Metformin and Glucose Concentration as Limiting Factors in Retinal Pigment Epithelial Cell Viability and Proliferation.

Metformin is a well-established drug for the treatment of type 2 diabetes; however, the mechanism of action has not been well described and many aspects of how it truly acts are still unknown. Moreover, regarding in vitro experiments, the glycaemic status when metformin is used is generally not considered, which, added to the suprapharmacological drug concentrations that are commonly employed in research, has resulted in gaps of its mechanism of action. The aim of this study was to determine how glucose and metformin concentrations influence cell culture. Considering that diabetic retinopathy is one of the most common complications of diabetes, a retinal pigment epithelial cell line was selected, and cell viability and proliferation rates were measured at different glucose and metformin concentrations. As expected, glucose concentration by itself positively influenced cell proliferation rates. When the metformin was considered, results were conditioned, as well, by metformin concentration. This conditioning resulted in cell death when high concentrations of metformin were used under physiological concentrations of glucose, while this did not happen when clinically relevant concentrations of metformin were used independently of glucose status. Our study shows the importance of in vitro cell growth conditions when drug effects such as metformin's are being analysed.

miR-24-3p and Body Mass Index as Type 2 Diabetes Risk Factors in Spanish Women 15 Years after Gestational Diabetes Mellitus Diagnosis.

Gestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance that is diagnosed for the first time during pregnancy. The objective of this study is to know the glucose tolerance status after 15 years of pregnancy in patients diagnosed with gestational diabetes and to assess the long-term effect of GDM on the circulating miRNA profile of these women. To answer these, 30 randomly selected women diagnosed with GDM during 2005-2006 were included in the study, and glucose tolerance was measured using the National Diabetes Data Group criteria. Additionally, four miRNAs (hsa-miR-1-3p, hsa-miR-24-3p, hsa-miR-329-3p, hsa-miR-543) were selected for their analysis in the plasma of women 15 years after the diagnosis of GDM. In our study we discovered that, fifteen years after the diagnosis of GDM, 50% of women have some degree of glucose intolerance directly related to body weight and body mass index during pregnancy. Dysglycemic women also showed a significantly increased level of circulating hsa-miR-24-3p. Thus, we can conclude that initial weight and BMI, together with circulating expression levels of hsa-miR-24-3p, could be good predictors of the future development of dysglycemia in women with a previous diagnosis of GDM.

Hypoglycemia during hyperosmolar hyperglycemic crises is associated with long-term mortality.

BACKGROUND: Previous research has indicated that hypoglycemia during hospitalization is a predictor of unfavorable outcomes in patients with diabetes. However, no studies have examined the long-term impact of hypoglycemia in adults admitted for hyperglycemic crises. The study was aimed to investigate the long-term implications of hypoglycemia during hyperosmolar hyperglycemic crises, particularly in terms of all-cause mortality. METHODS: This retrospective cohort study included 170 patients (82 men [48.2%], median age 72 years) admitted to a university hospital for hyperosmolar hyperglycemic crises, including pure hyperosmolar hyperglycemic states and hyperosmolar diabetic ketoacidoses. We separately investigated the prognostic significance of hypoglycemia on mortality during the initial intravenous insulin therapy phase and during the later subcutaneous insulin therapy phase, both during hospitalization and in the long term (median follow-up, 652 days; range 2-3460 days). RESULTS: Both hypoglycemia during the initial intravenous insulin therapy phase (observed in 26.5% of patients) and hypoglycemia during the later subcutaneous insulin therapy phase (observed in 52.7% of patients) were associated with long-term mortality. After adjusting for potential confounders, hypoglycemia during the initial intravenous insulin therapy phase remained associated with mortality (hazard ratio 2.10, 95% CI 1.27-3.46, p = 0.004). CONCLUSIONS: Hypoglycemia during hyperosmolar hyperglycemic crises is a marker of long-term mortality, especially when it occurs during the initial intravenous insulin therapy phase.

Circulating miRNA expression in long-standing type 1 diabetes mellitus.

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.

A long non-coding RNA that harbors a SNP associated with type 2 diabetes regulates the expression of TGM2 gene in pancreatic beta cells.

