The bile acid TUDCA reduces age-related hyperinsulinemia in mice.

Aging is associated with glucose metabolism disturbances, such as insulin resistance and hyperinsulinemia, which contribute to the increased prevalence of type 2 diabetes (T2D) and its complications in the elderly population. In this sense, some bile acids have emerged as new therapeutic targets to treat TD2, as well as associated metabolic disorders. The taurine conjugated bile acid, tauroursodeoxycholic acid (TUDCA) improves glucose homeostasis in T2D, obesity, and Alzheimer's disease mice model. However, its effects in aged mice have not been explored yet. Here, we evaluated the actions of TUDCA upon glucose-insulin homeostasis in aged C57BL/6 male mice (18-month-old) treated with 300 mg/kg of TUDCA or its vehicle. TUDCA attenuated hyperinsulinemia and improved glucose homeostasis in aged mice, by enhancing liver insulin-degrading enzyme (IDE) expression and insulin clearance. Furthermore, the improvement in glucose-insulin homeostasis in these mice was accompanied by a reduction in adiposity, associated with adipocyte hypertrophy, and lipids accumulation in the liver. TUDCA-treated aged mice also displayed increased energy expenditure and metabolic flexibility, as well as a better cognitive ability. Taken together, our data highlight TUDCA as an interesting target for the attenuation of age-related hyperinsulinemia and its deleterious effects on metabolism.

Rosiglitazone protects INS-1E cells from human islet amyloid polypeptide toxicity.

Human islet amyloid polypeptide (hIAPP or amylin) is a hormone co-secreted with insulin by pancreatic ß-cells, and is the main component of islet amyloid. Islet amyloid is found in the pancreas of patients with type 2 diabetes and may be involved in ß-cell dysfunction and death, observed in this disease. Thus, counteracting islet amyloid toxicity represents a therapeutic approach to preserve ß-cell mass and function. In this sense, thiazolidinediones (TZDs), as rosiglitazone, have shown protective effects against other harmful insults to ß-cells. For this reason, we investigated whether rosiglitazone could protect ß-cells from hIAPP-induced cell death and the underlying mechanisms mediating such effect. Here, we show that rosiglitazone improved the viability of hIAPP-exposed INS-1E cells. This benefit is not dependent on the insulin-degrading enzyme (IDE) since rosiglitazone did not modulate IDE protein content and activity. However, rosiglitazone inhibited hIAPP fibrillation and decreased hIAPP-induced expression of C/EBP homologous protein (CHOP) (CTL 100.0 ± 8.4; hIAPP 182.7 ± 19.1; hIAPP + RGZ 102.8 ± 9.5), activating transcription factor-4 (ATF4) (CTL 100.0 ± 3.1; hIAPP 234.9 ± 19.3; hIAPP + RGZ 129.6 ± 3.0) and phospho-eukaryotic initiation factor 2-alpha (p-eIF2α) (CTL 100.0 ± 31.1; hIAPP 234.1 ± 36.2; hIAPP + RGZ 150.4 ± 18.0). These findings suggest that TZDs treatment may be a promising approach to preserve ß-cell mass and function by inhibiting islet amyloid formation and decreasing endoplasmic reticulum stress hIAPP-induced.

Islet amyloid toxicity: From genesis to counteracting mechanisms.

Islet amyloid polypeptide (IAPP or amylin) is a hormone co-secreted with insulin by pancreatic ß-cells and is the major component of islet amyloid. Islet amyloid is found in the pancreas of patients with type 2 diabetes (T2D) and may be involved in ß-cell dysfunction and death, observed in this disease. Thus, investigating the aspects related to amyloid formation is relevant to the development of strategies towards ß-cell protection. In this sense, IAPP misprocessing, IAPP overproduction, and disturbances in intra- and extracellular environments seem to be decisive for IAPP to form islet amyloid. Islet amyloid toxicity in ß-cells may be triggered in intra- and/or extracellular sites by membrane damage, endoplasmic reticulum stress, autophagy disruption, mitochondrial dysfunction, inflammation, and apoptosis. Importantly, different approaches have been suggested to prevent islet amyloid cytotoxicity, from inhibition of IAPP aggregation to attenuation of cell death mechanisms. Such approaches have improved ß-cell function and prevented the development of hyperglycemia in animals. Therefore, counteracting islet amyloid may be a promising therapy for T2D treatment.

