The leaf idioblastome of the medicinal plant Catharanthus roseus is associated with stress resistance and alkaloid metabolism.

Catharanthus roseus leaves produce a range of monoterpenoid indole alkaloids (MIAs) that include low levels of the anticancer drugs vinblastine and vincristine. The MIA pathway displays a complex architecture spanning different subcellular and cell type localizations, and is under complex regulation. As a result, the development of strategies to increase the levels of the anticancer MIAs has remained elusive. The pathway involves mesophyll specialized idioblasts where the late unsolved biosynthetic steps are thought to occur. Here, protoplasts of C. roseus leaf idioblasts were isolated by fluorescence-activated cell sorting, and their differential alkaloid and transcriptomic profiles were characterized. This involved the assembly of an improved C. roseus transcriptome from short- and long-read data, IDIO+. It was observed that C. roseus mesophyll idioblasts possess a distinctive transcriptomic profile associated with protection against biotic and abiotic stresses, and indicative that this cell type is a carbon sink, in contrast to surrounding mesophyll cells. Moreover, it is shown that idioblasts are a hotspot of alkaloid accumulation, suggesting that their transcriptome may hold the key to the in-depth understanding of the MIA pathway and the success of strategies leading to higher levels of the anticancer drugs.

Prediabetes blunts DPP4 genetic control of postprandial glycaemia and insulin secretion.

AIMS/HYPOTHESIS: Imbalances in glucose metabolism are hallmarks of clinically silent prediabetes (defined as impaired fasting glucose and/or impaired glucose tolerance) representing dysmetabolism trajectories leading to type 2 diabetes. CD26/dipeptidyl peptidase 4 (DPP4) is a clinically proven molecular target of diabetes-controlling drugs but the DPP4 gene control of dysglycaemia is not proven. METHODS: We dissected the genetic control of post-OGTT and insulin release responses by the DPP4 gene in a Portuguese population-based cohort of mainly European ancestry that comprised individuals with normoglycaemia and prediabetes, and in mouse experimental models of Dpp4 deficiency and hyperenergetic diet. RESULTS: In individuals with normoglycaemia, DPP4 single-nucleotide variants governed glycaemic excursions (rs4664446, p=1.63x10-7) and C-peptide release responses (rs2300757, p=6.86x10-5) upon OGTT. Association with blood glucose levels was stronger at 30 min OGTT, but a higher association with the genetic control of insulin secretion was detected in later phases of the post-OGTT response, suggesting that the DPP4 gene directly senses glucose challenges. Accordingly, in mice fed a normal chow diet but not a high-fat diet, we found that, under OGTT, expression of Dpp4 is strongly downregulated at 30 min in the mouse liver. Strikingly, no genetic association was found in prediabetic individuals, indicating that post-OGTT control by DPP4 is abrogated in prediabetes. Furthermore, Dpp4 KO mice provided concordant evidence that Dpp4 modulates post-OGTT C-peptide release in normoglycaemic but not dysmetabolic states. CONCLUSIONS/INTERPRETATION: These results showed the DPP4 gene as a strong determinant of post-OGTT levels via glucose-sensing mechanisms that are abrogated in prediabetes. We propose that impairments in DPP4 control of post-OGTT insulin responses are part of molecular mechanisms underlying early metabolic disturbances associated with type 2 diabetes.

Fibrosis nonalcoholic steatohepatitis index validation and applicability considering glycaemic severity and T2D duration.

Nonalcoholic fatty liver disease (NAFLD) diagnosis without using invasive methods is extremely challenging, highlighting the need for simple indexes for this end. Recently, the fibrotic nonalcoholic steatohepatitis index (FNI) was developed and proposed as an affordable non-invasive score calculated with aspartate aminotransferase, high-density lipoprotein cholesterol and haemoglobin A1c. Herein, and given the link between NAFLD and diabetes, we aimed at validating FNI in a population with type 2 diabetes (T2D), also considering diabetes duration and glycaemic severity. The performance of FNI was higher than FIB-4 (AUROC = 0.89 vs 0.67, respectively). Additionally, using 0.1 as the rule-out cut-off of FNI, the sensitivity was 0.99 and the positive predictive value was 0.19. Both duration of diabetes and A1c did not impact FNI performance. In sum, FNI is a valuable score for predicting fibrotic nonalcoholic steatohepatitis not only for primary care units but also for diabetes specialized care.

