Type 1 diabetes is a chronic autoimmune disease which results in inefficient regulation of glucose homeostasis and can lead to different vascular comorbidities through life. In this study we aimed to analyse the circulating miRNA expression profile of patients with type 1 diabetes, and with no other associated pathology. For this, fasting plasma was obtained from 85 subjects. Next generation sequencing analysis was firstly performed to identify miRNAs that were differentially expressed between groups (20 patients vs. 10 controls). hsa-miR-1-3p, hsa-miR-200b-3p, hsa-miR-9-5p, and hsa-miR-1200 expression was also measured by Taqman RT-PCR to validate the observed changes (34 patients vs. 21 controls). Finally, through a bioinformatic approach, the main pathways affected by the target genes of these miRNAs were studied. Among the studied miRNAs, hsa-miR-1-3p expression was found significantly increased in patients with type 1 diabetes compared to controls, and positively correlated with glycated haemoglobin levels. Additionally, by using a bioinformatic approach, we could observe that changes in hsa-miR-1-3p directly affect genes involved in vascular development and cardiovascular pathologies. Our results suggest that, circulating hsa-miR-1-3p in plasma, together with glycaemic control, could be used as prognostic biomarkers in type 1 diabetes, helping to prevent the development of vascular complications in these patients.

Gestational diabetes mellitus is a daunting problem accompanied by severe fetal development complications and type 2 diabetes mellitus in postpartum. Diagnosis of diabetic conditions occurs only in the second trimester, while associated antenatal complications are typically revealed even later. We acquired an assay of peripheral and cord blood samples of patients with different types of diabetes mellitus who delivered either healthy newborns or associated with fetopathy complications. Obtained data were handled with qualitative and quantitative analysis. Pathways of molecular events involved in diabetes mellitus and fetopathy were reconstructed based on the discovered markers and their quantitative alteration. Plenty of pathways were integrated to differentiate the type of diabetes and to recognize the impact of the diabetic condition on fetal development. The impaired triglycerides transport, glucose uptake, and consequent insulin resistance are mostly affected by faulted lipid metabolism (APOM, APOD, APOH, APOC1) and encouraged by oxidative stress (CP, TF, ORM2) and inflammation (CFH, CFB, CLU) as a secondary response accompanied by changes in matrix architecture (AFM, FBLN1, AMBP). Alterations in proteomes of peripheral and cord blood were expectedly unequal. Both up- and downregulated markers were accommodated in the cast of molecular events interconnected with the lipid metabolism, RXR/PPAR-signaling pathway, and extracellular architecture modulation. The obtained results congregate numerous biological processes to molecular events that underline diabetes during gestation and uncover some critical aspects affecting fetal growth and development.

Daily glucose variability is higher in diabetic mellitus (DM) patients which has been related to the severity of the disease. However, it is unclear whether glycemic variability displays a specific pattern oscillation or if it is completely random. Thus, to determine glycemic variability pattern, we measured and analyzed continuous glucose monitoring (CGM) data, in control subjects and patients with DM type-1 (T1D). CGM data was assessed for 6 days (day: 08:00-20:00-h; and night: 20:00-08:00-h). Participants (n = 172; age = 18-80 years) were assigned to T1D (n = 144, females = 65) and Control (i.e., healthy; n = 28, females = 22) groups. Anthropometry, pharmacologic treatments, glycosylated hemoglobin (HbA1c) and years of evolution were determined. T1D females displayed a higher glycemia at 10:00-14:00-h vs. T1D males and Control females. DM patients displays mainly stationary oscillations (deterministic), with circadian rhythm characteristics. The glycemia oscillated between 2 and 6 days. The predictive model of glycemia showed that it is possible to predict hyper and hypoglycemia (R2 = 0.94 and 0.98, respectively) in DM patients independent of their etiology. Our data showed that glycemic variability had a specific oscillation pattern with circadian characteristics, with episodes of hypoglycemia and hyperglycemia at day phases, which could help therapeutic action for this population.

