Cardiovascular safety of oral semaglutide in patients with type 2 diabetes: Rationale, design and patient baseline characteristics for the PIONEER 6 trial.

AIMS: To assess the cardiovascular (CV) safety of oral semaglutide, the first tablet formulation of a glucagon-like peptide-1 receptor agonist. MATERIALS AND METHODS: PIONEER 6 is a multinational, randomized, placebo-controlled, double-blind trial in patients with type 2 diabetes at high risk of CV events (defined as being aged ≥50 years and having established CV disease [CVD] or moderate [stage 3] chronic kidney disease [CKD], or being aged ≥60 years with ≥1 other CV risk factor). Patients were randomized to once-daily oral semaglutide (up to 14 mg) or placebo added to standard of care. The primary composite endpoint is time to first occurrence of CV death or non-fatal myocardial infarction or non-fatal stroke. The primary hypothesis was to exclude an excess in CV risk with oral semaglutide by assessing non-inferiority versus placebo for the primary endpoint (non-inferiority margin of 1.8 for the upper boundary of the 95% confidence interval of the hazard ratio). PIONEER 6 is event-driven, with follow-up continuing until accrual of at least 122 primary outcome events. There is no pre-defined minimal duration. RESULTS: Overall, 3183 patients have been enrolled (mean age 66.1 years, 31.6% females) in 214 sites across 21 countries. At baseline, the mean duration of diabetes was 14.9 years, mean glycated haemoglobin concentration was 66 mmol/mol (8.2%), and 84.6% of patients had established CVD/moderate CKD. CONCLUSIONS: PIONEER 6 will provide evidence regarding the CV safety of oral semaglutide in patients with type 2 diabetes and high CV risk.

A Narrative Review of the Herbal Preparation of Ayurvedic, Traditional Chinese, and Kampo Medicines Applied as Radioprotectors.

In recent years, there has been growing scientific interest in the search for natural radioprotectors that can be used to mitigate the effects of radiation on patients, healthcare personnel, and even for space travel. This narrative review covers the past fifty years and focuses on herbal preparations of Ayurvedic, Traditional Chinese, and Kampo Medicines that have the potential to reduce or eliminate the harmful effects of radiation. Our findings highlight ten herbal preparations, namely Abana, Amalakyadi Churna, Amritaprasham, Brahma, Bu-zhong-yi-qi-tang (BZYQT), Chyavanaprasha, Cystone, Geriforte, Mentat, and Triphala, which have demonstrated potential radioprotective effects. This review examines their composition, properties, and possible mechanisms of action in relation to their radioprotective properties. Exploring the ethnobotany of traditional Asian medicine is particularly interesting as it may lead to the discovery of new active compounds with radioprotective properties.

Vitamins and Radioprotective Effect: A Review.

The radioprotective effect ex vivo, in vitro and in vivo of vitamins was reviewed using PubMed and Embase and conducted according to the PRISMA statement. A total of 38 articles were included in this review, which includes the radioprotective effect of vitamins from ex vivo, in vitro and in vivo studies. Vitamins A, C, D and E were used alone, in combination or with other nutritional and non-nutritional compounds. The use of vitamins in natural form or supplementation can be useful to reduce the radiation effect in the body, organs and/or cells. Only four (A, C, D and E) out of thirteen vitamins have been detected with radioprotective properties being mainly vitamin E followed by vitamin C, A and D.

Glucagon-Like Peptide-1 Receptor Agonist Use in People Living with Type 2 Diabetes Mellitus and Chronic Kidney Disease: A Narrative Review of the Key Evidence with Practical Considerations.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are incretin-mimetic agents that are effective adjuncts in the treatment of diabetes. This class of medications is also associated with promoting weight loss and a low risk of hypoglycemia, and some have been shown to be associated with a significant reduction of major cardiovascular events. Mounting evidence suggests that GLP-1 RAs have benefits beyond reducing blood glucose that include improving kidney function in people living with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD), a common microvascular complication of T2DM. Several large clinical studies, the majority of which are cardiovascular outcome trials, indicate that GLP-1 RA therapy is safe and tolerable for people living with T2DM and compromised renal function, and also suggest that GLP-1 RAs may have renoprotective properties. Although evidence from clinical trials has shown GLP-1 RAs to be safe and efficacious in people living with T2DM and renal impairment, their use is uncommon in this patient population. With continuing developments in the field of GLP-1 RA therapy, it is important for physicians to understand the benefits and practical use of GLP-1 RAs, as well as the clinical evidence, in order to achieve positive patient outcomes. Here, we review evidence on GLP-1 RA use in people living with T2DM and CKD and summarize renal outcomes from clinical studies. We provide practical considerations for GLP-1 RA use to provide an added benefit to guide treatment in this high-risk patient population.

