Decoding the Versatile Landscape of Autophagic Protein VMP1 in Cancer: A Comprehensive Review across Tissue Types and Regulatory Mechanisms.

Autophagy, a catabolic process orchestrating the degradation of proteins and organelles within lysosomes, is pivotal for maintaining cellular homeostasis. However, its dual role in cancer involves preventing malignant transformation while fostering progression and therapy resistance. Vacuole Membrane Protein 1 (VMP1) is an essential autophagic protein whose expression, per se, triggers autophagy, being present in the whole autophagic flux. In pancreatic cancer, VMP1-whose expression is linked to the Kirsten Rat Sarcoma Virus (KRAS) oncogene-significantly contributes to disease promotion, progression, and chemotherapy resistance. This investigation extends to breast cancer, colon cancer, hepatocellular carcinoma, and more, highlighting VMP1's nuanced nature, contingent on specific tissue contexts. The examination of VMP1's interactions with micro-ribonucleic acids (miRNAs), including miR-21, miR-210, and miR-124, enhances our understanding of its regulatory network in cancer. Additionally, this article discusses VMP1 gene fusions, especially with ribosomal protein S6 kinase B1 (RPS6KB1), shedding light on potential implications for tumor malignancy. By deciphering the molecular mechanisms linking VMP1 to cancer progression, this exploration paves the way for innovative therapeutic strategies to disrupt these pathways and potentially improve treatment outcomes.

Diabetic Ketoacidosis in Type 1 Diabetes Onset in Latin American Children.

OBJECTIVE: To describe the patterns of diabetic ketoacidosis (DKA) occurrence in children newly diagnosed with type 1 diabetes (T1DM) across several Latin American pediatric diabetes centers from 2018 to 2022. METHODS: A retrospective chart review included children under 18 with new-onset T1DM from 30 Latin American pediatric diabetes centers (Argentina, Chile, and Peru) between 30 December 2018 and 30 December 2022. Multiple logistic regression models examined the relationships between age, gender, medical insurance, BMI, and DKA at new-onset T1DM. As far as we know, there are no large studies in Latin American countries exploring the patterns of DKA in new-onset T1DM. RESULTS: A total of 2,026 (983 females) children, median age 9.12 (5.8 -11.7) years with new-onset-T1DM were included. Approximately 50% had no medical insurance. Mean glucose values were 467 mg/dL, pH 7.21, bicarbonate 13 mEq/L, HbA1c 11.3%, and BMI 18. The frequency of DKA was 1,229 (60.7%), out of which only 447 (36%) were severe. There was a significant decrease in the frequency of DKA as age increased: 373 (70.2%) in children under 6, 639 (61.6%) in those between 6 and 12, 217 and (47.5%) in those over 12. Children with medical insurance (58.8%) had a significantly lower frequency of DKA than those without (62.7%). The multiple logistic regression models showed that DKA was significantly and inversely associated with age [OR, 0.72 (95% CI 0.60-0.86)], BMI [OR, 0.95 (95% CI 0.92-0.99)], and medical insurance [OR, 0.75 (95% CI 0.60-0.94)] adjusted for sex. CONCLUSION: Latin American children with new-onset T1DM exhibited a substantial occurrence of DKA. Younger ages and the lack of medical insurance were significantly associated with DKA in new-onset T1DM.

Ubiquitination Is a Novel Post-Translational Modification of VMP1 in Autophagy of Human Tumor Cells.

Autophagy is a tightly regulated catabolic process involved in the degradation and recycling of proteins and organelles. Ubiquitination plays an important role in the regulation of autophagy. Vacuole Membrane Protein 1 (VMP1) is an essential autophagy protein. The expression of VMP1 in pancreatic cancer stem cells carrying the activated Kirsten rat sarcoma viral oncogene homolog (KRAS) triggers autophagy and enables therapy resistance. Using biochemical and cellular approaches, we identified ubiquitination as a post-translational modification of VMP1 from the initial steps in autophagosome biogenesis. VMP1 remains ubiquitinated as part of the autophagosome membrane throughout autophagic flux until autolysosome formation. However, VMP1 is not degraded by autophagy, nor by the ubiquitin-proteasomal system. Mass spectrometry and immunoprecipitation showed that the cell division cycle protein cdt2 (Cdt2), the substrate recognition subunit of the E3 ligase complex associated with cancer, cullin-RING ubiquitin ligase complex 4 (CRL4), is a novel interactor of VMP1 and is involved in VMP1 ubiquitination. VMP1 ubiquitination decreases under the CRL inhibitor MLN4924 and increases with Cdt2 overexpression. Moreover, VMP1 recruitment and autophagosome formation is significantly affected by CRL inhibition. Our results indicate that ubiquitination is a novel post-translational modification of VMP1 during autophagy in human tumor cells. VMP1 ubiquitination may be of clinical relevance in tumor-cell-therapy resistance.