Offspring from trained male mice inherit improved muscle mitochondrial function through PPAR co-repressor modulation.

Aim Investigate whether inheritance of improved skeletal muscle mitochondrial function and its association with glycemic control are multigenerational benefits of exercise. MAIN METHODS: Male Swiss mice were subjected to 8 weeks of endurance training and mated with untrained females. KEY FINDINGS: Trained fathers displayed typical endurance training-induced adaptations. Remarkably, offspring from trained fathers also exhibited higher endurance performance, mitochondrial oxygen consumption, glucose tolerance and insulin sensitivity. However, PGC-1α expression was not increased in the offspring. In the offspring, the expression of the co-repressor NCoR1 was reduced, increasing activation of PGC-1α target genes. These effects correlated with higher DNA methylation at the NCoR1 promoter in both, the sperm of trained fathers and in the skeletal muscle of their offspring. SIGNIFICANCE: Higher skeletal muscle mitochondrial function is inherited by epigenetic de-activation of a key PGC-1α co-repressor.

Energy homeostasis deregulation is attenuated by TUDCA treatment in streptozotocin-induced Alzheimer's disease mice model.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia. While cognitive deficits remain the major manifestation of AD, metabolic and non-cognitive abnormalities, such as alterations in food intake, body weight and energy balance are also present, both in AD patients and animal models. In this sense, the tauroursodeoxycholic acid (TUDCA) has shown beneficial effects both in reducing the central and cognitive markers of AD, as well as in attenuating the metabolic disorders associated with it. We previously demonstrated that TUDCA improves glucose homeostasis and decreases the main AD neuromarkers in the streptozotocin-induced AD mouse model (Stz). Besides that, TUDCA-treated Stz mice showed lower body weight and adiposity. Here, we investigated the actions of TUDCA involved in the regulation of body weight and adiposity in Stz mice, since the effects of TUDCA in hypothalamic appetite control and energy homeostasis have not yet been explored in an AD mice model. The TUDCA-treated mice (Stz + TUDCA) displayed lower food intake, higher energy expenditure (EE) and respiratory quotient. In addition, we observed in the hypothalamus of the Stz + TUDCA mice reduced fluorescence and gene expression of inflammatory markers, as well as normalization of the orexigenic neuropeptides AgRP and NPY expression. Moreover, leptin-induced p-JAK2 and p-STAT3 signaling in the hypothalamus of Stz + TUDCA mice was improved, accompanied by reduced acute food intake after leptin stimulation. Taken together, we demonstrate that TUDCA treatment restores energy metabolism in Stz mice, a phenomenon that is associated with reduced food intake, increased EE and improved hypothalamic leptin signaling. These findings suggest treatment with TUDCA as a promising therapeutic intervention for the control of energy homeostasis in AD individuals.

Effects of growth hormone-releasing hormone agonistic analog MR-409 on insulin-secreting cells under cyclopiazonic acid-induced endoplasmic reticulum stress.

The endoplasmic reticulum (ER) stress is one of the mechanisms related to decreased insulin secretion and beta cell death, contributing to the progress of type 2 diabetes mellitus (T2D). Thus, investigating agents that can influence this process would help prevent the development of T2D. Recently, the growth-hormone-releasing hormone (GHRH) action has been demonstrated in INS-1E cells, in which it increases cell proliferation and insulin secretion. As the effects of GHRH and its agonists have not been fully elucidated in the beta cell, we proposed to investigate them by evaluating the role of the GHRH agonist, MR-409, in cells under ER stress. Our results show that the agonist was unable to ameliorate or prevent ER stress. However, cells exposed to the agonist showed less oxidative stress and greater survival even under ER stress. The mechanisms by which GHRH agonist, MR-409, leads to these outcomes require further investigation.

Aging Reduces Insulin Clearance in Mice.

