Exposure to glyphosate-based herbicides (GBH) may affect metabolism and induce endocrine alterations. This study evaluated whether environmentally relevant low doses of GBH affect glucose homeostasis during pregnancy and the metabolism of offspring later in life. Pregnant Wistar rats received daily oral doses of either 0.5 or 50 mg/kg of GBH or water (control) throughout the gestation period. No significant changes were observed in biometric and metabolic parameters during pregnancy. However, hepatic alterations were detected in GBH-treated rats, including reduced glycogen content and decreased global genome methylation. Offspring exhibited a transient delay in neurodevelopmental reflexes. Body mass and food intake remained unchanged up to postnatal day 70. After this period, animals were subjected to a metabolic challenge with dexamethasone. While dexamethasone-treated animals showed metabolic alterations typical of glucocorticoid exposure (glucose intolerance, insulin insensitivity, dyslipidemia), maternal GBH exposure during pregnancy did not exacerbate these effects in the offspring. Additionally, changes in DNA methylation-related gene expression were observed in female but not male offspring. In vitro, GBH exhibited greater cytotoxicity than glyphosate alone, significantly reducing the viability of 3T3-L1 adipocytes and HepG2 hepatocytes, whereas glyphosate alone had no significant effects, even at higher concentrations. Overall, gestational exposure to GBH under regulatory safe doses does not cause substantial metabolic disturbances in dams or their offspring. However, the existence of alterations in hepatic glucose metabolism and effects on hepatic epigenetic regulation at these low doses, along with the cytotoxic in vitro effects of GBH at high concentrations, warrants attention regarding human exposure and health impacts.

Dexamethasone (DEX), a synthetic glucocorticoid (GC) widely used for its anti-inflammatory and immunosuppressive properties, is associated with adverse metabolic and diabetogenic effects. Whether early-life exposure to DEX modifies metabolic disturbances induced by subsequent treatments remains unclear. We investigated this by subjecting male Wistar rats to up to three treatment cycles initiated on postnatal days 30, 60, and 90. Each cycle consisted of five consecutive daily intraperitoneal injections of DEX (1.0 mg/kg) or saline (1 mL/kg). Animals were assigned to five groups according to exposure history: Control, 90, 30 + 90, 60 + 90, and 30 + 60 + 90. After the final cycle, glucose tolerance tests were performed, followed by blood and tissue collection. DEX reduced body mass gain and food intake across all regimens, leading to lower adult body mass, particularly after three cycles. All DEX-treated groups developed glucose intolerance, although this effect was attenuated in the 30 + 60 + 90 group. Hyperinsulinemia and increased hepatic triacylglycerol and glycogen content were observed in all groups except the 30 + 60 + 90 group. DEX-induced β-cell mass expansion was absent in animals exposed on postnatal day 30. Hepatic genes involved in glucose metabolism were upregulated after one or two exposures, without corresponding changes in protein levels. In contrast, repeated exposure (30 + 60 + 90) enhanced GC-responsive gene expression, indicating that upstream GC receptor signaling was preserved despite limited metabolic remodeling. Increased hypothalamic Zbtb16 mRNA expression further supported the integrity of central GC responsiveness. In summary, early-life DEX exposure impairs growth but attenuates several metabolic disturbances induced by later treatments, highlighting long-term consequences of GC therapy.

Objective: This study aimed to review the structural concepts, definition, classification, and macronutrient and food composition of carbohydrate-restricted diets (CRDs) for individuals with type 2 diabetes mellitus (T2DM). Methods: A scoping review was conducted following Joanna Briggs Institute guidelines. Searches were performed in Scopus, PubMed, Web of Science, and Embase, including texts published in Portuguese, English, and Spanish. Official documents from governments, regulatory agencies, and international diabetes organizations were also consulted. Results: In total, 79 articles and 17 official documents were analyzed. The following structural concept was identified: restricted carbohydrate intake decreases the need for endogenous and exogenous insulin, contributing to the maintenance of glycemic control, and justifies its consideration among the nutritional therapy options for individuals with T2DM. CRDs varied in definition, classification, and macronutrient composition. Studies failed to provide detailed information on the food composition of diets, precluding an in-depth understanding of metabolic effects. The existence of several approaches with varying recommendations makes it difficult to generalize the results. International CRD guidelines for T2DM adopt divergent definitions, compromising interpretation, recommendation, and even adherence. Conclusions: Although the concept of CRDs justifies their adoption within the nutritional therapy choices for T2DM, the multiple denominations can hinder understanding and comparison between studies. The lack of information on food composition and carbohydrate types compromises the assessment of the effects and adherence to CRD-based nutritional interventions. We emphasize the need for methodologically consistent studies that evaluate CRDs based on fresh and minimally processed foods with a low glycemic index to support official diabetes guidelines and organizations.

