New insights in the molecular pathways linking obesity, type 2 diabetes and cancer.

Steadily, cancer is becoming the first cause of mortality, with over 9 million deaths estimated in 2018. Increasing evidence supports a direct association between obesity, type 2 diabetes mellitus (T2DM) and cancer, with a higher risk of cancer mortality especially for some of the most common malignancies, such as breast, colon, and rectal cancers. So far, several mechanisms underlying the cancer-diabetes relationship have been investigated revealing dysregulations of the insulin-insulin-like growth factor (IGF) system as the most important paradigm. Other molecular mechanisms that seem to play a role in the association cancer-T2DM consist of alteration of the signaling pathways activated by inflammatory cytokines, adipocytokines or adhesion molecules. The overall aim of this review is to provide an overview of the molecular mechanisms linking obesity, T2DM and cancer, as related to the receptors and signaling pathways involved in these associations.

Influence of high density lipoprotein cholesterol levels on circulating monocytic angiogenic cells functions in individuals with type 2 diabetes mellitus.

BACKGROUND: High-density lipoproteins (HDLs) can exert anti-atherogenic effects. On top of removing excess cholesterol through reverse cholesterol transport, HDLs play beneficial actions on endothelial function and integrity. In particular, HDLs are strong determinant of endothelial progenitor cells (EPCs) number and function. To gain further insights into such an effect we characterized in vitro functionality of circulating "early" EPCs obtained from 60 type 2 diabetes individuals with low HDL-cholesterol (HDL-C) and 59 with high HDL-C levels. METHODS: After an overnight fast, venous blood was drawn in EDTA tubes and processed within 2-h from sampling. Peripheral blood mononuclear cells were isolated and plated on fibronectin coated culture dishes; after 3 days culture, adherent cells positive for Dil-ac-LDL/Lectin dual fluorescent staining were identified as monocytic angiogenic cells (MACs). After 5-7 days culture in EBM-2 medium, adherent cells were evaluated for viability/proliferation (MTT assay), senescence (beta-galactosidase activity detection), migration (modified Boyden chamber using VEGF as chemoattractant), adhesion capacity (on fibronectin-coated culture dishes) and ROS production (ROS-sensitive fluorescent probe CM-H2DCFDA). RESULTS: MACs obtained from diabetic individuals with high HDL-C had 23% higher viability compared to low HDL-C (111.6 ± 32.7% vs. 90.5 ± 28.6% optical density; p = 0.002). H2O2 exposure impaired MACs viability to a similar extent in both groups (109.2 ± 31.7% vs. 74.5 ± 40.8% in high HDL-C, p < 0.0001; 88.3 ± 25.5% vs. 72.3 ± 22.5% in low-HDL, p = 0.004). MACs senescence was comparable in the two groups (102.7 ± 29.8% vs. 99.2 ± 27.8%; p = 0.703) and was only slightly modified by exposure to H2O2. There was no difference in the MACs migration capacity between the two groups (91.3 ± 34.2% vs. 108.7 ± 39.5%; p = 0.111), as well as in MACs adhesion capacity (105.2 ± 32.7% vs. 94.1 ± 26.1%; p = 0.223). Finally, ROS production was slightly thought not significantly higher in MACs from type 2 diabetes individuals with low- than high-HDL. After stratification of HDL-C levels into quartiles, viability (p < 0.0001) and adhesion (p = 0.044) were higher in Q4 than in Q1-Q3. In logistic regression analysis, HDL-C was correlated to MACs viability and adhesion independently of HbA1c or BMI, respectively. CONCLUSIONS: Our data suggest that in type 2 diabetes subjects, HDL-cholesterol is an independent determinant of circulating MACs functional capacities-mainly viability, to a lesser extent adhesion-likely contributing also through this mechanism to cardiovascular protection even in type 2 diabetes.

Associations of smoking with cardiometabolic profile and renal function in a Romanian population-based sample from the PREDATORR cross-sectional study.

