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Background The global epidemic of diabetes mellitus continues to grow and affects developed and developing countries alike. Intensive glycemic control is thought to modify the risks for vascular complications, hence the risks for diabetes-related death. We investigated the trend of diabetic vascular complication-related deaths between 2000 and 2016 in the global diabetes landscape. Methods We collected 17 years of death certificates data from 108 countries in the World Health Organization mortality database between 2000 and 2016, with coding for diabetic complications. Crude and age-standardized proportions and rates were calculated. Trend analysis was done with annual average percentage change (AAPC) of rates computed by joinpoint regression. Results From 2000 through 2016, 7,108,145 deaths of diabetes were reported in the 108 countries. Among them, 26.8% (1,904,787 cases) were attributed to vascular complications in damaged organs, including the kidneys (1,355,085 cases, 71.1%), peripheral circulatory (515,293 cases, 27.1%), nerves (28,697 cases, 1.5%) and eyes (5751 cases, 0.3%). Overall, the age-standardized proportion of vascular complication-related mortality was 267.8 [95% confidence interval (95% CI), 267.5–268.1] cases per 1000 deaths and the rate was 53.6 (95% CI 53.5–53.7) cases per 100,000 person-years. Throughout the 17-year period, the overall age-standardized proportions of deaths attributable to vascular complications had increased 37.9%, while the overall age-standardized mortality rates related to vascular complications had increased 30.8% (AAPC = 1.9% [1.4–2.4%, p < 0.05]). These increases were predominantly driven by a 159.8% increase in the rate (AAPC = 2.7% [1.2–4.3%, p < 0.05]) from renal complications. Trends in the rates and AAPC of deaths varied by type of diabetes and of complications, as well as by countries, regions and domestic income. Conclusion Diabetic vascular complication-related deaths had increased substantially during 2000–2016, mainly driven by the increased mortality of renal complications.

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). 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. 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. Serum TNF-α level in T1DM patients has significantly elevated among all age, disease duration and ethnicity groups.

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.

Amyloid deposition is a histological hallmark of common human disorders including Alzheimer's disease (AD) and type 2 diabetes. Although some reports highlight that amyloid fibrils might activate the innate immunity system via pattern recognition receptors, here, we provide multiple lines of evidence for the protection by site-specific amyloid protein analogs and fibrils against autoimmune attacks: (1) strategies targeting clearance of the AD-related brain amyloid plaque induce high risk of deadly autoimmune destructions in subjects with cognitive dysfunction; (2) administration of amyloidogenic peptides with either full length or core hexapeptide structure consistently ameliorates signs of experimental autoimmune encephalomyelitis; (3) experimental autoimmune encephalomyelitis is exacerbated following genetic deletion of amyloid precursor proteins; (4) absence of islet amyloid coexists with T-cell-mediated insulitis in autoimmune diabetes and autoimmune polyendocrine syndrome; (5) use of islet amyloid polypeptide agonists rather than antagonists improves diabetes care; and (6) common suppressive signaling pathways by regulatory T cells are activated in both local and systemic amyloidosis. These findings indicate dual modulation activity mediated by amyloid protein monomers, oligomers, and fibrils to maintain immune homeostasis. The protection from autoimmune destruction by amyloid proteins offers a novel therapeutic approach to regenerative medicine for common degenerative diseases.

Diabetes and obesity are complex diseases associated with insulin resistance and fatty liver. The latter is characterized by dysregulation of the Akt, AMP-activated protein kinase (AMPK), and IGF-I pathways and expression of microRNAs (miRNAs). In China, multicomponent traditional Chinese medicine (TCM) has been used to treat diabetes for centuries. In this study, we used a three-herb, berberine-containing TCM to treat male Zucker diabetic fatty rats. TCM showed sustained glucose-lowering effects for 1 week after a single-dose treatment. Two-week treatment attenuated insulin resistance and fatty degeneration, with hepatocyte regeneration lasting for 1 month posttreatment. These beneficial effects persisted for 1 year after 1-month treatment. Two-week treatment with TCM was associated with activation of AMPK, Akt, and insulin-like growth factor-binding protein (IGFBP)1 pathways, with downregulation of miR29-b and expression of a gene network implicated in cell cycle, intermediary, and NADPH metabolism with normalization of CYP7a1 and IGFBP1 expression. These concerted changes in mRNA, miRNA, and proteins may explain the sustained effects of TCM in favor of cell survival, increased glucose uptake, and lipid oxidation/catabolism with improved insulin sensitivity and liver regeneration. These novel findings suggest that multicomponent TCM may be a useful tool to unravel genome regulation and expression in complex diseases.

We are aimed to systematically assess the worldwide trend in incidence of childhood type 1 diabetes mellitus (CT1DM) from 1965 to 2012 and to discuss whether climate affect incidence of CT1DM. We searched the relevant literatures in detail to judge the effect of different climates on incidence of CT1DM. The climates included Mediterranean, monsoon, oceanic, continental, savanna, and rainforest. According to different climates, we further researched relevant factor such as sunshine durations and latitudes. The overall incidence of CT1DM in 72 countries was 11.43 (95% CI 10.31–12.55) per 100,000 children/yr. The incidence of CT1DM in Oceanic climate [10.56 (8.69–12.42)] is highest compared with other climates; the incidence in 40°–66°34′N/S [14.71 (12.30–17.29)] is higher than other latitude groups; the incidence in sunshine durations with 3–4 hours per day [15.17 (11.14–19.20)] is highest compared with other two groups; the incidence of CT1DM from 2000 to 2012 [19.58 (14.55–24.60)] is higher than other periods; all p  < 0.01. Incidence of CT1DM was increasing from 1965 to 2012, but incidence in Oceanic climate is higher than other climates. Furthermore, it is higher in centers with higher latitude and lower sunshine durations. The climates might play a key role in inducing CT1DM.