Incidence and case-fatality rate of stroke in General Villegas, Buenos Aires, Argentina. The EstEPA population study.

OBJECTIVES: Stroke epidemiology varies among different populations. The burden of stroke is high in low- and middle-income countries. Reliable population data is needed to assess the impact of stroke and to develop policies aimed to improve stroke care in our region. EstEPA is a population-based project assessing prevalence, incidence, mortality and burden of stroke in General Villegas Department, Buenos Aires, Argentina (pop=30,864 inhabitants). We determined incidence of stroke (first-ever and recurrent stroke) and stroke case-fatality rate from 2017 to 2020. METHODS: First-ever strokes, recurrent strokes and transient ischemic attacks were ascertained and case-fatality rate was obtained. Diagnoses were based on standard AHA/WHO definitions. Study population included all persons residing in General Villegas during the three-year period. Hospitals, households, nursing homes, death certificates and several overlapping sources were surveyed. RESULTS: We assessed 92,592 person-years. There were 155 cerebrovascular events aged 70 years (SD ± 13 years), of which 115 were first-ever strokes (74%), 21 recurrent strokes (13.5%) and 19 transient ischemic attacks (12.5%). The crude overall incidence rate of first-ever strokes was 124.2 per 100,000 population (86.9 per 100,000 [95% CI 58.5-115.2] when standardized by WHO World population and 109.7 per 100,000 [95% CI 89.7-129.8] when standardized by Argentine population) and 317.0 per 100,000 population in subjects older than 40 years. Case fatality rate at 30 days of first-ever strokes was 27%. CONCLUSION: In this population-based comprehensive stroke epidemiological study in Argentina, first-ever stroke incidence in an urban population was 124.2 per 100,000 population (86.9 per 100,000 adjusted by the WHO World population). This is lower than the incidence in other countries in the region and similar to a recent incidence study in Argentina. It is also comparable to reported incidence in most middle- and high-income countries. Stroke case-fatality rate was comparable to other population-based Latin-American studies.

Autophagy in Inflammatory Response against SARS-CoV-2.

The coronavirus disease pandemic, which profoundly reshaped the world in 2019 (COVID-19), and is currently ongoing, has affected over 200 countries, caused over 500 million cumulative cases, and claimed the lives of over 6.4 million people worldwide as of August 2022. The causative agent is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Depicting this virus' life cycle and pathogenic mechanisms, as well as the cellular host factors and pathways involved during infection, has great relevance for the development of therapeutic strategies. Autophagy is a catabolic process that sequesters damaged cell organelles, proteins, and external invading microbes, and delivers them to the lysosomes for degradation. Autophagy would be involved in the entry, endo, and release, as well as the transcription and translation, of the viral particles in the host cell. Secretory autophagy would also be involved in developing the thrombotic immune-inflammatory syndrome seen in a significant number of COVID-19 patients that can lead to severe illness and even death. This review aims to review the main aspects that characterize the complex and not yet fully elucidated relationship between SARS-CoV-2 infection and autophagy. It briefly describes the key concepts regarding autophagy and mentions its pro- and antiviral roles, while also noting the reciprocal effect of viral infection in autophagic pathways and their clinical aspects.

Pharmacokinetic and pharmacodynamic study of three products of epoetin alfa as single subcutaneous dose in healthy volunteers.

