Arachidonic acid alleviates autoimmune diabetes in NOD mice.

BACKGROUND: Arachidonic acid (AA) is considered to link nutrient metabolism, to inflammation and immunity, suggesting it may have a role in autoimmune diseases. Our previous study suggests that DPP-4 inhibitors (DPP-4i) might regulate AA - relative signaling in type 1 diabetes. AIMS: To examine the effect of AA on autoimmune diabetes and its cross-talk with DPP-4i in The Non-Obese Diabetic (NOD) mice. METHODS: The NOD mice were divided randomly and equally into three groups: AA group, AA plus DPP-4i group and control group. The incidence of diabetes, blood glucose, insulitis and cytokine profiles were monitored. At the end of the experiment, pancreatic tissues were stained by H&E. Serum cytokine profiles were examined using a Mesco Scale Discovery multiplexed-assay kit. RESULTS: Even though AA or AA plus DPP-4i treatment has no effect on incidence of diabetes and weight, AA treatment reduces blood glucose, preserves islet morphology and alleviates inflammatory cell infiltration into pancreatic islets in NOD mice, accompanying with increased serum levels of IL-10, IL-1 ß, IL-6, IL-5, KC/GRO and TNF-α and decreased serum levels of IL-2. CONCLUSION: We observed that AA treatment alleviates autoimmune diabetes in NOD mice by reducing hyperglycemia, alleviating insulitis and improving cytokine profiles. DPP-4i might alleviate the effect of AA by cross-talk. We provide evidence of AA treatment to alleviate type 1 diabetes in NOD mice, which may provide a novel therapeutic option for type 1 diabetes.

Efficacy and safety of basal-bolus insulin at 1:1.5 ratio compared to 1:1 ratio using a weight-based initiation and titration (WIT2) algorithm in hospitalized patients with type 2 Diabetes: a multicenter, randomized, clinical study.

BACKGROUND: Most studies initiated basal-bolus insulin in a ratio of 1:1 and titrated based on glucose. This study aimed to investigate the effectiveness and safety of a weight-based and ratio of 1:1.5 basal-bolus insulin using an algorithm for both initiation and titration in hospitalized patients with type 2 diabetes (T2D). METHODS: Hospitalized patients with T2D were randomly assigned to two groups in equal numbers to receive 1:1.5 and 1:1 ratios of basal-bolus insulin using a weight-based algorithm for both initiation and titration. The primary outcome was the time taken to reach the fasting blood glucose (FBG) target and 2-h postprandial blood glucose (2hBG) targets after three meals. The secondary outcome included insulin dosage to achieve glycemic control and the incidence of hypoglycemia during hospitalization. RESULTS: 250 patients were screened between October 2021 and June 2022, 220 were randomly grouped, and 182 completed the trial (89 in the 1:1.5 and 93 in the 1:1 groups). The time taken to reach FBG targets was comparable between the two groups (3.4 ± 1.7 vs. 3.0 ± 1.3 days, p = 0.137) within about 3 days. The 2hBG after three meals was shorter in the 1:1.5 group than in the 1:1group (2.9 ± 1.5 vs. 3.4 ± 1.4 days, p = 0.015 for breakfast, 3.0 ± 1.6 vs. 3.6 ± 1.4 days, p = 0.005 for lunch, and 3.1 ± 2.1 vs. 4.0 ± 1.5 days, p = 0.002 for dinner). No significant difference in insulin dosages was found between the two groups at the end of the study. The incidence of hypoglycemia was similar in both groups. CONCLUSIONS: We demonstrated that fixed dose-ratio basal-bolus insulin at 1:1.5 calculated using a weight-based initiation and titration algorithm was simple, as effective, and safe as ratio at 1:1 in managing T2D in hospitalized patients. Trial Registration ChiCTR 2,100,050,963. Date of registration: September 8, 2021.

NLRP3 Inflammasome: Checkpoint Connecting Innate and Adaptive Immunity in Autoimmune Diseases.

