRATION NUMBER: NCT03296605 (registered at www. CLINICALTRIALS: gov on 12 October 2018).

Prevalence and risk factors of diabetic peripheral neuropathy: A population-based cross-sectional study in China.

AIMS: To assess the prevalence of diabetic peripheral neuropathy (DPN) and its risk factors in the type 2 diabetes mellitus (T2DM) population. METHODS: This cross-sectional study enroled patients with T2DM between July and December 2017 from 24 provinces in China. Diabetic peripheral neuropathy and its severity were assessed by the Toronto clinical scoring system, neuropathy symptoms score (NSS) and neuropathy disability score. The prevalence of DPN and its risk factors were analysed. RESULTS: A total of 14,908 patients with T2DM were enroled. The prevalence of DPN was 67.6%. Among 10,084 patients with DPN, 4808 (47.7%), 3325 (33.0%), and 1951 (19.3%) had mild, moderate, and severe DPN, respectively. The prevalence of DPN in females was higher than in males (69.0% vs. 66.6%, P = 0.002). The prevalence of DPN increased with age and course of diabetes and decreased with body mass index (BMI) and education level (all P for trend <0.05). The comorbidities and complications in patients with DPN were higher than in those without DPN, including hypertension, myocardial infarction, diabetic retinopathy, and diabetic nephropathy (all P < 0.001). Age, hypertension, duration of diabetes, diabetic retinopathy, diabetic nephropathy, glycated haemoglobin, high-density lipoprotein cholesterol, and lower estimated glomerular filtration rate were positively associated with DPN, while BMI, education level, fasting C-peptide, and uric acid were negatively associated with DPN. CONCLUSIONS: Among patients with T2DM in China, the prevalence of DPN is high, especially in the elderly, low-income, and undereducated patients.

Efficacy and safety of adding once-weekly dulaglutide to basal insulin for inadequately controlled type 2 diabetes in Chinese patients (AWARD-CHN3): A randomized, double-blind, placebo-controlled, phase III trial.

AIM: To determine the efficacy and safety of once-weekly dulaglutide added to basal insulin in Chinese patients with type 2 diabetes mellitus (T2DM) with inadequate glycaemic control. MATERIALS AND METHODS: In the phase III, double-blind AWARD-CHN3 study, Chinese patients with T2DM (N = 291) and glycated haemoglobin (HbA1c) ≥7.0% and ≤11.0% receiving stable doses of basal insulin glargine with metformin and/or acarbose were randomized (1:1) to receive add-on dulaglutide 1.5 mg once weekly or placebo once weekly. The primary endpoint was the superiority of dulaglutide/glargine to placebo/glargine for change from baseline in HbA1c at Week 28. RESULTS: The least squares (LS) mean ± standard error change in HbA1c from baseline to Week 28 was -2.0 ± 0.08% with dulaglutide/glargine and -1.1 ± 0.07% with placebo/glargine (LS mean difference: -1.0%, 95% confidence interval [CI] -1.1 to -0.8; P < 0.001), and more patients receiving dulaglutide/glargine achieved HbA1c levels <7.0% (75.9% vs. 33.8%; P < 0.001 vs. placebo/glargine). Body weight decreased with dulaglutide/glargine and increased with placebo/glargine (LS mean difference: -1.2 kg, 95% CI -1.8 to - 0.6; P < 0.001). Reductions in fasting serum glucose were greater with dulaglutide/glargine than with placebo/glargine (LS mean difference: -0.8 mmol/L, 95% CI -1.1 to - 0.5; P < 0.001). The incidence of hypoglycaemia was similar with dulaglutide/glargine and placebo/glargine (29.2% vs. 31.3%; P = 0.704); no patient in either group had severe hypoglycaemia. The most common treatment-emergent adverse events with dulaglutide/glargine were decreased appetite (22.2%), diarrhoea (13.2%) and nausea (10.4%). CONCLUSIONS: Dulaglutide added to basal insulin was efficacious and well tolerated in Chinese patients with T2DM.

Increased plasmablasts enhance T cell-mediated beta cell destruction and promote the development of type 1 diabetes.