Association between area- and individual-level socio-economic factors with glycated haemoglobin-Evidence from a Portuguese population-based study.

AIMS: This study aims to estimate the associations between area-level deprivation and individual-level socio-economic factors, as well as their interaction, with glycated haemoglobin (HbA1c ) levels. METHODS: We conducted a gamma multilevel regression analysis using individual-level data from the Portuguese National Health Examination Survey and a deprivation index built through factor analysis, at municipality level, with census variables. RESULTS: Living in a municipality with high material deprivation and having a low level of education were independently associated with an increase of 2.3% (95% confidence interval [CI] 0.6, 4.0) and of 1.6% (95% CI 0.6, 2.7) in the mean levels of HbA1c , respectively. The interaction between area material deprivation and individual-level education was not associated with the levels of HbA1c (0.5%, 95% CI -1.3, 2.3). CONCLUSIONS: Our findings support the collective resources model that argues that people in less deprived areas have better health because there are more collective resources. The results suggest that to reduce socio-economic inequalities associated with the levels of HbA1c and, consequently, with diabetes, will require attention to the area material deprivation and individual-level education. Upstream social determinants of health are thus highlighted.

Impact of blinded retrospective continuous glucose monitoring on clinical decision making and glycemic control in persons with type 2 diabetes on insulin therapy.

BACKGROUND AND AIMS: Blinded retrospective continuous glucose monitoring (rCGM) provides detailed information about real-life glycaemic profile. In persons with type 2 diabetes without adequate glycaemic control, the structured introduction of rCGM may be beneficial to sustain improvements in diabetes management. METHODS AND RESULTS: 102 individuals with insulin-treated type 2 diabetes, age less than 66 years old and HbA1c >7.5%, were recruited. Participants performed a 7-day blinded rCGM (iPro2) every four months for one year. Biochemical, anthropometric, and rCGM data was collected. Participants' and healthcare professionals' perceptions were assessed. 90 participants completed the protocol. HbA1c was 9.1 ± 0.1% one year prior to enrolment and 9.4 ± 0.1% at enrolment (p < 0.01). With the rCGM-based intervention, a decrease in HbA1c was achieved at 4 months (8.4 ± 0.1%, p < 0.0001), and 12 months (8.1 ± 0.1%, p < 0.0001). A significant increase in time-in-range was observed (50.8 ± 2.4 at baseline vs 61.5 ± 2.2% at 12 months, for 70-180 mg/dL, p < 0.001), with no difference in exposure time to hypoglycaemia. After 12 months, there was an increase in self-reported diabetes treatment satisfaction (p < 0.05). CONCLUSION: In persons with type 2 diabetes and poor metabolic control, specific data from blinded rCGM informed therapeutic changes and referral to targeted education consultations on nutrition and insulin administration technique. Therapeutic changes were made more frequently and targeted to changes in medication dose, timing, and/or type, as well as to lifestyle. Together, these brought significant improvements in clinical outcomes, effective shared decision-making, and satisfaction with treatment. REGISTRATION NUMBER: NCT04141111.

Impact of combined training with different exercise intensities on inflammatory and lipid markers in type 2 diabetes: a secondary analysis from a 1-year randomized controlled trial.

