Sexual dimorphism in the molecular mechanisms of insulin resistance during a critical developmental window in Wistar rats.

BACKGROUND: Insulin resistance (IR) is a condition in which the response of organs to insulin is impaired. IR is an early marker of metabolic dysfunction. However, IR also appears in physiological contexts during critical developmental windows. The molecular mechanisms of physiological IR are largely unknown in both sexes. Sexual dimorphism in insulin sensitivity is observed since early stages of development. We propose that during periods of accelerated growth, such as around weaning, at postnatal day 20 (p20) in rats, the kinase S6K1 is overactivated and induces impairment of insulin signaling in its target organs. This work aimed to characterize IR at p20, determine its underlying mechanisms, and identify whether sexual dimorphism in physiological IR occurs during this stage. METHODS: We determined systemic insulin sensitivity through insulin tolerance tests, glucose tolerance tests, and blood glucose and insulin levels under fasting and fed conditions at p20 and adult male and female Wistar rats. Furthermore, we quantified levels of S6K1 phosphorylated at threonine 389 (T389) (active form) and its target IRS1 phosphorylated at serine 1101 (S1101) (inhibited form). In addition, we assessed insulin signal transduction by measuring levels of Akt phosphorylated at serine 473 (S473) (active form) in white adipose tissue and skeletal muscle through western blot. Finally, we determined the presence and function of GLUT4 in the plasma membrane by measuring the glucose uptake of adipocytes. Results were compared using two-way ANOVA (With age and sex as factors) and one-way ANOVA with post hoc Tukey's tests or t-student test in each corresponding case. Statistical significance was considered for P values < 0.05. RESULTS: We found that both male and female p20 rats have elevated levels of glucose and insulin, low systemic insulin sensitivity, and glucose intolerance. We identified sex- and tissue-related differences in the activation of insulin signaling proteins in p20 rats compared to adult rats. CONCLUSIONS: Male and female p20 rats present physiological insulin resistance with differences in the protein activation of insulin signaling. This suggests that S6K1 overactivation and the resulting IRS1 inhibition by phosphorylation at S1101 may modulate to insulin sensitivity in a sex- and tissue-specific manner. Video Abstract.

Insulin regulates the synthesis of carbohydrates, lipids and proteins differently between males, and females. One of its primary functions is maintaining adequate blood glucose levels favoring glucose entry in muscle and adipose tissue after food consumption. Insulin resistance (IR) is a condition in which the response of organs to insulin is impaired. IR is frequently associated with metabolic dysfunction such as inflammation, obesity, or type 2 diabetes. However, physiological IR develops in healthy individuals during periods of rapid growth, pregnancy, or aging by mechanisms not fully understood. We studied the postnatal development, specifically around weaning at postnatal day 20 (p20) of Wistar rats. In previous works, we identified insulin resistance during this period in male rats. This work aimed to characterize IR at p20, determine its underlying mechanisms, and identify whether sexual dimorphism in physiological IR occurs during this stage. We found that p20 rats of both sexes have elevated blood glucose and insulin levels, low systemic insulin sensitivity, and glucose intolerance. We identified differences in insulin-regulated protein activation (S6K1, IRS1, Akt, and GLUT4) between sexes in different tissues and adipose tissue depots. Studying these mechanisms and their differences between males and females is essential to understanding insulin actions and their relationship with the possible development of metabolic diseases in both sexes.

[Clinical and microbiological characteristics of urinary tract infections in the first year after renal transplantation]. / Infecciones urinarias en el primer año postrasplante renal.