Type 2 diabetes mellitus (T2DM) is a common disorder characterized by insulin resistance and dysfunction of insulin-producing beta cells of the pancreas. People living with T2DM have an increased risk of developing complications, including chronic kidney disease (CKD), which itself is associated with increased mortality. Both the American Diabetes Association and Kidney Disease Improving Global Outcomes organization provide updated pharmacological recommendations for treating T2DM in people with CKD that include the use of sodium-glucose co-transporter-2 inhibitors (SGLT2i) or glucagon-like peptide-1 receptor agonists (GLP-1 RAs). GLP-1 RAs are effective and safe treatments for controlling blood sugar levels and reducing body weight, and evidence from large clinical trials also suggests that GLP-1 RAs may be renoprotective. Despite the benefits of GLP-1 RAs, they are not commonly prescribed in people living with T2DM and CKD. Healthcare practitioners need to be aware of the most recent information so that they can make informed decisions when selecting treatment options. The objective of this review is to summarize the main renal outcomes from clinical studies while providing practical guidance on the use of GLP-1 RAs.

Peptide Receptor Radionuclide Therapy with [177Lu]Lu-DOTA-TATE in Patients with Advanced GEP NENS: Present and Future Directions.

This review article summarizes findings published in the last years on peptide receptor radionuclide therapy in GEP NENs, as well as potential future developments and directions. Unanswered questions remain, such as the following: Which is the correct dose and individual dosimetry? Which is the place for salvage PRRT-Lu? Whicht is the role of PRRT-Lu in the pediatric population? Which is the optimal sequencing of PRRT-Lu in advanced GEP NETs? Which is the place of PRRT-Lu in G3 NENs? These, and future developments such as inclusion new radiopharmaceuticals and combination therapy with different agents, such as radiosensitizers, will be discussed.

Interplay between Intestinal Bacterial Communities and Unicellular Parasites in a Morbidly Obese Population: A Neglected Trinomial.

Obesity is an epidemic causing a metabolic health crisis. Herein, the interactions between the gut prokaryotic and eukaryotic communities, metabolic comorbidities and diet were studied. Stool samples from 56 subjects, 47 with type III obesity and 9 with type II obesity and cardiovascular risk or metabolic disease, were assessed for the richness, diversity and ecology of the bacterial gut community through metagenomics, together with the study of the presence of common unicellular eukaryote parasites (Blastocystis sp., Dientamoeba fragilis and Giardia intestinalis) by qPCR. Clinical information regarding metabolic comorbidities and non-alcoholic hepatic fatty liver disease was gathered. To assess the quality of the patients' diet, each participant filled in three dietary questionnaires. The most prevalent parasite Blastocystis sp. (46.4%), together with D. fragilis (8.9%), was found to be associated with higher mean diversity indexes regarding non-colonized subjects; the opposite of that which was observed in those with G. intestinalis (16.1%). In terms of phyla relative abundance, with Blastocystis sp. and D. fragilis, very slight differences were observed; on the contrary, G. intestinalis was related to an increase in Bacteroidetes and Proteobacteria, and a decrease in Firmicutes and Actinobacteria, presenting the lowest Firmicutes/Bacteroidetes ratio. At genus level, Blastocystis sp. and/or D. fragilis was accompanied with an increase in Lactobacillus spp., and a decrease in Akkermansia spp., Bifidobacterium spp. and Escherichia spp., while G. intestinalis was associated with an increase in Bacteroides spp., and a decrease in Faecalibacterium spp., Prevotella spp. and Lactobacillus spp., and the highest Bacteroides spp./Prevotella spp. ratio. Participants with non-alcoholic hepatic fatty liver presented a higher Firmicutes/Bacteroidetes ratio, and those with type 2 diabetes displayed a significantly lower Faecalibacterium spp./Escherichia spp. ratio, due to an overrepresentation of the genus Escherichia spp. The presence of parasites was associated with variations in the richness, diversity and distribution of taxa in bacterial communities, confirming a gain in diversity associated with Blastocystis sp. and providing different functioning of the microbiota with a potential positive effect on comorbidities such as type 2 diabetes, insulin resistance and metabolic syndrome. Future basic and clinical studies should assess the beneficial or pathogenic effect of these eukaryotes on obese subjects and focus on deciphering whether they may imply a healthier metabolic profile.