BACKGROUND: Exercise is a well-accepted strategy to improve lipid and inflammatory profile in individuals with type 2 diabetes (T2DM). However, the exercise intensity having the most benefits on lipids and inflammatory markers in patients with T2DM remains unclear. We aimed to analyse the impact of a 1-year combined high-intensity interval training (HIIT) with resistance training (RT), and a moderate continuous training (MCT) with RT on inflammatory and lipid profile in individuals with T2DM. METHODS: Individuals with T2DM (n = 80, aged 59 years) performed a 1-year randomized controlled trial and were randomized into three groups (control, n = 27; HIIT with RT, n = 25; MCT with RT, n = 28). Exercise sessions were supervised with a frequency of 3 days per week. Inflammatory and lipid profiles were measured at baseline and at 1-year follow-up. Changes in inflammatory and lipid markers were assessed using generalized estimating equations. RESULTS: After adjusting for sex, age and baseline moderate-to-vigorous physical activity (MVPA), we observed a time-by-group interaction for Interleukin-6 (IL-6) in both the MCT with RT (ß = - 0.70, p = 0.034) and HIIT with RT (ß = - 0.62, p = 0.049) groups, whereas, only the HIIT with RT group improved total cholesterol (ß = - 0.03, p = 0.045) and LDL-C (ß = - 0.03, p = 0.034), when compared to control. No effect was observed for C-reactive protein (CRP), cortisol, tumour necrosis factor-α (TNF-α), soluble form of the haptoglobin-hemoglobin receptor CD163 (sCD163), triglycerides and HDL-C in both groups (p > 0.05). CONCLUSIONS: Favorable adaptations on IL-6 were observed in both the HIIT and MCT combined with RT groups following a long-term 1-year exercise intervention in individuals with T2DM. However, only the HIIT with RT prevented further derangement of total cholesterol and LDL-C, when compared to the control group. Therefore, in order to encourage exercise participation and improve inflammatory profile, either exercise protocols may be prescribed, however, HIIT with RT may have further benefits on the lipid profile. Trial registration Clinicaltrials.gov ID: NCT03144505.

Combined effect of interventions with pure or enriched mixtures of (poly)phenols and anti-diabetic medication in type 2 diabetes management: a meta-analysis of randomized controlled human trials.

PURPOSE: (Poly)phenols have been reported to confer protective effects against type 2 diabetes but the precise association remains elusive. This meta-analysis aimed to assess the effects of (poly)phenol intake on well-established biomarkers in people with type 2 diabetes or at risk of developing diabetes. METHODS: A systematic search was conducted using the following selection criteria: (1) human randomized controlled trials involving individuals with prediabetes and type 2 diabetes; (2) one or more of the following biomarkers: glucose, glycated haemoglobin (HbA1c), insulin, pro-insulin, homeostatic model assessment of insulin resistance (HOMA-IR), islet amyloid polypeptide (IAPP)/amylin, pro-IAPP/pro-amylin, glucagon, C-peptide; (3) chronic intervention with pure or enriched mixtures of (poly)phenols. From 488 references, 88 were assessed for eligibility; data were extracted from 27 studies and 20 were used for meta-analysis. The groups included in the meta-analysis were: (poly)phenol mixtures, isoflavones, flavanols, anthocyanins and resveratrol. RESULTS: Estimated intervention/control mean differences evidenced that, overall, the consumption of (poly)phenols contributed to reduced fasting glucose levels (- 3.32 mg/dL; 95% CI - 5.86, - 0.77; P = 0.011). Hb1Ac was only slightly reduced (- 0.24%; 95% CI - 0.43, - 0.044; P = 0.016) whereas the levels of insulin and HOMA-IR were not altered. Subgroup comparative analyses indicated a stronger effect on blood glucose in individuals with diabetes (- 5.86 mg/dL, 95% CI - 11.34, - 0.39; P = 0.036) and this effect was even stronger in individuals taking anti-diabetic medication (- 10.17 mg/dL, 95% CI - 16.59, - 3.75; P = 0.002). CONCLUSIONS: Our results support that the consumption of (poly)phenols may contribute to lower glucose levels in individuals with type 2 diabetes or at risk of diabetes and that these compounds may also act in combination with anti-diabetic drugs.

Insights from qualitative research on NAFLD awareness with a cohort of T2DM patients: time to go public with insulin resistance?

