Yan-Hong Pan

Changes of Regulatory T Cells and of Proinflammatory and Immunosuppressive Cytokines in Patients with Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis

Objective. The aim of this study was to investigate the changes of regulatory T cells (Treg), interleukin-6 (IL-6), IL-10, transforming growth factor-β (TGF-β), and tumor necrosis factor-alpha (TNF-α) in patients with type 2 diabetes mellitus (T2DM). Methods. We performed a comprehensive search up to July 2016 for all clinical studies about the changes of Treg, IL-6, IL-10, IL-17, TGF-β, and TNF-α in T2DM patients versus healthy controls. Results. A total of 91 articles (5642 cases and 7378 controls) were included for this meta-analysis. Compared with the controls (all p < 0.001), the patients had increased serum levels of IL-6, TGF-β, and TNF-α but decreased the percentage of peripheral CD4+CD25+Foxp3+Treg and serum IL-10 level. Furthermore, the percentage of peripheral CD4+CD25+Foxp3+Treg (p < 0.001) and serum IL-10 level (p = 0.033) were significantly lower in the patients with complication and in the patients without complication, respectively. No significant changes about the percentage of CD4+CD25+Treg (p = 0.360) and serum IL-17 level (p = 0.459) were found in T2DM patients. Conclusions. T2DM patients have decreased the percentage of peripheral CD4+CD25+Foxp3+Treg and levels of serum IL-10 but elevated serum levels of IL-6, TGF-β, and TNF-α. Presence of diabetic complications further lowers the peripheral CD4+CD25+Foxp3+Treg number.

Changes of transforming growth factor beta 1 in patients with type 2 diabetes and diabetic nephropathy: A PRISMA-compliant systematic review and meta-analysis

Background: The existing evidence indicates increased levels of transforming growth factor beta 1 (TGF-&bgr;1) in patients with type 2 diabetes mellitus (T2DM) and those with type 2 diabetic nephropathy (T2DN); yet no meta-analysis displays a reliable result. Here we conducted a meta-analysis to evaluate characteristic changes of TGF-&bgr;1 in T2DM and diabetic nephropathy. Methods: A systematic search was conducted for eligible studies, which reported the association of TGF-&bgr;1 withT2DM and T2DN patients, in PubMed, Wangfang, Chinese-Cqvip, and China National Knowledge Infrastructure database, from February 1, 1991 to December 15, 2015. The association of serum and urine TGF-&bgr;1 in T2DM and T2DN patients should be evaluated in case-control studies. The Newcastle-Ottawa Scale was used to access the quality of the included studies, and pooling data were synthesized as standard mean difference (SMD) and 95% confidence interval (CI). The collected data were synthesized according to Cochrane Handbook for Systematic Reviews criteria. Subgroup analysis was conducted by albuminuria and ethnicity. Regression analysis and sensitivity analysis were used to explore the sources of heterogeneity. Publication bias was judged by the Egger test. Results: Sixty-three case-control studies of 364 T2DM patients (1604 T2DN patients) and 2100 healthy controls were included for meta-analysis. Compared with the controls, the cases had increased TGF-&bgr;1 levels in both serum (T2DM: SMD 1.78 &mgr;g/L; 95% CI 0.98–2.59, P < .001; T2DN: SMD 4.70 &mgr;g/L, 95% CI 3.55–5.85, P < .001) and urine samples (T2DM: SMD 1.27 pg/mg.creatinine, 95% CI 0.16–2.38, P < .001; SMD 1.19 ng/L, 95% CI 0.77–1.62, P < .001; T2DN: SMD 3.14 pg/mg.creatinine, 95% CI 2.15–4.13, P < .001; SMD 4.50 ng/L, 95% CI 3.16–5.83, P < .001). The increase of serum TGF-&bgr;1 persisted in patients with either microalbuminuria or macroalbuminuria (all P < .001) in Chinese and non-Chinese population. High heterogeneity exists in some comparisons and small-sample studies. Conclusions: Patients with T2DM and those with albuminuria, Chinese or non-Chinese, had increased serum and urine TGF-&bgr;1 levels.

Neuroendocrine hormone amylin in diabetes.