Gestational diabetes mellitus (GDM) and preeclampsia (PE) are both characterized by endothelial dysfunction and GDM women have higher incidence of PE. The placenta plays a key role in PE pathogenesis but its contribution to PE during GDM remains unclear. Herein, we compared placental and maternal blood anti-angiogenic soluble fms-like tyrosine kinase-1 (sFlt1) and pro-angiogenic Placental Growth Factor (PlGF) expressions in GDM and GDM-PE pregnancies compared to controls (CTRL) and PE cases. Electrochemiluminescence immunoassays showed a significantly higher maternal blood sFlt1/PlGF values in GDM-PE relative to CTRL and GDM pregnancies. We reported that placental PlGF gene expression was significantly decreased in GDM, PE and GDM-PE relative to CTRL. However, PlGF protein levels were significantly increased in GDM and GDM-PE relative to CTRL and PE placentae. Finally, sFlt1 gene expression was significantly increased in PE relative to CTRL, GDM and GDM-PE placentae. In contrast, sFlt1 protein expression was significantly decreased in GDM-PE relative to CTRL, GDM and PE placentae. Finally, higher sFlt1/PlGF ratio in GDM-PE maternal blood suggest that sFlt1 overproduction is related to PE onset also in GDM pregnancies even though characterized by a less severe endothelial dysfunction in terms of angiogenic biomarkers.

Understanding the gut microbiota in metabolic disorders, including type 2 diabetes mellitus (T2DM), is now gaining importance due to its potential role in disease risk and progression. We previously established a zebrafish model of T2DM, which shows glucose intolerance with insulin resistance and responds to anti-diabetic drugs. In this study, we analysed the gut microbiota of T2DM zebrafish by deep sequencing the 16S rRNA V3-V4 hypervariable regions, and imputed a functional profile using predictive metagenomic tools. While control and T2DM zebrafish were fed with the same kind of feed, the gut microbiota in T2DM group was less diverse than that of the control. Predictive metagenomics profiling using PICRUSt revealed functional alternation of the KEGG pathways in T2DM zebrafish. Several amino acid metabolism pathways (arginine, proline, and phenylalanine) were downregulated in the T2DM group, similar to what has been previously reported in humans. In summary, we profiled the gut microbiome in T2DM zebrafish, which revealed functional similarities in gut bacterial environments between these zebrafish and T2DM affected humans. T2DM zebrafish can become an alternative model organism to study host-bacterial interactions in human obesity and related diseases.

While predominant as a disease entity, knowledge voids exist regarding the pathogenesis of canine diabetes. To test the hypothesis that diabetic dogs have similar metabolomic perturbations to humans with type 1 diabetes (T1D), we analyzed serum metabolomic profiles of breed- and body weight-matched, diabetic (n = 6) and healthy (n = 6) dogs by liquid chromatography-mass spectrometry (LC-MS) profiling. We report distinct clustering of diabetic and control groups based on heat map analysis of known and unknown metabolites. Random forest classification identified 5/6 dogs per group correctly with overall out of bag error rate = 16.7%. Diabetic dogs demonstrated significant upregulation of glycolysis/gluconeogenesis intermediates (e.g., glucose/fructose, C6H12O6, keto-hexose, deoxy-hexose, (P < 0.01)), with significant downregulation of tryptophan metabolism metabolites (e.g., picolinic acid, indoxyl sulfate, anthranilate, (P < 0.01)). Multiple amino acids (AA), AA metabolites, and bile acids were also significantly lower in diabetic versus healthy dogs (P < 0.05) with the exception of the branched chain AA valine, which was elevated in diabetic animals (P < 0.05). Metabolomic profiles in diabetic versus healthy dogs shared similarities with those reported in human T1D (e.g., alterations in glycolysis/gluconeogensis metabolites, bile acids, and elevated branched chain AA). Further studies are warranted to evaluate the utility of canine diabetes to provide novel mechanistic insights to the human disorder.

Due to a poor availability of reliable biomarkers, detecting gestational diabetes mellitus (GDM) in early pregnancy remains a challenge. Novel biomarkers like Circular RNAs (circRNAs) may be a promising diagnostic tool. The aim of this study was (a) to identify circRNAs deregulated in GDM and (b) evaluate the potential of circRNAs in detecting GDM. The circRNAs expression profiling in 6 paired women (with and without GDM) was measured by microarray. The levels of five most relevant circRNAs were validated in 12 paired participants by qRT-PCR. To verify the reproducibility of qRT-PCR, significantly differential expressed circRNA levels were confirmed in 18 paired participants. A receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value. The areas under ROC curves of hsa_circRNA_102893 were 0.806 (95% CI 0.594-0.937) and 0.741 (0.568-0.872) in training set and test set, respectively. Circulating circRNAs reflect the presence of GDM. Hsa_circRNA_102893 may be a potential novel and stable noninvasive biomarker for detecting GDM in early pregnancy.