BACKGROUND: It is estimated that around 70% of Type 2 Diabetes Mellitus patients (T2DM) have Non-Alcoholic Fatty Liver Disease (NAFLD). Awareness and education are amongst the major shortcomings of the public health response to the increasing threat of NAFLD. Characterizing the specific NAFLD-related information needs of particular high-risk metabolic communities, for instance, T2DM patients, might aid in the development of evidence-based health promotion strategies, ultimately promoting NAFLD-awareness, treatment adherence and therapeutic success rates. METHODS: Semi-structured interviews with T2DM patients were conducted to gain insight into their awareness of NAFLD, including its relationship with insulin resistance and T2DM. RESULTS: Awareness of NAFLD as a disease entity, as well as its progression to end-stage liver disease or its relationship with other metabolic conditions, including insulin resistance and T2DM was low. Surveillance behaviours were also suboptimal and perceptions on the self-management knowledge and praxis regarding lifestyle intervention components of T2DM treatment seemed detached from those of NAFLD. CONCLUSIONS: Our findings could inform the integration of NAFLD-related content in T2DM health promotion strategies. Rising awareness on NAFLD progression and its relationship with T2DM using culturally and community-relevant constructs might facilitate the development of primary and secondary prevention programmes to promote the adherence to lifestyle interventions by influencing NAFLD threat perceptions.

Effects of combined training with different intensities on vascular health in patients with type 2 diabetes: a 1-year randomized controlled trial.

BACKGROUND: Exercise, when performed on a regular basis, is a well-accepted strategy to improve vascular function in patients with type 2 diabetes. However, the exercise intensity that yields maximal adaptations on structural and functional indices in patients with type 2 diabetes remains uncertain. Our objective was to analyze the impact of a 1-year randomized controlled trial of combined high-intensity interval training (HIIT) with resistance training (RT) vs. a combined moderate continuous training (MCT) with RT on structural and functional arterial indices in patients with type 2 diabetes. METHODS: Patients with type 2 diabetes (n = 80) were randomized into an exercise intervention with three groups: control, combined HIIT with RT and combined MCT with RT. The 1-year intervention had 3 weekly exercise sessions. High-resolution ultrasonography of the common carotid artery and central and peripheral applanation tonometry were used to assess the changes in structural and functional arterial indices. Generalized estimating equations were used to model the corresponding outcomes. RESULTS: After adjusting the models for sex, baseline moderate-to-vigorous physical activity, and mean arterial pressure changes, while using the intention-to-treat analysis, a significant interaction was observed on the carotid intima-media thickness (cIMT) for both the MCT (ß = - 4.25, p < 0.01) and HIIT group (ß = - 3.61, p < 0.01). However, only the HIIT observed favorable changes from baseline to 1-year on peripheral arterial stiffness indices such as carotid radial arterial pulse wave velocity (ß = - 0.10, p = 0.044), carotid to distal posterior tibial artery pulse wave velocity (ß = - 0.14, p < 0.01), and on the distensibility coefficient (ß = - 0.00, p < 0.01). No effect was found for hemodynamic variables after the intervention. CONCLUSIONS: Following a 1-year intervention in patients with type 2 diabetes, both the MCT and HIIT group reduced their cIMT, whereas only the HIIT group improved their peripheral arterial stiffness indices and distensibility coefficient. Taken together, HIIT may be a meaningful tool to improve long-term vascular complications in type 2 diabetes. Trial registration clinicaltrials.gov ID: NCT03144505.

Effectiveness of high-intensity interval training combined with resistance training versus continuous moderate-intensity training combined with resistance training in patients with type 2 diabetes: A one-year randomized controlled trial.

