Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The endocrine cells of the rat pancreatic islets of Langerhans, including insulin-producing beta-cells, turn over every 40-50 days by processes of apoptosis and the proliferation and differentiation of new islet cells (neogenesis) from progenitor epithelial cells located in the pancreatic ducts. However, the administration to rats of islet trophic factors such as glucose or glucagon-like peptide 1 for 48 h results in a doubling of islet cell mass, suggesting that islet progenitor cells may reside within the islets themselves. Here we show that rat and human pancreatic islets contain a heretofore unrecognized distinct population of cells that express the neural stem cell-specific marker nestin. Nestin-positive cells within pancreatic islets express neither the hormones insulin, glucagon, somatostatin, or pancreatic polypeptide nor the markers of vascular endothelium or neurons, such as collagen IV and galanin. Focal regions of nestin-positive cells are also identified in large, small, and centrolobular ducts of the rat pancreas. Nestin-positive cells in the islets and in pancreatic ducts are distinct from ductal epithelium because they do not express the ductal marker cytokeratin 19 (CK19). After their isolation, these nestin-positive cells have an unusually extended proliferative capacity when cultured in vitro (approximately 8 months), can be cloned repeatedly, and appear to be multipotential. Upon confluence, they are able to differentiate into cells that express liver and exocrine pancreas markers, such as alpha-fetoprotein and pancreatic amylase, and display a ductal/endocrine phenotype with expression of CK19, neural-specific cell adhesion molecule, insulin, glucagon, and the pancreas/duodenum specific homeodomain transcription factor, IDX-1. We propose that these nestin-positive islet-derived progenitor (NIP) cells are a distinct population of cells that reside within pancreatic islets and may participate in the neogenesis of islet endocrine cells. The NIP cells that also reside in the pancreatic ducts may be contributors to the established location of islet progenitor cells. The identification of NIP cells within the pancreatic islets themselves suggest possibilities for treatment of diabetes, whereby NIP cells isolated from pancreas biopsies could be expanded ex vivo and transplanted into the donor/recipient.
Diabetes 2001 Mar
PMID:Multipotential nestin-positive stem cells isolated from adult pancreatic islets differentiate ex vivo into pancreatic endocrine, exocrine, and hepatic phenotypes. 1124 71

Type 2 diabetes mellitus, a major health care problem in the Western world, is a disease typified by a relative deficiency of insulin, leading to vast derangements in glucose and lipid homeostasis with disastrous vascular complications. Despite immense research efforts aiming at a clear understanding of the etiology of this complex disease, the molecular mechanisms causing the disorder still remain elusive. Here we review extant data from recent publications implicating novel signal transduction pathways and neurohormonal agonists as important regulators of the insulin stimulus-secretion coupling in the pancreatic beta-cell. Specifically, attention is paid to incretins such as glucagon-like peptide 1 (GLP-1), galanin, and other peptides produced in the gastrointestinal tract and by neuronal cells with the potential of governing beta-cell function in physiological and diabetic states.
Exp Clin Endocrinol Diabetes 2001
PMID:Neurohormonal regulation of the insulin stimulus-secretion coupling in pancreatic islets. 1146 May 63

Although galanin has been shown to be present in pancreatic islet cells, there is no literature available on the pattern of distribution and the effect of galanin in the pancreas of diabetic animals or human models. The aim of this study was to examine whether galanin immunoreactivity changes after the onset of diabetes mellitus in the rat model. The present study used immunohistochemical techniques to examine the pattern of distribution of galanin-like immunoreactive cells in the pancreas of rats with streptozotocin-induced diabetes. The effect of galanin on insulin secretion from intact rat pancreatic tissue fragments was also investigated using a radioimmunoassay technique. Numerous galanin-like immunoreactive cells were observed in both the peripheral and central regions of the islet of Langerhans of normal rat pancreas. By contrast, the islets of diabetic rat pancreas contained significantly (P < 0.0001) fewer galanin-like immunoreactive cells than nondiabetic rats. Galanin was colocalized with insulin in the islets of normal and diabetic rats. Galanin had an inhibitory effect on insulin secretion from the isolated pancreatic tissue fragments of normal and diabetic rats at all concentrations (10(-12) to 10(-6) M) employed. Galanin at 10(-9) M caused a significant (P < 0.02) decrease in insulin secretion from normal rat pancreatic tissue fragments compared to basal. These observations indicate that galanin may play a significant role in the regulation of insulin secretion.
 ...
PMID:Large reduction in the number of galanin-immunoreactive cells in pancreatic islets of diabetic rats. 1148 87