Renin–angiotensin system and adenosine monophosphate–activated protein kinase signaling pathway both play important roles in carcinogenesis, but the interplay of renin–angiotensin system and adenosine monophosphate–activated protein kinase in carcinogenesis is not clear. In this study, we researched the interaction of renin–angiotensin system and adenosine monophosphate–activated protein kinase in renal carcinogenesis of uninephrectomized rats. A total of 96 rats were stratified into four groups: sham, uninephrectomized, and uninephrectomized treated with angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. Renal adenosine monophosphate–activated protein kinase and its downstream molecule acetyl coenzyme A carboxylase were detected by immunohistochemistry and western blot at 10 months after uninephrectomy. Meanwhile, we examined renal carcinogenesis by histological transformation and expressions of Ki67 and mutant p53. During the study, fasting lipid profiles were detected dynamically at 3, 6, 8, and 10 months. The results indicated that adenosine monophosphate–activated protein kinase expression in uninephrectomized rats showed 36.8% reduction by immunohistochemistry and 89.73% reduction by western blot. Inversely, acetyl coenzyme A carboxylase expression increased 83.3% and 19.07% in parallel to hyperlipidemia at 6, 8, and 10 months. The histopathology of carcinogenesis in remnant kidneys was manifested by atypical proliferation and carcinoma in situ, as well as increased expressions of Ki67 and mutant p53. Intervention with angiotensin-converting enzyme inhibitor or angiotensin receptor blocker significantly prevented the inhibition of adenosine monophosphate–activated protein kinase signaling pathway and renal carcinogenesis in uninephrectomized rats. In conclusion, the novel findings suggest that uninephrectomy-induced disturbance in adenosine monophosphate–activated protein kinase signaling pathway resulted in hyperlipidemia and carcinogenesis in tubular epithelial cells, which may be largely attenuated by renin–angiotensin system blockade, implying the interaction of renin–angiotensin system and adenosine monophosphate–activated protein kinase signaling pathway in renal carcinogenesis of uninephrectomized rats.

Autoimmune diabetes is a disorder of immune homeostasis that leads to targeted insulin-secreting islet β cell destruction characterized by insulitis. Human amylin (hA) is an important neuroendocrine hormone co-secreted with insulin by pancreatic β cells. Here, we report hA immune-modulatory action through inducing regulatory T cells. We ex vivo-treated human peripheral blood mononuclear cells (hPBMCs) with hA for 24 h and counted CD4+Foxp3+ regulatory T cells (Treg) using flow cytometry. Diabetic status was monitored and splenic Treg were measured in non-obese diabetic (NOD) male mice. NOD mice were intraperitoneally injected once daily with hA (n = 25) or solvent for control (n = 25) for 7 months continuously. Spleen tissues were collected at the end of intervention and processed for flow cytometry and Western blot. We found a 2.9-fold (p < 0.05) increase of CD4+Foxp3+ Treg in hPBMCs treated with 10 nmol/L hA compared with negative control. Incidence of diabetes in hA-treated NOD mice decreased 44% (p = 0.045) in the 6th month and 57% (p = 0.0002) in the 7th month. Meanwhile, the hA treatment induced a 1.5-fold increase of CD4+Foxp3+ Treg from mouse splenocytes (p = 0.0013). Expression of transforming growth factor-β (TGF-β) and toll-like receptor-4 (TLR-4) were upregulated in hA-treated mice. Human amylin might protect against autoimmune diabetes via the induction of CD4+Foxp3+ Treg, which suggests a novel approach to improve autoimmune conditions.

Aims: This study aims to investigate the association between renin-angiotensin system gene polymorphism and diabetic retinopathy (DR) in Chinese patients with type 2 diabetes. Methods: We consecutively included 1491 patients for the assessment of ACE I/D and AGT M/T gene polymorphisms in 345 DR cases and 1146 patients without retinopathy (DNR). Albuminuria was defined by urine albumin creatinine ratio and albumin excretion rate. Results: Compared with the NDR patients, the DR cases displayed a higher proportion of diabetic nephropathy (32.68% vs. 6.52%, χ2 = 150.713, p < 0.001). The DR cases and DNR individuals did not differ in the frequency of genotypes and alleles of ACE I/D and AGT M/T (all p > 0.05). Intriguingly, DR patients with obesity showed higher frequency of DD (χ2 = 4.181, p = 0.041), but no significant difference exists in the other stratified BMI and hypertension analyses (all p > 0.05). Binary logistic regression displays that the association of the ACE and AGT gene polymorphisms in DR patients is not significant after adjusting for confounding covariates in all the comparisons. Conclusions: The ACE and AGT gene polymorphisms are not associated with the progress of diabetes developing into retinopathy in Chinese patients with type 2 diabetes. However, more investigations are needed to further prove the association.