AIMS: To evaluate the impact of one-year high intensity interval training (HIIT) combined with resistance training (RT) vs continuous moderate intensity training (MCT) combined with RT on glycaemic control, body composition and cardiorespiratory fitness (CRF) in patients with type 2 diabetes. MATERIALS AND METHODS: A randomized controlled trial included 96 participants with type 2 diabetes for a one-year supervised exercise intervention with three groups: Control, HIIT with RT and MCT with RT). The control group received standard counseling regarding general PA guidelines, with no structured exercise sessions. The main outcome variable was HbA1c (%). Secondary outcomes were other glycaemic variables, body composition, anthropometry measurements, CRF and enjoyment of exercise. Generalized estimating equations (GEE) were used to model outcomes. RESULTS: Among the 96 participants enrolled in the intervention, 80 were randomized, with a mean (SD) age of 58.5 years (7.7) and a mean HbA1c of 7.2% (1.6). After adjusting the model for sex and total moderate-to-vigorous physical activity (MVPA), we found that both the MCT with RT (ß, 0.003; P, 0.921) and the HIIT with RT (ß, 0.025; P, 0.385) groups had no effect on HbA1c. A favourable effect was observed in the MCT with RT group, with a reduction in whole body fat index (ß, -0.062; P, 0.022), android fat index (ß, -0.010; P, 0.010) and gynoid fat index (ß, -0.013; P, 0.014). Additionally, CRF increased during the intervention, but only in the MCT with RT group (ß, 0.185; P, 0.019). CONCLUSIONS: The results from this study suggest that there was no effect of either MCT with RT or HIIT with RT on glycaemic control in individuals with type 2 diabetes. However, the combination of MCT and RT improved body composition and CRF following a one-year intervention.

Association between glycated haemoglobin, glycated albumin and fructosamine with neonatal birthweight and large-for-date status infants in gestational diabetes mellitus: a prospective cohort study.

This study aims to investigate associations between glycated haemoglobin (HbA1c), glycated albumin (GA) and fructosamine with neonatal birthweight in gestational diabetes mellitus (GDM). The prospective cohort consisted of 82 women with GDM and their newborns, enrolled between November 2016 and September 2017. Considering neonatal birthweight and birthweights ≥90th percentile for gestational age as outcomes, linear and logistic regression models were used, respectively. Fructosamine (R2=0.62) and GA (R2=0.61) performed very similarly between them and best than HbA1c (R2=0.58). The added value of GA or fructosamine to HbA1c resulted in increase in models' performances. GA attained the best discriminative ability regarding large-for-date status babies (AUC = 0.80, OR-estimate 1.58, p=.001) followed by fructosamine (AUC = 0.78, OR-estimate 1.42, p=.001) and HbA1c (AUC = 0.69, OR-estimate 3.09, p=.070). GA and fructosamine, besides from providing additional information to HbA1c, when used separately perform better than the traditional biomarker in predicting neonatal birthweight and large-for-date babies in pregnant women with GDM. Impact statement What is already known on this subject? HbA1c is the standard glycaemic indicator used in GDM. Its association with birthweight and large-for-date status has been previously reported. However, it has become increasingly questionable whether it is a suitable glycaemic marker in pregnancy. There is a growing interest in other non-traditional shorter-term glycaemic indicators, such as GA and fructosamine. Nevertheless, few studies exist and almost all are retrospective and with ethnically homogeneous study populations composed by pregnant women not only with GDM but also type 1 and type 2 diabetes mellitus. What do the results of this study add? Our prospective multi-ethnic cohort composed solely on pregnant women with GDM and their infants show that even though all of the aforementioned biomarkers are associated with birthweight and large-for-date status in GDM when used separately, GA and fructosamine seem to perform better than HbA1c. When used with HbA1c, they improve the predicting performance of the traditional marker. What are the implications of these findings for future clinical practice and/or further research? These findings suggest that GA and fructosamine can provide important additional or substitute information to HbA1c in GDM, namely in predicting birthweight and large-for-date status babies. Larger studies are needed to confirm if this non-traditional biomarkers can change clinical practice.

Beyond self-monitored plasma glucose and HbA1c: the role of non-traditional glycaemic markers in gestational diabetes mellitus.

Strict glycaemic management is the cornerstone of metabolic control in gestational diabetes mellitus (GDM). Current monitoring standards involve self-monitoring plasma glucose (SMBG) and haemoglobin A1c (HbA1c). However, both have important limitations. SMBG only reflects instantaneous blood glucose and the inconvenience of self-collecting blood frequently results in poor compliance. HbA1c provides information on blood glucose levels from the previous 2 to 3 months and it is influenced by iron-deficient states, common during pregnancy. There is an urgent need for new shorter-term glycaemic markers, as glycated albumin, fructosamine or 1,5-anhydroglucitol. Glycated albumin seems especially interesting as it provides information on blood glucose levels over the foregoing 2-3 weeks and it is not influenced by iron deficiency or the dilutional anaemia of pregnancy. Fructosamine has a precise and inexpensive measurement and it is not affected by haemoglobin characteristics. This review further discusses the potential value of these non-traditional indicators of glycaemic control in patients with GDM, outlining their possible future applications.