Hemax® is an epoetin alfa product developed by Biosidus S.A. in Argentina at the end of the 1980s and has been present in that market since 1991. The initial presentation was a lyophilized powder containing albumin as stabilizer, to best adapt to environmental conditions in developing countries; more recently, a prefilled syringe, albumin-free presentation was developed, since this presentation has become the preferred standard in many markets. The primary objective was to compare the pharmacokinetic profile of different formulations of epoetin alfa after a single subcutaneous administration to healthy volunteers of 40 000 IU of Eprex/Erypo® and Hemax® PFS. This clinical trial was conceived following an open-label, randomized, three-way three-period cross-over balanced, and sequential design. The study was conducted on 24 healthy volunteers. To analyze similarity between Hemax® PFS and the innovator product, Eprex®, area under the curve (AUC) and Cmax of both products have been compared. The 90% CI lower limit for the geometric mean ratios was higher than 80% for any comparisons, and the 90% CI upper limit for these geometric ratios was below 125% for all the comparisons made, thus demonstrating equivalence between both products. The comparison between Hemax® PFS and Eprex® resulted in similar 90% CI for Cmax , AUC(0-120 h) and AUC(0-inf) ratios, all of them within the 80-125% interval, with a power above 95% for each ratio. These findings suggest biosimilar patterns for absorption velocity (with Tmax close to 15 h), absorption extent, and elimination (with an elimination half-life close to 25-30 h for each formulation).

Association between hepcidin and type 2 diabetes markers in indigenous Argentinean children living at high altitude.

BACKGROUND: Hepcidin is a protein that regulates the metabolism of iron. In addition, a high iron load can cause insulin resistance and subsequent diabetes. OBJECTIVE: To investigate the association between hepcidin levels and glucose, insulin, lipids, HOMA-IR, and inflammatory markers, C reactive protein (CRP), ferritin, Lp (a), and leucocytes, in indigenous school children living at 4000 m above sea level. Data were collected cross-sectionally from the four schools in San Antonio de los Cobres (SAC). BMI, glucose, insulin, lipids, CRP, hemoglobin, leucocytes, iron, ferritin, transferrin, and hepcidin levels were obtained. RESULTS: Three hundred and seventy-six children (170 males) aged 9.6 ± 2.3 y were included. Fifty-five(15.2 %) children were underweight, 28 (7.4 %) overweight and 10 (2.7 %) obese. Univariate analysis showed a significant inverse correlation between hepcidin and glucose (r = -0.14) and HOMA-IR (r = -0.30). Furthermore, hepcidin was found to be directly and significantly correlated with Lp(a) (r = 0.18), leucocytes (r = 0.24,) CRP (r = 0.32), and ferritin (r = 0.32). Multiple linear regression analysis indicated that hepcidin was significantly and inversely associated with glucose and BMI and directly with Lp(a), CRP, leucocytes, and ferritin; adjusted for age and gender (R2 0.26). CONCLUSION: In this study, which included indigenous children living at high altitudes (4000 m), hepcidin was significantly and inversely associated with glucose and BMI and directly associated with inflammatory markers such as CRP, Lp(a), leucocytes, and ferritin, suggesting that hepcidin could be a reliable marker of future type 2 diabetes.

Protein expression in exocrine pancreatic diseases. Focus on VMP1 mediated autophagy.

The exocrine pancreas produces enzymes involved in the digestive process whereas endocrine pancreas mainly regulates glucose metabolism. Diseases of the exocrine pancreas are characterized by high morbidity and mortality. Acute pancreatitis is a painful disease in which pancreatic secretory proteins are prematurely activated causing the digestion of the gland. Pancreatic adenocarcinoma is one of the most malignant cancers due to its resistance to treatment, its late diagnosis and high capacity for metastasis. Autophagy is a catabolic process that aims at degrading cytoplasmic contents and damaged organelles, to preserve cell viability and homeostasis. VMP1 is a transmembrane protein that plays a key role in triggering autophagy and being part of the autophagosome membrane. A specific type of selective autophagy pathway called zymophagy protects the pancreas against self-digestion in the setting of acute pancreatitis by sequestering intracellularly activated zymogen granules. Mitophagy is also responsible for maintaining pancreatitis as a mild disease by preserving mitochondrial function. Dysregulation of these selective autophagic processes by pancreatitis itself constitutes a risk factor for development of severe disease. In pancreatic adenocarcinoma, VMP1 mediated autophagy promotes cancer cell survival and resistance to chemotherapy. Therefore, it is relevant to highlight a role for controlling VMP1 expression and targeting VMP1 molecular pathways to improve exocrine pancreatic diseases prognosis.

Ability of TyG Index as a Marker of Insulin Resistance in Argentinean School Children.