Physical exercise is crucial in type 2 diabetes management (T2D), and training in the aquatic environment seems to be a promising alternative due to its physical properties and metabolic, functional, cardiovascular, and neuromuscular benefits. Research on combined training in aquatic and dry-land training environments is scarce, especially in long-term interventions. Thus, this study aims to investigate the effects of combined training in both environments on health outcomes related to the management of T2D patients. This is a randomized, unicentric, single-blinded, comparator clinical trial with two parallel arms. Participants with T2D, of both sexes, aged at 45 to 80 years old, will be randomized into two groups (aquatic combined training (AQUA) and dry-land combined training (LAND)), both performing combined aerobic and resistance training three times a week on alternate days for 24 weeks. Aerobic training will be performed using continuous and pyramidal methods, with linear exercise intensity and duration progression. Intensity will be prescribed by rated effort perception (Borg scale 6 to 20). Resistance training will be performed using exercise for the trunk, upper and lower limbs maximum speed, and target repetition zone in aquatic and dry-land environments, respectively, using multiple sets in a linear dosage progression. Before, at 12 weeks, and after the 24 weeks of training, biochemical analyses, functional capacity, maximum muscle strength, body composition assessments, cardiovascular measures, and the administration of questionnaires to assess mental, cognitive, sleep quality, and quality of life will be conducted. Throughout the 24 weeks, the training load date and acute capillary glucose and blood pressure measurements will also be conducted. The data will be analyzed using the SPSS (29.0) statistical package, using a significance level of 0.05. For intra- and inter-group comparisons, generalized estimating equations will be applied and analyzed by intention-to-treat and per-protocol adopting the Bonferroni post hoc test. The obtained results may provide insights to enhance understanding of the benefits of the aquatic and dry-land environment on various health outcomes, as well as acute aspects and safety considerations of the training. Moreover, this could support the development of intervention strategies to optimize the T2D management. Brazilian Clinical Trial Registry (ReBEC) RBR-10fwqmfy. Registered on April 16, 2024.

Pramlintide is an amylin analog developed as a complementary treatment for diabetes. However, it requires several subcutaneous injections, reducing patients’ adherence. Since the intranasal route might be an alternative for drug administration, we evaluated whether intranasal pramlintide treatment exerts comparable actions with intraperitoneal administration. Adult male Swiss mice were submitted to a refeeding test in a dose-response study with intraperitoneal (PRAM i.p.) or intranasal (PRAM i.n.) pramlintide administration. Intraperitoneal liraglutide served as a positive control (LIRA). Then, the selected dose was administered to analyze gastric emptying after an acute exposure. We also evaluated an 8-day treatment (once daily) to determine food intake and body mass. Blood glucose and plasma triacylglycerides were measured on the euthanasia day. In the refeeding test, the anorexigenic dose for the PRAM i.p. or LIRA i.p groups was 200 µg/kg and 400 µg/kg, respectively. The PRAM i.n. group (200 µg/kg) exhibited a trend for that. The reduction in gastric emptying occurred for all treated groups compared with their respective controls (vehicle-treated). Neither the PRAM i.p. nor the PRAM i.n. groups exhibited reduced body mass and food intake in the subchronic experiment. No impact on biochemical parameters was observed regardless of the route of pramlintide administration. Although intranasal pramlintide is not comparable in magnitude to intraperitoneal administration at an equivalent administered dose, our evidence corroborates the development of novel intranasal formulations destined to overpass the bioavailability issue and potentially serve as an alternative route.