Introduction: Urinary tract infections (UTI) are the most frequent infection in kidney transplant (KT) patients. The main objective was to determine the clinical and microbiological characteristics of UTIs that occur during the first year after KT. Methods: Retrospective cohort study that included patients over 18 years of age who received KT between 2009-2020 in two hospitals in Córdoba city, Argentina. Patients were followed up during the first year after the transplant by recording them in the medical records, and those who presented at least one episode of UTI were analyzed. Results: During the study period, 568 KTs were performed, of which 207 (36.4%) had at least one episode of UTI. In total, there were 419 UTI episodes, 6 (1.4%) polymicrobial UTI episodes, so a total of 426 microorganisms were identified in the urine cultures. Of the total number of episodes, 206 (49.2%) occurred between 31 and 180 days post-transplant. The main etiological agent was E. coli with 225 isolates (52.8%) followed by Klebsiella sp. with 94 (22.1%). 52.1% of all episodes were caused by multi-resistant microorganisms (MRM). Among the E. coli isolates, 94 (41.8%) were MRM. In the multivariate analysis, the risk factors associated with UTI due to MRM were a history of recurrent UTI (Odds ratio 2.43; 95% CI: 1.37-4.30) and induction with basiliximab (Odds ratio 1.53; 95% CI: 1.029-2.29). Main conclusion: UTIs occurred in more than a third of kidney transplant patients, being slightly more than half caused by MOR.

Introducción: Las infecciones del tracto urinario (ITU) constituyen la infección más frecuente en los trasplantados renales (TR). El objetivo principal fue determinar las características clínicas y microbiológicas de las ITU que ocurren durante el primer año posterior al TR. Metodología: Estudio de cohorte retrospectivo, donde se incluyeron pacientes mayores 18 años que recibieron un TR entre 2009-2020 en dos hospitales de la ciudad de Córdoba. A través del registro en las historias clínicas se realizó seguimiento de los pacientes durante el primer año postrasplante y se analizaron los que presentaron al menos un episodio de ITU. Resultados: En el período de estudio, se realizaron 568 TR, de los cuales 207(36,4%) tuvieron al menos un episodio de ITU. En total hubo 419 episodios de ITU, 6(1,4%) episodios de ITU polimicrobianos, se identificaron un total de 426 microorganismos en total en los urocultivos. Del total de episodios 206(49,2%) ocurrieron entre los 31-180 días postrasplante. El principal agente etiológico fue E. coli con 225 aislamientos (52,8%) seguido de Klebsiella sp. con 94(22,1%). El 52,1% del total de episodios fueron causados por microorganismos multirresistentes (MOR). Entre los aislamientos de E. coli, 94(41,8%) fueron MOR. En el análisis multivariado los factores de riesgo asociados a ITU por MOR fueron el antecedente de ITU recurrente (Odds ratio 2.43; IC95%: 1.37-4.30) e inducción con basiliximab (Odds ratio 1.53; IC95%: 1.029-2.29). Conclusión: Las ITU se presentaron en más de un tercio de los pacientes trasplantados renales siendo un poco más de la mitad causados por MOR.

The incidence, risk factors and impact of acute kidney injury in hospitalized patients due to COVID-19.

The incidence of acute kidney injury (AKI) in hospitalized patients with COVID-19 is variable, being associated with worse outcomes. The objectives of the study were to evaluate the incidence, risk factors (considering demographic characteristics, comorbidities, initial clinical presentation and associated complications) and impact of AKI in subjects hospitalized for COVID-19 in two third-level hospitals in Córdoba, Argentina. A retrospective cohort study was conducted. We included 448 adults who were consecutively hospitalized for COVID-19 between March 3 and October 31, 2020 and were followed throughout the hospitalization. The incidence of AKI was 19% (n = 85; stage I = 43, stage II = 17, and stage III = 25, 18 required renal replacement therapy). In the multivariate analysis, the variables that were independently associated with AKI were: age (for every 10 years, adjusted odd ratio [95%CI] = 1.30 [1.04-1.63], p = 0.022), history of chronic kidney disease -CKD- (9.92 [4.52-21.77], p < 0.001), blood neutrophil count at admission -BNCA- (for every increase of 1000 BNCA, 1.09 [1.01-1.18], p = 0.037) and requirement for mechanical ventilation -MV- (6.69 [2.24-19.90], p = 0.001). AKI was associated with longer hospitalization, higher admission (63.5 vs. 29.7%; p < 0.001) and longer stay in the intensive care unit, a positive association with respiratory bacterial superinfection, sepsis, respiratory distress syndrome, MV requirement and mortality (mortality without AK I = 12.4% vs with AKI = 47.1%; stage I = 26%, stage II = 41% and stage III = 88%; p < 0.001). AKI was independently associated with higher mortality (3.32 [1.6-6.9], p = 0.001). In conclusion, the incidence of AKI in adults hospitalized for COVID-19 was 19% and had a clear impact on morbidity and mortality. The independent risk factors for AKI were: Age, CKD, BNCA and MV.

