Maria Paula Macedo

Inside the Diabetic Brain: Role of Different Players Involved in Cognitive Decline

Diabetes mellitus is the most common metabolic disease, and its prevalence is increasing. A growing body of evidence, both in animal models and epidemiological studies, has demonstrated that metabolic diseases like obesity, insulin resistance, and diabetes are associated with alterations in the central nervous system (CNS), being linked with development of cognitive and memory impairments and presenting a higher risk for dementia and Alzheimers disease. The rising prevalence of diabetes together with its increasing earlier onset suggests that diabetes-related cognitive dysfunction will increase in the near future, causing substantial socioeconomic impact. Decreased insulin secretion or action, dysregulation of glucose homeostasis, impairment in the hypothalamic-pituitary-adrenal axis, obesity, hyperleptinemia, and inflammation may act independently or synergistically to disrupt neuronal homeostasis and cause diabetes-associated cognitive decline. However, the crosstalk between those factors and the mechanisms underlying the diabetes-related CNS complications is still elusive. During the past few years, different strategies (neuroprotective and antioxidant drugs) have emerged as promising therapies for this complication, which still remains to be preventable or treatable. This Review summarizes fundamental past and ongoing research on diabetes-associated cognitive decline, highlighting potential contributors, mechanistic mediators, and new pharmacological approaches to prevent and/or delay this complication.

Effects of CPAP on nitrate and norepinephrine levels in severe and mild-moderate sleep apnea

BackgroundReduced plasma nitrate (NOx) levels and increased urinary norepinephrine (U-NE) levels have been described in severe obstructive sleep apnea (OSA), and are reverted by continuous positive airway pressure (CPAP). The effect of CPAP on these biomarkers in mild-moderate OSA is not well understood.The aim of this study was to compare NOx and U-NE levels and blood pressure (BP) between male patients with mild-moderate and severe OSA and determine the impact of 1 month of CPAP therapy on these parameters.MethodsWe undertook a prospective study of 67 consecutive OSA patients (36 mild-moderate, 31 severe). Measurements of plasma NOx at 11 pm, 4 am and 7 am, 24-h U-NE and ambulatory BP were obtained at baseline and after 1 month of CPAP.ResultsAt baseline, NOx levels showed a significant decrease during the night in both groups (p < 0.001). U-NE level and BP were significantly higher in the severe OSA group. After 1 month of CPAP, there was a significant increase in NOx levels and a reduction in U-NE level and BP only in patients with severe OSA.ConclusionsOne month of CPAP results in significant improvements in NOx levels, 24-h U-NE level and BP in patients with severe OSA, but not in patients with mild-moderate OSA.Trial registrationClinicalTrials.gov: http://NCT01769807

Understanding Postprandial Glucose Clearance by Peripheral Organs: The Role of the Hepatic Parasympathetic System

The hepatic parasympathetic system is one of the major contributors for preserving insulin sensitivity in the postprandial state. Postprandial hepatic vagal control of whole‐body glucose clearance and its effect on specific organs remains unknown. Our hypothesis is that, in the postprandial state, the hepatic parasympathetic nerves (HPN) are responsible for a considerable part of extra‐hepatic tissue glucose clearance. Two groups of 9‐week‐old Sprague–Dawley rats were studied, comparing sham‐operated versus hepatic parasympathetic denervated animals. Insulin sensitivity was evaluated in the postprandial state by the rapid insulin sensitivity test (RIST). [3H]2‐deoxy‐d‐glucose was administered during the RIST. Plasma glucose rate of the disappearance and clearance by skeletal muscle, adipose tissue, liver, pancreas, heart and kidney of this radioisotope was measured. The postprandial denervated group showed a decrease insulin sensitivity of 41.4 ± 5.2%. This group of animals showed a decrease in the rate of plasma [3H]2‐deoxy‐d‐glucose disappearance and skeletal muscle, heart and kidney glucose clearance by 45%, 35% and 67%, respectively. These studies show that the major contributor of postprandial whole‐body glucose clearance was skeletal muscle; in the range 69–38%, depending on HPN integrity. The results obtained in the present study indicate that HPN are crucial for postprandial action of insulin through a mechanism that is essential for maintenance of skeletal muscle, heart and kidney glucose clearance. These results suggest that hepatic parasympathetic dysfunction could lie at the genesis of type 2 diabetes complications, namely insulin resistance, nephropathy and cardiomyopathy.