Hyperglucagonemia has been implicated in the pathogenesis of type 2 diabetes (T2D). In contrast to β-cells, studies on the function of the pancreatic α-cell in T2D are scarce. Consequently, the processes underlying hyperglucagonemia and α-cell dysfunction are largely unknown, limiting the appropriate design of specific pharmacological and therapeutic strategies. In the current study, we aimed to analyze the alterations of the pancreatic α-cell and its glucagon responses in diabetic db/db mice at early stages of the disease. In this context of glucose intolerance, hyperinsulinemia, and β-cell dysfunction, hyperglucagonemia was only present at fed conditions and was associated with insulin resistance. Yet, we found that the glucagon-to-insulin ratio in db/db mice did not change with fed or fasted states, further supporting that the metabolic regulation of glucagon release was impaired. Pancreatic β-cell dysfunction in db/db mice was manifested by increased basal secretion from isolated islets along with reduced insulin content. In contrast, α-cells from diabetic animals presented upregulated secretion and islet content of glucagon compared with controls. Electrophysiological analysis of dispersed α-cells revealed that altered secretion was not the result of impaired exocytosis. Instead, we found defective regulation of Ca2+ signaling by glucose. Besides these functional alterations, we also observed augmented α-cell mass in diabetic mice, which was accompanied by disrupted islet cytoarchitecture as well as increased α-cell size and number, without pieces of evidence of upregulated proliferation. Overall, these findings indicate that hyperglucagonemia in early T2D results from multifaceted α-cell deregulation in mice.

AimsThis study investigates the role of Hepatocyte Nuclear Factor 4α (HNF4α) in the adaptation of pancreatic β-cells to an HFD-induced obesogenic environment, focusing on β cell mass expansion and metabolic adaptations.Main methodsWe utilized an HNF4α knockout (KO) mouse model, with CRE-recombinase enzyme activation confirmed through tamoxifen administration. KO and Control (CTL) mice were fed an HFD for 20 weeks. We monitored body weight, food intake, glucose tolerance, insulin sensitivity, and insulinemia. Also, to assess structural and metabolic changes, histological analyses of pancreatic islets and liver tissue were conducted.Key findingsKO mice displayed lower fasting blood glucose levels compared to CTL mice after tamoxifen administration, indicating impaired glucose-regulated insulin secretion. HFD-fed KO mice consumed less food but exhibited greater weight gain and perigonadal fat accumulation, reflecting higher energy efficiency. Histological analysis revealed more pronounced liver steatosis and fibrosis in KO mice on HFD. Glucose intolerance and insulin resistance were exacerbated in KO mice, highlighting their inability to adapt to increased metabolic demand. Structural analysis showed that KO mice failed to exhibit HFD-induced β cell mass expansion, resulting in reduced islet diameter and number, confirming the critical role of HNF4α in β cell adaptation.SignificanceThis study demonstrates that HNF4α is essential for the proper metabolic and structural adaptation of pancreatic β-cells in response to an obesogenic environment. The lack of HNF4α impairs β cell functionality, leading to increased susceptibility to glucose intolerance and insulin resistance. These findings underscore the importance of HNF4α in maintaining glucose homeostasis and highlight its potential as a therapeutic target for diabetes management in obesity.

Whether there is a relationship between bats' dietary patterns and evolutionary endocrine pancreas adaptation is not clearly understood. Aiming to contribute to this topic, we evaluated some metabolic and structural parameters in the following adult bats: the frugivorous Artibeus lituratus, the nectarivorous Anoura caudifer, the hematophagous Desmodus rotundus, and the insectivorous Molossus molossus. A. lituratus and A. caudifer diets consist of high amounts of simple carbohydrates, while D. rotundus and M. molossus diets consist of high amounts of proteins or protein and fat, respectively. In our results, A. lituratus and A. caudifer bats exhibited the highest values of relative islet mass (%), islet density (number of islets per pancreas area), and the lowest values of intestinal length among the four species. When adjusted by the body mass (mg/g of body mass), both D. rotundus and A. caudifer bats exhibited the highest islet mass values among the groups. Blood glucose was similar between A. lituratus, D. rotundus, and M. molossus, with the lowest values for the A. caudifer bats. M. molossus bats had the highest plasma cholesterol values among the studied species but exhibited similar plasma triacylglycerol with D. rotundus and A. caudifer bats. beta- and alpha-cell distribution within A. lituratus, A. caudifer, and M. molossus islets achieved an approximate average value of - 66% and - 28%, respectively, a pattern inverted in D. rotundus islets (53% of alpha cells and 40% of beta cells). A. caudifer and D. rotundus exhibited the highest and the lowest beta/alpha-cells ratio per islet, respectively. We conclude that the macronutrient predominance in each bat -eating niche correlates with the morphophysiological pancreas features being the nectarivorous A. caudifer the species with the highest islet mass per body mass and beta/alpha-cells ratio, while the hematophagous D. rotundus showed the highest alpha-cells apparatus.