Introduction: Most of the disease-associated single nucleotide polymorphisms (SNPs) lie in non- coding regions of the human genome. Many of these variants have been predicted to impact the expression and function of long non-coding RNAs (lncRNA), but the contribution of these molecules to the development of complex diseases remains to be clarified. Methods: Here, we performed a genetic association study between a SNP located in a lncRNA known as LncTGM2 and the risk of developing type 2 diabetes (T2D), and analyzed its implication in disease pathogenesis at pancreatic beta cell level. Genetic association study was performed on human samples linking the rs2076380 polymorphism with T2D and glycemic traits. The pancreatic beta cell line EndoC-bH1 was employed for functional studies based on LncTGM2 silencing and overexpression experiments. Human pancreatic islets were used for eQTL analysis. Results: We have identified a genetic association between LncTGM2 and T2D risk. Functional characterization of the LncTGM2 revealed its implication in the transcriptional regulation of TGM2, coding for a transglutaminase. The T2Dassociated risk allele in LncTGM2 disrupts the secondary structure of this lncRNA, affecting its stability and the expression of TGM2 in pancreatic beta cells. Diminished LncTGM2 in human beta cells impairs glucose-stimulated insulin release. Conclusions: These findings provide novel information on the molecular mechanisms by which T2D-associated SNPs in lncRNAs may contribute to disease, paving the way for the development of new therapies based on the modulation of lncRNAs.

Correlation between glucose measurement parameters of continuous flash monitoring and HbA1c. Real life experience in Asturias.

INTRODUCTION: Despite continuous glucose monitoring having been proven useful in patients with type 1 diabetes mellitus, A1C remains the gold standard for assessing disease management. MATERIAL AND METHODS: Descriptive, retrospective study which included 252 patients, 40.5% male, mean age 44.91±14.57 years, mean duration of diabetes 22.21±13.12 years, 88.1% on basal-bolus insulin therapy and 11.9% users of continuous subcutaneous insulin infusion. Glucose measurement, analytical and anthropometric data were obtained. RESULTS: The mean time in range was 60.18±15.60% and was associated with A1C after adjusting for age, gender, duration of diabetes, BMI, insulin regimen, %CV and time below range (ß: -0.548; p<0.01). The glucose management indicator (GMI) was 7.19±0.69% and was also associated with A1C (ß: 0.957; p<0.01) regardless of age, gender, duration of diabetes, BMI, insulin treatment, %CV and time in range. The average difference between A1C and GMI was 0.17±0.65% (-2.70-3.40%), being higher as A1C increased, in a linear and significant manner, without being influenced by the duration of diabetes or CV. CONCLUSIONS: Although we found a positive correlation between continuous glucose monitoring glucose measurement parameters and A1C, there is still not enough evidence to replace one parameter with another.

Prevalence of diabetes mellitus in Spain in 2016 according to the Primary Care Clinical Database (BDCAP). / Prevalencia de diabetes mellitus en 2016 en España según la Base de Datos Clínicos de Atención Primaria (BDCAP).

The prevalence of type 2 diabetes mellitus is increasing worldwide, including in Spain, and this disease has become a major challenge for health care. In Spain, the computerization of medical records in primary care, in the Primary Care Clinical Database (BDCAP), has made possible the diagnoses of diabetes in a representative sample of the nation as a whole. This article analyzes the prevalence of diabetes recorded in this database and compares the data of the different autonomous communities. The prevalence of diabetes in Spain is 6.66% of the total population assigned to primary care in the National Health System, is higher in men than in women (7.27% vs. 6.06%), and increases with age up to 80 years. There are significant differences in the adjusted prevalence of diabetes between autonomous communities, with lower prevalence rates in North and Central Spain and higher rates in the South and East, as well as the islands. The lowest prevalence is seen in Castile and Leon (4.51%), and the highest in the Canary Islands (9.72%).

[Gender differences in the mortality of people with type 2 diabetes: Asturias Study 2018]. / Diferencias de género en la mortalidad de personas con diabetes tipo 2: Estudio Asturias 2018.