Objective: To determine if the triglycerides and glucose index (TyG) can be used as a marker for insulin resistance (IR) in Argentinean schoolchildren according to age and sex. Methods: Anthropometric data, blood glucose levels, lipid profiles, and insulin levels were measured. The TyG index was defined by Ln [fasting triglyceride (mg/dL)* fasting glucose (mg/dL)/2]. A comparison of the ability of TyG to identify children with IR was performed using receiver operating characteristic (ROC) curves and the area under the ROC (AUROC) curve. IR was defined as HOMA-IR > III quartile. Results: A total of 915 (528, 57.7% males) apparently healthy schoolchildren, aged 9.3 ± 2.2, were evaluated. The AUROC using the HOMA-IR > III quartile as the dichotomous variable showed that TyG was a fair marker to identify IR (0.65, 95% CI, 0.61-0.69; p < 0.01). There was a significantly higher TyG AUROC in males (0.69, 95% CI, 0.63-0.75; p < 001) than in females (0.60, 95% CI, 0.54-0.66; p < 0.01). When children were divided according to age into two groups (5.0-9.9 and 10.0-14.9-year-olds); younger children (0.64, 95% CI, 0.58-0.69; p < 0.011) and older children (0.62, 95% CI, 0.55-0.68; p = 0.01) had a similar and fair AUROC. However, when children were divided by age and sex, females older than ten had a non-significant AUROC (0.53, 95% CI, 0.42-0.63; p = 0.61). The TyG index compared with HOMA-IR had low sensitivity and specificity, ranging from 0.62 to 0.56. Conclusion: The TyG index had a fair AUROC with low sensitivity and specificity, indicating poor discrimination in identifying IR in apparently healthy Argentinean children. The ability to use TyG for screening purposes seems limited in Argentinean schoolchildren.

Autophagy Dysregulation in Diabetic Kidney Disease: From Pathophysiology to Pharmacological Interventions.

Diabetic kidney disease (DKD) is a frequent, potentially devastating complication of diabetes mellitus. Several factors are involved in its pathophysiology. At a cellular level, diabetic kidney disease is associated with many structural and functional alterations. Autophagy is a cellular mechanism that transports intracytoplasmic components to lysosomes to preserve cellular function and homeostasis. Autophagy integrity is essential for cell homeostasis, its alteration can drive to cell damage or death. Diabetic kidney disease is associated with profound autophagy dysregulation. Autophagy rate and flux alterations were described in several models of diabetic kidney disease. Some of them are closely linked with disease progression and severity. Some antidiabetic agents have shown significant effects on autophagy. A few of them have also demonstrated to modify disease progression and improved outcomes in affected patients. Other drugs also target autophagy and are being explored for clinical use in patients with diabetic kidney disease. The modulation of autophagy could be relevant for the pharmacological treatment and prevention of this disease in the future. Therefore, this is an evolving area that requires further experimental and clinical research. Here we discuss the relationship between autophagy and Diabetic kidney disease and the potential value of autophagy modulation as a target for pharmacological intervention.

Cardiometabolic markers among Argentinean normal weight and overweight children with and without central obesity.

BACKGROUND: The association between central obesity and cardiometabolic complications justifies exploring its association in normal-weight and overweight/obese (OW/OB) schoolchildren. OBJECTIVE: To describe cardiometabolic markers in four groups according to BMI/WC categories: (i) normal weight with central OB; (ii) normal weight without central OB; (iii) OW/OB with central OB and (iv) OW/OB without central OB, in a sample of Argentinean schoolchildren. METHODS: A cross-sectional study of 1264 Argentinean schoolchildren (624 F), aged 9.5 ± 2.2 years was performed between November 2013 and 2015. Children's anthropometric measures, blood pressure (BP), glucose, lipids, and insulin were measured. Children were divided into four groups: (i) normal weight with central OB; (ii) normal weight without central OB; (iii) OW/OB with central OB and (iv) OW/OB without central OB. RESULTS: The prevalence of normal-weight children without central OB was 64.3% (796), normal weight with central OB 5% (66), OW/OB without central OB 11% (137), and OW/OB with central OB 21% (265). Normal weight with central OB had significantly higher triglycerides than normal-weight children without central OB (86 vs 70 mg/dL, respectively) and OW/OB children without central OB (81 vs 77 mg/dL). Multiple linear regression analyses showed that age, systolic BP, HDL-C, triglycerides, and maternal WC were significantly associated with children's WC; R2 = 0.50 as well as children's BMI; R2 = 0.37. CONCLUSION: This study found that children with central OB might be at future higher cardiometabolic risk than those without central OB independently of the presence of OW/OB. However, future longitudinal studies should be performed to confirm these findings.

