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)

Function and survival of cells depend in part on the presence of growth factors. We explored the autocrine regulation of insulin and nerve growth factor (NGF) on single adult rat pancreatic beta-cell survival and hormone secretion. When NGF or insulin signaling were blocked in culture media, cell survival decreased compared with control cells, with apoptosis being the main mechanism of cell death. To further explore the role of glucose in beta-cell survival, we cultured the cells for 16 h in 2.6 mmol/l glucose and observed that nearly 17% of the cells developed apoptosis; this effect was partially prevented by NGF and almost completely inhibited by insulin treatment. A high K+ concentration had the same effect, suggesting that insulin and NGF secretion by the cells was responsible for the survival effects and not glucose per se. Blocking NGF signaling with an NGF antibody or with K252a reduced insulin biosynthesis and secretion in the cells that survived the treatment. Moreover, the functional beta-cell subpopulation with a higher insulin secretion rate is more susceptible to K252a. These results further indicate that NGF and insulin play important autoregulatory roles in pancreatic beta-cell survival and function and strongly suggest the need to explore new focuses in diabetes treatment.
Diabetes 2004 Aug
PMID:Autocrine regulation of single pancreatic beta-cell survival. 1527 81

Diabetic cystopathy is one of the common complications of diabetes and current therapy is limited. In the present study, the effects of gene therapy, using replication-defective herpes simplex virus type 1 (HSV-1) vectors to deliver and express the nerve growth factor (NGF) gene (HSV-NGF) on tissue NGF levels and bladder function, were evaluated in streptozotocin (STZ)-induced diabetic rats. Diabetic rats exhibited a significant decrease in NGF levels in the bladder and lumbosacral dorsal root ganglia (DRG) detected by enzyme-linked immunosorbent assay and displayed marked bladder dysfunction 12 weeks after STZ injection. In contrast, rats with bladder wall injection of the NGF expression vector 8 weeks after STZ treatment exhibited a significant increase of NGF levels in the bladder and L6 DRG 4 weeks after HSV-NGF injection. Along with the restoration of tissue NGF expression, in metabolic cage studies and cystometry, HSV-NGF-injected rats also showed significantly reduced bladder capacity and postvoid residual volume than diabetic rats injected with the control vector (HSV-lacZ), indicating that voiding function was improved after HSV vector-mediated NGF gene delivery. Thus, HSV vector-mediated NGF gene therapy may prove useful to restore decreased NGF expression in the bladder and bladder afferent pathways, thereby improving hypoactive bladder function in diabetes.
Diabetes 2004 Oct
PMID:Gene therapy using replication-defective herpes simplex virus vectors expressing nerve growth factor in a rat model of diabetic cystopathy. 1544 8

We examined the effects of C-peptide replacement on unmyelinated fiber function in the hind paw, sural nerve C-fiber morphometry, sciatic nerve neurotrophins, and the expression of neurotrophic receptors and content of neuropeptides in dorsal root ganglia in type 1 diabetic BB/Wor-rats. C-peptide replacement from onset of diabetes had no effect on hyperglycemia, but it significantly prevented progressive thermal hyperalgesia and prevented C-fiber atrophy, degeneration, and loss. These findings were associated with preventive effects on impaired availability of nerve growth factor and neurotrophin 3 in the sciatic nerve and significant prevention of perturbed expression of insulin, insulin growth factor-1, nerve growth factor, and neurotrophin 3 receptors in dorsal root ganglion cells. These beneficial effects translated into prevention of the decreased content of dorsal root ganglia nociceptive peptides such as substance P and calcitonin gene-related peptide. From these findings we conclude that replacement of insulinomimetic C-peptide prevents abnormalities of neurotrophins, their receptors, and nociceptive neuropeptides in type 1 BB/Wor-rats, resulting in the prevention of C-fiber pathology and nociceptive sensory nerve dysfunction. The data indicate that perturbed insulin/C-peptide action plays an important pathogenetic role in nociceptive sensory neuropathy and that C-peptide replacement may be of benefit in treating painful diabetic neuropathy in insulin-deficient diabetic conditions.
 ...
PMID:C-peptide prevents nociceptive sensory neuropathy in type 1 diabetes. 1549 55