Autoimmune diseases are a broad spectrum of human diseases that are characterized by the breakdown of immune tolerance and the production of autoantibodies. Recently, dysfunction of innate and adaptive immunity is considered to be a key step in the initiation and maintenance of autoimmune diseases. NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a multimeric protein complex, which can detect exogenous pathogen irritants and endogenous danger signals. The main function of NLRP3 inflammasome is to promote secretion of interleukin (IL)-1ß and IL-18, and pyroptosis mediated by caspase-1. Served as a checkpoint in innate and adaptive immunity, aberrant activation and regulation of NLRP3 inflammasome plays an important role in the pathogenesis of autoimmune diseases. This paper reviewed the roles of NLRP3 inflammasome in autoimmune diseases, which shows NLRP3 inflammasome may be a potential target for autoimmune diseases deserved further study.

Serum levels of inhibitory costimulatory molecules and correlations with levels of innate immune cytokines in patients with pulmonary tuberculosis.

OBJECTIVE: To analyze serum levels of inhibitory costimulatory molecules and their correlations with innate immune cytokine levels in patients with pulmonary tuberculosis (PTB). METHODS: Data for 280 PTB patients and 280 healthy individuals were collected. Serum levels of immune molecules were measured using ELISA. Univariate, multivariate, subgroup, matrix correlation, and receiver operating characteristic curve analyses were performed. RESULTS: Host, environment, lifestyle, clinical features, and medical history all influenced PTB. Serum levels of soluble programmed death ligand 1 (sPD-L1), soluble T-cell immunoglobulin- and mucin-domain-containing molecule 3 (sTim-3), soluble galectin-9 (sGal-9), interleukin (IL)-4, and IL-33 were significantly higher in patients with PTB, while levels of IL-12, IL-23, IL-18, and interferon (IFN)-γ were significantly lower. Serum levels of sTim-3 were higher in alcohol users. Levels of sTim-3 were negatively correlated with those of IL-12. Levels of IL-12, IL-23, and IL-18 were positively correlated with those of IFN-γ, while levels of IL-12 were negatively correlated with those of IL-4. The areas under the curve of sPD-L1, sTim-3, sGal-9, IL-12, IL-23, IL-18, IFN-γ, IL-4, and IL-33 for identifying PTB were all >0.77. CONCLUSIONS: Inhibitory costimulatory molecules may be targets for controlling PTB. Immune molecules may be helpful for diagnosis of PTB.

Correlation between Occupational Stress and Coronary Heart Disease in Northwestern China: A Case Study of Xinjiang.

OBJECTIVE: To study the correlation between occupational stress and coronary heart disease in western China. METHOD: A case-control design was used. From June 2016 to May 2017, 310 patients with coronary heart disease (CHD) confirmed by coronary angiography (CAG) at the Heart Center of the First Affiliated Hospital of Xinjiang Medical University were recruited by cluster sampling, along with 536 healthy controls. The questionnaire was developed based on a Job Content Questionnaire (JCQ). An epidemiological survey was conducted to collect clinical data. Chi-squared test, analysis of variance, and binary logistic regression analysis were adopted. RESULTS: (1) In the Han population, there were statistically significant differences in the composition of smoking, diets, sleep duration, sleep quality, and physical activity between two groups (all P < 0.05). In the Uygur population, statistically significant differences in the composition of smoking, drinking, diets, sleep quality, and physical activity were found between two groups (all P < 0.05). (2) Differences in sleep duration and physical activity between the Han and Uygur case groups were statistically significant (P < 0.05). (3) Differences in Gensini scores between the Han and Uygur case groups were statistically significant (P < 0.05). Differences in coronary artery lesions between the Han and Uygur case groups were statistically significant (P < 0.05). (4) In the Uygur population, the difference between the occupational stress level and CHD were statistically significant (P < 0.05). (5) The differences between the number of different pathological changes and the level of occupational stress in the Han and Uygur case groups were not statistically significant (P > 0.05). In the Han and Uygur case groups, the difference between the occupational stress level and Gensini high-level group were statistically significant (P < 0.05). (6) After adjustment for age and sex, significant increased risk effects for Han patients with CHD were found to be associated with sleep quality (OR = 1.88; 95% CI: 1.047-1.782; P < 0.05). Uygur patients with CHD was significantly associated with smoking (OR = 3.094; 95% CI: 1.025-1.103; P < 0.05) and occupation stress (OR = 1.523; 95% CI: 1.757-3.062; P < 0.05). CONCLUSION: Occupational stress is correlated with CHD for the Uygur population.