Hyperinsulinemia is frequently associated with aging and may cause insulin resistance in elderly. Since insulin secretion and clearance decline with age, hyperinsulinemia seems to be maintained, primarily, due to a decrease in the insulin clearance. To investigate these aging effects, 3- and 18-month-old male C57BL/6 mice were subjected to intraperitoneal glucose and insulin tolerance tests (ipGTT and ipITT) and, during the ipGTT, plasma c-peptide and insulin were measure to evaluate in vivo insulin clearance. Glucose-stimulated insulin secretion in isolated pancreatic islets was also assessed, and liver samples were collected for molecular analyses (western blot). Although insulin sensitivity was not altered in the old mice, glucose tolerance, paradoxically, seems to be increased, accompanied by higher plasma insulin, during ipGTT. While insulin secretion did not increase, insulin clearance was reduced in the old mice, as suggested by the lower c-peptide:insulin ratio, observed during ipGTT. Carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM1) and insulin-degrading enzyme (IDE), as well as the activity of this enzyme, were reduced in the liver of old mice, justifying the decreased insulin clearance observed in these mice. Therefore, loss of hepatic CEACAM1 and IDE function may be directly related to the decline in insulin clearance during aging.

Reduced insulin sensitivity and increased ß/α cell mass is associated with reduced hepatic insulin-degrading enzyme activity in pregnant rats.

AIMS: Pregnancy is associated with the development of a transitory insulin resistance that parallels with the upregulation of pancreatic ß-cell function and mass. These metabolic adaptations guarantee the higher insulin demand, but there is no evidence of whether insulin clearance contributes to this process. Thus, we investigated some of the hepatic parameters related to insulin clearance during rat pregnancy. We also investigated some molecular parameters in the hypothalamus. MAIN METHODS: We evaluated the body mass and food intake, insulin sensitivity, ß- and α-cell masses, insulin clearance based on an exogenous insulin load, hepatic insulin-degrading enzyme (IDE) activity, and hepatic and hypothalamic protein content of IDE and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1) in three periods of gestation in Wistar rats. KEY FINDINGS: In the first week of pregnancy, both insulin sensitivity and clearance increased, a pattern that inverted in the third week of gestation (reduced insulin sensitivity and clearance). Diminished insulin clearance was associated with lower hepatic IDE activity and higher pancreatic ß- and α-cell masses. No alteration in the hepatic IDE and CEACAM protein content was observed throughout pregnancy, but hypothalamic IDE protein content was significantly reduced in the late gestation period. SIGNIFICANCE: In conclusion, elevated insulin demand in the late period of gestation occurs not only as a result of increased ß-cell mass and function but also by a potential reduction in hepatic insulin clearance. Knowing this physiological process may be valuable when considering gestational diabetes mellitus results from a failure in insulin supply during pregnancy.

Paternal Exercise Improves the Metabolic Health of Offspring via Epigenetic Modulation of the Germline.

BACKGROUND/AIMS: Epigenetic regulation is considered the main molecular mechanism underlying the developmental origin of health and disease's (DOHAD) hypothesis. Previous studies that have investigated the role of paternal exercise on the metabolic health of the offspring did not control for the amount and intensity of the training or possible effects of adaptation to exercise and produced conflicting results regarding the benefits of parental exercise to the next generation. We employed a precisely regulated exercise regimen to study the transgenerational inheritance of improved metabolic health. METHODS: We subjected male mice to a well-controlled exercise -training program to investigate the effects of paternal exercise on glucose tolerance and insulin sensitivity in their adult progeny. To investigate the molecular mechanisms of epigenetic inheritance, we determined chromatin markers in the skeletal muscle of the offspring and the paternal sperm. RESULTS: Offspring of trained male mice exhibited improved glucose homeostasis and insulin sensitivity. Paternal exercise modulated the DNA methylation profile of PI3Kca and the imprinted H19/Igf2 locus at specific differentially methylated regions (DMRs) in the skeletal muscle of the offspring, which affected their gene expression. Remarkably, a similar DNA methylation profile at the PI3Kca, H19, and Igf2 genes was present in the progenitor sperm indicating that exercise-induced epigenetic changes that occurred during germ cell development contributed to transgenerational transmission. CONCLUSION: Paternal exercise might be considered as a strategy that could promote metabolic health in the offspring as the benefits can be inherited transgenerationally.