BACKGROUND: Although type 1 diabetes (T1D) is typically described as a T cell-mediated autoimmune disease, increasing evidence for a role of B cells has emerged. However, the pivotal disease-relevant B cell subset and its contribution to islet autoimmunity remain elusive. METHODS: The frequencies and phenotypic characteristics of circulating B cell subsets were analyzed using flow cytometry in individuals with new-onset T1D, long-term T1D, type 2 diabetes, and nondiabetic controls, and also in a prospective cohort of patients receiving mesenchymal stromal cell (MSC) transplantation. NOD mice and adoptive transfer assay were used to dissect the role of the certain B cell subset in disease progression. An in-vitro coculture system of islets with immune cells was established to examine the response against islets and the underlying mechanisms. RESULTS: We identified that plasmablasts, a B cell subset at the antibody-secreting stage, were significantly increased and correlated with the deterioration of beta cell function in patients with new-onset T1D. Further, a fall of plasmablast number was associated with the preservation of beta cell function in patients who received MSC transplantation after 3 months of follow-up. Meanwhile, a gradual increase of plasmablasts in pancreatic lymph nodes during the natural progression of insulitis was observed in non-obese diabetic (NOD) mice; adoptive transfer of plasmablasts together with T cells from NOD mice accelerated diabetes onset in NOD/SCID recipients. CONCLUSIONS: Our study revealed that plasmablasts may function as antigen-presenting cells and promote the activation and proinflammatory response of CD4+ T cells, further contributing to the T cell-mediated beta cell destruction. Our results provide insights into the pathogenic role of plasmablasts in islet autoimmunity and may offer new translational strategies for inhibiting T1D development.

Clinical application guidelines for blood glucose monitoring in China (2022 edition).

Glucose monitoring is an important component of diabetes management. The Chinese Diabetes Society (CDS) has been producing evidence-based guidelines on the optimal use of glucose monitoring since 2011. In recent years, new technologies in glucose monitoring and more clinical evidence, especially those derived from Chinese populations, have emerged. In this context, the CDS organised experts to revise the Clinical application guidelines for blood glucose monitoring in China in 2021. In this guideline, we focus on four methods of glucose monitoring that are commonly used in clinical practice, including capillary glucose monitoring, glycated haemoglobin A1c, glycated albumin, and continuous glucose monitoring. We describe the definitions and technical characteristics of these methods, the factor that may interfere with the measurement, the advantages and caveats in clinical practice, the interpretation of glucose metrics, and the relevant supporting evidence. The recommendations for the use of these methods are also provided. The various methods of glucose monitoring have their strengths and limitations and cannot be replaced by one another. We hope that these guidelines could aid in the optimal application of common methods of glucose monitoring in clinical practice for better diabetes care.

Neuropathy scale score as an independent risk factor for myocardial infarction in patients with type 2 diabetes.

AIMS: To investigate whether peripheral neuropathy scale scores are associated with myocardial infarction (MI) in patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: In this cross-sectional study, 32,463 T2DM patients were enroled from 103 tertiary hospitals in 25 Chinese provinces. Based on a history of MI, participants were divided into the MI group (n = 4170) and the non-MI group (n = 28,293). All patients were assessed using four neuropathy scales, namely, Neurological Symptom Score (NSS), Neurological Disability Score (NDS), Toronto Clinical Scoring System (TCSS), and Michigan Neuropathy Screening Instrument (MNSI), and some of the patients underwent evaluation of nerve conduction velocity (NCV) (n = 20,288). The relationship between these scores and myocardial infraction was analysed. RESULTS: The neuropathy scale scores in the MI group were higher than those in the non-MI group (p < 0.001). After dividing patients into four groups based on the grading criteria, our results showed that, in addition to aggravating the degree of neuropathy signs, the incidence of MI increased (p < 0.001). Logistic regression analysis results showed that neuropathy scale scores and NCV were both independent risk factors for MI (p < 0.001). Furthermore, among the scales used, MNSI presented a higher odds ratio and area under the curve (AUC; 0.625, p < 0.001) than the other three scales (AUCNSS  = 0.575, AUCNDS  = 0.606, and AUCTCSS  = 0.602, p < 0.001) for MI. CONCLUSIONS: Increased scores on these neuropathy scales (NSS, NDS, TCSS, and MNSI) and NCV were significantly associated with increased risk of MI and were considered independent risk factors.

Immunogenicity of LY2963016 insulin glargine and Lantus® insulin glargine in Chinese patients with type 1 or type 2 diabetes mellitus.