Cartilage Oligomeric Matrix Protein Induced Arthritis-A New Model for Rheumatoid Arthritis in the C57BL/6 Mouse.

The most commonly used strains in experimental research, including genetically modified strains, are C57BL/6 mice. However, so far, no reliable model for rheumatoid arthritis is available, mainly due to the restriction by the MHC class II haplotype H-2b. Collagen-induced arthritis (CIA) is the most widely used animal model of rheumatoid arthritis, but C57BL/6 strain is resistant to CIA because there is no collagen II peptide associated with H-2b. To establish a rheumatoid arthritis model in C57BL/6 mice, we immunized C57BL/6NJ (B6N) mice with human cartilage oligomeric matrix protein (COMP), which induced severe arthritis with high incidence, accompanied by a strong auto-antibody response. Native COMP was required, as denatured COMP lost its ability to induce arthritis in B6N mice. An immunodominant COMP peptide was identified as the key T cell epitope, with a perfect fit into the Ab class II peptide binding pocket. A critical amino acid in this peptide was found to be phenylalanine at position 95. Recombinant COMP mutated at position 95 (COMP_F95S) lost its ability to induce arthritis or a strong immune response in the B6N mice. In conclusion, A new model for RA has been established using C57BL/6 mice through immunization with COMP, which is dependent on a COMP specific peptide binding Ab, thus in similarity with CIA in Aq expressing strains.

Islet Function and Insulin Sensitivity in Latent Autoimmune Diabetes in Adults Taking Sitagliptin: A Randomized Trial.

CONTEXT: The long-term effects of dipeptidyl peptidase-4 inhibitors on ß-cell function and insulin sensitivity in latent autoimmune diabetes in adults (LADA) are unclear. OBJECTIVE: To investigate the effects of sitagliptin on ß-cell function and insulin sensitivity in LADA patients receiving insulin. DESIGN AND SETTING: A randomized controlled trial at the Second Xiangya Hospital. METHODS: Fifty-one patients with LADA were randomized to sitagliptin + insulin (SITA) group or insulin alone (CONT) group for 24 months. MAIN OUTCOME MEASURES: Fasting C-peptide (FCP), 2-hour postprandial C-peptide (2hCP) during mixed-meal tolerance test, △CP (2hCP - FCP), and updated homeostatic model assessment of ß-cell function (HOMA2-B) were determined every 6 months. In 12 subjects, hyperglycemic clamp and hyperinsulinemic euglycemic clamp (HEC) tests were further conducted at 12-month intervals. RESULTS: During the 24-month follow-up, there were no significant changes in ß-cell function in the SITA group, whereas the levels of 2hCP and △CP in the CONT group were reduced at 24 months. Meanwhile, the changes in HOMA2-B from baseline were larger in the SITA group than in the CONT group. At 24 months, first-phase insulin secretion was improved in the SITA group by hyperglycemia clamp, which was higher than in the CONT group (P < .001), while glucose metabolized (M), insulin sensitivity index, and M over logarithmical insulin ratio in HEC were increased in the SITA group (all P < .01 vs baseline), which were higher than in the CONT group. CONCLUSION: Compared with insulin intervention alone, sitagliptin plus insulin treatment appeared to maintain ß-cell function and improve insulin sensitivity in LADA to some extent.