Do Intestinal Unicellular Parasites Have a Role in the Inflammatory and Redox Status among the Severely Obese?

The diagnosis of obesity comprises subjects with totally different phenotypes and metabolic profiles. Systemic inflammation and oxidative stress derived from the white adipose tissue are suggested as the link between this disease and the development of insulin resistance and metabolic comorbidities. The presence of unicellular eukaryotic parasites colonizing the human gut ecosystem is a common circumstance, and yet their influence on the inflammatory and redox status of the obese host has not been assessed. Herein, a set of inflammatory and redox biomarkers were assessed together with a parasitological analysis of 97 severely obese subjects. Information was also collected on insulin resistance and on the antioxidant composition of the diet. The global prevalence of intestinal unicellular parasites was 49.5%, with Blastocystis sp. the most prevalent protozoan found (42.3%). Colonized subjects displayed a higher total antioxidant capacity and a trend towards higher extracellular superoxide dismutase activity, regardless of their insulin resistance status, along with lower reduced glutathione/oxidized glutathione (GSH/GSSG) ratios in plasma in the insulin-resistant subgroup. No changes in malondialdehyde levels, or in inflammatory cytokines in plasma, were found in regard to the colonization status. In conclusion, enteric eukaryotic unicellular parasites may play an important role in modulating the antioxidant defenses of an obese host, thus could have beneficial effects with respect to the development of systemic metabolic disorders.

Cost Analysis of FreeStyle Libre® 2 System in Type 2 Diabetes Mellitus Population.

INTRODUCTION: FreeStyle Libre® 2 system is a sensor-based flash-monitoring system that measures interstitial fluid glucose. The study aimed to compare cost of FreeStyle Libre 2 system and self-monitoring of blood glucose (SMBG) in the type 2 diabetes mellitus (T2DM) population from the Spanish Health System perspective. METHODS: On the basis of data collected from a literature review, the cost of glucose monitoring was modelled for patients with T2DM on a basal-bolus insulin regimen. The cost estimate included annual consumption for glucose monitoring (strips, lancets and sensors) and severe hypoglycaemic events (SHE) management. A published rate of SHE (2.5 episodes/patient-year) was considered. A reduction of SHE (- 48.8%) associated with FreeStyle Libre 2 system, derived from the REPLACE trial, was applied. Hospital attendance for 20.5% of SHEs (with subsequent hospitalization in 16.0%) was applied. Consumption of strips and lancets was set at 6/day for SMBG (derived from national monitoring recommendations), and 0.2/day for FreeStyle Libre 2 system users, with 26 FreeStyle Libre 2 sensors/year. Unitary costs (€, year 2020 excluding VAT) were derived from literature (€0.28/strip; €0.09/lancet; €3.09/daily FM sensor; €3804/hospitalized SHE; €1794/hospital-attended non-admitted SHE; €389/community-attended SHE). RESULTS: Costs were €2700 and €2120/year/patient using SMBG or FreeStyle Libre 2 system, respectively. For 1000 patients with T2DM using basal-bolus insulin, 1220 SHEs/year (with 48 hospitalizations) could be prevented and FreeSytle Libre 2 system could generate cost savings of up to €580,953/year versus SMBG (- 21.5%). CONCLUSION: FreeStyle Libre 2 system is a potential cost-saving strategy in patients with T2DM in Spain on a basal-bolus insulin regimen.

Aflatoxins in organs and biological samples from children affected by kwashiorkor, marasmus and marasmic-kwashiorkor: A scoping review.

Originally, the kwashiorkor is a pathology justified by the low consumption of proteins and high carbohydrates in weaned children. However, today, it can appear due to multifactorial causes, one of the hypotheses being the presence of aflatoxins in foods consumed by the child population and detected in biological fluids. The objective of this work is to scoping review the presence of aflatoxins in kwashiorkor, marasmus and marasmic-kwashiorkor from organs and biological samples in children. Results reflected that the presence of aflatoxins in kwashiorkor is greater compared to marasmic-kwashiorkor and marasmus in the organs and biological samples analyzed. The relationship of this mycotoxin with the pathology shows that it can affect both genders, even up to 12 years, in addition they are detected in eight biological samples and organs, except in the spleen, and in ten African countries and in the Philippines. The appearance of this pathology has been associated in children when after weaning they consume foods with low protein content and rich in carbohydrates, but coincidentally coincides with foods where the growth of aflatoxigenic fungi is more prevalent, and even the presence of other fungi that can generate other mycotoxins, such as ochratoxin A and fumonisin B1.