Los objetivos del estudio fueron evaluar la incidencia, los factores de riesgo (considerando características demográficas, comorbilidades, presentación clínica inicial y complicaciones asociadas) y el impacto de la lesión renal aguda ­LRA­ en sujetos hospitalizados por COVID-19 en dos instituciones de alta complejidad de Córdoba, Argentina. Se realizó un estudio de cohorte retrospectivo. Se incluyeron 448 adultos que fueron hospitalizados por COVID-19 entre el 3 de marzo y el 31 de octubre del 2020 con seguimiento durante toda la hospitalización. La incidencia de LRA fue 19% (estadio I = 43, estadio II = 17 y estadío III = 25, 18 requirieron diálisis). Las variables que se asociaron de manera independiente con el LRA fueron: edad (por cada 10 años, odd ratio ajustado [IC95%] = 1.30 [1.04-1.63], p = 0.022), enfermedad renal crónica ­ERC­ (9.92 [4.52-21.77], p < 0.001), recuento de neutrófilos sanguíneos al ingreso ­NSI­ (por cada incremento de 1000 NSI, 1.09 [1.01­1.18], p = 0.037) y asistencia respiratoria mecánica ­ARM­ (6.69 [2.24­19.90], p = 0.001). Los sujetos con LRA presentaron una internación más prolongada, mayor requerimiento (63.5 vs. 29.7%; p < 0.001) y estadía más prolongada en unidad de cuidados intensivos, una asociación positiva con sobreinfección respiratoria bacteriana, sepsis, síndrome de distrés respiratorio, requerimiento de ARM y mortalidad (mortalidad sin LRA 12.4% vs. con LRA 47.1%; estadio I = 26%, estadio II = 41% y estadio III = 88%; p < 0.001). LRA se asoció de manera independiente a mayor mortalidad (3.3 [1.6­6.9], p = 0.001). En conclusión, la incidencia de LRA en adultos hospitalizados por COVID-19 fue del 19% y tuvo un claro impacto en la morbi-mortalidad. Los factores de riesgo independientes de LRA fueron: edad, ERC, NSI y ARM.

The incidence, risk factors and impact of acute kidney injury in hospitalized patients due to COVID-19 / Incidencia, factores de riesgo e impacto de la lesión renal aguda en pacientes hospitalizados por COVID-19

Abstract The incidence of acute kidney injury (AKI) in hospitalized patients with COVID-19 is variable, being associated with worse outcomes. The objectives of the study were to evaluate the incidence, risk factors (considering demographic characteristics, comorbidities, initial clinical presentation and associated complications) and impact of AKI in subjects hospitalized for COVID-19 in two third-level hospitals in Córdoba, Argentina. A retrospective cohort study was conducted. We included 448 adults who were consecutively hospitalized for CO VID-19 between March 3 and October 31, 2020 and were followed throughout the hospitalization. The incidence of AKI was 19% (n = 85; stage I = 43, stage II = 17, and stage III = 25, 18 required renal replacement therapy). In the multivariate analysis, the variables that were independently associated with AKI were: age (for every 10 years, adjusted odd ratio [95%CI] = 1.30 [1.04-1.63], p = 0.022), history of chronic kidney disease -CKD- (9.92 [4.52-21.77], p < 0.001), blood neutrophil count at admission -BNCA- (for every increase of 1000 BNCA, 1.09 [1.01-1.18], p = 0.037) and requirement for mechanical ventilation -MV- (6.69 [2.24-19.90], p = 0.001). AKI was associated with longer hospitalization, higher admission (63.5 vs. 29.7%; p < 0.001) and longer stay in the intensive care unit, a positive association with respiratory bacterial superinfection, sepsis, respiratory distress syndrome, MV requirement and mortality (mortality without AK I = 12.4% vs with AKI = 47.1%; stage I = 26%, stage II = 41% and stage III = 88%; p < 0.001). AKI was independently associated with higher mortality (3.32 [1.6-6.9], p = 0.001). In conclusion, the incidence of AKI in adults hospitalized for COVID-19 was 19% and had a clear impact on morbidity and mortality. The independent risk factors for AKI were: Age, CKD, BNCA and MV.