Long-term inhibition of dipeptidyl-peptidase 4 reduces islet infiltration and downregulates IL-1ß and IL-12 in NOD mice.

Dipeptidyl-peptidase 4 (DPP-4) inhibitor (sitagliptin) is a novel anti-hyperglycemia drug in the treatment of type 2 diabetes. However, its potential in type 1 diabetes is still unclear. Recent studies show that increased infection, especially respiratory tract infection, is significantly associated with DPP-4 inhibitors. In this study, we aimed to explore the effects of long-term inhibition of DPP- 4 on innate immunity in type 1 diabetes. Forty mice were randomly divided into 4 groups (n = 10 in each group): control group, lipopolysaccharide (LPS) group, sitagliptin group and sitagliptin + LPS group. The concentrations of IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, TNF-α and IFN-γ were measured with Mesco Scale Discovery multiplexed-assay kit. Immunohistochemistry staining of pancreases was performed and insulitis scores for each islet were determined. The results showed that DPP-4 inhibition has no effect on incident rate of diabetes and metabolic parameters in NOD mice. Long-term inhibition of DPP-4 reduced CD4+T cells to infiltrate into islets and ameliorated insulitis in NOD mice. DPP-4 inhibition downregulated serum interleukin IL-1ß and IL-12 in NOD mice. However, it had no significant effect on LPS-induced IL-1ß, IL-6, IL-10, IL-12, tumor necrosis factor (TNF)-α and interferon (IFN)-γ in NOD mice. In conclusion, Long-term inhibition of DPP-4 exists anti-inflammatory effect in type 1 diabetes probably by reducing CD4+T cells to infiltrate into islets and downregulating L-1ß and IL-12 in serum.

Comparison of weight-based insulin titration (WIT) and glucose-based insulin titration using basal-bolus algorithm in hospitalized patients with type 2 diabetes: a multicenter, randomized, clinical study.

INTRODUCTION: Subcutaneous administration of insulin is the preferred method for achieving glucose control in non-critically ill patients with diabetes. Glucose-based titration protocols were widely applied in clinical practice. However, most of these algorithms are experience-based and there is considerable variability and complexity. This study aimed to compare the effectiveness and safety of a weight-based insulin titration algorithm versus glucose-based algorithm in hospitalized patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: This randomized clinical trial was carried out at four centers in the South, Central and North China. Inpatients with T2DM were randomly assigned (1:1) to receive weight-based and glucose-based insulin titration algorithms. The primary outcome was the length of time for reaching blood glucose (BG) targets (fasting BG (FBG) and 2-hour postprandial BG (2hBG) after three meals). The secondary outcome included insulin dose for achieving glycemic control and the incidence of hypoglycemia during hospitalization. RESULTS: Between January 2016 and June 2019, 780 patients were screened, and 575 completed the trial (283 in the weight-based group and 292 in the glucose-based group). The lengths of time for reaching BG targets at four time points were comparable between two groups. FBG reached targets within 3 days and 2hBG after three meals within 4 days. There is no significant difference in insulin doses between two groups at the end of the study. The total daily dosage was about 1 unit/kg/day, and the ratio of basal-to-bolus was about 2:3 in both groups. The incidence of hypoglycemia was similar in both groups, and severe hypoglycemia was not detected in either of the groups. CONCLUSIONS: Weight-based insulin titration algorithm is equally effective and safe in hospitalized patients with T2DM compared with glucose-based algorithm. TRIAL REGISTRATION NUMBER: NCT03220919.

Case-Control Study on the Interaction Effects of rs10757278 Polymorphisms at 9p21 Locus and Traditional Risk Factors on Coronary Heart Disease in Xinjiang, China.