Influence of Telemedicine on the Number of Visits and HbA1c Determinations in Latin American Children with Type 1 Diabetes.

Objective: To measure the changes in the number of medical visits and the number of hemoglobin A1c (HbA1c) determinations according to telemedicine access in children with type 1 diabetes (T1DM) during the pandemic 2020 compared with 2019 and 2018. Methods: This is a multinational study of children with T1DM from four Latin American countries. The number of medical visits, the number of HbA1c determinations, and access to telemedicine during 2020 were extracted from their records. Results: Two hundred twenty-seven children (59% females) aged 12.7 ± 3.2 years with a duration of 5.4 ± 2.7 years of T1DM in 2018 were evaluated. There was a higher prevalence of children with telemedicine access in the pandemic 2020 versus those without [145 (63.9%) vs. 82 (36.1%); P < 0.01]. There was a higher number of medical visits during 2020 in children with telemedicine access versus those without (6.9 vs. 2.6; P < 0.01). Children with telemedicine access had a higher number of visits in 2020 versus 2018 (6.87 vs. 5.04, P < 0.01), but similar to 2019. Children without access had a lower number of visits in 2020 versus 2019 (2.6 vs. 5.5; P < 0.01) and versus 2018 (2.6 vs. 5.1; P < 0.01). In 2020, the number of HbA1c determinations in children with telemedicine access was higher versus those without (1.8 vs. 0.9; P < 0.01). Children with telemedicine access had a lower number of HbA1c determinations in 2020 versus 2019 (1.8 vs. 2.4; P < 0.01), but similar to 2018. Furthermore, children without access had a lower number of HbA1c determinations in 2020 versus 2019 (0.9 vs. 1.9; P < 0.01) and versus 2018 (0.9 vs. 2.0; P < 0.01). Conclusions: We found that children with T1DM with telemedicine access had a significantly higher number of medical visits and HbA1c determinations during lockdown than those without access in different Latin American centers.

Association Between High Birth Weight and Later Central Obesity in 9-Year-Old Schoolchildren.

Background and Objective: Studies have suggested that birth weight (BW) is associated with body mass index (BMI), but its association with waist circumference (WC) in children should be further explored. To determine the association between central obesity (OB) in 9-year-old Argentinean schoolchildren and high BW. Methods: Schoolchildren (n = 2567, 1157 males) aged 8.7 ± 2.1 years from 10 elementary schools in 5 states in Argentina were examined between April 2017 and September 2019. Mothers submitted children's BW information. Pediatricians assessed anthropometric measures and blood pressure (BP). Central OB was defined for children as WC ≥90th percentile for age and gender. Results: The prevalence of overweight (OW) and OB (OW/OB) was 42.7% (1095) and that of central OB was 34.8% (856) in 9-year-old children. The prevalence of low BW (<2500 grams) and high BW (>4000 grams) was 6.6% (n = 169) and 7.4% (n = 190), respectively. BW (3.25 vs. 3.36 kg), weight (31.38 vs. 42.88 kg), BMI (17.29 vs. 22.25 kg/m2), BMI z-scores (z-BMI; 0.25 vs. 1.63), systolic BP (96 vs. 98 mmHg), and diastolic BP (59 vs. 60 mmHg) were significantly lower in 9-year-old children without central OB than in those with central OB, respectively. Multiple logistic regression analysis using central OB as the dependent variable showed that high BW [odds ratio, 1.98 (95% confidence interval 1.44-2.73)] was associated with central OB, adjusted for age, gender, and systolic and diastolic BP. Conclusion: This study shows that central OB in 9-year-old children was associated with high BW. Future longitudinal studies should be performed to confirm this finding. Clinical Registration number, IATIMET-08102019.

A Novel E2F1-EP300-VMP1 Pathway Mediates Gemcitabine-Induced Autophagy in Pancreatic Cancer Cells Carrying Oncogenic KRAS.