Chloroquine (CQ) and hydroxychloroquine, are promising anti-inflammatory drugs for the treatment of Diabetes mellitus (DM) to prevent associated complications. Therefore, this study evaluated the anti-inflammatory effects of CQ-free and CQ-incorporated polylactic acid nanoparticles (NPs) in the peripheral blood mononuclear cells (PBMCs) of patients with type 1 Diabetes mellitus (T1DM). In total, 25 normoglycemic individuals and 25 patients with T1DM aged 10-16 years were selected and glycemic controls evaluated. After cell viability assessed by MTT assay, T1DM PBMCs were subjected to a CQ concentration of 10 µM in three different conditions: not treated (NT), treated with CQ, and treated with CQ NPs. The cells were incubated for 48 h, and the mRNA expressions of cytokines IL1B, IFNG, TNFA, IL12, and IL10 were determined by relative quantification through real-time PCR at 24 h intervals. IL1B expression decreased in CQ and CQ NP-treated cells after 48 h (p < 0.001) and 24 h (p < 0.05) of treatment, respectively. IFNG and IL12 expressions significantly decreased (p < 0.001) in cells treated with CQ and CQ NPs at 24 and 48 h compared to NT. TNFA and IL10 expressions significantly decreased after 48 h (p < 0.001) and 24 h (p < 0.002), respectively, by both CQ and CQ NPs treatment. Despite being a preliminary in vitro study, CQ has anti-inflammatory activity in the primary cells of T1DM patients and could represent an alternative and adjuvant anti-inflammatory therapy to prevent diabetes complications.

Type 1 diabetes (T1D) is an autoimmune disease. Different factors, including genetics and viruses may contribute to T1D, but the causes of T1D are not fully known, and there is currently no cure. The advent of high-throughput technologies has revolutionized the field of medicine and biology, and analysis of multi-source data along with clinical information has brought a better understanding of the mechanisms behind disease pathogenesis. The aim of this work was the development of a data repository linking clinical information and interactome studies in T1D. To address this goal, we analyzed the electronic health records and online databases of genes, proteins, miRNAs, and pathways to have a global view of T1D. There were common comorbid diseases such as anemia, hypertension, vitreous diseases, renal diseases, and atherosclerosis in the phenotypic disease networks. In the protein-protein interaction network, CASP3 and TNF were date-hub proteins involved in several pathways. Moreover, CTNNB1, IGF1R, and STAT3 were hub proteins, whereas miR-155-5p, miR-34a-5p, miR-23-3p, and miR-20a-5p were hub miRNAs in the gene-miRNA interaction network. Multiple levels of information including genetic, protein, miRNA and clinical data resulted in multiple results, which suggests the complementarity of multiple sources. With the integration of multifaceted information, it will shed light on the mechanisms underlying T1D; the provided data and repository has utility in understanding phenotypic disease networks for the potential development of comorbidities in T1D patients as well as the clues for further research on T1D comorbidities.

Obesity is a major cause of type 2 diabetes mellitus (T2DM) in mammals. We have previously established a zebrafish model of diet-induced obesity (DIO zebrafish) by overfeeding Artemia. Here we created DIO zebrafish using a different method to induce T2DM. Zebrafish were overfed a commercially available fish food using an automated feeding system. We monitored the fasting blood glucose levels in the normal-fed group (one feed/day) and overfed group (six feeds/day) over an 8-week period. The fasting blood glucose level was significantly increased in DIO zebrafish compared with that of normal-fed zebrafish. Intraperitoneal and oral glucose tolerance tests showed impaired glucose tolerance by overfeeding. Insulin production, which was determined indirectly by measuring the EGFP signal strength in overfed Tg(-1.0ins:EGFP) sc1 zebrafish, was increased in DIO zebrafish. The anti-diabetic drugs metformin and glimepiride ameliorated hyperglycaemia in the overfed group, suggesting that this zebrafish can be used as a model of human T2DM. Finally, we conducted RNA deep sequencing and found that the gene expression profiling of liver-pancreas revealed pathways common to human T2DM. In summary, we developed a zebrafish model of T2DM that shows promise as a platform for mechanistic and therapeutic studies of diet-induced glucose intolerance and insulin resistance.