OBJECTIVE: To study the interaction effects of rs10757278 polymorphisms at 9p21 locus and traditional risk factors on coronary heart disease (CHD) in Xinjiang, China. METHODS: This case-control study consecutively enrolled 310 unrelated consecutive CHD patients aged 18-70 years old. All study participants were recruited between January and December 2017 from The Heart Center of The First Affiliated Hospital of Xinjiang Medical University. CHD patients were confirmed by coronary angiography (≥50% diameter stenosis in at least one of the major coronary arteries) according to the American Heart Association criteria for the confirmation of CHD. Healthy subjects were randomly selected from the occupational population, who received physical examination in our hospital and matched to cases on the basis of age (±3 years) and sex, those without medical history of cardiovascular diseases, and 536 subjects were selected as the control group after medical history inquiry, physical examination, cardiac ultrasound, electrocardiogram, and other blood biochemical examinations in the hospital. The occupational stress was evaluated by an effort-reward imbalance questionnaire. An epidemiological survey was conducted to collect clinical data. Chi-squared test, analysis of variance, and binary logistic regression analysis were adopted. RESULTS: Both the case and the control groups showed significant difference in smoking, drinking, physical activity, hypertension, diabetes mellitus, family history of CHD, and body mass index (BMI) (all P < 0.05); prevalence of CHD was not related to occupational stress. There was no significant difference in occupational stress level between the 2 groups (P > 0.05); Differences in rs10757278 genotype between the case group and the control groups were statistically significant; binary logistic regression analysis was used to evaluate the risk factors of CHD. After adjustment for age and sex, significant increased risk effects for CHD were found to be associated with smoking [odds ratio (OR) = 2.311; 95% confidence interval (CI): 1.04-2.499; P < 0.001], physical exercise (OR = 1.365; 95% CI: 1.137-1.639; P < 0.001), hypertension (OR = 4.627; 95% CI: 2.165-10.764; P < 0.001), family history of CHD (OR = 4.103; 95% CI: 3.169-6.892; P < 0.001), BMI (OR = 2.484; 95% CI: 2.036-3.03; P < 0.001), and GG genotype at rs10757278 (OR = 1.978; 95% CI: 1.413-2.769; P < 0.001); We noted that a significant interaction association between GG genotype at rs10757278 and CHD differs across categories of smoking, hypertension, family history of CHD, and BMI. CONCLUSION: GG genotype at rs10757278 may be a risk factor for CHD. And there are interaction effects between GG genotype of rs10757278 in region 9p21 gene and traditional risk factors.

CD26 in autoimmune diseases: The other side of "moonlight protein".

Dipeptidyl peptidase 4 (DPP-4) is a serine protease, which has enzymatic activity to selectively clean the N-terminal dipeptide of peptides and proteins with proline or alanine in the second position. DPP-4 inhibitor has been widely used for the treatment of type 2 diabetes by increasing the level of the glucagon-like peptide-1 and decreasing the glucose level. DPP-4, also known as lymphocyte cell surface protein CD26, plays a core role of T cell immunity. Many roles of CD26 in other immune cells have been found. As a "moonlight protein", the effect of CD26 in autoimmune diseases has attracted more and more attention. The paper reviewed the function and potential effect of CD26 in autoimmune diseases, which shows CD26 may be a new target of autoimmune diseases deserved further study.

Liraglutide Exerts Potential Anti-inflammatory Effect in Type 1 Diabetes by Inhibiting IFN-γ Production via Suppressing JAK-STAT Pathway.