Giardia intestinalis and Fructose Malabsorption: A Frequent Association.

Nowadays, scientific studies are emerging on the possible etiological role of intestinal parasites in functional digestive disorders. Our study was carried out with healthy individuals (control group; n = 82) and symptomatic patients with lactose or fructose malabsorption, including positive (malabsorbers; n = 213) and negative (absorbers; n = 56) breath test, being analyzed for the presence of intestinal parasites. A high parasitic prevalence was observed in malabsorbers (41.8%), exclusively due to single-cell eukaryotes but not helminths. Giardia intestinalis was the predominant parasite in cases of abnormal absorption (26.5%), significantly associated with fructose malabsorption and doubling the probability of developing this pathology. Within controls, Blastocystis sp. (13.4%) was almost the only parasite, being the second among patients (12.6%), and Cryptosporidium parvum, the last species of clinical relevance, was detected exclusively in two malabsorbers (0.9%). The consumption of ecological food and professions with direct contact with humans arose as risk factors of parasitism. A diagnosis of carbohydrate malabsorption in adulthood is the starting point, making the search for the primary cause necessary. Accurate parasitological diagnosis should be considered another tool in the clinical routine for patients with recurrent symptoms, since their condition may be reversible with adequate therapeutic intervention.

Outcomes in patients with diabetes 10 years after liver transplantation.

BACKGROUND: There are discrepancies between studies regarding the effect of diabetes mellitus on morbidity and mortality in patients undergoing liver transplantation. The aim of the present study was to compare mortality, risk of liver graft rejection, and cardiovascular events in patients with and without diabetes undergoing liver transplantation over a 10-year follow-up period. METHODS: A retrospective study was performed on 183 patients who underwent liver transplantation in 2005 and 2006. Mortality and morbidity data were collected until 2016, including information on mortality and survival time, graft rejection and graft survival time, coronary heart disease, stroke, and peripheral arterial ischemia. RESULTS: During the follow-up, 41.3% and 27.8% of patients in the groups with and without diabetes, respectively, died. A trend for lower survival time was observed in patients with diabetes, although this effect was not confirmed by the Cox regression model. There was an increased risk of graft rejection in the group with diabetes compared with the group without diabetes ( P < 0.001). In the survival analysis, diabetes was associated with reduced graft survival time ( P = 0.001). Cardiovascular events were also more likely in the group with diabetes ( P = 0.005). CONCLUSIONS: In the present study diabetes was associated with a higher risk of liver graft rejection and cardiovascular events. There was also a trend for higher mortality, although the effect was not statistically significant. These findings suggest that patients with diabetes require a more rigorous pretransplant evaluation and closer monitoring after transplantation in order to try to reduce associated complications.

Insulin-induced normoglycemia reduces islet number needed to achieve normoglycemia after allogeneic islet transplantation in diabetic mice.

The Edmonton protocol established that insulin independence could be reached with the transplantation of an appropriate number of islet cells. However, to effect a cure, islets from two or three pancreases are needed. The aim of this study was to examine whether normoglycemia, with insulin treatment before and after transplantation, reduces the islet number needed to achieve normoglycemia in allogeneic islet transplantation. Swiss mice were used as donors and recipients. Diabetes was induced by i.p. administration of streptozotocin (180 mg/kg BW). Diabetic mice were transplanted with 300 (n = 16), 400 (n = 16), or 500 (n = 16) islets under the left kidney capsule. For every group, half the animals were kept normoglycemic with insulin treatment from day 4 before transplantation to day 10 after transplantation. At the end of the study, all normoglycemic mice were given an i.p. glucose tolerance test (IPGTT). For statistical analysis, paired or unpaired Student's t-test or ANOVA was used. Only insulin-treated mice achieved normoglycemia by the end of the study (37.5% of animals transplanted with 400 islets and 50% transplanted with 300 or 500 islets). At the end of the study, normoglycemic mice transplanted with 300 allogeneic islets showed better glycosylated hemoglobin (HbA1C) than did normoglycemic mice transplanted with 500 islets (300 islets: 2.7 +/- 0.2%; 500 islets: 3.6 +/- 0.2%; p < 0.05). After the IPGTT, insulin-treated mice transplanted with 500 islets showed abnormal glucose tolerance; however, insulin-treated mice transplanted with 300 or 400 islets showed normal glucose tolerance. Insulin treatment reduced the islet number needed to achieve normoglycemia in allogeneic islet transplantation. The HbA1C and IPGTT results suggest that transplanting smaller numbers of allogeneic islets improves beta-cell function; some studies suggest that this may be due to lower immunogenicity, hypoxia, and inflammation.