Autophagy is an evolutionarily preserved degradation process of cytoplasmic cellular constituents, which participates in cell response to disease. We previously characterized VMP1 (Vacuole Membrane Protein 1) as an essential autophagy related protein that mediates autophagy in pancreatic diseases. We also demonstrated that VMP1-mediated autophagy is induced by HIF-1A (hypoxia inducible factor 1 subunit alpha) in colon-cancer tumor cell lines, conferring resistance to photodynamic treatment. Here we identify a new molecular pathway, mediated by VMP1, by which gemcitabine is able to trigger autophagy in human pancreatic tumor cell lines. We demonstrated that gemcitabine requires the VMP1 expression to induce autophagy in the highly resistant pancreatic cancer cells PANC-1 and MIAPaCa-2 that carry activated KRAS. E2F1 is a transcription factor that is regulated by the retinoblastoma pathway. We found that E2F1 is an effector of gemcitabine-induced autophagy and regulates the expression and promoter activity of VMP1. Chromatin immunoprecipitation assays demonstrated that E2F1 binds to the VMP1 promoter in PANC-1 cells. We have also identified the histone acetyltransferase EP300 as a modulator of VMP1 promoter activity. Our data showed that the E2F1-EP300 activator/co-activator complex is part of the regulatory pathway controlling the expression and promoter activity of VMP1 triggered by gemcitabine in PANC-1 cells. Finally, we found that neither VMP1 nor E2F1 are induced by gemcitabine treatment in BxPC-3 cells, which do not carry oncogenic KRAS and are sensitive to chemotherapy. In conclusion, we have identified the E2F1-EP300-VMP1 pathway that mediates gemcitabine-induced autophagy in pancreatic cancer cells. These results strongly support that VMP1-mediated autophagy may integrate the complex network of events involved in pancreatic ductal adenocarcinoma chemo-resistance. Our experimental findings point at E2F1 and VMP1 as novel potential therapeutic targets in precise treatment strategies for pancreatic cancer.

Adiposity, lifestyle behaviors, and cardiometabolic markers in Argentinean schoolchildren.

BACKGROUND: We determined the association between schoolchildren's OW/OB with age, sex, lifestyle behaviors, and cardiometabolic markers. METHODS: Age, sex, anthropometric measures, and BP (blood pressure) were recorded in 1249 (554 M) schoolchildren. OW/OB was defined as BMI > 85%ile and BMI > 95%ile respectively. A validated questionnaire for lifestyle behaviors was performed. We offered free laboratory testing to a subgroup of 168 children. RESULTS: Schoolchildren aged 8.8 ± 2.1 y from 9 elementary schools in 4 areas of Argentina were examined between April and September 2019. 265 (21.2%) of the children were OW, 265 (21.2%) were OB, and 425 (35%) had central OB. OW/OB was associated with low milk intake (OR = 1.92; 95% CI, 1.1-3.3), skipping breakfast (OR = 2.00; 95% CI, 1.2-3.4), a family history of hypertension (OR = 1.74; 95% CI, 1.1-2.9), and systolic BP (OR = 1.03; 95% CI, 1.01-1.05); adjusted for confounding variables. The subgroup analysis showed that OW/OB children had lower iron (83 vs. 94 ug/dl, respectively) and HDL-C (43 vs. 47 mg/dl) levels, but higher non-HDL-C (107 vs. 99 mg/dl) levels than normal-weight children. Multiple logistic regression analysis showed that OW/OB was inversely associated with iron (OR = 0.99; 95% CI, 0.98-0.998) and HDL-C (OR = 0.94; 95% CI, 0.91-0.97) levels; adjusted for confounding variables. CONCLUSION: Adiposity in schoolchildren was associated with unhealthy lifestyle behaviors, higher atherogenic risk, and lower iron concentrations, suggesting that OW/OB children are at increased risk for anemia and cardiometabolic disease.

Dyslipidemia: The untreated metabolic dysfunction in people with type 2 diabetes in Latin America. ARETAEUS study outcomes.

OBJECTIVE: To assess oral antihyperglycemic agents (OAHA) and/or statin treatment initiation in patients with type 2 diabetes (T2D) and time from diagnosis to both types of treatment initiation and intensification. RESEARCH DESIGN AND METHODS: We reviewed 662 retrospective medical records of patients with T2D diagnosed by 31 general practitioner or specialist sites across Mexico, Argentina, and Brazil. Demographic and clinical information was abstracted from patients' medical records and summarized using descriptive statistics. Between-group differences were assessed with Student's t-test for continuous variables and Fisher's exact test for categorical variables. The starting time of each therapy (OAHA and statins, separately) was assessed using Kaplan-Meier estimates. RESULTS: At diagnosis, patients' mean age was 53 years; 44% had hypertension, 42% were obese, and 23% had dyslipidemia. During the 2-year follow-up, 95% of patients received OAHAs but only 29% of those eligible for statins received this prescription. Mean ±â€¯SD and median (Q1, Q3) time to first OAHA was 59 ±â€¯141 days and 1 (1, 31) day, respectively, and 230 ±â€¯232 days and 132 (30, 406) days, respectively, for a statin. During follow-up, 51-53% of patients with HbA1c/FPG values above target did not intensify hyperglycemia treatment. CONCLUSION: Dyslipidemia treatment in patients with T2D was delayed despite its known deleterious effect on atherosclerosis development and ß-cell mass/function. Anti-hyperglycemic treatment was not intensified when targets were not attained. This prescriptive inertia needs to be corrected because attainment of HbA1c treatment goals becomes more difficult, favoring the development of diabetes complications.