BACKGROUND: Type 1 diabetes is a T cell-mediated autoimmune disease. Interferon γ plays a critical role in the pathogenesis of type 1 diabetes. Signal transducer and activator of transcription transduces type I interferon cytokines in T cells, leading to Th1 cell differentiation and production of interferon γ. Recent studies suggest that liraglutide reduces the plasma concentration of C-reative protein in patients with type 1 diabetes and protects ß cell function in the non-obese diabetic mouse. OBJECTIVE: The study aimed to explore the effect of glucagon-like peptide-1 analogue on interferon γ production and the underlying signaling pathway in vitro. METHODS: Jurkat E6-1 cells were intervened with different concentrations of glucose and liraglutide during different time periods. Protein was extracted from Jurkat E6-1 cells. The target proteins (total and activated Janus kinase 2, signal transducers and activators of transcription 4 and interferon γ) were detected by Western blot. RESULTS: Glucose stimulates interferon γ expression and activates Janus kinase 2/signal transducers and activators of transcription 4 signaling pathway in Jurkat E6-1 cells in a concentration and timedependent manner. Under high glucose condition, liraglutide inhibits interferon γ expression and Janus kinase 2/signal transducers and activators of transcription 4 signaling pathway in Jurkat E6-1 cells in a concentration and time-dependent manner. The Janus kinase responsible for liraglutide-inhibited signal transducers and activators of transcription 4 phosphorylation is Janus kinase 2, which is also required for the interferon γ induction. Finally, we demonstrated that under high glucose condition, liraglutide inhibits interferon γ expression via Janus kinase 2/signal transducers and activators of transcription 4 signaling pathway in Jurkat E6-1 cells. CONCLUSION: Liraglutide inhibits Jurkat E6-1 cells to produce interferon γ via the Janus kinase/signal transducers and activators of transcription signaling pathway under high glucose condition, which implies its potential in the immunoregulatory effect of type 1 diabetes.

Lack of coordination between partners: investigation of Physician-Preferred and Patient-Preferred (4P) basal insulin titration algorithms in the real world.

BACKGROUND: Patient-centered care is respectful to a patient's preference. All prior clinical trials on patient self-titration algorithms for basal insulin were decided by physicians. We hypothesized that patients and physicians have different preferences. PATIENTS AND METHODS: Physicians and diabetes patients were asked to choose their preferred insulin glargine self-titration algorithm among 5 algorithms. Algorithm 1, 1 U increase once daily; algorithm 2, 2 U increase every 3 days; algorithm 3, 3 U increase every 3 days; algorithm 4, titration every 3 days according to fasting blood glucose, and algorithm 5, weekly titration 2-8 U based on 3-day mean fasting blood glucose levels. RESULTS: Eleven (5.2%) out of 210 physicians and 180 (90.9%) out of 198 patients preferred algorithm 1 (χ2=300.4, p=0.000). In contrast, 195 (92.9%) physicians and 18 (9.1%) patients preferred algorithm 2 (χ2=286.6, p=0.000). In addition, 4 (1.9%) physicians but no patients preferred algorithm 3 (χ2=2.099, p=0.124). Neither physicians nor patients chose algorithms 4 or 5. Most physicians preferred algorithm 2 since it is recommended by guidelines, but most patients preferred algorithm 1 for its simplicity. CONCLUSION: Patients had different preferences compared with physicians. Attention should be given to patients' preferences to increase adherence and improve glycemic control.

[Increased serum levels of soluble T cell immunoglobulin mucin molecule 3 and IL-4 and decreased IFN-γ in patients with pulmonary tuberculosis].

Objective To detect the serum levels of soluble T cell immunoglobulin mucin molecule 3 (sTim-3), IFN-γ and IL-4 in patients with pulmonary tuberculosis. Methods Peripheral blood was collected from 48 patients with pulmonary tuberculosis and 20 healthy controls. The serum level of sTim-3 was detected by ELISA. The levels of IFN-γ and IL-4 were determined by cytokine bead array (CBA). The correlations between sTim-3, IFN-γ and IL-4 levels in sera of patients with pulmonary tuberculosis were analyzed by Pearson correlation test. Results Compared with the control group, the serum levels of sTim-3 and IL-4 increased significantly, while the level of IFN-γ decreased significantly. Pearson analysis showed that there was a negative correlation between sTim-3 and IFN-γ as well as between IFN-γ and IL-4 in patients with pulmonary tuberculosis, while sTim-3 and IL-4 were positively correlated. Conclusion The serum levels of sTim-3 and IL-4 increase, but IFN-γ decreases in the patients with pulmonary tuberculosis.

