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- Recent advances in cell replacement therapies for the treatment of type 1 diabetes. [JOURNAL ARTICLE]
- Endocrinology 2014 Nov 11.:en20141691.
Exogenous insulin administration is currently the only treatment available to all type 1 diabetes patients, but it is not a cure. By helping to regulate circulating blood glucose levels, it has significantly improved life expectancy, but there are still long-term complications associated with the disease, that may be preventable with a treatment strategy that can provide better glycemic control. Isolated islet (or whole pancreas) transplantation, xenotransplantation, and the transplant of human pluripotent stem cell-derived β-cells provide the potential to restore endogenous insulin production and re-establish normoglycemia. Here we discuss the latest advances in these fields, including the use of encapsulation technology, as well as some of the hurdles that still need to be overcome for these alternative therapies to become mainstream and/or progress to clinical development.
- Mitigating or Exacerbating Effects of Maternal-Fetal Programming of Female Mice Through the Food Choice Environment. [JOURNAL ARTICLE]
- Endocrinology 2014 Nov 11.:en20141523.
Humans live, eat, and become overweight/obese in complex surroundings where there are many available food choices. Prenatal exposure to poor food choices predisposes offspring to increased negative health risks, including obesity. Many animal experiments have analyzed intergenerational body weight parameters in an environment without food choices, which may not be directly translatable to the human food environment. In this study, offspring from mothers with a defined high fat or low fat diet were arbitrarily assigned to either an exclusively low fat diet (LFD), a high fat diet (HFD), or to a diet where they have a choice between LFD and HFD (CHOICE). Offspring displayed negative outcomes of increased body weight, body fat, serum leptin and blood glucose levels when given the CHOICE diet, as compared to offspring on LFD. Conversely, improved energy expenditure was found for offspring given the CHOICE diet, compared to offspring from HFD dams given LFD. In addition, maternal diet-specific influences on offspring metabolic parameters were identified, especially in offspring from HFD dams, including positive outcomes of reduced leptin in LFD offspring, reduced corticosterone and cholesterol levels in HFD offspring, and increased exercise levels in CHOICE offspring, as well as the negative outcome of increased calorie intake in LFD offspring from HFD dams. This defined model can now be used as the basis for future studies to characterize the cycle of inter and intragenerational obesity, and whether more realistic diet environments, especially those including choice, can mitigate phenotype.
- Diabetes: β cells at last. [JOURNAL ARTICLE]
- Nat Rev Endocrinol 2014 Nov 11.
- Neuroendocrinology: Role for adiponectin in effects of exercise in depression. [JOURNAL ARTICLE]
- Nat Rev Endocrinol 2014 Nov 11.
- Paraganglioma and phaeochromocytoma: from genetics to personalized medicine. [REVIEW]
- Nat Rev Endocrinol 2014 Nov 11.
Paragangliomas and phaeochromocytomas are neuroendocrine tumours whose pathogenesis and progression are very strongly influenced by genetics. A germline mutation in one of the susceptibility genes identified so far explains ∼40% of all cases; the remaining 60% are thought to be sporadic cases. At least one-third of these sporadic tumours contain a somatic mutation in a predisposing gene. Genetic testing, which is indicated in every patient, is guided by the clinical presentation as well as by the secretory phenotype and the immunohistochemical characterization of the tumours. The diagnosis of an inherited form drives clinical management and tumour surveillance. Different 'omics' profiling methods have provided a neat classification of these tumours in accordance with their genetic background. Transcriptomic studies have identified two main molecular pathways that underlie development of these tumours, one in which the hypoxic pathway is activated (cluster 1) and another in which the MAPK and mTOR (mammalian target of rapamycin) signalling pathways are activated (cluster 2). DNA methylation profiling has uncovered a hypermethylator phenotype in tumours related to SDHx genes (a group of genes comprising SDHA, SDHB, SDHC, SDHD and SDHAF2) and revealed that succinate acts as an oncometabolite, inhibiting 2-oxoglutarate-dependent dioxygenases, such as hypoxia-inducible factor prolyl-hydroxylases and histone and DNA demethylases. 'Omics' data have suggested new therapeutic targets for patients with a malignant tumour. In the near future, new 'omics'-based tests are likely to be transferred into clinical practice with the goal of establishing personalized medical management for affected patients.