Type 3 Diabetes (T3D) is a neuroendocrine disorder that represents the progression of Type 2 Diabetes Mellitus (T2DM) to Alzheimer's disease (AD). T3D contributes in the increase of the total load of Alzheimer's patients worldwide. The protein network based strategies were used for the analysis of protein interactions and hypothesis was derived describing the possible routes of communications among proteins. The hypothesis provides the insight on the probable mechanism of the disease progression for T3D. The current study also suggests that insulin degrading enzyme (IDE) could be the major player which holds the capacity to shift T2DM to T3D by altering metabolic pathways like regulation of beta-cell development, negative regulation of PI3K/AKT pathways and amyloid beta degradation.

Recent studies have shown that gestational diabetes mellitus (GDM) is associated with an increased risk for cardiovascular disease. GDM has also been shown to be a risk factor for type 2 diabetes (T2DM) after pregnancy. However, there is limited evidence regarding the role of intercurrent T2DM on the relationship between GDM and future CVD. Thus, we investigated the risks of incident cardiovascular events among women with GDM during pregnancy compared to women without GDM and whether the increased CVD risk is dependent on intercurrent development of T2DM. We conducted a population-based retrospective cohort study using the Korean National Health Insurance Service claims database. Outcomes were the first occurrence of any CVD (myocardial infarction, treatment with coronary revascularization, heart failure, and cerebrovascular disease). Cox proportional hazard models were used to assess the association between GDM and incident CVD events, using landmark analysis at 4 years. A total of 1,500,168 parous women were included in the analysis, of which 159,066 (10.60%) had GDM. At a median follow-up of 12.8 years, 13,222 incident cases of total CVD were observed. Multivariable-adjusted hazard ratio for total CVD among women with prior GDM, compared with those without GDM, was 1.08 (95% CI 1.02-1.14). Further classifying GDM by progression to T2DM in relation to total CVD risk indicated a positive association for GDM with progression to T2DM vs no GDM or T2DM (HR 1.74; 95% CI 1.40-2.15), and no statistically significant association for GDM only (HR 1.06; 95% CI 1.00-1.12). GDM with subsequent progression to T2DM were linked with an increased risk of cardiovascular diseases. These findings highlight the need for more vigilant postpartum screening for diabetes and the implementation of diabetes interventions in women with a history of GDM to reduce future CVD risk.

The role of hepatitis virus infection in glucose homeostasis is uncertain. We examined the associations between hepatitis B virus (HBV) or hepatitis C virus (HCV) infection and the development of diabetes in a cohort (N = 439,708) of asymptomatic participants in health screening examinations. In cross-sectional analyses, the multivariable-adjusted odds ratio for prevalent diabetes comparing hepatitis B surface antigen (HBsAg) (+) to HBsAg (-) participants was 1.17 (95% CI 1.06-1.31; P = 0.003). The corresponding odds ratio comparing hepatitis C antibodies (HCV Ab) (+) to HCV Ab (-) participants was 1.43 (95% CI 1.01-2.02, P = 0.043). In prospective analyses, the multivariable-adjusted hazard ratio for incident diabetes comparing HBsAg (+) to HbsAg (-) participants was 1.23 (95% CI 1.08-1.41; P = 0.007). The number of incident cases of diabetes among HCV Ab (+) participants (10 cases) was too small to reliably estimate the prospective association between HCV infection and diabetes. In this large population at low risk of diabetes, HBV and HCV infections were associated with diabetes prevalence and HBV infection with the risk of incident diabetes. Our studies add evidence suggesting that diabetes is an additional metabolic complication of HBV and HCV infection.