Resumen Los objetivos del estudio fueron evaluar la incidencia, los factores de riesgo (consi derando características demográficas, comorbilidades, presentación clínica inicial y complicaciones asociadas) y el impacto de la lesión renal aguda -LRA- en sujetos hospitalizados por COVID-19 en dos instituciones de alta complejidad de Córdoba, Argentina. Se realizó un estudio de cohorte retrospectivo. Se incluyeron 448 adul tos que fueron hospitalizados por COVID-19 entre el 3 de marzo y el 31 de octubre del 2020 con seguimiento durante toda la hospitalización. La incidencia de LRA fue 19% (estadio I = 43, estadio II = 17 y estadío III = 25, 18 requirieron diálisis). Las variables que se asociaron de manera independiente con el LRA fueron: edad (por cada 10 años, odd ratio ajustado [IC95%] = 1.30 [1.04-1.63], p = 0.022), enfermedad renal crónica -ERC- (9.92 [4.52-21.77], p < 0.001), recuento de neutrófilos sanguíneos al ingreso -NSI- (por cada incremento de 1000 NSI, 1.09 [1.01-1.18], p = 0.037) y asistencia respiratoria mecánica -ARM- (6.69 [2.24-19.90], p = 0.001). Los sujetos con LRA presentaron una internación más prolongada, mayor requerimiento (63.5 vs. 29.7%; p < 0.001) y estadía más prolongada en unidad de cuidados intensivos, una asociación positiva con sobreinfección respi ratoria bacteriana, sepsis, síndrome de distrés respiratorio, requerimiento de ARM y mortalidad (mortalidad sin LRA 12.4% vs. con LRA 47.1%; estadio I = 26%, estadio II = 41% y estadio III = 88%; p < 0.001). LRA se asoció de manera independiente a mayor mortalidad (3.3 [1.6-6.9], p = 0.001). En conclusión, la incidencia de LRA en adultos hospitalizados por COVID-19 fue del 19% y tuvo un claro impacto en la morbi-mortalidad. Los factores de riesgo independientes de LRA fueron: edad, ERC, NSI y ARM.

Transcriptome landmarks of the functional maturity of rat beta-cells, from lactation to adulthood.

Research on the postnatal development of pancreatic beta-cells has become an important subject in recent years. Understanding the mechanisms that govern beta-cell postnatal maturation could bring new opportunities to therapeutic approaches for diabetes. The weaning period consists of a critical postnatal window for structural and physiologic maturation of rat beta-cells. To investigate transcriptome changes involved in the maturation of beta-cells neighboring this period, we performed microarray analysis in fluorescence-activated cell-sorted (FACS) beta-cell-enriched populations. Our results showed a variety of gene sets including those involved in the integration of metabolism, modulation of electrical activity, and regulation of the cell cycle that play important roles in the maturation process. These observations were validated using reverse hemolytic plaque assay, electrophysiological recordings, and flow cytometry analysis. Moreover, we suggest some unexplored pathways such as sphingolipid metabolism, insulin-vesicle trafficking, regulation of transcription/transduction by miRNA-30, trafficking proteins, and cell cycle proteins that could play important roles in the process mentioned above for further investigation.