The bile acid TUDCA improves glucose metabolism in streptozotocin-induced Alzheimer's disease mice model.

Alzheimer's disease (AD) is a neurodegenerative disorder and the major cause of dementia. According to predictions of the World Health Organization, more than 150 million people worldwide will suffer from dementia by 2050. An increasing number of studies have associated AD with type 2 diabetes mellitus (T2DM), since most of the features found in T2DM are also observed in AD, such as insulin resistance and glucose intolerance. In this sense, some bile acids have emerged as new therapeutic targets to treat AD and metabolic disorders. The taurine conjugated bile acid, tauroursodeoxycholic (TUDCA), reduces amyloid oligomer accumulation and improves cognition in APP/PS1 mice model of AD, and also improves glucose-insulin homeostasis in obese and type 2 diabetic mice. Herein, we investigated the effect of TUDCA upon glucose metabolism in streptozotocin-induced AD mice model (Stz). The Stz mice that received 300 mg/kg TUDCA during 10 days (Stz + TUDCA), showed improvement in glucose tolerance and insulin sensitivity, reduced fasted and fed glycemia, increased islet mass and ß-cell area, as well as increased glucose-stimulated insulin secretion, compared with Stz mice that received only PBS. Stz + TUDCA mice also displayed lower neuroinflammation, reduced protein content of amyloid oligomer in the hippocampus, improved memory test and increased protein content of insulin receptor ß-subunit in the hippocampus. In conclusion, TUDCA treatment enhanced glucose homeostasis in the streptozotocin-induced Alzheimer's disease mice model, pointing this bile acid as a good strategy to counteract glucose homeostasis disturbance in AD pathology.

ARHGAP21 Acts as an Inhibitor of the Glucose-Stimulated Insulin Secretion Process.

ARHGAP21 is a RhoGAP protein implicated in the modulation of insulin secretion and energy metabolism. ARHGAP21 transient-inhibition increase glucose-stimulated insulin secretion (GSIS) in neonatal islets; however, ARHGAP21 heterozygote mice have a reduced insulin secretion. These discrepancies are not totally understood, and it might be related to functional maturation of beta cells and peripheral sensitivity. Here, we investigated the real ARHGAP21 role in the insulin secretion process using an adult mouse model of acute ARHGAP21 inhibition, induced by antisense. After ARHGAP21 knockdown induction by antisense injection in 60-day old male mice, we investigated glucose and insulin tolerance test, glucose-induced insulin secretion, glucose-induced intracellular calcium dynamics, and gene expression. Our results showed that ARHGAP21 acts negatively in the GSIS of adult islet. This effect seems to be due to the modulation of important points of insulin secretion process, such as the energy metabolism (PGC1α), Ca2+ signalization (SYTVII), granule-extrusion (SNAP25), and cell-cell interaction (CX36). Therefore, based on these finds, ARHGAP21 may be an important target in Diabetes Mellitus (DM) treatment.

Mice born to females with oocyte-specific deletion of mitofusin 2 have increased weight gain and impaired glucose homeostasis.

Offspring born to obese and diabetic mothers are prone to metabolic diseases, a phenotype that has been linked to mitochondrial dysfunction and endoplasmic reticulum (ER) stress in oocytes. In addition, metabolic diseases impact the architecture and function of mitochondria-ER contact sites (MERCs), changes which associate with mitofusin 2 (MFN2) repression in muscle, liver and hypothalamic neurons. MFN2 is a potent modulator of mitochondrial metabolism and insulin signaling, with a key role in mitochondrial dynamics and tethering with the ER. Here, we investigated whether offspring born to mice with MFN2-deficient oocytes are prone to obesity and diabetes. Deletion of Mfn2 in oocytes resulted in a profound transcriptomic change, with evidence of impaired mitochondrial and ER function. Moreover, offspring born to females with oocyte-specific deletion of Mfn2 presented increased weight gain and glucose intolerance. This abnormal phenotype was linked to decreased insulinemia and defective insulin signaling, but not mitochondrial and ER defects in offspring liver and skeletal muscle. In conclusion, this study suggests a link between disrupted mitochondrial/ER function in oocytes and increased risk of metabolic diseases in the progeny. Future studies should determine whether MERC architecture and function are altered in oocytes from obese females, which might contribute toward transgenerational transmission of metabolic diseases.