The neuroendocrine hormone amylin, also known as islet amyloid polypeptide, is co-localized, co-packaged and co-secreted with insulin from adult pancreatic islet β cells to maintain glucose homeostasis. Specifically, amylin reduces secretion of nutrient-stimulated glucagon, regulates blood pressure with an effect on renin-angiotensin system, and delays gastric emptying. The physiological actions of human amylin attribute to the conformational α-helix monomers whereas the misfolding instable oligomers may be detrimental to the islet β cells and further transform to β-sheet fibrils as amyloid deposits. No direct evidence proves that the amylin fibrils in amyloid deposits cause diabetes. Here we also have performed a systematic review of human amylin gene changes and reported the S20G mutation is minor in the development of diabetes. In addition to the metabolic effects, human amylin may modulate autoimmunity and innate inflammation through regulatory T cells to impact on both human type 1 and type 2 diabetes.

Renin–angiotensin system blockade for the risk of cancer and death

Introduction: The effects of renin–angiotensin system blockade with angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type 1 receptor blockers (ARBs) on cancer remain inconsistent. Methods: We searched existing databases from 1960 to August 2015, for randomised controlled trials and observational studies (case–control studies and cohort studies) of ARB/ACEI therapy with a minimal one year of follow-up. Outcomes were incidence and mortality of cancer. Results: We included 14 randomised controlled trials and 17 observational studies of 3,957,725 participants (350,329 ARB/ACEI users). The users had a lower incidence of cancer in the observational studies (RR 0.82, 95% CI 0.73–0.93) but not in the randomised controlled trials (RR 1.00, 95% CI 0.92–1.08). The protection persisted for lung cancer (RR 0.85, 95% CI 0.75–0.97) but not for other sites of cancer. The relative risk of cancer associated with renin–angiotensin system blockade was reduced along with time of follow-up. Mortality reduction with ARB/ACEI was marginally significant in the observational studies (RR 0.71, 95% CI 0.55–0.93) but not in the randomised controlled trials (RR 0.99, 95% CI 0.89–1.09). Conclusions: The significant benefits of renin–angiotensin system blockade observed in case–control studies and cohort studies might diminish in randomised controlled trials. Clinical design, site of cancer and duration of follow-up may affect the clinical outcomes.

The change of serum tumor necrosis factor alpha in patients with type 1 diabetes mellitus: A systematic review and meta-analysis.

Objective The aim of this study was used meta-analysis to investigate changes of serum tumor necrosis factor-alpha (TNF-α) in patients with type 1 diabetes mellitus (T1DM). Methods Relevant literatures were identified from PubMed, Cochrane Library, CNKI, WanFang and Chinese-Cqvip databases (published from January 1, 1999 to September 30, 2016). Eligible reports were included for pooled analysis of serum TNF-α level and subgroup analysis was performed in relation with age, disease duration and ethnicity. Results A total of 23 articles (1631 T1DM cases, 1429 healthy controls) were included for this meta-analysis. Compared with the controls, the patients had significantly increased serum TNF-α level (P < 0.001). Similar results were also found among all subgroup analysis of different age, disease duration and ethnicity (with the exception of Asian) (all P < 0.05). Regression analysis indicated that age (P = 0.680), disease duration (P = 0.957), and ethnicity (P = 0.526) of patients were not significant impact factors for the high heterogeneity. The results were stable according to the sensitivity analysis and no publication bias existed in this meta-analysis. Conclusions Serum TNF-α level in T1DM patients has significantly elevated among all age, disease duration and ethnicity groups.

Serum TNF-α concentrations in type 2 diabetes mellitus patients and diabetic nephropathy patients: A systematic review and meta-analysis