Gastrointestinal transit (GI) in the nonobese diabetic (NOD) mouse, an animal model of human diabetes type 1, was examined in animals with short- (duration 1-5 days) and long-term (duration 28-35 days) diabetes. Blood glucose level, serum insulin concentration, and gut neuroendocrine peptide content were also measured. GI was significantly rapid in NOD mice with long-term diabetes (LTD), but was not correlated with blood glucose level, serum insulin concentration, or pancreatic insulin content. GI was correlated with duodenal secretin content, but not with the content of other neuroendocrine peptides in the different segments investigated. Whereas antral vasoactive intestinal peptide (VIP) content in NOD mice with LTD was significantly higher, colonic VIP was lower in NOD mice with short-term diabetes (STD). In the duodenum, whereas the concentration of secretin in NOD mice with both STD and LTD was lower, the gastrin content was higher. Duodenal somatostatin content in NOD mice with LTD was lower. In colon, the content of galanin in NOD mice with LTD was higher than in controls. The decreased content of secretin may be among the factors that cause rapid GI in NOD mice with LTD. Changes in the antral content of VIP, duodenal somatostatin, and colonic galanin in NOD mice with LTD may cause low intestinal secretion and, together with rapid GI, give rise to diarrhoea, which is a common symptom in diabetes.
J Diabetes Complications
PMID:Gastrointestinal transit in nonobese diabetic mouse: an animal model of human diabetes type 1. 1156 57

Targeting of dorsal root ganglia by diabetes could account for the selective sensory abnormalities that patients with early diabetic polyneuropathy develop. In this work, we addressed survival, phenotype and gene expression in sensory neurones in lumbar dorsal root ganglia in a long-term model of experimental streptozotocin-induced diabetes in rats, designed to reflect human disease. Motor and sensory conduction slowing developed early, by the 2-month time point. At 2 months, sensory neurones had no detectable alterations in their calibre or gene expression, assessed using quantitative in situ hybridization studies for mRNA markers that included alpha CGRP, beta CGRP, NFM, t alpha 1-tubulin, SP, VIP, B50 (GAP43), galanin, somatostatin, PACAP, HSP27, c-jun, SNAP 25, p75, TrkA, TrkB and TrkC. By 12 months, however, diabetics had developed neurone perikaryal and distal axon atrophy, accompanied by generalized downregulation of mRNA expression, particularly of CGRP transcripts, PACAP, SP, NFM, p75, trkA and trkC. With the exception of HSP-27, no elevation in mRNAs that increase after injury, such as VIP, galanin, CCK, PACAP, B50 and t alpha 1-tubulin, was observed and constitutive levels, when detectable, trended towards lower rather than increased levels. There was relative preservation of neurone numbers at 12 months; only a non-significant trend towards fewer diabetic neurones was detected using a rigorous and systematic physical dissector counting approach through the entire L5 ganglia. There was no change in the relative populations of CGRP- and SP-immunoreactive neurones. Our findings indicate that even long-term experimental diabetes is associated with relative preservation of sensory neurone populations, but the neurones are atrophic and their gene expression is altered. This pattern of change differs from that following axotomy, implies a degenerative rather than an injury phenotype and has important implications for how such neurones might be rescued.
 ...
PMID:Does diabetes target ganglion neurones? Progressive sensory neurone involvement in long-term experimental diabetes. 1167 32

