Volume 09 · Issue 10 · 2017

The immune system includes innate and acquired immunity, and their role is to recognize and eliminate pathogenic microorganisms. Among them, the natural immune system is the first line of defense for the body to resist the invasion of foreign microorganisms, including peripheral blood mononuclear cells, phagocytes such as neutrophils and macrophages, and dendritic cells (DCs). The relationship between type 1 diabetes mellitus (T1DM) and acquired immunity has been clearly defined, and the relationship with innate immunity has been paid more and more attention.

There are a variety of immune cell subtypes in the acquired immune system, among which immunosuppressive T cells are essential for maintaining the immune balance of the body. regulatory T cells (Treg) are a subset of inhibitory T cells expressing surface molecules such as CD4, CD25, cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and forkhead box P3 (FOXP3), which are crucial for maintaining immune homeostasis^[1]。 The development and dysfunction of Treg cells can lead to a variety of immune-related diseases, including autoimmune diseases, acute and chronic infections, tumors, transplant rejection, and allergic diseases. Recent studies have shown that the physiological function of Treg has been confirmed to be involved in the occurrence of many previously thought non-immune-related diseases. Diabetes is a group of metabolic diseases characterized by hyperglycemia due to defective insulin secretion and/or impaired insulin action. Persistent hyperglycemia and long-term metabolic disorders can lead to dysfunction and failure of multiple tissues and organs in the whole body. Diabetes is mainly divided into two categories: type 1 and type 2 diabetes. Type 1 diabetes is considered a T-cell mediated autoimmune disease triggered by excessive production and activation of T cells that recognize islet beta cell autoantigens. The immune system is also involved in the pathogenesis of type 2 diabetes. This article will briefly introduce FOXP3⁺Differentiation function of Treg, with emphasis on discussion of FOXP3⁺Recent advances in Treg in the prevention and treatment of diabetes.

Obesity can cause a variety of diseases including type 2 diabetes, cardiovascular disease, cancer, etc., greatly increasing the risk of death^[1]。 The incidence of obesity has risen sharply worldwide. According to the latest statistics, there are 603.7 million obese adults and 107.7 million obese children worldwide^[2]。 The number of obese patients and diabetes patients caused by obesity in China is also increasing year by year^[3]。 The occurrence of obesity is closely related to genetics, diet and lifestyle habits. Recent studies have shown that the inflammation of adipose tissue in obesity is an important factor in inducing various obesity-related diseases, and obesity-related diseases can be improved by immunomodulation of adipose tissue.

To explore the effects of Janus kinase 2 (Jak2) depletion on pancreatic β cell survival and function.

Rip-CreER-Jak2^f/f male mice hybridized by Rip-CreER mice and Jak2^f/f mice (8 weeks old and 20-22 grams weight) were induced by tamoxifen to generate β cell-specific Jak2 knockout (KO) mice (KO group, n=40). Jak2^f/f male mice induced by tamoxifen were as control group (n=40). Jak2 gene depleted at day 7 after tamoxifen-induction and confirmed by Polymerase chain reaction (PCR) and western blotting analyses. β cell function were evaluated by random glucose levels and intraperitoneal glucose tolerance test (IPGTT). The pathogenic, sub-pathogenic and lethal doses of streptozocin (STZ) were administrated respectively to observe the effects of Jak2 on β cell survival. Comparison of the two treatments were analyzed using the student's t-test, the incidence of diabetes and the mortality of mice were analyzed by Kaplan-Meier survival model.

Inducible pancreatic β cell-specific Jak2 knockout mouse model were established successfully. None of the KO mice developed diabetes spontaneously. There were no significant differences in the incidence of diabetes between KO and control mice either stimulated with pathogenic or sub-pathogenic doses of STZ (83.3% vs 91.6%, P=0.392 8; 20% vs 20%, P>0.05; respectively); No significant differences were found in the average glucose levels between KO and control mice [(11.0±6.6) vs (12.0±5.7) mmol/L, P=0.425 8]. There were no significant differences in the motility rate between KO and control mice when stimulated with lethal dose of STZ (92.3% vs 93.75%, P=0.554 0).

Jak2 gene is highly expressed in pancreatic β cell, however, Jak2 has no effects on β cell survival and function.