HbA1c, Fructosamine, and Glycated Albumin in the Detection of Dysglycaemic Conditions

Glycated haemoglobin (HbA1c) is currently the gold standard for glucose monitoring in patients with diabetes, and has been increasingly adopted as a criteria for diabetes diagnosis. However, conditions that determine alterations in haemoglobin metabolism can interfere with the reliability of HbA1c measurements. Glycated albumin and fructosamine (total glycated serum proteins) are alternative markers of glycaemia, which have been recognised to provide additional information to HbA1c or to provide a reliable measure when HbA1c is observed not to be dependable. Additionally, while HbA1c monitors the exposure to circulating glycaemia in the previous 3 months, glycated albumin and fructosamine represent exposure for a shorter period, which may be beneficial to monitor rapid metabolic alterations or changes in diabetes treatment. The present review further discusses the relative value of HbA1c, glycated albumin, and fructosamine, in prediabetes and diabetes diagnosis, evaluation of glucose variability, and complications risk prediction. Also, a novel molecular role for albumin is presented by which glycated albumin contributes to glucose intolerance development and thus to progression to diabetes, besides the role of glycated albumin as a pro-atherogenic factor.

Bridging Type 2 Diabetes and Alzheimer's Disease: Assembling the Puzzle Pieces in the Quest for the Molecules With Therapeutic and Preventive Potential

Type 2 diabetes (T2D) and Alzheimers disease (AD) are two age‐related amyloid diseases that affect millions of people worldwide. Broadly supported by epidemiological data, the higher incidence of AD among type 2 diabetic patients led to the recognition of T2D as a tangible risk factor for the development of AD. Indeed, there is now growing evidence on brain structural and functional abnormalities arising from brain insulin resistance and deficiency, ultimately highlighting the need for new approaches capable of preventing the development of AD in type 2 diabetic patients. This review provides an update on overlapping pathophysiological mechanisms and pathways in T2D and AD, such as amyloidogenic events, oxidative stress, endothelial dysfunction, aberrant enzymatic activity, and even shared genetic background. These events will be presented as puzzle pieces put together, thus establishing potential therapeutic targets for drug discovery and development against T2D and diabetes‐induced cognitive decline—a heavyweight contributor to the increasing incidence of dementia in developed countries. Hoping to pave the way in this direction, we will present some of the most promising and well‐studied drug leads with potential against both pathologies, including their respective bioactivity reports, mechanisms of action, and structure–activity relationships.

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.

Postprandial insulin resistance in Zucker diabetic fatty rats is associated with parasympathetic-nitric oxide axis deficiencies.

The Zucker diabetic fatty (ZDF) rat is an obesity and type 2 diabetes model. Progression to diabetes is well characterised in ZDF rats, but only in the fasted state. We evaluated the mechanisms underlying postprandial insulin resistance in young ZDF rats. We tested the hypothesis that the overall postprandial action of insulin is affected in ZDF rats as a result of impairment of the hepatic parasympathetic‐nitric oxide (PSN‐NO) axis and/or glutathione (GSH), resulting in decreased indirect (PSN‐NO axis) and direct actions of insulin. Nine‐week‐old male ZDF rats and lean Zucker rats (LZR, controls) were used. The action of insulin was assessed in the fed state before and after parasympathetic antagonism atropine. Basal hepatic NO and GSH were measured, as well as NO synthase (NOS) and γ‐glutamyl‐cysteine synthethase (GCS) activity and expression. ZDF rats presented postprandial hyperglycaemia (ZDF, 201.4 ± 12.9 mg/dl; LZR, 107.7 ± 4.3 mg/dl), but not insulinopaenia (ZDF, 5.9 ± 0.8 ng/ml; LZR, 1.5 ± 0.3 ng/ml). Total postprandial insulin resistance was observed (ZDF, 78.6 ± 7.5 mg glucose/kg; LZR, 289.2 ± 24.7 mg glucose/kg), with a decrease in both the direct action of insulin (ZDF, 54.8 ± 7.0 mg glucose/kg; LZR, 173.3 ± 20.5 mg glucose/kg) and the PSN‐NO axis (ZDF, 24.5 ± 3.9 mg glucose/kg; LZR, 115.9 ± 19.4 mg glucose/kg). Hepatic NO (ZDF, 117.2 ± 11.4 μmol/g tissue; LZR, 164.6 ± 4.9 μmol/g tissue) and GSH (ZDF, 4.9 ± 0.3 μmol/g; LZR, 5.9 ± 0.2 μmol/g) were also compromised as a result of decreased NOS and GCS activity, respectively. These results suggest a compromise of the mechanism responsible for potentiating insulin action after a meal in ZDF rats. We show that defective PSN‐NO axis and GSH synthesis, together with an impaired direct action of insulin, appears to contribute to postprandial insulin resistance in this model.