Prolonged bisphenol-A exposure decreases endocrine pancreatic proliferation in response to obesogenic diet in ovariectomized mice.

Research on the deleterious actions of bisphenol (BP)-A have focused on its effects on insulin secretion during pre/perinatal periods or adulthood. Estrogens also modulate endocrine pancreas physiology in females during aging; however, the effects of BPA on islet morphophysiology after menopause have not been investigated. We evaluated the effects of BPA exposure on glucose homeostasis and islet morphofunction in ovariectomized (OVX) mice fed on a high-fat diet (HFD). Adult Swiss female mice were underwent to bilateral ovariectomy, and with the confirmation of the establishment of surgical menopause, the females were then submitted, or not,to a normolipidic diet or HFD [control (CTL) and HFD groups, respectively] without or with 1 µg/mL BPA in their drinking water (CBPA and HBPA groups) for 90 days. HFD females displayed obesity, hyperglycemia, hyperinsulinemia, glucose intolerance and insulin resistance. BPA did not modulate HFD-induced obesity or body glucose impairments in HBPA females, and islets isolated from both the HFD and HBPA groups exhibited insulin hypersecretion. The HBPA islets, however, displayed enlarged islet cells and reduced proliferation, in association with the downregulation of mRNAs encoding PDX-1, NGN3 and CCND2 and upregulation of mRNAs encoding ER-ß, GPR30, TNF-α and IL-1ß in HBPA islets. BPA consumption in OVX mice impaired the islet-cell hyperplasia response to the HFD, partly mediated by increased expression of ER-ß and GPR30, which impaired the expression of major genes involved in islet-cell survival and functionality. Together with higher pro-inflammatory cytokines expression in the islet milieu, these alterations may accelerate ß-cell failure in postmenopause.

Swimming training reduces glucose-amplifying pathway and cholinergic responses in islets from lean- and MSG-obese rats.

Here, we investigate the effects of exercise training on glucose- and cholinergic-induced insulin secretion in pancreatic islets from obese and lean rats. Male Wistar rats were treated with monosodium glutamate (MSG) for the first 5 days of life, while control (CON) rats received saline. At 21 days, the rats were divided into exercised (EXE) and sedentary (SED) groups. The EXE rats swam for 30 minutes, three times/week, for 10 weeks. After this, MSG-SED rats showed hyperglycaemia, hypertriglyceridaemia and hyperinsulinaemia. Besides, islets from MSG-SED rats exhibited increased glucose-stimulated insulin secretion (GSIS), followed by impaired glucose sensitivity, absence of glucose-amplifying pathway and weak cholinergic response. In contrast, adiposity, hyperinsulinaemia and hypertriglyceridaemia were reduced in MSG-EXE rats. Moreover, islets from MSG-EXE rats exhibited lower GSIS and improved islet glucose sensitivity, without restoration of the glucose-amplifying pathway or alteration in the weak cholinergic effect of these islets. In islets from CON-EXE rats we also observed reduced GSIS and absence of glucose-amplifying effects and an accentuated reduction in cholinergic insulinotropic responses, without effect on glucose sensitivity in pancreatic islets from this group. Neither obesity nor exercise modified Muscarinic Receptor 3 (M3R) immunocontent or its downstream pathways (PKC and PKA). Moreover, only CON-EXE showed increased GSIS in the presence of calcium blocker, Thapsigargin. In conclusion, swimming training reduces GSIS and cholinergic responsiveness in isolated pancreatic islets from lean and hypothalamic obese rats, which could be due to the inhibition of glucose-amplifying pathways.

Hyperinsulinemia is associated with increasing insulin secretion but not with decreasing insulin clearance in an age-related metabolic dysfunction mice model.