To investigate the immunoregulation effects of Exendin-4 on peripheral blood mononuclear cells (PBMC) in patients with type 1 diabetes mellitus (T1DM).

PBMC samples from 11 T1DM subjects were used to investigate the effects of Exendin-4 on PBMCs in vitro. Intervention group (0, 10, 100 nmol/L) and antagonist group (50 nmol/L Exendin 9(39)+100 nmol/L Exendin-4) were set according to the concentration of cyclic adenosine monophospphate (cAMP) in PBMCs. Cytokines [interleukin(IL)10, tumor necrosis factor α(TNF-α)] were measured by cytometric bead array and real-time quantitative PCR (RT-qPCR) analysis, respectively.

(1) GLP-1R was detected in PBMC of T1DM. Compared with control group, the expression of GLP-1R mRNA was significantly increased in 100 nmol/L Exendin-4 treated group (1.97±0.24 vs 1, P<0.05), and was inhibited by GLP-1R antagonist Exendin-9 (39) (0.56±0.10 vs 1, P<0.05). (2) Compared with the control group, 1 10 100 nmol/L Exendin-4 had no significant effects on PBMC activity in patients with T1DM (F=0.362, 0.393, 0.374, all P>0.05). (3)10 nmol/L and 100 nmol/L Exendin-4 had significant effects on levels of cAMP (7.51±0.01 vs 2.56±0.01, 17.21±0.04 vs 2.56±0.01, respectively, both P<0.05) . (4) The mRNA expression levels of TNF-α, TNF-α levels in the cellular supernatant were significantly decreased after Exendin-4 intervention (F=5.54, 5.12, P<0.05), and was inhibited by GLP-1R antagonist Exendin-9 (39) (F=5.43, 5.97, P<0.05). The levels of IL-10 in supernatant were elevated (F=5.95, 6.01, P<0.05) although IL-10 mRNA levels maintained stable in PBMC.

Exendin-4 could down-regulate TNF-α secretion and up-regulate IL-10 secretion in PBMC of T1DM patients. These results suggest that exendin-4 might down-regulate pro-inflammatory responses.

To evaluate positive rate of serum tissue transglutaminase antibody (tTGA), which is a specific antibody of celiac disease (CD), and clinical symptoms of CD in patients with type 1 diabetes mellitus (T1DM).

T1DM (n=130) and type 2 diabetes mellitus (T2DM) (n=178) patients with disease course less than 12 months were recruited. 109 healthy volunteers were recruited as control group. The general data of all subjects were recorded and clinical symptoms of CD collected through screening tables. Fasting plasma glucose (FPG) and HbA_1c were measured. The levels of tTGA were detected by radioligand assay. T1DM patients were divided into juvenile T1DM group (age ≤18 years) and adult T1DM group (age> 18 years), and the positive rate of tTGA was analyzed in T1DM patients with different ages. In addition, T1DM patients were classified to tTGA-positive group and tTGA-negative group, and the correlation between clinical symptoms and tTGA levels were evaluated. Quantitative data were analyzed byt-test or one-way ANOVA and enumeration data were accessed by Chi-square test.

The positive rate of tTGA in patients with T1DM was significantly higher than that in patients with T2DM and in control subjects (19.2% vs 2.2%, 19.2% vs 0.9%, respectively, χ ²=13.466-33.879, both P<0.05). The positive rate of tTGA in juvenile T1DM group was higher than that in adult T1DM group (26.7% vs 12.9%, χ ²=3.967, P=0.046). The incidence of CD-related clinical symptoms (≥ 1 CD symptoms and ≥ 3 CD symptoms) in tTGA-positive patients was significantly higher than those in tTGA-negative patients (64.0% vs 19.0%, 24.0% vs 5.7%, respectively, χ ²=20.377-8.058, both P<0.05). The top three highest incidence of CD-related clinical symptoms were: (1) chronic abdominal pain, diarrhea, abdominal distension (9/25, 36.0%);(2) weight loss, fatigue (8/25, 32.0%); (3) nausea, vomiting (6/25, 24.0%).