OBJECTIVES The aim of this study was to investigate whether the concentrations of serum tumor necrosis factor-α (TNF-α), a pro-inflammatory cytokine, increased in type 2 diabetes mellitus (T2DM) and type 2 diabetic nephropathy (T2DN) patients. METHODS The four databases (PubMed, CNKI, WanFang and Chinese-Cqvip) were searched from Jan 1, 1999 to October 1, 2016 for all clinical case-control studies about the serum TNF-α concentrations in T2DM and T2DN patients. All relevant data were extracted from published reports. The meta-analysis was performed to compare the changes of serum TNF-α concentrations of T2DN and T2DM patients in Eastern and Western with healthy controls. We further evaluated concentrations of serum TNF-α in T2DN patients with mincroalbuminuria or macroalbuminuria. Random-effects models were adopted to assess the pooling data among various variations. RESULTS In total of 6 studies (744 patients and 277 healthy controls) were included in this study. Compared with healthy controls (both p<0.01), the groups of different albuminuria levels and ethnicities both showed that the serum TNF-α levels were significantly elevated in T2DN patients as well as in eastern T2DN patients (p=0.001), but not significant changed in western T2DN patients (p=0.081). The results were stable through sensitivity analysis and no significant publications bias existed in this meta-analysis. CONCLUSIONS Serum TNF-α concentrations are obviously increased in T2DN and T2DM patients, but higher in T2DN patients, suggesting an elevated inflammatory burden in T2DN patients.

Correlation between serum interleukin-6 level and type 1 diabetes mellitus: A systematic review and meta-analysis

HighlightsThe serum IL‐6 level had increased in patients with type 1 diabetes mellitus.The age, disease duration, and ethnic of patients had no effects on IL‐6 level.IL‐6 may be a key inflammatory factor for T1DM pathogenesis. Objective: This report aimed to explore the association between the change of circulating interleukin‐6 (IL‐6) in patients and the development of type 1 diabetes mellitus (T1DM). Methods: Four databases (PubMed, CNKI, WanFang and Civip) were used to search and list all clinical case‐control studies about serum IL‐6 level in T1DM patients between Jan 1, 2000 and Aug 31, 2016. Results: A total of 20 case‐control studies with 1238 T1DM patients and 742 healthy controls were included in this study. Compared to healthy controls, the serum content of IL‐6 in patients with T1DM was significantly greater (overall: SMD, 1.49; 95% CI, 1.04 to 1.93; p < 0.001), and notably increased in all subgroup with different age, ethnic and disease duration (all p < 0.001). Furthermore, the analysis in subgroup exhibited that serum levels of IL‐6 in the age greater than 20‐year old (SMD, 1.64; 95% CI, 0.57–2.71; p < 0.001), the diseased duration among 0–10 years (SMD, 2.43; 95% CI, 1.42–3.44; p < 0.001) and the sorted American group (SMD, 1.68; 95% CI, 0.85–2.51; p < 0.001) were higher than those in control groups. Conclusions: Patients with T1DM were found to be linked to elevated level of serum IL‐6, which the age, ethnic and disease durations in T1DM patients had no effect on the serum IL‐6 levels for promoting diabetes mellitus.

Cross-talk between AMP-activated protein kinase and renin–angiotensin system in uninephrectomised rats

Introduction: The renal renin–angiotensin system (RAS) and the ultrasensitive energy sensor AMP-activated protein kinase (AMPK) have been implicated in normal and aberrant states of the kidney, but interaction between the RAS and AMPK remains unknown. Methods: Ninety-six rats were stratified into four groups: sham, uninephrectomised, uninephrectomised rats treated with the angiotensin-converting enzyme inhibitor lisinopril or the angiotensin receptor blocker losartan. Histopathological examination at 9 months post-operation and biochemical measurements at 3, 6 and 9 months were performed for changes in renal structure and function. The expression of AMPK and angiotensin II at 9 months was detected by immunofluorescence microscopy and western blot. Results: Compared with sham rats, uninephrectomised rats demonstrated progressive glomerulosclerosis, tubular atrophy with cast formation and chronic inflammatory infiltration, in parallel to elevated serum urea, creatinine, urine total protein to creatinine ratio and reduced serum albumin. Overexpression of angiotensin II coexisted with a 85.6% reduction of phosphorylated to total AMPK ratio in the remnant kidney of uninephrectomised rats. RAS blockade by the angiotensin-converting enzyme inhibitor or angiotensin receptor blocker substantially normalised AMPK expression, morphological and functional changes of the remnant kidney. Conclusions: Uninephrectomy-induced RAS activation and AMPK inhibition in the remnant kidney could be substantially corrected by RAS blockade, suggesting a cross-talk between AMPK and RAS components in uninephrectomised rats.

