The effects of type 1 diabetes on the hypothalamic, pituitary and testes axis

Type 1 diabetes is an autoimmune disorder characterized by a lack of insulin production by the beta cells of the pancreas. This lack of insulin causes a variety of systemic effects on whole-body metabolism. Poorly managed type 1 diabetes can lead to cardiovascular disease, diabetic neuropathy, and diabetic retinopathy. Increasingly, even well-managed type 1 diabetic patients show damage to peripheral organs related to complications from the disease. The central role of insulin in energy homeostasis also renders it an important signaling factor in the reproductive tract. type 1 diabetes has now been demonstrated to cause defects in sperm and testes. The aim of this review is to present the known effects of insulin's role in the function of the male reproductive tract. These effects might be mediated through hormonal alterations in the hypothalamic pituitary gonadal axis or through the direct interaction of insulin on the testes and sperm cells. Although fertility complications also occur in type 2 diabetic males, this review will focus on the defects specifically linked with the lack of insulin seen in type 1 diabetes.     

An intercellular pathway for glucose transport into mouse oocytes

Glucose is an essential nutrient for mammalian cells. Emerging evidence suggests that glucose within the oocyte regulates meiotic maturation. However, it remains controversial as to whether, and if so how, glucose enters oocytes within cumulus-oocyte complexes (COCs). We used a fluorescent glucose derivative (6-NBDG) to trace glucose transport within live mouse COCs and employed inhibitors of glucose transporters (GLUTs) and gap junction proteins to examine their distinct roles in glucose uptake by cumulus cells and the oocyte. We showed that fluorescent glucose enters both cumulus-enclosed and denuded oocytes. Treating COCs with GLUT inhibitors leads to simultaneous decreases in glucose uptake in cumulus cells and the surrounded oocyte but no effect on denuded oocytes. Pharmacological blockade of of gap junctions between the oocyte and cumulus cells significantly inhibited fluorescent glucose transport to oocytes. Moreover, we find that both in vivo hyperglycemic environment and in vitro high-glucose culture increase free glucose levels in oocytes via gap junctional channels. These findings reveal an intercellular pathway for glucose transport into oocytes: glucose is taken up by cumulus cells via the GLUT system and then transferred into the oocyte through gap junctions. This intercellular pathway may partly mediate the effects of high-glucose condition on oocyte quality.     

Ethnobotanical study and conservation status of trees in the district Sargodha,Punjab, Pakistan

Sargodha district is one of the least studied regions of Pakistan regarding its ethnobotanical values. This paper is the first report related to the documentation and conservation status of the tree species in the Sargodha district, and their folk ethnobotanical uses. An interview base survey was conducted in the study area in 2010-2013. The ethnobotanical data revealed the use of 100 tree species (6 gymnosperms, 94 angiosperms) belonging to 77 genera (6 gymnosperms, 71 angiosperms) and 39 families (4 gymnosperms, 35 angiosperms), with the Fabaceae ranking first with 19 tree species, followed by the Moraceae (12 species). Tree species like Aegle marmelos, Butea monosperma, Diospyrus malabarica, Gmelina arborea, Kigelia africana, Manilkara hexandra, Manilkara zapota, Mimusops elengi, Nyctanthes arbor-tristis, Putranjiva roxburghii, Terminalia arjuna and Terminalia bellerica are not only unique in their medicinal value but also interesting because of their unusual occurrence here. Thevetia peruviana, Cassia fistula, Celtis australis, Delonix regia, Diospyrus malabarica, Grevillea robusta, Haplophragma adenophylum, Jacaranda mimosifolia, Lagerstroemia speciosa, Plumeria rubra, Pterospermum acerifolium, Roystonea regia, Taxodium distichum and Tectona grandis are included among the worth looking ornamental tree species. Capparis decidua, Dalbergia sissoo, Tamarix aphylla, Tamarix dioica, Prosopis cineraria and Ziziphus mauritiana are the most commonly used timber species. Other common ethnobotanical utilization of these trees includes either sheltering or fuel or agricultural uses. Lack of awareness about the potential uses of these species, and particularly ignorance of the concerned authorities, have led to a decline in the population of this precious tree flora. Documentation of this tree flora, and as-sociated indigenous knowledge, can be used as a basis for developing management plans for conservation and sustainable use of this flora in the study area. A well-organized management is critical to restore and conserve this endangered natural resource in the District Sargodha, Pakistan. The immense medicinal and timber value of these tree species make it necessary to promote their conservation to simultaneously alleviate the poverty and improve the socio-economic status of the study area.     