Comparison of the Efficacy and Safety of Insulin Detemir and Insulin Glargine in Hospitalized Patients with Type 2 Diabetes: A Randomized Crossover Trial.

INTRODUCTION: Previous studies comparing insulin detemir versus insulin glargine showed conflicting results, and included only outpatients. This study compared the two insulin analogs once daily in hospitalized patients with type 2 diabetes (T2D). METHODS: A total of 55 patients aged 18-80 years with hyperglycemia admitted to the endocrinology wards were screened between June 2014 and February 2015. Forty-two enrolled patients were randomly assigned to receive either insulin detemir followed by insulin glargine once daily (n = 21), or vice versa (n = 21). The two insulin analogs were titrated 0.1 U/kg once daily based on fasting blood glucose (FBG). After achieving FBG <7.8 mmol/L (the first period), subjects were switched from one analog to the other (the second period) with no change in the dose. The second period lasted for 3 days. When hypoglycemia occurred in the second period, the observation was discontinued. Six-point blood glucose including FBG, 2 h after breakfast, lunch, dinner, bedtime, and at 3:00 am was tested every day. The glucose profiles of the final days in the two periods were compared. RESULTS: At the end of the first period, days for achieving FBG target (4.0 ± 0.5 days vs. 3.3 ± 0.4 days, t = 1.079, P = 0.286) and total daily dose (30.1 ± 2.4 U vs. 30.1 ± 2.9 U, t = 0.002, P = 0.999) between insulin detemir and insulin glargine were similar. There was no significant difference in the 24-h glucose control between the two analogs. No hypoglycemia occurred with both analogs in the first period. However, in the second period, when insulin glargine was switched to insulin detemir, two, three and, one patients had hypoglycemia events on day 1, day 2 and day 3 of the second period, respectively. One patient had severe hypoglycemia on day 1. CONCLUSION: When both basal insulin analogs were given once daily in T2D, insulin detemir achieved similar efficacy to insulin glargine. On the other hand, there may be differences in action of the compared basal insulins. Further studies with larger patient samples are necessary to support evidence and reveal possible mechanisms.

Latent autoimmune diabetes in adults with low-titer GAD antibodies: similar disease progression with type 2 diabetes: a nationwide, multicenter prospective study (LADA China Study 3).

OBJECTIVE: This study investigated the relationship between GAD autoantibody (GADA) titers and changing of ß-cell function in patients with latent autoimmune diabetes in adults (LADA). RESEARCH DESIGN AND METHODS: This 3-year prospective study enrolled 95 subjects from 15 Chinese cities including 25 high-titer (GADA ≥180 units/mL) LADA patients, 42 low-titer (GADA <180 units/mL) LADA patients, and 28 type 2 diabetic patients, the latter two groups as controls of similar age, sex, and BMI. Clinical characteristics were determined annually, including glycosylated hemoglobin (HbA1c), fasting C-peptide (FCP), and 2-h postprandial C-peptide (PCP). RESULTS: Despite similar initial FCP and PCP, FCP and PCP both decreased more in subjects with high GADA titer (FCP from mean 0.49 nmol/L at entry to 0.13 nmol/L at the third year; P < 0.05) than with low GADA titer (FCP from mean 0.48 to 0.38 nmol/L) and type 2 diabetes (FCP from mean 0.47 to 0.36 nmol/L); the latter two groups being similar. After 3 years, residual ß-cell function (FCP >0.2 nmol/L) was detected in only 42% with an initial high GADA titer compared with 90% with a low GADA titer and 97% with type 2 diabetes (P < 0.01 for both). GADA positivity at the third year persisted more in subjects with initially high GADA (92%) than with low GADA (26%) titers (P < 0.01). CONCLUSIONS: In selected LADA patients, initial GADA titers identified subjects with different degrees of persistent autoimmunity and disease progression. LADA patients with a low GADA titer had metabolic phenotypes and loss of ß-cell function similar to type 2 diabetic patients.