Over long periods, feeding and metabolism are tightly regulated at the central level. The total amount of nutrients ingested is thought to result from a delicate balance between orexigenic and anorexigenic factors expressed and secreted by specialized hypothalamic neuronal populations. We have developed a system of perifused hypothalamic neurons to characterize the relationships existing between the orexigenic peptide galanin and two other physiological modulators of feeding: neuropeptide Y (NPY) and corticotropin-releasing hormone (CRH). We demonstrated that galanin stimulates CRH and NPY secretion from hypothalamic neurons in a dose-dependent manner. Exposure to leptin for 24 h before galanin stimulation decreased NPY secretion by 30%, leaving the responsiveness of CRH neurons intact. These results suggest that CRH and NPY neurons participate to the intrahypothalamic signaling pathway of galanin, an observation that can explain the lower potency of galanin to stimulate food intake in vivo compared with NPY. The differential effects exerted by leptin on CRH and NPY suggest that there exists a subset of NPY neurons that are exquisitely sensitive to marked variations in leptin levels, and that the CRH neurons are less responsive to increases in leptin concentrations.
Diabetes 2001 Dec
PMID:Interplay between galanin and leptin in the hypothalamic control of feeding via corticotropin-releasing hormone and neuropeptide Y. 1172 48

Exposure to maternal gestational diabetes (GD) "programs" offspring for obesity in childhood and later life. Recent clinical data suggest that neonatal ingestion of breast milk from diabetic mothers might be crucially involved. Mediobasal hypothalamic nuclei such as the ventromedial nucleus (VMN), the paraventricular nucleus (PVN) and the arcuate nucleus (ARC) play a key role in the central nervous system regulation of food intake and body weight. In the ARC, orexigenic neuropeptides such as neuropeptide Y (NPY), galanin (GAL), and agouti-related peptide (AGRP) and anorexigenic neuropeptides such as proopiomelanocortin (POMC) and alpha-melanocyte-stimulating hormone (MSH) are expressed. We investigated the effects of neonatal exposure to milk from GD rat dams on the development of hypothalamic nuclei in weanling rats. Offspring of control (CO) rat dams cross-fostered to GD rat dams (CO-GD) developed early postnatal growth delay. On d 21 of life, CO-GD rats showed structural and functional hypothalamic "malprogramming." The ARC of CO-GD rats showed increased immunopositivity of both NPY and AGRP under basal conditions, despite normal levels of glucose, leptin, and insulin. Conversely, CO-GD rats showed decreased immunopositivity of both POMC and MSH and decreased density of immunopositive neurons, compared with offspring of control rat dams cross-fostered to control rat dams. No morphometric alterations were found in the VMN, whereas CO-GD rats showed an increased total number of neurons in the PVN. In summary, neonatal exposure to maternal diabetes through the intake of dam's milk in rats leads to a complex malprogramming of hypothalamic orexigenic and anorexigenic circuits that are critically involved in the lifelong regulation of food intake, body weight, and metabolism.
 ...
PMID:Cross-fostering to diabetic rat dams affects early development of mediobasal hypothalamic nuclei regulating food intake, body weight, and metabolism. 1498 62

Galanin peptide in primary sensory neurons may confer analgesia following injury. Its presence in regenerative axon sprouts where pain may be initiated has not been examined. We examined very early outgrowth of peptidergic axon sprouts after sciatic nerve crush in mice with experimental streptozotocin-induced diabetes. Diabetic mice had a retarded wave of outgrowing galanin axons, but those expressing calcitonin gene-related peptide grew normally. Diabetic mice also developed early, then persistent excessive autotomy behaviour, an index of pain behaviour in complete nerve lesions. Diabetes is associated with variations in the early outgrowth of peptide-containing axons. A relative delay in galanin axon outgrowth could contribute to heightened neuropathic pain in diabetes.
 ...
PMID:Heightened pain and delayed regeneration of galanin axons in diabetic mice. 1507 19