OBJECTIVE: To investigate the influence of gender on mortality according to the presence or absence of type 2 diabetes mellitus (DM2) and other cardiovascular risk factors in the Asturias Study cohort. METHOD: The Asturias Study (started in 1998) is an observational, prospective cohort study of a representative sample of a population of Asturias aged 30-75 years. The population was divided into groups according to the presence or absence of DM2 and according to gender to assess control of cardiovascular risk factors. In addition, aware of the vital status of the cohort 18 years after the beginning of the study, we analyzed differences in causes of mortality according to the previous categories. RESULTS: In 1998, 1034 people started the study, 561 women (54.25%) and 473 men (45.75%). Of these, 131 (12.66%) had diabetes (75 men and 56 women). The women with T2D presented a hazard ratio (HR) for total mortality of 1.64 (95% confidence interval [95%CI]: .97-2.77), which was 1.63 (95%CI: 1.07-2.50) for the men and, for cardiovascular mortality, 3.06 (95%CI: 1.44-6.47) for the females, versus 1.49 (95%CI: 0.64-3.46) for the males. The mortality rate for people with T2D of both sexes was higher than for people without T2D. CONCLUSIONS: Women with T2D have a risk more than three times higher than women without diabetes of dying from cardiovascular causes. We should implement treatment strategies in women with this condition.

Estimation of body fat mass using the CUN-BAE index and mortality risk by sex in the Asturias Study cohort. / Estimación de grasa corporal según ecuación CUN-BAE e IMC y riesgo de mortalidad por sexos en la cohorte del Estudio Asturias.

INTRODUCTION AND OBJECTIVES: In epidemiological studies, excess body fat (BF) has been associated with cardiometabolic risk factors, some types of cancer, and other causes of death. A new anthropometric method has been defined: The CUN-BAE index (University of Navarra Clinic-Body Fat Estimator), which is based on BMI, sex, and age. BMI and CUN-BAE index were used to assess their contribution to mortality risk from any cause in the Asturias Study cohort. MATERIAL AND METHODS: The Asturias study is a cohort study including 1.034 individuals aged 30-75years who participated in the first study phase (1998-1999). The study included a clinical survey, physical examination, and an oral glucose tolerance test. Vital status was determined in the cohort after 18years of follow-up. RESULTS: Two hundred and four subjects died: 93 females and 111 males (16.6% and 23.5% respectively men). Baseline values of both BMI and %BF suggesting obesity (BMI>30kg/m2 and CUN-BAE >25% in males and >35% in females) were found in most subjects. After adjusting for T2DM, HBP, CVD, and tobacco, the risk of all-cause and cardiovascular mortality was significantly higher as CUN-BAE increased, especially in females. CONCLUSIONS: The CUN-BAE equation is a useful tool, especially in females, to detect those who will have a greater risk of mortality, regardless of cardiovascular risk factors.

Iodine nutrition in pregnant women from Oviedo area. Is iodine supplementation necessary?

BACKGROUND AND OBJECTIVE: In Asturias, where iodine deficiency was eradicated in school children by the year 2000, iodine deficiency persisted in pregnant women, who were recommended to use of iodine supplementation. The aim of this study was to determine the iodine nutrition of pregnant women in our area and whether or not iodine supplements are needed. MATERIAL AND METHODS: Throughout May and June 2013 we studied the iodine nutrition and thyroid function during the first trimester of pregnancy in 173 women in the health area of Oviedo. RESULTS: The median urinary iodine was 197 µg/L. Iodinated supplements were used by 47% of women, which had a yoduria median higher than those not taking iodinated supplements (247 vs. 138 µg/L; p<.001), and also a higher TSH (2.30 vs 1.94 mU/L) although not significantly different. Yoduria was also higher in women who took more than 2 servings of dairy products (median: 230 µg/L) than those who took less (median: 191 µg/L). Within the group of women who were not taking iodine supplements, those regularly using iodized salt in the kitchen (47%) had a median urinary iodine concentration of 190µg/L indicating iodine sufficiency. CONCLUSIONS: Iodinated supplements seem unnecessary nowadays in pregnant women of Oviedo who regularly take iodized salt and our recommendation in these cases should be to continue the use of iodized salt in the recommended amounts during pregnancy and consume at least two daily servings of milk or dairy products.