Moringa seeds have been used traditionally in the management of type 2 diabetes mellitus (T2DM) and contain potent bioactive isothiocyanates. This study evaluated the efficacy of an isothiocyanate-rich moringa seed extract in delaying the onset of T2DM in UC Davis T2DM rats, a well validated model which closely mimics T2DM in humans. Rats were separated into three groups; control, moringa seed extract at 0.4%, and a weight matched group. Rats were fed respective diets for 8 months, during which energy intake, body weight, the onset of diabetes circulating hormones, metabolites and markers of inflammation and liver function, and were monitored. The MS group had a significantly slower rate of diabetes onset p = 0.027), lower plasma glucose (p = 0.043), and lower HbA1c (p = 0.008) compared with CON animals. There were no significant differences in food intake and body weight between all groups. This study demonstrated MS can delay the onset of diabetes in the UC Davis T2DM rat model to a greater extent than moderate caloric restriction (by comparison to the WM group). The results support its documented traditional uses and a bioactive role of moringa isothiocyanates and suggest the potential efficacy for moringa supplementation for diabetes management in populations at risk for T2DM.

There is limited knowledge on the prevalence and risk factors of diabetic retinopathy (DR) in dialysis patients. We have investigated the association between diabetes mellitus and lipid-related biomarkers and retinopathy in hemodialysis patients. We reviewed 1,255 hemodialysis patients with type 2 diabetes mellitus (T2DM) who participated in the German Diabetes and Dialysis Study (4D Study). Associations between categorical clinical, biochemical variables and diabetic retinopathy were examined by logistic regression. On average, patients were 66 ± 8 years of age, 54% were male and the HbA1c was 6.7% ± 1.3%. DR, found in 71% of the patients, was significantly and positively associated with fasting glucose, HbA1c, time on dialysis, age, systolic blood pressure, body mass index and the prevalence of other microvascular diseases (e.g. neuropathy). Unexpectedly, DR was associated with high HDL cholesterol and high apolipoproteins AI and AII. Patients with coronary artery disease were less likely to have DR. DR was not associated with gender, smoking, diastolic blood pressure, VLDL cholesterol, triglycerides, and LDL cholesterol. In summary, the prevalence of DR in patients with type 2 diabetes mellitus requiring hemodialysis is higher than in patients suffering from T2DM, who do not receive hemodialysis. DR was positively related to systolic blood pressure (BP), glucometabolic control, and, paradoxically, HDL cholesterol. This data suggests that glucose and blood pressure control may delay the development of DR in patients with diabetes mellitus on dialysis.

We aimed to characterize the type 2 diabetes mellitus (T2DM) epidemic and the role of key risk factors in Jordan between 1990-2050, and to forecast the T2DM-related costs. A recently-developed population-level T2DM mathematical model was adapted and applied to Jordan. The model was fitted to six population-based survey data collected between 1990 and 2017. T2DM prevalence was 14.0% in 1990, and projected to be 16.0% in 2020, and 20.6% in 2050. The total predicted number of T2DM cases were 218,326 (12,313 were new cases) in 1990, 702,326 (36,941 were new cases) in 2020, and 1.9 million (79,419 were new cases) in 2050. Out of Jordan's total health expenditure, 19.0% in 1990, 21.1% in 2020, and 25.2% in 2050 was forecasted to be spent on T2DM. The proportion of T2DM incident cases attributed to obesity was 55.6% in 1990, 59.5% in 2020, and 62.6% in 2050. Meanwhile, the combined contribution of smoking and physical inactivity hovered around 5% between 1990 and 2050. Jordan's T2DM epidemic is predicted to grow sizably in the next three decades, driven by population ageing and high and increasing obesity levels. The national strategy to prevent T2DM needs to be strengthened by focusing it on preventive interventions targeting T2DM and key risk factors.

Common marmosets have attracted considerable attention as a small standard primate model in biomedical research. However, no marmoset diabetes model is available. Here, we established a marmoset diabetes model via the combination of partial pancreatectomy and intravenous streptozotocin (STZ). A partial pancreatectomy was performed in 11 common marmosets and multiple STZ doses were intravenously administered. Diabetes was diagnosed upon sustained hyperglycaemia (nonfasting blood glucose level >200 mg/dl). Blood glucose and biochemistry were periodically assessed, in addition to glucose tolerance testing, continual blood glucose determination using a continuous glucose monitoring system, urine testing and histological evaluation. In 8 of the 11 animals (73%), diabetes mellitus was induced. The diabetic marmosets also showed abnormal intravenous and oral glucose tolerance test results. Blood glucose levels decreased in response to human insulin administration. The hyperglycaemic state was irreversible and persisted for more than 3 months, and the animals' condition was manageable via daily insulin administration. Thus, diabetes can be successfully induced and maintained in the common marmoset via partial pancreatectomy and STZ administration. This protocol effectively generates a valuable animal model for studying disease pathogenesis, risk factors and therapeutic interventions, including islet transplantation.