Role of glucose in cloned mouse embryo development

Cloned mouse embryos display a marked preference for glucose-containing culture medium, with enhanced development to the blastocyst stage in glucose-containing medium attributable mainly to an early beneficial effect during the first cell cycle. This early beneficial effect of glucose is not displayed by parthenogenetic, fertilized, or tetraploid nuclear transfer control embryos, indicating that it is specific to diploid clones. Precocious localization of the glucose transporter SLC2A1 to the cell surface, as well as increased expression of glucose transporters and increased uptake of glucose at the one- and two-cell stages, is also seen in cloned embryos. To examine the role of glucose in early cloned embryo development, we examined glucose metabolism and associated metabolites, as well as mitochondrial ultrastructure, distribution, and number. Clones prepared with cumulus cell nuclei displayed significantly enhanced glucose metabolism at the two-cell stage relative to parthenogenetic controls. Despite the increase in metabolism, ATP content was reduced in clones relative to parthenotes and fertilized controls. Clones at both stages displayed elevated concentrations of glycogen compared with parthenogenetic controls. There was no difference in the number of mitochondria, but clone mitochondria displayed ultrastructural alterations. Interestingly, glucose availability positively affected mitochondrial structure and localization. We conclude that cloned embryos may be severely compromised in terms of ATP-dependent processes during the first two cell cycles and that glucose may exert its early beneficial effects via positive effects on the mitochondria.     

Studies with GIP/Ins cells indicate secretion by gut K cells is KATP channel independent

K cells are a subpopulation of enteroendocrine cells that secrete glucose-dependent insulinotropic polypeptide (GIP), a hormone that promotes glucose homeostasis and obesity. Therefore, it is important to understand how GIP secretion is regulated. GIP-producing (GIP/Ins) cell lines secreted hormones in response to many GIP secretagogues except glucose. In contrast, glyceraldehyde and methyl pyruvate stimulated hormone release. Measurements of intracellular glucose 6-phosphate, fructose 1,6-bisphosphate, and pyruvate levels, as well as glycolytic flux, in glucose-stimulated GIP/Ins cells indicated that glycolysis was not impaired. Analogous results were obtained using glucose-responsive MIN6 insulinoma cells. Citrate levels increased similarly in glucose-treated MIN6 and GIP/Ins cells. Thus pyruvate entered the tricarboxylic acid cycle. Glucose and methyl pyruvate stimulated 1.4- and 1.6-fold increases, respectively, in the ATP-to-ADP ratio in GIP/Ins cells. Glyceraldehyde profoundly reduced, rather than increased, ATP/ADP. Thus nutrient-regulated secretion is independent of the ATP-dependent potassium (K(ATP)) channel. Antibody staining of mouse intestine demonstrated that enteroendocrine cells producing GIP, glucagon-like peptide-1, CCK, or somatostatin do not express detectable levels of inwardly rectifying potassium (Kir) 6.1 or Kir 6.2, indicating that release of these hormones in vivo may also be K(ATP) channel independent. Conversely, nearly all cells expressing chromogranin A or substance P and approximately 50% of the cells expressing secretin or serotonin exhibited Kir 6.2 staining. Compounds that activate calcium mobilization were potent secretagogues for GIP/Ins cells. Secretion was only partially inhibited by verapamil, suggesting that calcium mobilization from intracellular and extracellular sources, independent from K(ATP) channels, regulates secretion from some, but not all, subpopulations of enteroendocrine cells.     

Decreased glucose transporter expression triggers BAX-dependent apoptosis in the murine blastocyst

We report that a decrease in facilitative glucose transporter (GLUT1) expression and reduced glucose transport trigger apoptosis in the murine blastocyst. Inhibition of GLUT1 expression either by high glucose conditions or with antisense oligodeoxynucleotides significantly lowers protein expression and function of GLUT1 and as a result induces a high rate of apoptosis at the blastocyst stage. Similar to wild-type mice, embryos from streptozotocin-induced diabetic Bax -/- mice experienced a significant decrease in glucose transport compared with embryos from non-diabetic Bax -/- mice. However, despite this decrease, these blastocysts demonstrate significantly fewer apoptotic nuclei as compared with blastocysts from hyperglycemic wild-type mice. This decrease in preimplantation apoptosis correlates with a decrease in resorptions and malformations among the infants of the hyperglycemic Bax -/- mice versus the Bax +/+ and +/- mice. These findings suggest that hyperglycemia by decreasing glucose transport acts as a cell death signal to trigger a BAX-dependent apoptotic cascade in the murine blastocyst. This work also supports the hypothesis that increased apoptosis at a blastocyst stage because of maternal hyperglycemia may result in loss of key progenitor cells and manifest as a resorption or malformation, two adverse pregnancy outcomes more common in diabetic women.     

Glucose transport and apoptosis

The transport and metabolism of glucose modify programmed cell death in a number of different cell types. This review presents three cell death paradigms that link a decrease in glucose transport to apoptosis. Although these pathways overlap, the glucose-dependent stimuli that trigger cell death differ. These paradigms include glucose deprivation-induced ATP depletion and stimulation of the mitochondrial death pathway cascade; glucose deprivation-induced oxidative stress and triggering of Bax-associated events including the JNK/MAPK signalling pathways; and finally hypoglycemia-regulated expression of HIF-1, stabilization of p53 leading to an increase in p53-associated apoptosis. Several examples of each paradigm are presented. Future studies of glucose transport-associated apoptotic events will allow better understanding of the role of cellular metabolism in programmed cell death.