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.

Efficacy of low-protein diet in diabetic nephropathy: a meta-analysis of randomized controlled trials.

PURPOSE: We aimed to systematically assess the efficacy of low-protein diet preventing progression of diabetic nephropathy based on randomized controlled trials (RCTs). METHODS: A systematic and electronic search was conducted. Initial searches of literature updated to September 2018 were made using the following databases including CNKI, VIP, Wanfang, Cochrane, PubMed, and Embase using the index words for qualified RCTs. Additional searches were performed to identify linked literature sources. Data of RCTs on low-protein diet versus control diet, efficacy analysis of kidney function, nutritional status or proteinuria were extracted. Random effects model and fixed effects model were applied to combine the data which were further analyzed by Chi-squared test and I2tests. The main outcomes were then analyzed through the use of relative risks (RR), mean difference (MD) and its 95% confidence interval (95% CI). RESULTS: Twenty articles were included in the present meta-analysis with a total of 690 patients in the low-protein diet group (LPD) and a total of 682 patients in the control group. Moderate to strong evidence indicated that LPD was significantly effective for decreasing the urinary albumin excretion rate (SMD:0.62, 95%CI:0.06-1.19) and proteinuria (SMD:0.69, 95%CI:0.22-1.16) versus the control group. No statistical difference, however, was found in glycosylated hemoglobin (SMD:0.17, 95%CI:-0.18-0.51), serum creatinine (SMD:0.20, 95%CI:-0.26-0.66), as well as glomerular filtration rate (SMD:0.21, 95%CI:-0.29-0.71) between the two groups. CONCLUSION: The current meta-analysis reveals an effective role of low-protein diet in improving diabetic nephropathy. However, the small number of involved patients may limit the accuracy of results. High-quality RCTs with a larger sample size in the future are required to confirm the current findings.

ß-arrestin-2 is involved in irisin induced glucose metabolism in type 2 diabetes via p38 MAPK signaling.

Type 2 diabetes mellitus (T2DM) is a common metabolic disease worldwide. It has been reported that irisin play regulatory role in glucose metabolism in T2DM. However, the underlying mechanism involved in that is not completely known. Herein, we determined the novel role of ß-arrestin-2 in irisin-induced glucose utilization in diabetes. Effects of irisin and ß-arrestin-2 on glucose utilization were investigated in a rat model of diabetes and in diabetic C2C12 cells in vitro. Results showed that irisin had positive role in glucose metabolism via regulating glucose tolerance as well as uptake in cardiac and skeletal muscle tissues, as evidenced by IPGTT, 2-deoxyglucose uptake and plasma membrane GLUT-4 assay. ß-arrestin-2 also improved glucose utilization in diabetes by increasing the glucose uptake and insulin sensitivity, as shown in mice overexpressing ß-arrestin-2. In diabetic C2C12 myocytes, irisin-induced GLUT4 and glucose uptake were restrained by ß-arrestin-2 inhibition, but was enhanced by ß-arrestin-2 overexpression. Additionally, irisin and ß-arrestin-2 increased the activation of p38 MAPK in diabetic C2C12 cells, and the repression of p38 MAPK activation decreased the glucose uptake and plasma membrane GLUT-4 was enhanced by irisin and ß-arrestin-2 overexpression in diabetic C2C12 cells. In conclusion, we demonstrated that ß-arrestin-2 has a crucial role in irisin induced glucose metabolism in T2DM by regulating the p38 MAPK signaling. This might present a novel therapeutic target of treatment for human diabetes.

[Intervention and therapeutic effect of siRNA-HDAC5 on abnormal histone modification in non-obese diabetic mice].

OBJECTIVE: To evaluate therapeutic eff ect of siRNA-HDAC5 on non-obese diabetic (NOD) mice by using small interference RNA (siRNA) technique to knock down the expression of HDAC5 in spleen CD4+ T cells. METHODS: NOD mice, 12-weeks old, were randomly divided into 3 groups and were given normal saline, siRNA-Control or siRNA-HDAC5 through caudal vein injection. The spleens and other samples were collected at the 18th, 24th or 30th week. The blood glucose was tested by blood glucose meter. The urinary albumin and serum levels of IL-1, IL-6, IL-18, and TNF-α were detected by ELISA. The mRNA levels of CD11a, CCR5, and CX3CR1 in spleen CD4+ T cells were measured by quantitative Real-time PCR. The HDAC5 protein level in spleen CD4+ T cell was detected by Western blot. RESULTS: Compared with the control group, the siRNA-HDAC5 group showed a significant decrease in blood glucose, urine albumin excretion rate, serum cytokine and the mRNA levels of CD11a, CCR5, and CX3CR1, consist with the decrease in protein level of HDAC5. CONCLUSION: Inhibition of HDAC5 expression in NOD mice could effectively alleviate the onset and development of kidney damage caused by diabetes.

Serum fibroblast growth factor 21 levels are related to subclinical atherosclerosis in patients with type 2 diabetes.

BACKGROUND: Fibroblast growth factor 21 (FGF21), a glucose and lipid metabolic regulator, has recently been demonstrated to be associated with cardiovascular diseases (CVD) such as carotid atherosclerosis, coronary heart disease and carotid artery plaques. However, the relationship between circulating FGF21 and subclinical atherosclerosis or atherosclerosis of other arteries such as the femoral and iliac artery remains unclear. In this study, we evaluated the association of serum FGF21 with intima-media thickness (IMT) and subclinical atherosclerosis in type 2 diabetic patients. METHODS: Serum FGF21 levels were detected by enzyme-linked immunosorbent assay in 212 newly diagnosed type 2 diabetic patients without clinical symptoms of atherosclerosis or cardiovascular diseases. IMT of the carotid, femoral, and iliac arteries were measured by high-resolution B-mode ultrasound to determine the presence of subclinical atherosclerosis, which was defined as having an IMT > 1.0 mm and/or plaque on one or more of the three arteries without any clinical manifestations. The relationship between serum FGF21 levels and subclinical atherosclerosis was analyzed. RESULTS: Serum FGF21 levels were significantly higher in patients with subclinical atherosclerosis compared to those without [261.3 (135.1-396.4) versus 144.9 (95.9-223.0) ng/L, P < 0.001]. These differences were also observed in both men and women with subclinical atherosclerosis compared to their respective groups without [men: 243.2 (107.6-337.0) versus 136.8 (83.6-212.8) ng/L, P = 0.048; women: 292.4 (174.2-419.9) versus 160.4 (115.3-258.5) ng/L, P = 0.001]. Moreover, serum FGF21 levels showed a significantly positive correlation with carotid IMT in women (r = 0.23, P = 0.018) and with iliac IMT in both genders (women: r = 0.27, P = 0.005; men: r = 0.22, P = 0.024). Multiple logistic regression analysis further showed that serum FGF21 was an independent impact factor for subclinical atherosclerosis in patients with type 2 diabetes. CONCLUSIONS: Serum FGF21 is elevated in newly diagnosed type 2 diabetes, and positively correlates with carotid and iliac lesions in patients with subclinical atherosclerosis, especially in women. High levels of FGF21 may be a compensatory reaction to offset atherosclerosis.

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.

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.