- Expression and distribution of glucagon-like peptide-1 receptor mRNA, protein and binding in the male nonhuman primate (Macaca mulatta) brain. [JOURNAL ARTICLE]
- Endocrinology 2014 Nov 7.:en20141675.
Glucagon-like peptide-1 (GLP-1) is released from endocrine L-cells lining the gut in response to food ingestion. However, GLP-1 is also produced in the nucleus of the solitary tract (NTS) where it acts as an anorectic neurotransmitter and key regulator of many autonomic and neuroendocrine functions. The expression and projections of GLP-1-producing neurons is highly conserved between rodent and primate brain, although a few key differences have been identified. The GLP-1 receptor (GLP-1R) has been mapped in the rodent brain, but no studies have described the distribution of GLP-1Rs in the nonhuman primate central nervous system. Here, we characterized the distribution of GLP-1R mRNA and protein in the adult macaque brain using in situ hybridization, radioligand receptor autoradiography and immunohistochemistry with a primate specific GLP-1R antibody. Immunohistochemistry demonstrated that the GLP-1R is localized to cell bodies and fiber terminals in a very selective distribution throughout the brain. Consistent with the functional role of the GLP-1R system, we find the highest concentration of GLP-1R-immunoreactivity present in select hypothalamic and brainstem regions that regulate feeding including the paraventricular and arcuate hypothalamic nuclei, as well as the area postrema, NTS, and dorsal motor nucleus of the vagus. Together, our data demonstrate that GLP-1R distribution is highly conserved between rodent and primate although a few key species differences were identified including the amygdala where GLP-1R expression is much higher in primate than in rodent.
- Role of Retinoic Acid and Platelet-Derived Growth Factor Receptor crosstalk in the regulation of neonatal gonocyte and embryonal carcinoma cell differentiation. [JOURNAL ARTICLE]
- Endocrinology 2014 Nov 7.:en20141524.
Neonatal gonocytes are direct precursors of spermatogonial stem cells, the cell pool that supports spermatogenesis. Although unipotent in vivo, gonocytes express pluripotency genes common with embryonic stem cells. Previously, we found that all-trans retinoic acid (RA) induced the expression of differentiation markers and a truncated form of PDGFRβ in rat gonocytes, as well as in F9 mouse embryonal carcinoma cells, an embryonic stem cell-surrogate that expresses somatic lineage markers in response to RA. The present study is focused on identifying the signaling pathways involved in RA-induced gonocyte and F9 cell differentiation. MEK1/2 activation was required during F9 cell differentiation towards somatic lineage, whereas its inhibition potentiated RA-induced Stra8 expression, suggesting that MEK1/2 acts as a lineage specification switch in F9 cells. In both cell types, RA increased the expression of the spermatogonial/pre-meiotic marker Stra8, which is in line with F9 cells being at a stage prior to somatic-germline lineage specification. Inhibiting PDGFR kinase activity reduced RA-induced Stra8 expression. Interestingly, RA increased the expression of PDGFRα variant forms in both cell types. Together, these results suggest a potential crosstalk between RA and PDGFR signaling pathways in cell differentiation. RARα inhibition partially reduced RA effects on Stra8 in gonocytes, indicating that RA acts in part via RARα. RA-induced gonocyte differentiation was significantly reduced by inhibiting SRC and JAK2/STAT5 activities, implying that these signaling molecules play a role in gonocyte differentiation. These results suggest that gonocyte and F9 cell differentiation is regulated via crosstalk between RA and PDGFRs using different downstream pathways.
- ErbB receptor-driven prolactinomas respond to targeted lapatinib treatment in female transgenic mice. [JOURNAL ARTICLE]
- Endocrinology 2014 Nov 6.:en20141627.