Stroke Epidemiology in Argentina. Design of a Population-Based Study in General Villegas (EstEPA).

BACKGROUND: Epidemiological data on stroke is scarce in Latin America. Estudio Epidemiológico Poblacional sobre Accidente Cerebrovascular (EstEPA) is a population-based program planned to assess prevalence, incidence, mortality, and burden of disease for stroke in the Department of General Villegas, province of Buenos Aires, Argentina. METHODS AND DESIGN: Prevalence study will consist of a two-phase survey approach in the urban area of General Villegas. First, trained social workers with a structured questionnaire will collect data in 2000 randomly selected housing units. Those subjects screened positive for possible strokes will be interviewed and examined by stroke neurologists to confirm diagnosis. The incidence study will be performed according to the methodology of WHO STEPS stroke surveillance manual and will detect all new strokes in the department during a 5-year period. General and disease-specific mortality rates will be assessed monthly during a 5-year period, using different sources of information. To assess the overall burden of cerebrovascular disease, disability adjusted life years will be calculated. DISCUSSION: EstEPA will assess for the first time all aspects of stroke epidemiology in Argentina. Its results will help to implement population-based interventions and to properly allocate public health resources.

Metformin and Pregnancy Outcomes: Evidence Gaps and Unanswered Questions.

BACKGROUND: Metformin is sometimes used as an alternative to insulin in gestational diabetes mellitus (GDM). It is also used to achieve ovulation in polycystic ovary syndrome (PCOS). Pre-natal exposure to metformin results from its continuation after a successful ovulation in women with PCOS, its maintenance in women with pre-gestational diabetes or the installation of metformin in GDM. Little is known about the potential consequences of metformin exposure on pregnancy outcomes and offspring development. The aim of this review is to summarize the metformin effects on pregnancy outcomes and offspring development. Gaps in the available evidence and unanswered questions are also discussed. METHODS: A comprehensive literature search was carried out to identify eligible studies from MEDLINE/PubMed, EMBASE and SCIELO databases through 1995 first semester. RESULTS: Several factors limit the effect of metformin on embryos. In contrast, placental transport of metformin is effective allowing for a higher fetal exposure; the impact of this finding remains unclear. It seems that the interruption of metformin after a pregnancy diagnosis in women with PCOS is not associated with a higher miscarriage risk and it continuation does not seem to impair the maternal metabolic prognosis or prevent emerging GDM. CONCLUSIONS: It seems to have no sense to prolong the use of metformin after a pregnancy diagnosis in women with PCOS. Patients with GDM may be treated with metformin under on judicious basis, and a careful attachment to clinical guidelines and regulations is recommended. The long-term effects of pre-natal exposure to metformin on the offspring remain uncertain.

Social vulnerability and hypoglycemia among patients with diabetes.

Lower-income populations are hit harder by the diabetes epidemic as regards both prevalence and the risk of complications. Food Insecurity is one of the mechanisms through which poverty may predispose people with low socio-economic status to poorer control and higher complication rates. The United Nations Food and Agriculture Organization defined food security as "the right to have access to sufficient nutritional and culturally acceptable food choices." Adults suffering from diabetes with limited income have a 40% greater chance of having food insecurity and an inadequate blood glucose control. Such patients have a two-fold greater risk of developing severe hypoglycemia. In addition, several studies have shown that social vulnerability resulting from food insecurity, low socioeconomic status, low educational levels, and poor health education is an independent risk factor for hypoglycemia, even after conventional predictors are controlled. This review analyzes the literature available on social vulnerability as a non-conventional risk factor for development of hypoglycemia in diabetic subjects.