White adipose tissue (WAT) is a major endocrine and secretory organ, which releases a wide range of protein signals and factors termed adipokines. A number of adipokines, including leptin, adiponectin, tumour necrosis factor alpha, IL-1beta (interleukin 1beta), IL-6, monocyte chemotactic protein-1, macrophage migration inhibitory factor, nerve growth factor, vascular endothelial growth factor, plasminogen activator inhibitor 1 and haptoglobin, are linked to inflammation and the inflammatory response. Obesity is characterized by a state of chronic mild inflammation, with raised circulating levels of inflammatory markers and the expression and release of inflammation-related adipokines generally rises as adipose tissue expands (adiponectin, which has anti-inflammatory action is an exception). The elevated production of inflammation-related adipokines is increasingly considered to be important in the development of diseases linked to obesity, particularly Type II diabetes and the metabolic syndrome. WAT is involved in extensive cross-talk with other organs and multiple metabolic systems through the various adipokines.
 ...
PMID:Signalling role of adipose tissue: adipokines and inflammation in obesity. 1624 49

An increasing number of researchers of the metabolic syndrome assume that many mechanisms are involved in its complex pathophysiology such as an increased sympathetic activity, disorders of the hypothalamo-pituitary-adrenal axis, the action of chronic subclinical infections, proinflammatory cytokines, and the effect of adipocytokines or psychoemotional stress. An increasing body of scientific research in this field confirms the role of the neurotrophins and mastocytes in the pathogenesis of inflammatory and immune diseases. Recently it has been proved that neurotrophins and mastocytes have metabotrophic effects and take part in the carbohydrate and lipid metabolism. In the early stage of the metabolic syndrome we established a statistically significant increase in the plasma levels of the nerve growth factor. In the generalized stage the plasma levels of the neutrophines were statistically decreased in comparison to those in the healthy controls. We consider that the neurotrophin deficit is likely to play a significant pathogenic role in the development of the metabolic anthropometric and vascular manifestations of the generalized stage of MetSyn. We suggest a hypothesis for the etiopathogenesis of the metabolic syndrome based on the neuro-immuno-endocrine interactions. The specific pathogenic pathways of MetSyn development include: (1) increased tissue and plasma levels of proinflammatory cytokines Interleukin-1(IL-1), Interleukin-6 (IL-6 ) and tumor necrosis factor - alpha (TNF-alpha) caused by inflammatory and/or emotional distress; (2) increased plasma levels of neurotrophin - nerve growth factor (NGF) caused by the high IL-1, IL-6 and TNFalpha levels; (3) high plasma levels of NGF which enhance activation of: the autonomous nerve system--vegetodystonia (disbalance of neurotransmitters); Neuropeptide Y (NPY)--enhanced feeding, obesity and increased leptin plasma levels; hypothalamo-pituitary-adrenal axis--increased corticotropin-releasing hormone (CRH) and cortisol (hormonal disbalance); immune cells--increased number and degranulation of mastocytes (MC)--immunological disbalance; (4) as a result of 1-3 insulin resistance is exhibited leading to diabetes mellitus. The hypothesis is confirmed by results obtained after 6-month nonsteroid anti-inflammatory treatment of patients with MetSyn. These results are reported in a separate publication.
 ...
PMID:Metabolic syndrome--neurotrophic hypothesis. 1654 15

Death receptors belong to the TNF (tumor necrosis factor)/NGF (nerve growth factor) receptor superfamily. Signaling via death receptors plays a distinct role, e.g. in the immune system, where it contributes to regulation of the adaptive immune response in various ways, most notably by triggering activation-induced cell death (AICD) of T cells. Thus, dysregulation of death receptor signaling, either allowing too much or too little apoptosis, can lead to autoimmune disorders and also impacts on tumorigenesis or other diseases. In this chapter we address components, molecular mechanisms and regulation of death receptor signaling with particular focus on CD95 (APO-1, Fas). We discuss the role of death receptor-mediated AICD in regulation of the adaptive immune response against foreign and self antigens in comparison to cytokine deprivation-mediated death by neglect. Finally, the contribution of dysregulated death receptor/ligand systems to autoimmune diseases such as diabetes, multiple sclerosis and Hashimoto's thyroiditis is discussed.
 ...
PMID:Death receptor signaling and its function in the immune system. 1639 52