Study Objectives Sleep deprivation is a potential risk factor for metabolic diseases, including obesity and type 2 diabetes. We evaluated the impacts of moderate chronic sleep deprivation on glucose and lipid homeostasis in adult rats.Methods Wistar rats (both sexes) were sleep-perturbed daily for 2 hours at the early (06:00-08:00) and the late light cycle (16:00-18:00) five days a week (except weekends) for 4 weeks.Results Sleep perturbation (SP) resulted in reduced body weight gain in both sexes, associated with altered food intake and reduced adiposity. SP did not alter the short- or long-term memories or cause anxiogenic behavior. No major changes were observed in the plasma insulin, leptin, triacylglycerol, non-esterified fatty acids, and blood glucose upon SP. After SP, females exhibited a transitory glucose intolerance, while males became glucose intolerant at the end of the experimental period. Male rats also developed higher insulin sensitivity at the end of the SP protocol. Morphometric analyses revealed no changes in hepatic glycogen deposition, pancreatic islet mass, islet-cell distribution, or adrenal cortex thickness in SP rats from both sexes, except for lower adipocyte size compared with controls. We did not find homogeneous changes in the relative expression of circadian and metabolic genes in muscle or hepatic tissues from the SP rats.Conclusions Moderate chronic SP reduces visceral adiposity and causes glucose intolerance with a more pronounced impact on male rats, reinforcing the metabolic risks of exposure to sleep disturbances. Graphical Abstract

Whether the endocrine pancreas exhibits structural features to couple with dietary patterns is not fully explored. Considering the lack of data comparing endocrine pancreas and islet cell distribution among different bat species in the same study, we considered this an opportunity to explore the topic, including five species within three different predominant diets. For this, we applied morphometric techniques to compare the islets of frugivorous Artibeus lituratus and Carollia perspicillata, insectivorous Molossus molossus and Myotis nigricans, and nectarivorous Glossophaga soricina bats. Data for islet size, cellularity, and mass were equivalent between frugivorous A. lituratus and nectarivorous G. soricina, which differed from insectivorous bats. The frugivorous C. perspicillata bat exhibited morphometric islet values between A. lituratus and the insectivorous species. A. lituratus and G. soricina but not C. perspicillata bats had higher islet mass than insectivorous species due to larger size, instead of a higher number of islets per area. Insectivorous bats, on the other hand, had a higher proportion of α-cells per islet. These differences in the endocrine pancreas across species with different eating habits indicate the occurrence of species-specific adjustments along the years of evolution, with the demand for α-cells higher in bats with higher protein intake.

Background: Exogenous glucocorticoids (CGs) possess relevant therapeutic effects but exert diabetogenic actions when in excess. Thus, ligands with potential therapeutic applications and fewer adverse effects are needed. To this, we analyzed whether mometasone furoate (MF), a CG expected to cause fewer side effects, given through systemic routes, could maintain the anti-inflammatory actions without relevant repercussions on metabolism. Methods: The anti-inflammatory effect of MF was evaluated with both peritonitis and colitis models in rodents. Glucose and lipid metabolism were investigated in male and female rats treated daily with MF with different doses and routes of administration for seven days. The involvement of glucocorticoid receptor (GR) on MF ac-tions was assessed in animals pretreated with mifepristone. Also, the potential reversibility of the adverse effects was assessed. Dexamethasone was used as a positive control. Results: MF treatment resulted in glucose intolerance in male rats treated through intraperitoneal (ip) but not oral gavage route (og). In female rats, none of the routes led to glucose intolerance. MF treatment attenuated insulin sensitivity and increased pancreatic beta-cell mass, regardless of the sex and route of administration. MF treatment through og route did not result in dyslipidemia, as observed in rats treated through the ip route (both sexes). The anti-inflammatory and metabolic adverse effects of MF were GR-dependent, and metabolic outcomes altered by MF administration were reversible. Conclusion: MF maintains anti-inflammatory activity when administered by systemic routes and exerts less impact on metabolism when administered orally in male and female rats, effects that are GR-dependent and reversible. Category: Metabolic Disorders and Endocrinology.