Hemoglobin Glycosylation Index is not related with blood glucose.

OBJECTIVE: Accurate assessment of blood glucose control is essential to prevent chronic complications in diabetes. Hemoglobin Glycosylation Index (HGI) quantifies the degree to which individuals demonstrate a HbA(1C) higher or lower than average for the population. This study has aimed to assess the relationship between HGI and blood glucose. METHODS: 25 type 1 diabetes subjects (12 men and 13 women), 22.0+/-5.2 (17-34) years old, were instructed to self-monitor glucose with the One Touch Profile capillary glucose meter. HbA(1C) was determined and self-monitored blood glucose levels were studied every 3 months. Diabetic patients were monitored for 3-9 months and 62 measurements of HbA(1C) were included. HbA(1C) was measured by HPLC. Mean blood glucose (MBG) was calculated from self-monitored blood glucose records. A linear regression was calculated between HbA(1C) and MBG during the 60 days before sampling to determine HbA(1C). For each diabetic patient's MBG, a predicted HbA(1C) was calculated from the population regression equation. HGI was then calculated as HGI=observed HbA(1C)-predicted HbA(1C). Blood glucose was analyzed within target range (WTR), below target range (BTR) and above target range (ATR) according to The European Diabetes Policy Group Consensus for type 1 diabetes. RESULTS: A good linear regression between HbA(1C) and MBG was observed (r=.71, r(2)=.497, P=.000). No correlation was found between HGI and the percentage of WTR, BTR or ATR values. Moreover, the percentage of self-monitored blood glucose ATR and BTR was the same for high glycosylators (HGI<0 and ATR: 56.2+/-20.9%; HGI<0 and BTR: 34.5+/-17.5%) as for low glycosylators (HGI>0 and ATR: 52.8+/-25.5%; HGI>0 and BTR: 25.1+/-15.0%). CONCLUSIONS: HGI is determined for both physiological factors and blood glucose. A prospective study is necessary to assess whether HGI, together with HbA(1C), can predict the incidence and severity of chronic complications in diabetic patients.

Insulin-Induced Normoglycemia Reduces Islet Number Needed to Achieve Normoglycemia after Allogeneic Islet Transplantation in Diabetic Mice.

The Edmonton protocol established that insulin independence could be reached with the transplantation of an appropriate number of islet cells. However, to effect a cure, islets from two or three pancreases are needed. The aim of this study was to examine whether normoglycemia, with insulin treatment before and after transplantation, reduces the islet number needed to achieve normoglycemia in allogeneic islet transplantation. Swiss mice were used as donors and recipients. Diabetes was induced by IP administration of streptozotocin (180 mg/kg BW). Diabetic mice were transplanted with 300 (n = 16), 400 (n = 16), or 500 (n = 16) islets under the left kidney capsule. For every group, half the animals were kept normoglycemic with insulin treatment from day 4 before transplantation to day 10 after transplantation. At the end of the study, all normoglycemic mice were given an IP glucose tolerance test (IPGTT). For statistical analysis, paired or unpaired Student's t-test or ANOVA was used. Only insulin-treated mice achieved normoglycemia by the end of the study (37.5% of animals transplanted with 400 islets and 50% transplanted with 300 or 500 islets). At the end of the study, normoglycemic mice transplanted with 300 allogeneic islets showed better glycosylated hemoglobin (HbA1C) than did normoglycemic mice transplanted with 500 islets (300 islets: 2.7 ± 0.2%; 500 islets: 3.6 ± 0.2%; p < 0.05). After the IPGTT, insulin-treated mice transplanted with 500 islets showed abnormal glucose tolerance; however, insulin-treated mice transplanted with 300 or 400 islets showed normal glucose tolerance. Insulin treatment reduced the islet number needed to achieve normoglycemia in allogeneic islet transplantation. The HbA1C and IPGTT results suggest that transplanting smaller numbers of allogeneic islets improves ß-cell function; some studies suggest that this may be due to lower immunogenicity, hypoxia, and inflammation.