Sex differences in the regulation of spatially distinct cardiac mitochondrial subpopulations.

Spatially distinct mitochondrial subpopulation may mediate myocardial pathology through permeability transition pore opening (MPTP). The goal of this study was to assess sex differences on the two spatially distinct mitochondrial subpopulations: subsarcolemmal mitochondria (SSM) and intermyofibrillar mitochondria (IFM) based on morphology, membrane potential, mitochondrial function, oxidative phosphorylation, and MPTP. Aged matched Wistar rats were used to study SSM and IFM. Mitochondrial size was larger in SSM than in IFM in both genders. However, SSM internal complexity, yield, and membrane potential were higher in male than in female. The maximal rate of mitochondrial respiration, states 3 and 4, using glutamate + malate as substrate, were higher in IFM and SSM in the male group compared to female. The respiratory control ratio (RCR-state3/state 4), was not different in both SSM and IFM with glutamate + malate. The ADP:O ratio was found higher in IFM and SSM from female compared to males. When pyruvate was used, state 3 was found unchanged in both IFM and SSM, state 4 was also greater in male IFM compared to female. The RCR increased in the SSM while IFM remained the same. State 4 was higher in male SSM while in the IFM remained the same. The IFM presented a higher Ca(2+) retention capacity compared with SSM, however, there was a greater sensitivity to Ca(2+)-induced MPTP in SSM and IFM in the male group compared to female. In conclusion, our data show that spatially distinct mitochondrial subpopulations have sex-based differences in oxidative phosphorylation, morphology, and calcium retention capacity.

A description of clinician reported diagnosis of type 2 diabetes and other non-type 1 diabetes included in a large international multicentered pediatric diabetes registry (SWEET).

BACKGROUND: Although type 1 diabetes (T1D) remains the most frequent form of diabetes in individuals aged less than 20 years at onset, other forms of diabetes are being increasingly recognized. OBJECTIVES: To describe the population of children with other forms of diabetes (non-type 1) included in the multinational SWEET (Better control in Pediatric and Adolescent diabeteS: Working to crEate CEnTers of Reference) database for children with diabetes. METHODS: Cases entered in the SWEET database are identified by their physician as T1D, type 2 diabetes (T2D) and other types of diabetes according to the ISPAD classification. Etiologic subgroups are provided for other types of diabetes. Descriptive analyses were tabulated for age at onset, gender, daily insulin doses, and hemoglobin A1c (A1C) for each type and subtype of diabetes and when possible, values were compared. RESULTS: Of the 27 104 patients included in this report, 95.5% have T1D, 1.3% T2D, and 3.2% other forms of diabetes. The two most frequent etiologies for other forms of diabetes were maturity onset diabetes of the young (MODY) (n = 351) and cystic fibrosis-related diabetes (CFRD) (n = 193). The cause was unknown or unreported in 10% of other forms of diabetes. Compared with T1D, children with T2D and CFRD were diagnosed at an older age, took less insulin and had lower A1C (all P < .0001). CONCLUSION: In centers included in SWEET, forms of diabetes other than type 1 remain rare and at times difficult to characterize. Sharing clinical information and outcome between SWEET centers on those rare forms of diabetes has the potential to improve management and outcome.

The Effect of Corticosteroid Withdrawal on Glucose Metabolism and Anti-GAD Antibodies in Simultaneous Pancreas-Kidney Transplant Patients.