BACKGROUND: The impact of smoking on morbidity is well known, but in Romania, limited data are available regarding the smoking prevalence and relationship with cardiometabolic profile and kidney function. OBJECTIVES: To assess the association of smoking with cardiometabolic traits and kidney function, in a Romanian population-based sample from the PREDATORR study. METHODS: PREDATORR was an epidemiological cross-sectional study. Between 2012 and 2014, participants were randomly selected from the lists of general practitioners and enrolled if they were aged 20 to 79 years, born and living in the past 10 years in Romania. Sociodemographic and lifestyle characteristics were collected through interviewer-administered questionnaires. RESULTS: Overall, 2704 participants were included in the analysis, 18% of them being current smokers and 30.8% former smokers. Current smokers compared to non-smokers had higher total cholesterol (220.6 ± 50.4 versus 213.9 ± 86.8 mg/dl, P = 0.017), LDL-cholesterol (137.8 ± 45.2 versus 130.7 ± 83.7 mg/dl, P = 0.004) and glomerular filtration rate (96.9 ± 16.8 versus 90.7 ± 19.1 ml/min/1.73 m2, P <0.001) in women and higher triglycerides (170.7 ± 129.8 versus 144.3 ± 94.2 mg/dl, P = 0.007), glomerular filtration rate (97.6 ± 17 versus 90.3 ± 18 ml/min/1.73 m2, P < 0.001) and lower HDL-cholesterol (48 ± 15.5 versus 50.4 ± 14.1 mg/dl, P = 0.002) in men. Active smoking was associated with hypercholesterolaemia [OR: 1.40 (95% CI: 1.01-1.96), P = 0.04] and low HDL-cholesterolaemia [OR: 1.39 (95% CI: 1.01-1.91), P = 0.04] and negatively associated with overweight/obesity [OR: 0.67 (95% CI: 0.48-0.94), P = 0.02]. Male former smokers had higher prevalence of abdominal obesity (82.4% versus 76.4%, P = 0.02), hypertriglyceridaemia (43.6% versus 35.6%, P = 0.01), hypertension (64% versus 56.4%, P = 0.01) and ischaemic vascular disease (40.5% versus 30.9%, P = 0.003) than male non-smokers. CONCLUSION: The PREDATORR study showed a high prevalence of smoking in the adult Romanian population providing data on the association of smoking with cardiometabolic traits.

Prevalence of diabetes mellitus and prediabetes in the adult Romanian population: PREDATORR study.

BACKGROUND: The PREDATORR (PREvalence of DiAbeTes mellitus, prediabetes, overweight, Obesity, dyslipidemia, hyperuricemia and chronic kidney disease in Romania) study is the first national study analyzing the prevalence of diabetes mellitus (DM) and prediabetes, and their association with cardiometabolic, sociodemographic, and lifestyle risk factors in the Romanian population aged 20-79 years. METHODS: This was an epidemiological study with a stratified, cross-sectional, cluster random sampling design. Sociodemographic, lifestyle, and anamnestic data were collected through self- and interviewer-administered questionnaires, and biochemical assays and oral glucose tolerance tests were performed. RESULTS: In all, 2728 participants from 101 clinics of general practitioners were randomly selected, with a probability proportional to population size according to the 2002 Romanian Census. The participation rate was 99.6%. Impaired glucose regulation (prediabetes, known and unknown DM) was found in 28.1% of the study population. The overall age- and sex-adjusted prevalence of DM was 11.6% (95% CI 9.6%-13.6%), of which 2.4% (95% CI 1.7%-3.1%) had unknown DM. The prevalence of DM increased with age and was higher in men than in women. The age- and sex-adjusted prevalence of prediabetes was 16.5% (95%CI 14.8%-18.2%), with the highest percentage in the 60-79 year age group and in women. Obesity, abdominal obesity, dyslipidemia, low education level, and a family history of diabetes were associated with glucose metabolism disorders. CONCLUSIONS: The PREDATORR study shows a high prevalence of impaired glucose regulation in the adult Romanian population, providing data on the prevalence of DM and prediabetes and their association with several risk factors.

Prevalence of chronic kidney disease and its association with cardio-metabolic risk factors in the adult Romanian population: the PREDATORR study.