TTGA should be routinely screened in T1DM patients and this would contribute to early prevention and diagnosis of CD. TTGA-positive patients with typical clinical symptoms of CD should be further confirmed by small intestinal mucosal biopsy and administrated treatment when necessary.

To explore the correlations between circulating plasmacytoid dendritic cells (pDCs) and other immune cells, clinical parameters in patients with type 1 diabetes mellitus (T1DM), and to investigate the role of pDCs in the pathogenesis of T1DM.

A total of 62 patients with T1DM who visited endocrinology at the First Affiliated Hospital of Nanjing Medical University from December 2015 to June 2017 were recruited as study group. A total of 74 age and gender matched healthy volunteers were as the control group. Clinical parameters of all subjects including age, sex, duration of diabetes and HbA_1c were recorded. The proportions of circulating pDCs and other immune cells [CD3⁺, CD4⁺, CD8⁺, CD4⁺ interferonγ⁺ (IFN-γ⁺), CD4⁺ tumor necrosis factor α ⁺(TNF-α⁺), CD4⁺ interleukin 4⁺ (IL-4⁺), CD4⁺IL-17⁺/CD4⁺ CD25⁺ Foxp3⁺ T cells/CD19⁺/CD19⁺ CD24^hi CD38^hi B cells] were detected by flow cytometry. Pearson correlation analysis was performed to explore the correlation.

The differences in the proportions of pDCs between T1DM patients and healthy controls were statistically significant [(0.21±0.13)% vs (0.28±0.14) %, P=0.006]. Pearson correlation analysis showed that the frequency of circulating pDCs were negatively correlated with the frequency of CD4⁺IFN-γ⁺ and CD4⁺TNF-α⁺ T cells (r=-0.260, 0.473, respectively, both P<0.05), and positively correlated with the frequency of CD4⁺ CD25⁺ Foxp3⁺ T cells and CD19⁺ CD24^hi CD38 ^hi B cells (r=0.417, 0.523, respectively, both P<0.05).There was also a negatively correlation between the frequency of circulating pDCs and HbA_1c (r=-0.316, P<0.05).

There is a deficiency of circulating pDCs in peripheral blood of patients with T1DM, which might be correlated with immune imbalance of T1DM, and be involved in the pathogenesis of T1DM.

To investigate the impact of status of medical insurance on self-management compliance and metabolic control in patients with type 2 diabetes mellitus (T2DM) in China.

This was an observational cross-sectional study including 5 852 patients with T2DM across 50 representative centers in China. Among these patients, 4 824 patients were covered by medical insurance (medical insurance group, MI group) whereas 1 028 patients were not (self-payment group, SP group). The data of demographics, medical history, metabolic parameters, diabetes related costs and self-management obedience were collected by questionnaire survey. A total of 1 281 subjects were included in the analysis which were 1∶2 propensity score matched by sex, smoking, body mass index (BMI), smoking, diabetes duration, education level and age. One-way ANOVA and Chi-squared test were used to test the differences between the two groups. Pearson correlation analysis was applied in correlation test.

(1)The average coverage of medical insurance was 82.43% in this population. Patients in MI group had lower levels of glycated hemoglobin A_1c (HbA_1c), fasting plasma glucose (FPG), 2 hours postprandial plasma glucose (2hPG), triglycerides (TG) and total cholesterol (TC) than patients in SP group [HbA_1c (8.6±2.4)% vs (9.0±2.4)%; FPG (8±3) vs (9±4) mmol/L;2hPG (12±5) vs (13±5) mmol/L; TG (2.0±1.6) vs (2.3±2.1) mmol/L; TC(4.8±1.4) vs (5.0±1.5) mmol/L, F=4.229-21.620, all P<0.05]. Pearson correlation analysis also revealed a negative correlation between the status of medical insurance and the metabolic parameters previously mentioned (the corresponding correlation indexes were -0.079, -0.129, -0.129, -0.102, -0.057, respectively, all P<0.05) . The prevalence of chronic complications in SP group were slightly higher than that in MI group but with no statistical significance (all P>0.05). Patients in MI group had higher costs related to diabetes [5 000 (3 000, 10 000) vs 4 500(2 415, 8 000) RMB, P<0.05] and higher compliance of self-management including diabetes education (81.26% vs 71.20%), reexamination (55.85% vs 45.67%), exercise (37.35% vs 29.27%), drug program (70.84% vs 58.54%), self-monitoring (24.82% vs 20.37%) and doctor visits (26.81% vs 18.74%) (χ²=2.906-18.838, all P<0.05 except the self-monitoring, P=0.088). Pearson correlation analysis revealed that MI had a positive correlation with diabetes self-management obedience (correlation indexes were 0.114, 0.096, 0.115, 0.109, 0.077, respectively).