Aims: Investigate whether the coadministration of olanzapine exacerbates the diabetogenic effects of dexa-methasone, two agents used in the antiemetic cocktails indicated to mitigate the adverse effects of chemotherapy.Main methods: Adult Wistar rats (both sexes) were treated daily with dexamethasone (1 mg/kg, body mass (b.m.), intraperitoneal (i.p.)) with or without olanzapine (10 mg/kg, b.m., orogastric (o.g.)) for 5 consecutive days. During and at the end of the treatment, we evaluated biometric data and parameters involving glucose and lipid metabolism.Key findings: Dexamethasone treatment resulted in glucose and lipid intolerance, higher plasma insulin and triacylglycerol levels, higher content of hepatic glycogen and fat, and higher islet mass in both sexes. These changes were not exacerbated by concomitant treatment with olanzapine. However, coadministration of olan-zapine worsened the weight loss and plasma total cholesterol in males, while in females resulted in lethargy, higher plasma total cholesterol, and higher hepatic triacylglycerol release.Significance: Coadministration of olanzapine does not exacerbate any diabetogenic dexamethasone effect on glucose metabolism and exerts a minor impact on the lipid homeostasis of rats. Our data favor the addition of olanzapine in the antiemetic cocktail considering the low incidence of metabolic adverse effects for the period and dosage analyzed in male and female rats.

Studies indicate that the pesticide malathion may have a role in diabetes. Herein, we determined the effects of different concentrations of malathion on survival, ultrastructure, and electrophysiologic islet cell parameters. Acutely, high concentrations of malathion (0.5 or 1 mM) increased cell death in rat islet cells, while low con-centrations (0.1 mM) caused signs of cell damage in pancreatic alpha and beta cells. Exposure of RINm5F cells to malathion for 24 or 48 h confirmed the reduction in beta-cell viability at lower concentrations (0.001-100 mu M). Chronic exposure of mouse pancreatic alpha and beta cells to 3 nM of malathion led to increased voltage-gated K+ (Kv) currents in alpha-cells. Our findings show a time and concentration dependency for the malathion effect on the reduction of islet cell viability and indicate that pancreatic alpha cells are more sensitive to malathion effects on Kv currents and cell death.

Mometasone furoate (MF) is a synthetic glucocorticoid used clinically to treat specific inflammatory disorders including superior and inferior respiratory tract. Due to its poor bioavailability we further investigated whether nanoparticles (NPs) made of zein protein may constitute a safe and effective choice to incorporate MF. Thus, in this work, we loaded MF into zein NPs aiming to evaluate possible advantages that could result from oral delivery and extend the range of MF application such as inflammatory gut diseases. MF-loaded zein NPs presented an average size in the range of 100 and 135 nm, narrow size distribution (polydispersity index < 0.300), zeta potential of around + 10 mV and association efficiency of MF over 70%. Transmission electron microscopy imaging revealed that NPs had a round shape and presented a smooth surface. The zein NPs showed low MF release in a buffer that mimics the gastric condition (pH = 1.2) and slower and controlled MF release in the intestinal condition (pH = 6.8). The short and intermediate safety of zein NPs was confirmed assessing the incubation against Caco-2 and HT29-MTX intestinal cells up to 24 h. Permeability studies of MF across Caco-2/HT29-MTX co-culture monolayer evidenced that zein NPs modulated MF transport across cell monolayer resulting in a stronger and prolonged interaction with mucus, potentially extending the time of absorption and overall local and systemic bioavailability. Overall, zein NPs showed to be suitable to carry MF to the intestine and future studies can be developed to investigate the use of MF-loaded zein NPs to treat intestinal inflammatory diseases.