The case is compelling for the involvement of nerve growth factor (NGF) in the pathogenesis of lower urinary tract disease, especially in conditions with altered neural function. Remodeling of the micturition pathways occurs following experimental bladder-outlet obstruction, denervation, spinal cord injury, cystitis, and diabetes mellitus. Clinically, NGF levels are elevated in the bladders of men with benign prostatic hyperplasia, women with interstitial cystitis and in patients with idiopathic overactive bladder. Blockade of NGF, using either an endogenous antibody or an antibody against the NGF receptor, prevents neural plasticity and bladder overactivity in experimental models of these conditions. The ability of NGF to trigger bladder overactivity might rely on altering the properties of sodium or potassium channels (or their expression) in bladder afferent fibers. Therapies based on altered NGF levels, or changes in channel properties in afferent nerves, represent an intriguing avenue of investigation for the management of detrusor overactivity or diabetic cystopathy.
 ...
PMID:Mechanisms of Disease: the role of nerve growth factor in the pathophysiology of bladder disorders. 1647 Feb 9

Biological substances with neurotrophic activities, such as nerve growth factor (NGF) and monosialoganglioside GM1, have been considered as agents for diabetic peripheral neuropathy. Because recent studies have suggested that decreased availability of these substances might contribute to the pathogenesis of diabetic peripheral neuropathy, some clinical trials of NGF for diabetic peripheral neuropathy have been conducted and have led to mixed conclusions. The major reasons were its limited delivery to the nervous system and adverse effects induced by subcutaneous injection, which was necessary because NGF is a polypeptide. The current study investigates whether an orally active sialic acid derivative, MCC-257, has neuroprotective properties in diabetic peripheral nerves. MCC-257 augmented NGF activity in cultured dorsal root ganglia and PC12 (pheochromocytoma 12) cells. Treatment with MCC-257 elevated NGF levels in the sciatic nerve, accompanied by improvement in nerve conduction velocity in streptozotocin-induced diabetic animals. More importantly, MCC-257 ameliorated small fiber dysfunctions, including thermal hypoalgesia, substance P content, and histopathological innervation in the plantar skin of diabetic animals. Thus, the orally active neurotrophin enhancer provides a new option for the clinical treatment of diabetic peripheral neuropathy.
Diabetes 2006 Mar
PMID:Orally active neurotrophin-enhancing agent protects against dysfunctions of the peripheral nerves in hyperglycemic animals. 1650 23

We investigated short-term in vivo and in vitro effects of streptozotocin (STZ) on pancreatic beta cells. Male Wistar rats were treated with 75 mg/kg STZ, and, after 4 hrs blood glucose and insulin were measured and islet cells were isolated, cultured for 16 hrs, and challenged with 5.6 and 15.6 mM glucose. Treated rats showed hyperglycemia (approximately 14 mM) and a 70% decrease in serum insulin levels as compared with controls. Although insulin secretion by isolated beta cells from STZ-treated rats was reduced by more than 80%, in both glucose concentrations, nerve growth factor (NGF) secretion by the same cells increased 10-fold. Moreover, NGF messenger RNA (mRNA) expression increased by 30% as compared with controls. Similar results were obtained in an in vitro model of islet cells, in which cells were exposed directly to STZ for 1, 2, and 4 hrs and then challenged for 3 hrs with the same glucose concentrations. Our data strongly suggest that an early increase in NGF production and secretion by beta cells could be an endogenous protective response to maintain cell survival and that diabetes mellitus may occur when this mechanism is surpassed.
 ...
PMID:Nerve growth factor increases in pancreatic beta cells after streptozotocin-induced damage in rats. 1656 35

Glucose sensing is essential for the ability of pancreatic beta-cells to produce insulin in sufficient quantities to maintain blood glucose within the normal range. Stress causes the release of adrenergic hormones that increase circulating glucose by promoting glucose production and inhibiting insulin release. We have shown that extracellular signal-regulated kinases 1 and 2 (ERK1/2) are responsive to glucose in pancreatic beta-cells and that glucose activates ERK1/2 by mechanisms independent of insulin. Here we show that glucose-induced activation of ERK1/2 is inhibited by epinephrine through the alpha2-adrenergic receptor. Epinephrine and the selective alpha2-adrenergic agonist UK14304 reduced insulin secretion and glucose-stimulated ERK1/2 activation in a pertussis toxin-sensitive manner, implicating the alpha subunit of a Gi family member. Alpha2-adrenergic agonists also reduced stimulation of ERK1/2 by glucagon-like peptide 1 and KCl, but not by phorbol ester or nerve growth factor. Our findings suggest that alpha2-adrenergic agonists act via a Gi family member on early steps in ERK1/2 activation, supporting the idea that ERK1/2 are regulated in a manner that reflects insulin demand.
Diabetes 2006 Apr
PMID:Inhibition of glucose-stimulated activation of extracellular signal-regulated protein kinases 1 and 2 by epinephrine in pancreatic beta-cells. 1656 30


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>