There are 17.57% patients with T2DM not covered by medical insurance in this survey. Lacking of medical insurance may be associated with lower medical expenditure and self-management compliance, and consequently may lead to poorer metabolic control. These results suggest that the coverage of medical insurance for T2DM patients might play a potential role in the improvement of metabolic control.

To explore the regulation of Na⁺-H⁺ exchanger 1 inhibitor (Carporide, CAR) on cardiac Calpain and Glycogen synthase kinase 3β (GSK-3β) in type 2 diabetic db/db mice.

Sixteen 7 week old male C57BL/KS db/db mice and 16 wild-type mice were divided into four groups: Control group (WT), CAR group (WT+CAR), Model group (db/db) and CAR treated group (db/db+CAR). The cardiac hemodynamics were measured after administration with CAR for 10 weeks. Fasting plasma glucose (FPG), triglyceride (TG) and total cholesterol (TC) and insulin were determined and insulin resistance index (HOMA-IR) was calculated. The pathological changes of myocardium were observed and the oxidative/nitrifying stress responses were measured. The mRNA expressions of Nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase p22^phox and gp91^phox, transforming growth factor β1 (TGF-β1), matrix metalloproteinase 2 (MMP-2) and matrix metalloproteinase 9 (MMP-9) were detected by Reverse Transcription-Polymerase Chain Reaction. The protein expressions of Calpain-1, Calpain-2, Calcineurin, AKT and GSK-3β were detected by western blotting.

(1) Compared with db/db group, FPG, TC, TG and HOMA-IR decreased after CAR treatment in db/db mice (t=1.213-2.112, P>0.05) . (2) Compared with the WT group, the collagen content and the mRNA levels of TGF-β₁ and MMP-2 in the db/db group increased significantly whereas the mRNA level of MMP-9 decreased significantly (t=3.098~4.905, P<0.05). Administration of CAR significantly reversed the changes (t=2.491-2.925, P<0.05). (3) Compared with WT mice, the LVEDP of mice in db/db group increased and the absolute value of ±dp/dt_max decreased which were significantly reversed by administration of CAR (t=2.865-6.404, P<0.05). (4) Compared with db/db group, the oxidative/nitrifying stress responses were significantly reversed by administration of CAR (t=2.519-4.845, P<0.05). (5) Compared with the db/db group, CAR can reduce Calpain, CaN activity and protein content of myocardial tissues (t=2.634-3.253, P<0.05) and increase the expressions of p-AKT and p-GSK-3β (t=2.827, 4.090, P<0.05).

These results suggest that CAR exerts potent cardioprotective effects against heart injury in type 2 diabetic db/db mice and its mechanism may be involved in preservation of insulin sensitivity, antioxidant stress ability and regulation of Calpain and AKT/GSK-3β pathway.

To summarize the current status and change of anti-diabetic medication regimen of diabetic patients hospitalized to different departments in Chinese PLA General Hospital.

The clinical data of patients with diabetes admitted to Chinese PLA General Hospital from January 2001 to May 2014 were collected(the patients hospitalized in the Department of Endocrinology were excluded). Total of 10 041 patients were selected by stratified random sampling. The type of anti-diabetic medication regimen in different departments and the variation on antihyperglycemic treatment strategies with time were retrospectively analyzed. Data were compared with chi-square among the groups.

