Canagliflozin in the treatment of diabetes: Perspectives

The worldwide prevalence of type 2 diabetes mellitus (T2DM) has surpassed more than 380 million people in 2014 and the projections of new T2DM cases for the next years are not encouraging. At present, combination of diet and exercise do not guarantee an adequate control of glucose homeostasis in T2DM patients. Thus, oral agents that act improving peripheral insulin sensitivity and/or pancreatic beta-cell function are additionally used as monotherapy or in combination. However, many patients still experience inadequate control with the pharmacotherapy ‘weapons’ currently available. Canagliflozin is a novel selective inhibitor of sodium-glucose co-transporter 2 (SGLT2) that lowers blood glucose concentration mainly by augmenting urinary glucose excretion. Besides having an effective action in reducing HbA1c, canagliflozin treatment also may benefit those patients aiming to control body weight, blood pressure and hypoglycemia episodes since this drug positively impact on such parameters. Among the adverse effects, genital infections are the most frequent. Much caution is required for some groups of patients including those elderly and with chronic kidney disease since canagliflozin can worse their quality of life. Given its overall cardiometabolic improvements, canagliflozin seems to be an important ally to the treatment of a selective group of T2DM patients and its efficacy and safety must be kept under monitoring through long-term clinical trials as well as experimental studies to certify whether this class of drug comes to stay among T2DM therapy

Glucocorticoid treatment and endocrine pancreas function: implications for glucose homeostasis, insulin resistance and diabetes

Glucocorticoids (GCs) are broadly prescribed for numerous pathological conditions because of their anti-inflammatory, antiallergic and immunosuppressive effects, among other actions. Nevertheless, GCs can produce undesired diabetogenic side effects through interactions with the regulation of glucose homeostasis. Under conditions of excess and/or long-term treatment, GCs can induce peripheral insulin resistance (IR) by impairing insulin signalling, which results in reduced glucose disposal and augmented endogenous glucose production. In addition, GCs can promote abdominal obesity, elevate plasma fatty acids and triglycerides, and suppress osteocalcin synthesis in bone tissue. In response to GC-induced peripheral IR and in an attempt to maintain normoglycaemia, pancreatic β-cells undergo several morphofunctional adaptations that result in hyperinsulinaemia. Failure of β-cells to compensate for this situation favours glucose homeostasis disruption, which can result in hyperglycaemia, particularly in susceptible individuals. GC treatment does not only alter pancreatic β-cell function but also affect them by their actions that can lead to hyperglucagonaemia, further contributing to glucose homeostasis imbalance and hyperglycaemia. In addition, the release of other islet hormones, such as somatostatin, amylin and ghrelin, is also affected by GC administration. These undesired GC actions merit further consideration for the design of improved GC therapies without diabetogenic effects. In summary, in this review, we consider the implication of GC treatment on peripheral IR, islet function and glucose homeostasis.This study was supported by grants from the Spanish foundations Ministry of Science and Innovation (BFU2013-42789; BFU2011-28358)This study was supported by grants from the European Foundation for the Study of Diabetes (EFSD / BI Basic Program and the Albert Renold Fellowship)This study was supported by grants from the Brazilian National Council for Scientific and Technological Development (CNPq 471397 / 2011-3

Glucose Homeostasis Is Not Affected in a Murine Model of Parkinson’s Disease Induced by 6-OHDA