Prenatal corticosteroids exposure is associated with important adverse effects on fetuses development. In this study histomorphometric evaluation of the mandibular bone and mandibular first molar from fetuses exposed to exogenous glucocorticoid in the final period of pregnancy was performed. For this study, six female rats were housed with two male rats for 8 days. The pregnant rats were assigned into two groups (n=3 each): control group and dexamethasone group. The dexamethasone received 0.2 mg.kg-1.day-1 water-soluble dexamethasone dose daily diluted in the drinking water from day 14-19 of pregnancy. In the 20th day of gestation, rats were sacrificed and the fetuses were obtained by cesarean derivation. The weight of each fetus was recorded and then were euthanized and the head was fixed in 10% phosphate-buffered formalin. Selected samples were evaluated by light microscopy, and the following measurements were recorded: the perimeter of mandibular bone, Meckel's cartilage and tooth germ; buccolingual length, vertical distance, anteroposterior distance and area of the tooth germ, by the Image J program. There was statistical significance difference with regarding birth weight, mandible perimeter, tooth germ vertical distance and buccolingual distance; area of dental germ and germ perimeter were lower in the dexamethasone versus control. There was no statistical significance difference on Meckel's cartilage perimeter and anteroposterior distance of tooth germ between groups. In conclusion, prenatal exposure to excess dexamethasone impairs mandibular bone and tooth development.

ABSTRACT Objectives: To evaluate the effect of sitagliptin treatment in early type 2 diabetes mellitus (T2DM) and the impact of different macronutrient compositions on hormones and substrates during meal tolerance tests (MTT). Materials and methods: Half of the drug-naive patients with T2DM were randomly assigned for treatment with 100 mg of sitagliptin, q.d., or placebo for 4 weeks and then submitted to 3 consecutive MTT intercalated every 48 h. The MTTs differed in terms of macronutrient composition, with 70% of total energy from carbohydrates, proteins, or lipids. After 4 weeks of washout, a crossover treatment design was repeated. Both patients and researchers were blinded, and a repeated-measures ANOVA was employed for statistical analysis. Results: Sitagliptin treatment reduced but did not normalize fasting and post-meal glucose values in the three MTTs, with lowered area-under-glucose-curve values varying from 7% to 15%. The sitagliptin treatment also improved the insulinogenic index (+86%) and the insulin/glucose (+25%), glucagon-like peptide-1/glucose (+46%) incremental area under the curves. Patients with early T2DM maintained the lowest glucose excursion after a protein- or lipid-rich meal without any major change in insulin, C-peptide, glucagon, or NEFA levels. Conclusion: We conclude that sitagliptin treatment is tolerable and contributes to better control of glucose homeostasis in early T2DM, irrespective of macronutrient composition. The blood glucose excursion during meal ingestion is minimal in protein- or fat-rich meals, which can be a positive ally for the management of T2DM. Clinical trial no: NCT00881543

Overexposure to glucocorticoids during gestation can lead to long-term mental disorders. Given the higher prevalence of depression in females, we investigated whether late gestational administration of dexamethasone could generate a depressive-like phenotype in the adult female offspring and if vitamin D could have a neuroprotective effect in this context. Pregnant rats received vitamin D (VitD, 500 IU/day) or vehicle (CTL) during gestation. Other pregnant rats received dexamethasone (Dex 0.1 mg/kg/ - 14th to the 19th gestational day) or dexamethasone + vitamin D (DexVitD). The offspring were tested for anhedonia (sucrose preference) and depressive-like behavior (forced swimming test) at postnatal months (PNM) 3, 6 and 12. Components of the serotonergic system, as well as glucocorticoids' receptors, were evaluated in the dorsal raphe nucleus at PNM 6 and 12. Prenatal vitamin D and dexamethasone increased sucrose preference at PNM 12. Prenatal vitamin D had an antidepressant-like effect at PNM 3 in rats overexposed to dexamethasone. However, at PNM 12, this effect was blunted in the DexVitD group. Prenatal dexamethasone reduced the protein content of SEPT, TPH, and 5-HT1A receptors in the dorsal raphe nucleus at 6 but not at 12 PNM. The glucocorticoids' receptors expression was similar in all groups. We concluded that prenatal overexposure to dexamethasone does not change emotional behaviors in females, but it blunts the antidepressant-like effect of gestational vitamin D in an age-dependent manner. The antidepressant-like activity of vitamin D in the offspring was not related either to alterations of the serotonergic system or the glucocorticoids' receptors expression in the dorsal raphe nucleus.