AIMS: To evaluate the immunogenicity of LY2963016 insulin glargine (LY IGlar) versus originator insulin glargine (IGlar [Lantus®]) in Chinese patients with type 1 (T1DM) or type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: ABES and ABET were prospective, randomized, active control, open-label, phase III studies, which enrolled Chinese patients with T1DM (N = 272) and T2DM (N = 536), respectively. Using data from these trials, immunogenicity of LY IGlar and IGlar was evaluated by comparing the proportion of patients with detectable anti-insulin glargine antibodies and the median antibody levels (percent binding) between the treatment groups. The incidence of anti-insulin antibodies and treatment-emergent antibody response (TEAR) were compared using Fisher's exact test or Pearson's chi-squared test. Levels of anti-insulin antibodies were compared using the Wilcoxon rank-sum test. We also evaluated the relationship between antibody formation or TEAR and clinical outcomes using analysis of covariance, negative binomial regression, or partial correlations. RESULTS: There were no significant treatment differences in the incidence of detectable anti-insulin antibodies, median antibody levels or TEAR, overall or at Week 24 with last observation carried forward, and median antibody levels were low (<5%) after 24 weeks of treatment, in patients with T1DM or T2DM. Levels of anti-insulin antibodies and development of TEAR were not associated with efficacy (glycated haemoglobin, insulin dose [U/kg/d] and hypoglycaemia) or safety outcomes. CONCLUSIONS: The immunogenicity profiles of LY IGlar and IGlar are similar, with low levels of anti-insulin antibodies observed for both insulins. No association was observed between antibody levels or TEAR status and clinical outcomes.

Effect of liver dysfunction on outcome of radioactive iodine therapy for Graves' disease.

Liver dysfunction is a common complication of Graves' disease (GD) that may be caused by excessive thyroid hormone (TH) or anti-thyroid drugs (ATDs). Radioactive iodine (RAI) therapy is one of the first-line treatments for GD, but it is unclear whether it is safe and effective in patients with liver dysfunction. 510 consecutive patients with GD receiving first RAI were enrolled in the study, and followed up at 3-, 6- and 12-month. Liver dysfunction was recorded in 222 (43.5%) patients. GD patients with liver dysfunction had higher serum levels of free triiodothyronine (FT3) (median 27.6 vs. 20.6 pmol/L, p < 0.001) and free thyroxine (FT4) (median 65.4 vs. 53.5 pmol/L, p < 0.001) levels than those with normal liver function. Binary logistic regression analysis showed that duration of disease (OR = 0.951, 95% CI: 0.992-0.980, p = 0.001) and male gender (OR = 1.106, 95% CI: 1.116-2.384; p = 0.011) were significant differential factors for liver dysfunction. Serum TSH levels were higher in patients with liver dysfunction at all 3 follow-up time points (p = 0.014, 0.008, and 0.025 respectively). FT3 level was lower in patients with liver dysfunction at 3-month follow-up (p = 0.047), but the difference disappeared at 6 and 12 months (p = 0.351 and 0.264 respectively). The rate of euthyroidism or hypothyroidism was higher in patients with liver dysfunction than in those with normal liver function at 3 months (74.5% vs 62.5%; p = 0.005) and 6 months (82.1% vs 69.1%; p = 0.002) after RAI treatment, but the difference did not persist at 12-month follow-up (89.6% vs 83.2%, p = 0.081).There were no statistically significant differences in treatment efficacy (94.48% vs 90.31%, p = 0.142), incidence of early-onset hypothyroidism (87.73% vs 83.67%, p = 0.277), and recurrence rate (4.91% vs 7.14%, p = 0.379) between the 2 groups at 12-month follow-up. In conclusion, the efficacy of RAI was comparable in GD patients with liver dysfunction and those with normal liver function.

Decreased Serum Wnt Antagonist Levels in Patients With Active Acromegaly.

OBJECTIVE: The Wnt signaling pathway is an important modulator of bone metabolism. This study aims to clarify the changes in Wnt antagonists in active and biochemically controlled acromegalic patients. METHODS: We recruited 77 patients recently diagnosed with acromegaly. Of those, 41 patients with complete follow-up data were included. Thirty healthy patients matched for age, sex, and body mass index served as controls. At baseline and posttreatment, Wnt antagonists (sclerostin [SOST], dickkopf-related protein 1 [DKK-1], and Wnt inhibitory factor 1 [WIF-1]), bone turnover markers (osteocalcin, procollagen type 1 N-terminal propeptide [P1NP], and C-terminal telopeptide of type 1 collagen [CTX]) and the bone remodeling index were investigated. RESULTS: Acromegalic patients had higher serum osteocalcin, P1NP, and CTX and a higher bone remodeling index than controls (P < .01). Serum SOST, DKK-1, and WIF-1 levels were significantly decreased in patients compared to controls (all P < .01). Serum SOST and WIF-1 levels were negatively correlated with growth hormone levels; SOST levels were positively correlated with WIF-1. After treatment, serum bone turnover markers and the bone remodeling index decreased, while SOST and WIF-1 significantly increased (P < .05). DKK-1 levels did not change compared to baseline (P > .05). In biochemically controlled patients, SOST and WIF-1 levels and bone turnover markers were restored and did not differ from those of the control participants (all P > .05). CONCLUSION: Patients with active acromegaly exhibited significantly decreased Wnt antagonist levels. The reduction in Wnt antagonists is a compensatory mechanism to counteract increased bone fragility in active acromegaly.