Efficacy and safety of pramlintide injection adjunct to insulin therapy in patients with type 1 diabetes mellitus: a systematic review and meta-analysis

Aims We aim to assess the efficacy and safety of pramlintide plus insulin therapy in patients with type 1 diabetes. Methods We included clinical studies comparing pramlintide plus insulin to placebo plus insulin. Efficacy was reflected by glycemic control and reduction in body weight and insulin use. Safety concerns were hypoglycemia and other adverse events. Subgroup analysis was performed for different doses (30, 60, 90 µg/meal) and durations (≤4, 26, 29, >29 weeks) of the treatment. Results A total of 10 randomized placebo-controlled studies were included for this meta-analysis (pramlintide, n=1978; placebo, n=1319). Compared with controls, patients given pramlintide had significantly lower HbA1c (p < 0.001), total daily insulin dose (p = 0.024), mean mealtime insulin dose (p < 0.001), body weight (p < 0.001) and postprandial glucose level (p = 0.002). The addition of pramlintide increased the incidence of nausea (p < 0.001), vomiting (p < 0.001), anorexia (p < 0.001) and hypoglycemia (p < 0.05) at the initiation of the treatment. The efficacy and adverse reactions of pramlintide were largely significant for the different doses and durations of the treatment. Conclusions The addition of pramlintide to insulin therapy in patients with type 1 diabetes improves glycemic control and reduces insulin requirement and body weight while bringing transient hypoglycemia and digestive disorders.AIMS We aim to assess the efficacy and safety of pramlintide plus insulin therapy in patients with type 1 diabetes. METHODS We included clinical studies comparing pramlintide plus insulin to placebo plus insulin. Efficacy was reflected by glycemic control and reduction in body weight and insulin use. Safety concerns were hypoglycemia and other adverse events. Subgroup analysis was performed for different doses (30, 60, 90 µg/meal) and durations (≤4, 26, 29, >29 weeks) of the treatment. RESULTS A total of 10 randomized placebo-controlled studies were included for this meta-analysis (pramlintide, n=1978; placebo, n=1319). Compared with controls, patients given pramlintide had significantly lower HbA1c (p < 0.001), total daily insulin dose (p = 0.024), mean mealtime insulin dose (p < 0.001), body weight (p < 0.001) and postprandial glucose level (p = 0.002). The addition of pramlintide increased the incidence of nausea (p < 0.001), vomiting (p < 0.001), anorexia (p < 0.001) and hypoglycemia (p < 0.05) at the initiation of the treatment. The efficacy and adverse reactions of pramlintide were largely significant for the different doses and durations of the treatment. CONCLUSIONS The addition of pramlintide to insulin therapy in patients with type 1 diabetes improves glycemic control and reduces insulin requirement and body weight while bringing transient hypoglycemia and digestive disorders.

ACE Gene I/D Polymorphism and Obesity in 1,574 Patients with Type 2 Diabetes Mellitus

Association between ACE gene I/D polymorphism and the risk of overweight/obesity remains controversial. We investigated the possible relationship between ACE gene I/D polymorphism and obesity in Chinese type 2 diabetes mellitus (T2DM) patients. In this study, obesity was defined as a body mass index (BMI) value ≥ 25 kg/m2 and subjects were classified into 4 groups (lean, normal, overweight, and obese). PCR (polymerase chain reaction) was used to detect the ACE gene I/D polymorphism in T2DM patients. Metabolic measurements including blood glucose, lipid profile, and blood pressure were obtained. Frequencies of the ACE genotypes (DD, ID, and II) were not significant among the 4 groups of BMI-defined patients (P = 0.679) while ACE II carriers showed higher systolic blood pressure (SBP) and pulse pressure (PP) (all P < 0.050). Hyperglycemia, hypertension, and dyslipidemia in these T2DM patients were found to be significantly associated with BMI. In conclusion, the relationship of ACE gene I/D polymorphism with obesity is insignificant in Chinese patients with T2DM. SBP and PP might be higher in the ACE II carriers than in the DD and ID carriers.