PURPOSE: PREDATORR is the first national study analyzing the prevalence of chronic kidney disease and its prognosis and association with socio-demographic, cardio-metabolic and lifestyle risk factors in the adult Romanian population. METHODS: Chronic kidney disease was defined according to the KDIGO 2012 criteria as an estimated glomerular filtration rate <60 mL/min/1.73 m(2) and/or urinary albumin-to-creatinine ratio ≥30 mg/g. The socio-demographic, lifestyle and anamnestic data were collected through interviewer-administered questionnaires. Physical examination and biochemical assays were also performed. RESULTS: This cross-sectional study conducted between December 2012 and February 2014 in Romania included 2717 adults. The overall age- and sex-adjusted prevalence of chronic kidney disease was 6.74 % (95 %CI 5.60-7.88 %), of which 3.31 % (2.50-4.13 %) had only reduced kidney function (estimated glomerular filtration rate <60 mL/min/1.73 m(2)), 2.98 % (2.21-3.76 %) had only albuminuria, and 0.45 % (0.14-0.74 %) had both. The prevalence of chronic kidney disease increased with age and was similar in women and in men. Age, hyperuricemia, impaired glucose regulation (diabetes/prediabetes), hypertriglyceridemia and a family history of renal disease were independent risk factors for the presence of chronic kidney disease. CONCLUSIONS: The PREDATORR study showed a high prevalence of chronic kidney disease in the adult Romanian population providing data on its prognosis and association with several cardio-metabolic risk factors.

Pitfalls in diagnosing a pancreatic neuroendocrine tumor: a case report.

Pancreatic neuroendocrine tumors are a rare subset of pancreatic neoplasms. We report the case of a 33-year-old female patient who was admitted to the Diabetes Clinic of Craiova, Romania, due to a two-year history of episodic neuroglycopenic hyperinsulinemic hypoglycemic symptoms, suggestive for insulinoma associated with facial and upper trunk flushing characteristic to carcinoid syndrome. During these episodes, the laboratory investigations showed hypoglycemia (38 mg/dL), hyperinsulinemia (54.72 µU/mL) and normal values of beta-hydroxybutyrate, chromogranin A, serotonin, anti-insulin antibodies and urinary levels of 5-hydroxyindoleacetic acid. Endoscopic ultrasound with SonoVue and 3T MRI revealed an 18.3/16.3 mm hypervascular tissular mass situated in the uncinate process of the pancreatic head in close contact with the superior mesenteric vein without invasion and no other detectable secondary lesions in the pancreas or any other abdominal viscera. Patient underwent enucleation of pancreatic tumor. The histological and immunohistochemical findings indicated a functional well-differentiated pancreatic neuroendocrine tumor, G1 category according to the World Health Organization (WHO) criteria, with uncertain behavior (Ki67 index was 3%), confined to the pancreas, but with tumoral invasion of the delimiting conjunctive capsule. No evidence of tumoral CK19 staining, mitoses and necrosis, angioinvasion or extra-pancreatic invasion was observed. A post-operative nine-month follow-up showed resolution of hypoglycemic symptoms, normalized blood glucose and insulin levels and no evidence of recurrence. Our case report highlights the pitfalls in diagnosing a functional pancreatic neuroendocrine tumor due to atypical symptoms, the difficulty of identification and precise location of the small-size tumor and uncertain histopathological and immunohistochemical behavior.

Matrix metalloproteinase -7, -8, -9 and -13 in gingival tissue of patients with type 1 diabetes and periodontitis.