The new insights from DPP-4 inhibitors: their potential immune modulatory function in autoimmune diabetes.

Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of anti-diabetic agents that are widely used in clinical practice to improve glycemic control and protect ß-cell function in patients with type 2 diabetes. DPP-4 is also known as lymphocyte cell surface protein CD26 and plays an important role in T-cell immunity. Autoimmune diabetes, a T-cell mediated organ-specific disease, is initiated by the imbalance between pathogenic and regulatory T-lymphocytes. DPP-4 inhibitors can suppress pathogenic effects of Th1 and Th17 cells and up-regulate Th2 cells and regulatory T cells, which play a critical role in ameliorating autoimmune diabetes. This provides a basis for the potential use of DPP-4 inhibitors in the treatment of autoimmune diabetes. Recent studies suggest that DPP-4 inhibitors improve ß-cell function and attenuate autoimmunity in type 1 diabetic mouse models. However, there are few clinical studies on the treatment of autoimmune diabetes with DPP-4 inhibitors. Further studies are warranted to confirm the therapeutic effects of DPP-4 inhibitors on autoimmune diabetes in humans.

Dipeptidyl peptidase 4 inhibitor sitagliptin maintains ß-cell function in patients with recent-onset latent autoimmune diabetes in adults: one year prospective study.

CONTEXT: Dipeptidyl peptidase 4 (DPP-4) inhibitors have been widely used in type 2 diabetes. An important unanswered question concerns the effect of DPP-4 inhibition on ß-cell function in patients with autoimmune diabetes. OBJECTIVE: The objective of the study was to investigate the effects of the DPP-4 inhibitor on ß-cell function in patients with recent-onset latent autoimmune diabetes in adults (LADA). DESIGN AND SETTING: This study was an open-label, randomized-controlled study conducted in the Department of Endocrinology at the Second Xiangya Hospital. PATIENTS AND INTERVENTION: Thirty recently diagnosed LADA patients were randomized 1:1 to receive insulin therapy with 100 mg/d sitagliptin (group A, n = 15) or without sitagliptin (group B, n = 15) for 12 months. MAIN OUTCOME MEASURES: Fasting and 2-hour postprandial blood samples were obtained at baseline and after 3, 6, 9, and 12 months of treatment to determine blood glucose, glycosylated hemoglobin, and C-peptide levels. RESULTS: There were no differences in the clinical baseline data between the two groups. During the 12 months of follow-up, there were no significant differences in glucose and glycosylated hemoglobin levels between the two groups. At 12 months, fasting C-peptide (FCP), 2-hour postprandial C-peptide (CP), and ΔCP (ΔCP = 2 h CP-FCP) levels were not different in group A (P > .05) compared with baseline, whereas in group B the levels of FCP, 2-hour CP and ΔCP were significantly decreased compared with baseline (P < .05). Levels of 2-hour CP were higher in group A than group B at 12 months (P < .05). CONCLUSIONS: LADA patients treated with sitagliptin and insulin maintained ß-cell function by comparison with insulin alone.

Dipeptidyl peptidase-4 inhibitors: multitarget drugs, not only antidiabetes drugs.

Dipeptidyl peptidase (DPP)-4 inhibitors are a new class of antidiabetic agents that reduce blood glucose by preventing the degradation of the endogenous incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. Protection by DPP-4 inhibitors of ß-cell function has been demonstrated in patients with type 2 diabetes. Because DPP-4 is an enzyme widely expressed in humans, DPP-4 inhibitors are speculated to be multitarget agents. However, other potential therapeutic benefits of DPP-4 inhibitors remain unknown. Recently, some therapeutic effects of DPP-4 inhibitors, such as immune regulation, cardiovascular protection, and anti-inflammatory effects, have been observed. This article provides a systematic and comprehensive review of current research into the newly found effects and mechanism of action of DPP-4 inhibitors in a therapeutic context.