Obesity and diabetes implicate in various health complications and increased mortality caused by infection. Innate immune system is broadly affected by these diseases, leading the patients to an immunosuppressive state. A mechanism that leads innate immune cells to a less capacity of killing microorganism is the impaired TLR4 activation. TLR4 recognizes a component of the outer membrane of Gram-negative bacteria, lipopolysaccharide (LPS), and when activated increases the production of inflammatory substances. Neutrophils are components of the innate immune system and are the first responders to an invading agent. The correct activation of TLR4 in these cells is required for the initiation of the inflammatory process and elimination of the microorganisms. The aim of this study was to evaluate the influence of type 2 diabetes and obesity in the TLR4 pathway in rat neutrophils. Two experimental models were used: Goto-Kakizaki rats and high-fat-diet induced obese Wistar rats. To evaluate neutrophil response to LPS, intratracheal LPS instillation was used. Neutrophils from obese and diabetic animals exhibited tolerance to LPS, mainly by the impaired production of cytokines and chemokines and the low content of phospho-NFκB and phospho-IKBα. Neutrophils from both experimental models had increased cell death, impaired in vivo migration and myeloperoxidase activity.

The high prevalence of diabetes mellitus (DM) among multidrug resistant tuberculosis (MDR-TB) patients is a serious cause for concern. We conducted a meta-analysis to determine whether DM is an independent risk factor for MDR-TB. Electronic literature searches of the PubMed, Web of Science and EMBASE databases up to July 12, 2016 were conducted. The pooled adjusted odds ratio (OR) and 95% confidence intervals (CIs) were calculated using the random effects model with STATA 12.0 software. In total 13 studies, including 9289 individuals with TB, were included in this meta-analysis. Significant association between DM and MDR-TB (OR = 1.71; 95% CI = 1.32, 2.22) was identified. Subgroup analyses showed that: 1) Pooled OR was 1.25 (95% CI: 0.82-1.91) for cross-sectional studies, and was 2.14 (95% CI: 1.51-3.02) for longitudinal studies; 2) The pooled OR was 1.69 (95% CI:1.09-2.62) for primary MDR-TB, 1.94 (95% CI:1.42-2.65) for any MDR-TB, and 0.85 for secondary MDR-TB (95% CI: 0.29-2.54); 3) DM was significantly associated with MDR-TB in both Caucasian (OR = 2.26, 95% CI: 1.66-3.07) and Asian (OR = 1.40, 95% CI: 1.01-1.95) subgroups. No evidence of publication bias was identified. In conclusion, the pooling analysis indicated that DM was an independent risk factor for MDR-TB, especially for primary MDR-TB.

We performed integrative analysis of genes associated with type 2 Diabetes Mellitus (T2DM) associated complications by automated text mining with manual curation and also gene expression analysis from Gene Expression Omnibus. They were analysed for pathogenic or protective role, trends, interaction with risk factors, Gene Ontology enrichment and tissue wise differential expression. The database T2DiACoD houses 650 genes, and 34 microRNAs associated with T2DM complications. Seven genes AGER, TNFRSF11B, CRK, PON1, ADIPOQ, CRP and NOS3 are associated with all 5 complications. Several genes are studied in multiple years in all complications with high proportion in cardiovascular (75.8%) and atherosclerosis (51.3%). T2DM Patients' skeletal muscle tissues showed high fold change in differentially expressed genes. Among the differentially expressed genes, VEGFA is associated with several complications of T2DM. A few genes ACE2, ADCYAP1, HDAC4, NCF1, NFE2L2, OSM, SMAD1, TGFB1, BDNF, SYVN1, TXNIP, CD36, CYP2J2, NLRP3 with details of protective role are catalogued. Obesity is clearly a dominant risk factor interacting with the genes of T2DM complications followed by inflammation, diet and stress to variable extents. This information emerging from the integrative approach used in this work could benefit further therapeutic approaches. The T2DiACoD is available at www.http://t2diacod.igib.res.in/ .