Human life expectancy is increasing faster lately and, consequently, the number of patients with age-related diseases such as type 2 diabetes (T2D) is rising every year. Cases of hyperinsulinemia have been extensively reported in elderly subjects and this alteration in blood insulin concentration is postulated to be a cause of insulin resistance, which in some cases triggers T2D onset. Thus, it is important to know the underlying mechanisms of age-dependent hyperinsulinemia to find new strategies to prevent T2D in elderly subjects. Two processes control blood insulin concentration: Insulin secretion by the endocrine portion of the pancreas and insulin clearance, which occurs mainly in the liver by the action of the insulin-degrading enzyme (IDE). Here, we demonstrated that 10-month-old mice (old) display increased body and fat pad weight, compared with 3-month-old mice (control), and these alterations were accompanied by glucose and insulin intolerance. We also confirm hyperinsulinemia in the old mice, which was related to increased insulin secretion but not to reduced insulin clearance. Although no changes in insulin clearance were observed, IDE activity was lower in the liver of old compared with the control mice. However, this decreased IDE activity was compensated by increased expression of IDE protein in the liver, thus explaining the similar insulin clearance observed in both groups. In conclusion, at the beginning of aging, 10-month-old mice do not display any alterations in insulin clearance. Therefore, hyperinsulinemia is initiated primarily due to a higher insulin secretion in the age-related metabolic dysfunction in mice.

Glucose intolerance in monosodium glutamate obesity is linked to hyperglucagonemia and insulin resistance in α cells.

Obesity predisposes to glucose intolerance and type 2 diabetes (T2D). This disease is often characterized by insulin resistance, changes in insulin clearance, and ß-cell dysfunction. However, studies indicate that, for T2D development, disruptions in glucagon physiology also occur. Herein, we investigated the involvement of glucagon in impaired glycemia control in monosodium glutamate (MSG)-obese mice. Male Swiss mice were subcutaneously injected daily, during the first 5 days after birth, with MSG (4 mg/g body weight [BW]) or saline (1.25 mg/g BW). At 90 days of age, MSG-obese mice were hyperglycemic, hyperinsulinemic, and hyperglucagonemic and had lost the capacity to increase their insulin/glucagon ratio when transitioning from the fasting to fed state, exacerbating hepatic glucose output. Furthermore, hepatic protein expressions of phosphorylated (p)-protein kinase A (PKA) and cAMP response element-binding protein (pCREB), and of phosphoenolpyruvate carboxykinase (PEPCK) enzyme were higher in fed MSG, before and after glucagon stimulation. Increased pPKA and phosphorylated hormone-sensitive lipase content were also observed in white fat of MSG. MSG islets hypersecreted glucagon in response to 11.1 and 0.5 mmol/L glucose, a phenomenon that persisted in the presence of insulin. Additionally, MSG α cells were hypertrophic displaying increased α-cell mass and immunoreactivity to phosphorylated mammalian target of rapamycin (pmTOR) protein. Therefore, severe glucose intolerance in MSG-obese mice was associated with increased hepatic glucose output, in association with hyperglucagonemia, caused by the refractory actions of glucose and insulin in α cells and via an effect that may be due to enhanced mTOR activation.

ARHGAP21 as a master regulator of multiple cellular processes.

The cellular cytoskeleton is involved with multiple biological processes and is tightly regulated by multiple proteins and effectors. Among these, the RhoGTPases family is one of the most important players. RhoGTPAses are, in turn, regulated by many other elements. In the past decade, one of those regulators, the RhoGAP Rho GTPase Activating Protein 21 (ARHGAP21), has been overlooked, despite being implied as having an important role on many of those processes. In this paper, we aimed to review the available literature regarding ARHGAP21 to highlight its importance and the mechanisms of action that have been found so far for this still unknown protein involved with cell adhesion, migration, Golgi regulation, cell trafficking, and even insulin secretion.

Nighttime light exposure enhances Rev-erbα-targeting microRNAs and contributes to hepatic steatosis.