A total of 10 041 patients with diabetes mellitus were selected, of whom 5 502 (54.8%) were male and 4 539 (45.2%) were female. The overall mean age was (62±14) years. Of all the patients, 49.8% were treated with oral antidiabetic drugs (OADs) alone, 37.2% used insulin only and 13.0% of the patients received OADs plus insulin. About 54.7% of patients in internal medicine department were treated with OADs, among which, monotherapy accounted for 36.5%, two OADs combination took up 16.5%, three or more OADs combination took up 1.7%. While those in surgical department preferred insulin for treatment when compared their counterparts in internal medicine departments [56.2%(2 526/4 497) vs 45.3%(2 510/5 544), χ ²=117.928, P<0.001]. During the past 15 years, the number of patients treated with OADs alone reduced [71.1% (589/828) vs 46.0% (2 315/5 036), χ ²=271.087, P<0.01], while the number of those using insulin alone or OADs plus insulin increased [22.1%(183/828) vs 38.9%(1 963/5 036), 6.8%(56/828) vs 15.1%(758/5 036), χ ²=120.369, 96.989, both P<0.01].

The anti-diabetic medication regimen is different in different departments. Insulin therapy was more common in surgical department than in internal medicine department. In the past 15 years, the percentage of patients using insulin alone or OADs plus insulin increases with time.

To evaluate the relationship between serum levels of 25(OH)D and peripheral neuropathy in type 2 diabetes by Meta analysis.

We searched the papers published before June 2016 from the database of PubMed, Cochrane,CNKI,VIP and Wanfang. Thirty one articles were found. Studies were screened and their quality were evaluated by Newcastle-Ottawa Scale (NOS). Meta-analysis were performed by RevMan 5.3 software.

A total of 1 373 cases from 10 articles were involved. The results showed that the serum levels of 25(OH)D in type 2 diabetes with peripheral neuropathy was lower apparently than that of controls [WMD=-7.28, 95%CI (-9.21, -5.34) , P<0.000 01].

There is an association between 25(OH)D and peripheral neuropathy in type 2 diabetes.

To analyze the epidemiological characteristics of patients with diabetic oculopathy in a population based health information platform in Ningbo area.

Two databases including the diabetes mellitus database and the oculopathy database of Ningbo between 2011 and 2015 were matched, merged and analyzed. The characteristics of all types of diabetes mellitus and diabetes mellitus complicated with oculopathy were compared. The correlation analyses were conducted using multivariate Logistic regression method.

There were 207 425 diabetes mellitus cases altogether, among which 21 626 cases (10.43%) were diagnosed with oculopathy. The 196 221 cases were type 2 diabetes mellitus, and oculopathy was found in 10.73% of these patients. The time intervals from the diagnosis of type 2 diabetes mellitus to the occurrence of oculopathy were mostly between 1 and 4 years, accounting for 39.96% (n=78 410). The main type of oculopathy was cataract, accounting for 17.53% (n=34 398). Age, body mass index at report and the course of diabetes mellitus in patients with oculopathy were higher than those without oculopathy (t=11.70, 5.10, 3.80, all P<0.01) . Compared to patients with the duration less than 1 year, patients with the duration of 1-9 years had a lower risk, whereas patients with the duration longer than 10 years had a higher risk of oculopathy (OR=1.12, 95%CI: 1.05-1.18) .

The high risk of oculopathy in diabetes mellitus must not be ignored, especially in elderly patients or those with long duration of diabetes mellitus.

Eruptive xanthoma is a type of xanthomatosis. The clinical manifestation is a cluster of small orange yellow papules, which tend to occur in the buttocks, limbs, groin and axillary parts, with or without systemic lipid metabolism disorders and other system abnormalities. Currently, the treatment of xanthomatosis, including eruptive xanthomas, is limited and the efficacy is uncertain. Berberine combined with metformin and pioglitazone as a regimen for the treatment of xanthomatosis is rarely reported. A patient with eruptive xanthomatosis was admitted to our department, followed up for 3 years, and good results were obtained, which are reported below.

The main goal of diabetes therapy is to prevent chronic complications, improve the quality of life of patients and prolong their life through good metabolic control. Since 2008, a number of large-scale clinical studies and follow-up results on intensive hypoglycemia in type 2 diabetes have been released one after another, suggesting that early intensive hypoglycemia can significantly reduce long-term microvascular complications and improve the progression of macrovascular complications to a certain extent, slowing down the occurrence of cardiovascular events. Therefore, early intensive hypoglycemic therapy for early or newly diagnosed patients is one of the important strategies to optimize blood glucose management.