Galanin-like peptide (GALP) is a 60-amino-acid peptide with structural similarities to galanin and a high affinity for galanin receptors. GALP is expressed by a discrete population of neurons in the arcuate nucleus (ARC) and median eminence of the hypothalamus of several species, including the rat. GALP neurons express leptin receptors and GALP mRNA levels are decreased slightly in fasted rats and stimulated significantly by acute leptin treatment in combination with fasting. In studies to further explore the leptin dependence of GALP expression, we examined GALP mRNA levels in the hypothalamus of obese Zucker and streptozotocin-induced diabetic (STZ-DM) rats. In leptin receptor-deficient obese Zucker rats, with 75% higher body weight than lean littermates, GALP mRNA levels in the ARC were decreased by 75%, while neuropeptide Y (NPY) mRNA levels were increased 7-fold (n = 5, p < 0.001), consistent with earlier reports. In hypoleptinemic diabetic rats with 4.5-fold higher blood glucose and 15% lower body weight than controls, GALP mRNA levels in the ARC were decreased by 90%, while NPY mRNA levels were increased 9-fold (n = 5, p < 0.001). GALP is also expressed by pituicytes in the neural lobe of the rat pituitary gland and GALP expression is increased by osmotic stimulation such as dehydration and salt loading. Thus, in STZ-DM rats that are in a hyperosmotic state with elevated plasma vasopressin levels, GALP mRNA levels were increased by approximately 20-fold in the neural lobe relative to control (n = 4, p < 0.001). The current findings are consistent with a strong tonic influence of leptin receptor signalling on hypothalamic GALP expression under normal conditions, and possible abnormalities in GALP neuronal signalling and their putative targets, thyrotropin-releasing hormone and gonadotropin hormone-releasing hormone neurons, under pathophysiological conditions such as diabetes and obesity. Our data in STZ-DM rats also clearly demonstrate that GALP gene expression is differentially regulated in neurons and pituicytes.
 ...
PMID:Galanin-like peptide mRNA alterations in arcuate nucleus and neural lobe of streptozotocin-diabetic and obese zucker rats. Further evidence for leptin-dependent and independent regulation. 1525 10

In diabetes, peripheral nerves suffer deficient neurotrophic support-a situation which resembles axotomy. This raises the question: does inappropriate establishment of an axotomised neuronal phenotype contribute to diabetic neuropathy, and in extremis, does this provoke apoptosis? We hybridized reverse-transcribed RNA, from the dorsal root ganglia (DRG) of 8-week streptozotocin (STZ)-induced diabetic rats, to Affymetrix Rat Genome U34A chips and scanned the array for expression of (a) genes that are upregulated by axotomy, (b) proapoptotic and (c) anti-apoptotic genes. Expression of the axotomy-responsive genes coding for growth-associated protein 43 (GAP-43), galanin, neuropeptide Y (NPY), pre-pro-vasoactive intestinal polypeptide (pre-pro-VIP), neuronal nitric oxide synthase (nNOS), protease nexin 1, heat-shock protein 27 (HSP 27) and myosin light chain kinase II (MLCK II) was unaffected in ganglia from diabetic rats compared to controls; thus, no axotomised phenotype was established. The expression of the majority of proapoptotic genes in the DRG was also unaltered (bax, bad, bid, bok, c-Jun, p38, TNFR1, caspase 3 and NOS2). Similarly there was no change in expression of the majority of antiapoptotic genes (bcl2, bcl-xL, bcl-w, NfkappaB). These alterations in gene expression make it clear that neither axotomy nor apoptotic phenotypes are established in neurones in this model of diabetes.
 ...
PMID:Expression of axotomy-inducible and apoptosis-related genes in sensory nerves of rats with experimental diabetes. 1558 61


<< Previous 1 2 3 4 5 6 7 Next >>