CONTEXT: Corticosteroid withdrawal may reduce insulin resistance; however, it could also influence pancreatic autoantibody profile in simultaneous pancreas-kidney (SPK) transplant patients. OBJECTIVE: To evaluate the effect of corticosteroid withdrawal on glucose metabolism and anti-glutamic acid decarboxylase (GAD) antibody titers in SPK patients with type 1 diabetes after 12 months of follow-up. DESIGN: In this retrospective study, fasting glucose and glycated hemoglobin (A1c) were compared before and after 3, 6, and 12 months of corticosteroid withdrawal in 80 SPK patients. In addition, weight, anti-GAD, and C-peptide levels were compared before and after withdrawal. Finally, fasting and postglucose, insulin, and C-peptide levels were compared before and after withdrawal in 25 patients undergoing oral glucose tolerance test (OGTT). RESULTS: Fasting glucose levels did not change during corticosteroid discontinuation. After 12 months, A1c slightly increased from 4.6% (0.4%) to 4.8% (0.6%) (P < .01) and C-peptide decreased from 2.8 (1.1) ng/mL to 2.4 (1.3) ng/mL (P <. 01). In patients submitted to OGTT, glucose, insulin, and C-peptide levels did not change. There was no alteration in the proportion of anti-GAD positive tests (41% vs 45%). Anti-GAD titers remained stable or decreased in 70% of positive patients. CONCLUSION: Corticosteroid withdrawal has no significant effect on glucose metabolism and on anti-GAD profile among SPK patients.

Cardiac protein changes in rats after soybean oil treatment: a proteomic study.

BACKGROUND: Several studies show that the consumption of vegetable oils, such as soybean oil, rich in polyunsaturated fatty acids (PUFAs) has beneficial health effects by preventing or reducing the risk factors of cardiovascular diseases. While the demonstration of beneficial effects of the consumption of unsaturated fatty acids on the cardiovascular system has been proven in a macroscopic level, the molecular/cellular mechanisms responsible for this phenomenon are poorly understood. METHODS: In this work, a comparative proteomic approach, two-dimensional gel electrophoresis (2-DE) coupled to mass spectrometry (MALDI-TOF/TOF), was applied to investigate proteome differences in the left ventricle (LV) of rats that received 0.1 mL of soybean oil intramuscularly for 15 days (treated group-TR) and rats that had not (control group-CT). RESULTS: Soybean oil treatment improved left ventricular function, TR animals presented lower value of LVEDP and significantly changed LV proteome. The protein profile of VE revealed differences in the expression of 60 protein spots (p<0.05) between the experimental groups (CT and TR), 14 of those were identified by MS and MS/MS, and 12 of the 14 being non-redundant proteins. Robust changes were detected in proteins involved in cellular structure and antioxidant system and muscular contraction. CONCLUSIONS: The TR group presented an increase in the intensity of proteins involved in muscle contraction (myosin light chain-3 (3-MCL), creatine kinase M (CKM)) and thireodoxin, an antioxidant enzyme. Low intensity cytoskeletal protein, desmin, was also detected in TR animals. The results suggest that soybean oil induces changes in the levels of heart proteins which may partially account for the underlying mechanisms involved in the benefits provided by oils rich in polyunsaturated fatty acids.

Cardiac mitochondrial proteome dynamics with heavy water reveals stable rate of mitochondrial protein synthesis in heart failure despite decline in mitochondrial oxidative capacity.

We recently developed a method to measure mitochondrial proteome dynamics with heavy water ((2)H2O)-based metabolic labeling and high resolution mass spectrometry. We reported the half-lives and synthesis rates of several proteins in the two cardiac mitochondrial subpopulations, subsarcolemmal and interfibrillar (SSM and IFM), in Sprague Dawley rats. In the present study, we tested the hypothesis that the mitochondrial protein synthesis rate is reduced in heart failure, with possible differential changes in SSM versus IFM. Six to seven week old male Sprague Dawley rats underwent transverse aortic constriction (TAC) and developed moderate heart failure after 22weeks. Heart failure and sham rats of the same age received heavy water (5% in drinking water) for up to 80days. Cardiac SSM and IFM were isolated from both groups and the proteins were separated by 1D gel electrophoresis. Heart failure reduced protein content and increased the turnover rate of several proteins involved in fatty acid oxidation, electron transport chain and ATP synthesis, while it decreased the turnover of other proteins, including pyruvate dehydrogenase subunit in IFM, but not in SSM. Because of these bidirectional changes, the average overall half-life of proteins was not altered by heart failure in both SSM and IFM. The kinetic measurements of individual mitochondrial proteins presented in this study may contribute to a better understanding of the mechanisms responsible for mitochondrial alterations in the failing heart.