OBJECTIVE: The exposure to artificial light at night (ALAN) disrupts the biological rhythms and has been associated with the development of metabolic syndrome. MicroRNAs (miRNAs) display a critical role in fine-tuning the circadian system and energy metabolism. In this study, we aimed to assess whether altered miRNAs expression in the liver underlies metabolic disorders caused by disrupted biological rhythms. RESULTS: We found that C3H/HePas mice exposed to ALAN developed obesity, and hepatic steatosis, which was paralleled by decreased expression of Rev-erbα and up-regulation of its lipogenic targets ACL and FAS in liver. Furthermore, the expression of Rev-erbα-targeting miRNAs, miR-140-5p, 185-5p, 326-5p and 328-5p were increased in this group. Consistently, overexpression of these miRNAs in primary hepatocytes reduced Rev-erbα expression at the mRNA and protein levels. Importantly, overexpression of Rev-erbα-targeting miRNAs increased mRNA levels of Acly and Fasn. CONCLUSION: Thus, altered miRNAs profile is an important mechanism underlying the disruption of the peripheral clock caused by exposure to ALAN, which could lead to hepatic steatosis.

Prolactin protects against cytokine-induced beta-cell death by NFκB and JNK inhibition.

Type 1 diabetes is caused by an autoimmune assault that induces progressive beta-cell dysfunction and dead. Pro-inflammatory cytokines, such as interleukin 1 beta (IL1B), tumor necrosis factor (TNF) and interferon gamma (IFNG) contribute for beta-cell death, which involves the activation of the nuclear factor kappa B (NFκB) and c- Jun N-terminal kinase (JNK). Prolactin (PRL), a physiological mediator for beta-cell proliferation, was shown to protect beta cells against cytokines pro-apoptotic effects. We presently investigated the mechanisms involved in the protective effects of prolactin against cytokine-induced beta-cell death. The findings obtained indicate that STAT3 activation is involved in the anti-apoptotic role of PRL in rat beta cells. PRL prevents the activation of JNK via AKT and promotes a shift from expression of pro- to anti-apoptotic proteins downstream of the JNK cascade. Furthermore, PRL partially prevents the activation of NFκB and the transcription of its target genes IkBa, Fas, Mcp1, A20 and Cxcl10 and also decreases NO production. On the other hand, the pro-survival effects of PRL do not involve modulation of cytokine-induced endoplasmic reticulum stress. These results suggest that the beneficial effects of PRL in beta cells involve augmentation of anti-apoptotic mechanisms and, at the same time, reduction of pro-apoptotic effectors, rendering beta cells better prepared to deal with inflammatory insults. The better understanding of the pro-survival mechanisms modulated by PRL in beta cells can provide tools to prevent cell demise during an autoimmune attack or following islet transplantation.

Whole body ARHGAP21 reduction improves glucose homeostasis in high-fat diet obese mice.

GTPase activating proteins (GAPs) are ubiquitously expressed, and their role in cellular adhesion and membrane traffic processes have been well described. TBC1D1, which is a Rab-GAP, is necessary for adequate glucose uptake by muscle cells, whereas increased TCGAP, which is a Rho-GAP, decreases GLUT4 translocation, and consequently glucose uptake in adipocytes. Here, we assessed the possible involvement of ARHGAP21, a Rho-GAP protein, in glucose homeostasis. For this purpose, wild type mice and ARHGAP21 transgenic whole-body gene-deficiency mice (heterozygous mice, expressing approximately 50% of ARHGAP21) were fed either chow (Ctl and Het) or high-fat diet (Ctl-HFD and Het-HFD). Het-HFD mice showed a reduction in white fat storage, reflected in a lower body weight gain. These mice also displayed an improvement in insulin sensitivity and glucose tolerance, which likely contributed to reduced insulin secretion and pancreatic beta cell area. The reduction of body weight was also observed in Het mice and this phenomenon was associated with an increase in brown adipose tissue and reduced muscle weight, without alteration in glucose-insulin homeostasis. In conclusion, the whole body ARHGAP21 reduction improved glucose homeostasis and protected against diet-induced obesity specifically in Het-HFD mice. However, the mechanism by which ARHGAP21 leads to these outcomes requires further investigation.