As ErbB receptors are expressed in prolactinomas and exhibit downstream effects on PRL production and cell proliferation, we generated transgenic mice using a PRL enhancer/promoter expression system to restrict lactotroph-specific expression of human epidermal growth factor receptor (EGFR) or human epidermal growth factor receptor 2 (HER2). EGFR or HER2 transgenic mice developed prolactinomas between 13 and 15 months, and confocal immunofluorescence and western blotting analysis confirmed lactotroph-restricted PRL and EGFR or HER2 co-expression. Serum prolactin (PRLlevels in EGFR and HER2 transgenic mice were increased 5- and 3.8-fold, respectively. Inhibiting EGFR or HER2 signaling with oral lapatinib (100 mg/kg), a dual tyrosine kinase inhibitor (TKI) for both EGFR and HER2, suppressed serum PRL by 72 and attenuated tumor PRL expression by 80 %, and also attenuated downstream tumor EGFR/HER2 signaling. This model demonstrates the role of ErbB receptors underlying prolactinoma tumorigenesis, and the feasibility of targeting these receptors for translation to treatment of refractory prolactinomas.
- TLR4 expression in bone marrow-derived cells is both necessary and sufficient to produce the insulin resistance phenotype in diet-induced obesity. [JOURNAL ARTICLE]
- Endocrinology 2014 Nov 6.:en20141552.
The anomalous activation of toll-like receptor 4 (TLR4) by dietary fats is one of the most important mechanisms linking obesity to insulin resistance. TLR4 is expressed in most tissues of the body, but its activity in cells of the immune system is expected to underlie its most important roles of inducing inflammation and insulin resistance. Here, we explore the hypothesis that TLR4 expression in bone marrow-derived cells mediates most of the actions of this receptor as an inducer of insulin resistance. Wild type and TLR4-mutant mice were employed in bone marrow transplant experiments producing chimeras that harbored the functional receptor in all cells of the body except bone marrow-derived cells or only in bone marrow-derived cells. Transplanted mice were fed chow or a high-fat diet, and glucose homeostasis was evaluated by glucose and insulin tolerance tests. Insulin signal transduction and the expression of markers of inflammation were evaluated in the liver and white adipose tissue. In addition, we performed liver histology and evaluated the expression of gluconeogenic enzymes. The expression of TLR4 in bone marrow-derived cells only, but not in non-bone-marrow-derived tissues only, was a determining factor in the induction of diet-induced insulin resistance, which was accompanied by increased expression of inflammatory markers in both white adipose tissue and liver as well as increased liver steatosis and increased expression of gluconeogenic enzymes. TLR4 expressed in bone marrow-derived cells is an important mediator of obesity-associated insulin resistance in mice.
- Anogenital distance (AGD) plasticity in adulthood: Implications for its use as a biomarker of fetal androgen action. [JOURNAL ARTICLE]
- Endocrinology 2014 Nov 6.:en20141534.
Androgen action during the fetal masculinization-programming window (MPW) determines the maximum potential for growth of androgen-dependent organs (e.g. seminal vesicles, prostate, penis, perineum) and is reflected in anogenital distance (AGD). As such, determining AGD in postnatal life has potential as a lifelong easily accessible biomarker of overall androgen action during the MPW. However, whether the perineum remains androgen-responsive in adulthood and thus responds plastically to perturbed androgen drive remains unexplored. To determine this, we treated adult male rats with either the anti-androgen Flutamide, or the estrogen Diethylstilbestrol (DES) for five weeks, followed by a four-week wash-out period of no treatment. We determined AGD, and its correlate anogenital index (AGI; AGD relative to bodyweight), at weekly intervals across this period and compared this to normal adult rats (male and female), castrated male rats, and appropriate vehicle controls. These data showed that, in addition to reducing circulating testosterone and seminal vesicle weight, castration significantly reduced AGD (by ∼17), demonstrating that there is a degree of plasticity in AGD in adulthood. Flutamide treatment increased circulating testosterone yet also reduced seminal vesicle weight due to local antagonism of androgen receptor. Despite this suppression, surprisingly, Flutamide treatment had no effect on AGD at any time-point. In contrast, whilst DES treatment suppressed circulating testosterone and reduced seminal vesicle weight, it also induced a significant reduction in AGD (by ∼11%), which returned to normal one week after cessation of DES treatment. We conclude that AGD in adult rats exhibits a degree of plasticity, which may be mediated by modulating local androgen/estrogen action. The implications of these findings regarding the use of AGD as a life-long clinical biomarker of fetal androgen action are discussed.