Aging is associated with a decline in peripheral insulin sensitivity and an increased risk of impaired glucose tolerance and type 2 diabetes. During conditions of reduced insulin sensitivity, pancreatic β cells undergo adaptive responses to increase insulin secretion and maintain euglycemia. However, the existence and nature of β-cell adaptations and/or alterations during aging are still a matter of debate. In this study, we investigated the effects of aging on β-cell function from control (3-month-old) and aged (20-month-old) mice. Aged animals were further categorized into 2 groups: high insulin sensitive (aged-HIS) and low insulin sensitive (aged-LIS). Aged-LIS mice were hyperinsulinemic, glucose intolerant, and displayed impaired glucose-stimulated insulin and C-peptide secretion, whereas aged-HIS animals showed characteristics in glucose homeostasis similar to controls. In isolated β cells, we observed that glucose-induced inhibition of KATP channel activity was reduced with aging, particularly in the aged-LIS group. Glucose-induced islet NAD(P)H production was decreased in aged mice, suggesting impaired mitochondrial function. In contrast, voltage-gated Ca2+ currents were higher in aged-LIS β cells, and pancreatic islets of both aged groups displayed increased glucose-induced Ca2+ signaling and augmented insulin secretion compared with controls. Morphological analysis of pancreas sections also revealed augmented β-cell mass with aging, especially in the aged-LIS group, as well as ultrastructural β-cell changes. Altogether, these findings indicate that aged mouse β cells compensate for the aging-induced alterations in the stimulus-secretion coupling, particularly by adjusting their Ca2+ influx to ensure insulin secretion. These results also suggest that decreased peripheral insulin sensitivity exacerbates the effects of aging on β cells.

AIMS:Synthetic glucocorticoids, including dexamethasone (DEX), are clinically prescribed due to their immunoregulatory properties. In excess they can perturb glucose homeostasis, with individuals predisposed to glucose intolerance more sensitive to these negative effects. While DEX is known to negatively impact β-cell function, it is unclear how. Hence, our aim was to investigate the effect of DEX on β-cell function, both alone and in combination with a diabetogenic milieu in the form of elevated glucose and palmitate. MAIN METHODS:Human pancreatic EndoC-βH1 cells were cultured in the presence of high glucose and palmitate (glucolipotoxicity) and/or a pharmacological concentration of DEX, before functional and molecular analyses. KEY FINDINGS:Either treatment alone resulted in reduced insulin content and secretion, while the combination of DEX and glucolipotoxicity promoted a strong synergistic effect. These effects were associated with reduced insulin biosynthesis, likely due to downregulation of PDX1, MAFA, and the proinsulin converting enzymes, as well as reduced ATP response upon glucose stimulation. Genome-wide DNA methylation analysis found changes on PDE4D, MBNL1 and TMEM178B, all implicated in β-cell function, after all three treatments. DEX alone caused very strong demethylation of the glucocorticoid-regulated gene ZBTB16, also known to influence the β-cell, while the combined treatment caused altered methylation of many known β-cell regulators and diabetes candidate genes. SIGNIFICANCE:DEX treatment and glucolipotoxic conditions separately alter the β-cell epigenome and function. The combination of both treatments exacerbates these changes, showing that caution is needed when prescribing potent glucocorticoids in patients with dysregulated metabolism.

Obesity is a major risk factor for breast cancer, especially in post-menopausal women. In the breast tissue of obese women, cyclooxygenase-2 (COX-2)-dependent prostaglandin E2 (PGE2) production has been correlated with inflammation and local estrogen biosynthesis via aromatase. Using a mouse model of 7,12-dimethylbenz[a]anthracene/medroxyprogesterone-acetate (DMBA/MPA)-induced carcinogenesis, we demonstrated that an obesogenic diet promotes mammary tissue inflammation and local estrogen production, and accelerates mammary tumor formation in a COX-2-dependent manner. High-sugar/fat (HSF) diet augmented the levels of the pro-inflammatory mediators MCP-1, IL-6, COX-2, and PGE2 in mammary tissue, and this was accompanied by crown-like structures of breast (CLS-B) formation and aromatase/estrogen upregulation. Treatment with a COX-2 selective inhibitor, etoricoxib, decreased PGE2, IL-6, MCP-1, and CLS-B formation as well as reduced aromatase protein and estrogen levels in the mammary tissue of mice fed a HSF diet. Etoricoxib-treated mice showed increased latency and decreased incidence of mammary tumors, which resulted in prolonged animal survival when compared to HSF diet alone. Inhibition of tumor angiogenesis also seemed to account for the prolonged survival of COX-2 inhibitor-treated animals. In conclusion, obesogenic diet-induced COX-2 is sufficient to trigger inflammation, local estrogen biosynthesis, and mammary tumorigenesis.