There is scientific data to support the existence of a two-way relationship between diabetes and periodontitis, with diabetes increasing the risk for periodontitis, and periodontal inflammation negatively affecting the diabetic status. Our study aims to investigate the expression of MMP-7, -8, -9 and -13 in the gingiva of the young patients with aggressive periodontitis (AP) and type 1 diabetes mellitus (T1D). Gingival biopsies were harvested from five adult patients aged 19-29 years with T1D+AP with moderate (three cases) to severe (two cases) forms of AP and from four adult patients aged 18-28 years with moderate AP without T1D. The MMP-7 immunoreaction was positive in the five cases with T1D+AP with different staining patterns. The MMP-8 immunostaining was positive in all cases. The reaction was more intense in cases with T1D+AP, especially in those with severe periodontitis. The MMP-9 immunoreaction was present in all the structures of the gingival mucosa with different intensity, being frequently present surrounding the blood vessels of the chorion. In most of the patients, reaction to MMP-9 was intense, localized at the level of the cells in the superficial chorion and very rarely at the level of some dispersed cells in the connective vascular islands. MMP-13 was present in all cases, but it was more intense in the two cases with T1D+AP with probing depth (PD)>6 mm when it had similar patterns as MMP-9 staining and in one case with AP when the staining was observed strictly in the lamina propria associated with moderate chronic inflammatory infiltrate. The expression of MMP-7, -8, -9 and -13 in the gingiva of the young patients with aggressive periodontitis and T1D was positive in all studied cases supporting the hypothesis that both are inflammatory diseases with common pathogenic mechanisms involving inflammatory mediators and may be possible biomarkers of disease status.

The association of the rs1049353 polymorphism of the CNR1 gene with hypoadiponectinemia.

The endocannabinoid system (ECS) is an important physiological system that modulates appetite, food intake, energy homeostasis, substance addiction. It is comprised of the cannabinoid receptors (CB1 and CB2), the endogenous lipid ligands of these receptors and the enzymes that mediate the endogenous ligands' biosynthesis and degradation. CB1 receptor is expressed in the brain, adipose tissue, liver, skeletal muscle, gastrointestinal tract and pancreas. The CB1 receptor is encoded by CNR1 gene located at 6q14-q15 level. The aim of our study was to investigate the possible correlation between rs1049353 polymorphism of the CNR1 gene with levels of adiponectin in a group of subjects from Romania. The study included 305 subjects divided in two groups according to their fasting adiponectin levels. Fasting adiponectin levels were determined using ELISA technique. The genotyping of the rs1049353 polymorphism of the CNR1 gene was made using the Real-Time PCR technique. The statistical analysis was performed using De Finetti's program. The differences between the allelic frequencies indicated that the presence of G-wild allele seems to confer risk for expressing low levels of adiponectin (OR=1.917; 95%C.I.=1.353-2.715; p=0.00023) and A-mutant allele seems to be protective (OR=0.522; 95%C.I.=0.368-0.739; p=0.00023). At the test of allelic positivity, the presence of the G-allele conferred risk of hypoadiponectinemia (OR=2.113; 95%C.I.=1.324-3.373). In conclusion, this study indicates that the rs1049353 polymorphism of the CNR1 gene is associated with decreased levels of adiponectin. Further research is needed in order to elucidate the link between the polymorphisms of the CNR1 gene and adiponectin levels.

Impact of obesity and omega-3 polyunsaturated fatty acids on fibrogenesis and responsiveness to antiviral therapy in chronic hepatitis C.

Chronic Hepatitis C (CHC) and obesity inflict significant health and economic burdens on the world. A complex interplay between these conditions results in the ultimate phenotype of liver disease. Taking into consideration the increasing prevalence of obesity in patients with CHC and the decreasing rate of sustained virologic response (SVR), it would be advantageous to identify potential therapeutic strategy to improve liver histology and responsiveness to antiviral therapy. The adipokines-leptin, adiponectin, TNF-alpha-, which are modified in obesity, have been proposed as determinant factors of non-responsiveness to the IFN-alpha/Ribavirin treatment and of liver fibrosis extension in patients with CHC and obesity. Weight loss and long-term maintenance of optimal weight resulted in a sustained improvement in hepatic fibrosis and an increased rate of SVR in obese patients with CHC. The ability to exert antiviral activities and the anti-obesity effect of omega-3 PUFA provide a good basis for clinical use of these very interesting nutrients, both as dietary components and as future drugs with potentially beneficial effects and few side effects. We reviewed the mechanisms underlying the correlation of obesity with the nonresponsiveness to antiviral therapy and with fibrosis extension in CHC, and the mechanisms by which PUFA omega-3 may be associated with an increased efficacy of interferon-based therapies and an antifibrogenic effect in obese individuals with CHC.