There is a mutual relationship between metabolic and neurodegenerative diseases. However, the causal relationship in this crosstalk is unclear and whether Parkinson’s disease (PD) causes a posterior impact on metabolism remains unknown. Considering that, this study aimed to evaluate the appearance of possible changes in metabolic homeostasis due to 6-hydroxydopamine (6-OHDA) administration, a neurotoxin that damage dopaminergic neurons leading to motor impairments that resemble the ones observed in PD. For this, male Wistar rats received bilateral 6-OHDA administration in the dorsolateral striatum, and the motor and metabolic outcomes were assessed at 7, 21, or 35 days post-surgical procedure. Dexamethasone, a diabetogenic glucocorticoid (GC), was intraperitoneally administered in the last 6 days to challenge the metabolism and reveal possible metabolic vulnerabilities caused by 6-OHDA. Controls received only vehicles. The 6-OHDA-treated rats displayed a significant decrease in locomotor activity, exploratory behavior, and motor coordination 7 and 35 days after neurotoxin administration. These motor impairments paralleled with no significant alteration in body mass, food intake, glucose tolerance, insulin sensitivity, and biochemical parameters (plasma insulin, triacylglycerol, and total cholesterol levels) until the end of the experimental protocol on days 35–38 post-6-OHDA administration. Moreover, hepatic glycogen and fat content, as well as the endocrine pancreas mass, were not altered in rats treated with 6-OHDA at the day of euthanasia (38th day after neurotoxin administration). None of the diabetogenic effects caused by dexamethasone were exacerbated in rats previously treated with 6-OHDA. Thus, we conclude that bilateral 6-OHDA administration in the striatum causes motor deficits in rats with no impact on glucose and lipid homeostasis and does not exacerbate the adverse effects caused by excess GC. These observations indicate that neurodegeneration of dopaminergic circuits in the 6-OHDA rats does not affect the metabolic outcomes

Prenatal dexamethasone exposure affects mandibular bone and tooth development in rats

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.A exposição pré-natal aos corticosteroides é associada a efeitos adversos importantes no desenvolvimento do feto. Neste estudo foi realizada análise histomorfométrica do osso mandibular e primeiro molar inferior de fetos expostos a glicocorticóide exógeno no período final da gravidez. Para este estudo, seis ratos fêmeas foram alojadas com dois ratos machos durante 8 dias. As ratas grávidas foram divididas em dois grupos (n=3 cada): grupo controle e grupo dexametasona. A dexametasona recebeu 0,2 mg.kg-1.dia-1 dose diária de dexametasona solúvel diluída na água de beber do 14º ao 19º dia de gestação. No 20º dia de gestação, as ratas foram sacrificadas e os fetos coletados. O peso de cada feto foi registrado e, em seguida, foram eutanasiados e a cabeça fixada em formalina tamponada com fosfato a 10%. As amostras selecionadas foram avaliadas por microscopia de luz, sendo registradas as seguintes medidas: perímetro do osso mandibular, cartilagem de Meckel e germe dentário; comprimento vestíbulo-lingual, distância vertical, distância anteroposterior e área do germe dentário, pelo programa Image J. Houve diferença estatística significativa com relação ao peso ao nascer, perímetro mandibular, distância vertical do germe dentário e distância vestíbulo-lingual; a área do germe dental e o perímetro do germe foram menores na dexametasona. Não houve diferença estatística significativa no perímetro da cartilagem de Meckel e na distância anteroposterior do germe dentário entre os grupos. Em conclusão, a exposição pré-natal a dexametasona influencia o desenvolvimento ósseo e dentário da mandíbula

Dexamethasone Administration During Late Gestation Has No Major Impact on Lipid Metabolism, but Reduces Newborn Survival Rate in Wistar Rats

A rise in plasma triacylglycerol levels is a common physiological occurrence during late gestation and excess of glucocorticoids (GCs) has been shown to impair lipid metabolism. Based on those observations, we investigated whether the administration of dexamethasone during the late gestational period could exacerbate this pregnancy associated hypertriacylglycerolemia in rats. For this, female Wistar rats were treated with dexamethasone (0.2 mg/kg of body mass in the drinking water on days 14–19 of pregnancy; DP group) or equivalent days in the virgin rats (DV group). Untreated pregnant rats (control pregnant group) and age-matched virgin rats (control virgin group) were used as controls. Functional, biochemical, and molecular analyses were carried out after treatment with GC and in the control groups. Euthanasia was performed on day 20 of pregnancy. The metabolic parameters of the mothers (dams) at the time of weaning and 6 months later, as well as newborn survival, were evaluated. We observed that neither dexamethasone nor pregnancy affected blood glucose or glucose tolerance. Hypertriacylglycerolemia associated with lipid intolerance or reduced hepatic triacylglycerol clearance was observed during the late gestational period. GC treatment caused a further increase in basal plasma triacylglycerol levels, but did not have a significant effect on lipid tolerance and hepatic triacylglycerol clearance in pregnant rats. GC, but not pregnancy, caused few significant changes in mRNA expression of proteins involved in lipid metabolism. Dexamethasone during pregnancy had no impact on lipid metabolism later in the dams’ life; however, it led to intra-uterine growth restriction and reduced pup survival rate. In conclusion, GC exposure during the late gestational period in rats has no major impact on maternal lipid homeostasis, soon after parturition at weaning, or later in the dams’ life, but GC exposure is deleterious to the newborn when high doses are administered at late gestation. These data highlight the importance of performing an individualized and rigorous control of a GC treatment during late pregnancy considering its harmful impact on the fetuses’ health