Diabetes hinders community-acquired pneumonia outcomes in hospitalized patients.

Objectives This study aimed to estimate the prevalence of diabetes mellitus (DM) in hospitalized patients with community-acquired pneumonia (CAP) and its impact on hospital length of stay and in-hospital mortality. Research design and methods We carried out a retrospective, nationwide register analysis of CAP in adult patients admitted to Portuguese hospitals between 2009 and 2012. Anonymous data from 157 291 adult patients with CAP were extracted from the National Hospital Discharge Database and we performed a DM-conditioned analysis stratified by age, sex and year of hospitalization. Results The 74 175 CAP episodes that matched the inclusion criteria showed a high burden of DM that tended to increase over time, from 23.7% in 2009 to 28.1% in 2012. Interestingly, patients with CAP had high DM prevalence in the context of the national DM prevalence. Episodes of CAP in patients with DM had on average 0.8 days longer hospital stay as compared to patients without DM (p<0.0001), totaling a surplus of 15 370 days of stay attributable to DM in 19 212 admissions. In-hospital mortality was also significantly higher in patients with CAP who have DM (15.2%) versus those who have DM (13.5%) (p=0.002). Conclusions Our analysis revealed that DM prevalence was significantly increased within CAP hospital admissions, reinforcing other studies’ findings that suggest that DM is a risk factor for CAP. Since patients with CAP who have DM have longer hospitalization time and higher mortality rates, these results hold informative value for patient guidance and healthcare strategies.

Bridges in translational medicine: a case for metabolism, inflammation, and nutrition.

Type 2 diabetes (T2D) is a complex multifactorial disorder for which the etiology is still a cause for debate. However it is generally accepted that dysregulated glucose sensing and (or) insulin secretion leading to insufficient compensation for peripheral insulin resistance is a major feature of the pathogenesis of TD2 (Patarrão et al. 2012). The prevalence of this chronic disease is a global public health concern, and insufficient health care guidelines have been developed to address its prevention based on education, lifestyle intervention, and therapeutics. On the other hand, there is already comprehensive knowledge about insulin signaling and insulin receptor substrates (irs), specifically irs1 and irs2, which mediate the pleiotropic effects of insulin. Irs1 acts mainly in skeletal muscle insulin signaling and growth, whereas irs2 is widely expressed and has a broader role in insulin signaling. The paper by Oliveira et al. in this issue of CJPP reviews the role of irs2 in several perspectives, highlighting the involvement of irs2 in protecting against beta-cell failure; an important feature of all types of diabetes. Moreover, irs2 is also relevant for the maintenance of glucose metabolism in T2D. White et al. contributed to establishing this theory when they found that irs2-deficient mice develop diabetes (Withers et al. 1999; White 2006). In their review, Oliveira et al. (2014b) also focus on therapies that target IRS2 signaling to prevent the development of diabetes in Irs2−/− mice. In their recent paper they observed that sodium tungstate attenuates beta-cell apoptosis by decreasing the expression of proapoptotic genes in Irs2−/− islets, with increased beta-cell mass and improvement of glucose homeostasis preventing the development to T2D (Oliveira et al. 2014a). Another important topic, which was addressed by Bouzakri et al., is the implication of inflammatory factors in irs2 function and degradation (Bouzakri et al. 2009). Experiments with tumour necrosis factor alpha (TNF ) revealed a mechanism linking inflammatory cytokines to dysmetabolism, as TNF promotes serine phosphorylation of IRS2, correlating closely with insulin resistance. Although a subclinical inflammatory state occurs in T2D, is still not clear how inflammation is triggered. A case has been put forward connecting changes in the intestinal microbiota and development of T2D. These observations suggested that increased concentrations of circulating lipopolysaccharide (LPS), promoted by changes in intestinal permeability, might have a pivotal role in the progression to T2D. Understanding the main trigger of this alteration in our gut microbial communities is essential, as diet, nutritional status, the immune system, and microbial ecology in humans at different stages of life may have a role in the T2D etiological complex. It has become clear that food shapes the gut microbiome. Whether the interdependent effects of diet– microbiota–TNF have a direct impact on pancreatic irs2 signaling, making beta cells more susceptible to failure or unable to compensate for peripheral insulin resistance, is an issue that remains to be proven. Nevertheless, from an interventional standpoint, this vicious cycle needs to be broken. If this hypothesis is proven to be correct, we should start to integrate the impact on intestinal microbiota composition and subsequent inflammatory responses in the nutritional value of foods, as a proxy for predicting the potential to evoke dysmetabolic states (Fig. 1).