Risk of postprandial insulin resistance: the liver/vagus rapport.

Ingestion of a meal is the greatest challenge faced by glucose homeostasis. The surge of nutrients has to be disposed quickly, as high concentrations in the bloodstream may have pathophysiological effects, and also properly, as misplaced reserves may induce problems in affected tissues. Thus, loss of the ability to adequately dispose of ingested nutrients can be expected to lead to glucose intolerance, and favor the development of pathologies. Achieving interplay of several organs is of upmost importance to maintain effectively postprandial glucose clearance, with the liver being responsible of orchestrating global glycemic control. This dogmatic role of the liver in postprandial insulin sensitivity is tightly associated with the vagus nerve. Herein, we uncover the behaviour of metabolic pathways determined by hepatic parasympathetic function status, in physiology and in pathophysiology. Likewise, the inquiry expands to address the impact of a modern lifestyle, especially one's feeding habits, on the hepatic parasympathetic nerve control of glucose metabolism.

Dietary fat and heart failure: moving from lipotoxicity to lipoprotection.

There is growing evidence suggesting that dietary fat intake affects the development and progression of heart failure. Studies in rodents show that in the absence of obesity, replacing refined carbohydrate with fat can attenuate or prevent ventricular expansion and contractile dysfunction in response to hypertension, infarction, or genetic cardiomyopathy. Relatively low intake of n-3 polyunsaturated fatty acids from marine sources alters cardiac membrane phospholipid fatty acid composition, decreases the onset of new heart failure, and slows the progression of established heart failure. This effect is associated with decreased inflammation and improved resistance to mitochondrial permeability transition. High intake of saturated, monounsaturated, or n-6 polyunsaturated fatty acids has also shown beneficial effects in rodent studies. The underlying mechanisms are complex, and a more thorough understanding is needed of the effects on cardiac phospholipids, lipid metabolites, and metabolic flux in the normal and failing heart. In summary, manipulation of dietary fat intake shows promise in the prevention and treatment of heart failure. Clinical studies generally support high intake of n-3 polyunsaturated fatty acids from marine sources to prevent and treat heart failure. Additional clinical and animals studies are needed to determine the optimal diet in terms of saturated, monounsaturated, and n-6 polyunsaturated fatty acids intake for this vulnerable patient population.

Incident Use of Hydroxychloroquine for the Treatment of Rheumatoid Arthritis and Systemic Lupus Erythematosus During the COVID-19 Pandemic.

OBJECTIVE: We studied whether the use of hydroxychloroquine (HCQ) for COVID-19 resulted in supply shortages for patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). METHODS: We used US claims data (IQVIA PHARMETRICS® Plus for Academics [PHARMETRICS]) and hospital electronic records from Spain (Institut Municipal d'Assistència Sanitària Information System [IMASIS]) to estimate monthly rates of HCQ use between January 2019 and March 2022, in the general population and in patients with RA and SLE. Methotrexate (MTX) use was estimated as a control. RESULTS: More than 13.5 million individuals (13,311,811 PHARMETRICS, 207,646 IMASIS) were included in the general population cohort. RA and SLE cohorts enrolled 135,259 and 39,295 patients, respectively, in PHARMETRICS. Incidence of MTX and HCQ were stable before March 2020. On March 2020, the incidence of HCQ increased by 9- and 67-fold in PHARMETRICS and IMASIS, respectively, and decreased in May 2020. Usage rates of HCQ went back to prepandemic trends in Spain but remained high in the United States, mimicking waves of COVID-19. No significant changes in HCQ use were noted among patients with RA and SLE. MTX use rates decreased during HCQ approval period for COVID-19 treatment. CONCLUSION: Use of HCQ increased dramatically in the general population in both Spain and the United States during March and April 2020. Whereas Spain returned to prepandemic rates after the first wave, use of HCQ remained high and followed waves of COVID-19 in the United States. However, we found no evidence of general shortages in the use of HCQ for both RA and SLE in the United States.