Augmented β-cell function and mass in glucocorticoid-treated rodents are associated with increased islet ir-β /AKT/mTOR and decreased AMPK/ACC and AS160 signaling

FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOGlucocorticoid (GC) therapies may adversely cause insulin resistance (IR) that lead to a compensatory hyperinsulinemia due to insulin hypersecretion. The increased β-cell function is associated with increased insulin signaling that has the protein kinase B (AKT) substrate with 160 kDa (AS160) as an important downstream AKT effector. In muscle, both insulin and AMP-activated protein kinase (AMPK) signaling phosphorylate and inactivate AS160, which favors the glucose transporter (GLUT)-4 translocation to plasma membrane. Whether AS160 phosphorylation is modulated in islets from GC-treated subjects is unknown. For this, two animal models, Swiss mice and Wistar rats, were treated with dexamethasone (DEX) (1 mg/kg body weight) for 5 consecutive days. DEX treatment induced IR, hyperinsulinemia, and dyslipidemia in both species, but glucose intolerance and hyperglycemia only in rats. DEX treatment caused increased insulin secretion in response to glucose and augmented β-cell mass in both species that were associated with increased islet content and increased phosphorylation of the AS160 protein. Protein AKT phosphorylation, but not AMPK phosphorylation, was found significantly enhanced in islets from DEX-treated animals. We conclude that the augmented β-cell function developed in response to the GC-induced IR involves inhibition of the islet AS160 protein activity.Glucocorticoid (GC) therapies may adversely cause insulin resistance (IR) that lead to a compensatory hyperinsulinemia due to insulin hypersecretion. The increased β-cell function is associated with increased insulin signaling that has the protein kinase2014114FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOsem informaçãosem informaçã

Dexamethasone during pregnancy impairs maternal pancreatic β-cell renewal during lactation

Pancreatic islets from pregnant rats develop a transitory increase in the pancreatic β-cell proliferation rate and mass. Increased apoptosis during early lactation contributes to the rapid reversal of those morphological changes. Exposure to synthetic glucocorticoids during pregnancy has been previously reported to impair insulin secretion, but its impacts on pancreatic islet morphological changes during pregnancy and lactation have not been described. To address this issue, we assessed the morphological and molecular characteristics of pancreatic islets from rats that underwent undisturbed pregnancy (CTL) or were treated with dexamethasone between the 14th and 19th days of pregnancy (DEX). Pancreatic islets were analyzed on the 20th day of pregnancy (P20) and on the 3rd, 8th, 14th and 21st days of lactation (L3, L8, L14 and L21, respectively). Pancreatic islets from CTL rats exhibited transitory increases in cellular proliferation and pancreatic β-cell mass at P20, which were reversed at L3, when a transitory increase in apoptosis was observed. This was followed by the appearance of morphological features of pancreatic islet neogenesis at L8. Islets from DEX rats did not demonstrate an increase in apoptosis at L3, which coincided with an increase in the expression of M2 macrophage markers relative to M1 macrophage and T lymphocyte markers. Islets from DEX rats also did not exhibit the morphological characteristics of pancreatic islet neogenesis at L8. Our data demonstrate that maternal pancreatic islets undergo a renewal process during lactation that is impaired by exposure to DEX during pregnancy