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)

Both blood vessels and nerves are guided to their tissue targets by "specific" growth factors such as vascular endothelial growth factor (VEGF) and nerve growth factor (NGF), originally discovered as growth factors specific for endothelial and neuronal cells, respectively. While the eminent role of VEGF in the formation of new blood vessels (angiogenesis) is unquestioned, recent studies indicate that VEGF also has direct effects on the nervous system in terms of neuronal growth, survival (neurotrophic), axonal outgrowth (neurotropic), and neuroprotection. Conversely, NGF, a neurotrophin that plays a crucial role in promoting neurotrophic and neurotropic effects in sympathetic neurons, has recently been identified as a novel angiogenic molecule exerting a variety of effects on endothelial cells and in the cardiovascular system in general. VEGF and NGF have also been implicated in both neurodegenerative and vascular diseases. The pleiotropic effects of these growth factors have raised interest in assessing their therapeutic potential. The challenge for the future is to unravel to what extent the effects of these growth factors are interrelated with regards to their angiogenic, and neurotrophic effects and how to design selective drugs interfering with their respective actions. Most biological actions of NGF and VEGF are mediated by their cognate receptor protein tyrosine kinases, tropomyosin related kinase (trkA for NGF) and kinase insert domain-containing receptor (KDR, VEGFR-2, flk-1 for VEGF), which activate a complex and integrated network of signaling pathways in neurons and endothelial cells. Two small molecules, K252a and SU-5416, which are antagonists of trkA and VEGFR-2, respectively, may serve as key tools in dissecting the role of NGF and VEGF in angiogenesis and neurogenesis. Development of selective drugs specific for the trkA and VEGFR-2 subtypes of receptors will provide new tools for the treatment of neurodegenerative diseases, such as Alzheimer's and Parkinson's, as well as of numerous angiogenesis-dependent diseases, such as cancer, diabetes, and arthritis.
 ...
PMID:Cross talk between the cardiovascular and nervous systems: neurotrophic effects of vascular endothelial growth factor (VEGF) and angiogenic effects of nerve growth factor (NGF)-implications in drug development. 1684 61

Storage symptoms such as urgency, frequency, and nocturia, with or without urge incontinence, are characterized as overactive bladder (OAB). OAB can lead to urge incontinence. Disturbances in nerves, smooth muscle, and urothelium can cause this condition. In some respects the division between peripheral and central causes of OAB is artificial, but it remains a useful paradigm for appreciating the interactions between different tissues. Models have been developed to mimic the OAB associated with bladder instability, lower urinary tract obstruction, neuropathic disorders, diabetes, and interstitial cystitis. These models share the common features of increased connectivity and excitability of both detrusor smooth muscle and nerves. Increased excitability and connectivity of nerves involved in micturition rely on growth factors that orchestrate neural plasticity. Neurotransmitters, prostaglandins, and growth factors, such as nerve growth factor, provide mechanisms for bidirectional communication between muscle or urothelium and nerve, leading to OAB with or without urge incontinence.
 ...
PMID:Pathophysiology of overactive bladder and urge urinary incontinence. 1698 23

To explore the mechanism of diabetic erectile dysfunction, we studied the distribution of neurotrophins in the penises of diabetic rats, including nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4). Male Sprague-Dawley rats were injected with 65 mg/kg streptozotocin to induce diabetes mellitus (DM). The control rats were raised as age-matched control. Eight weeks later, the intercavernous pressure (ICP) of the rats was measured after electrostimulation and before sacrifice. Each peeled penis was divided into 2 parts, one for immunohistochemistry and the other for Western blot analysis. The ICP of the DM group rats was significantly decreased as compared to the vehicle control rats. There were significantly more NGF-positive neurons in the penises of the diabetic rats than in those of the control rats, while the opposite results were observed for BDNF-positive neurons. In the Western blot analysis, the proteins of NGF, NT-3, and NT-4 were all increased, while that of BDNF was decreased in diabetic rats. This is the first study revealing the expression of NT-4 protein in cavernous tissue. The abnormal level of these 4 neurotrophins in cavernous tissue may be one of the factors of the pathogenesis of diabetic ED. The increase of neurotrophins may reflect the degree of cavernous tissue denervation and may represent a compensatory mechanism. The lesion of the retrograde axonal transport of the nerves caused by hyperglycemia may be related to this phenomenon.
 ...
PMID:Differential expression of neurotrophins in penises of streptozotocin-induced diabetic rats. 1707 42

We examined the therapeutic effects of C-peptide on established nociceptive neuropathy in type 1 diabetic BB/Wor rats. Nociceptive nerve function, unmyelinated sural nerve fiber and dorsal root ganglion (DRG) cell morphometry, nociceptive peptide content, and the expression of neurotrophic factors and their receptors were investigated. C-peptide was administered either as a continuous subcutaneous replacement dose via osmopumps or a replacement dose given once daily by subcutaneous injection. Diabetic rats were treated from 4 to 7 months of diabetes and were compared with control and untreated diabetic rats of 4- and 7-month duration. Osmopump delivery but not subcutaneous injection improved hyperalgesia and restored the diabetes-induced reduction of unmyelinated fiber number (P < 0.01) and mean axonal size (P < 0.05) in the sural nerve. High-affinity nerve growth factor (NGF) receptor (NGFR-TrkA) expression in DRGs was significantly reduced at 4 months (P < 0.01). Insulin receptor and IGF-I receptor (IGF-IR) expressions in DRGs and NGF content in sciatic nerve were significantly decreased in 7-month diabetic rats (P < 0.01, 0.05, and 0.005, respectively). Osmopump delivery prevented the decline of NGFR-TrkA, insulin receptor (P < 0.05), and IGF-IR (P < 0.005) expressions in DRGs and improved NGF content (P < 0.05) in sciatic nerve. However, subcutaneous injection had only marginal effects on morphometric and molecular changes in diabetic rats. We conclude that C-peptide exerts beneficial therapeutic effects on diabetic nociceptive neuropathy and that optimal effects require maintenance of physiological C-peptide concentrations for a major proportion of the day.
Diabetes 2006 Dec
PMID:C-Peptide reverses nociceptive neuropathy in type 1 diabetes. 1713 May 7

Human diabetic patients often lose touch and vibratory sensations, but to date, most studies on diabetes-induced sensory nerve degeneration have focused on epidermal C-fibers. Here, we explored the effects of diabetes on cutaneous myelinated fibers in relation to the behavioral responses to tactile stimuli from diabetic mice. Weekly behavioral testing began prior to streptozotocin (STZ) administration and continued until 8 weeks, at which time myelinated fiber innervation was examined in the footpad by immunohistochemistry using antiserum to neurofilament heavy chain (NF-H) and myelin basic protein (MBP). Diabetic mice developed reduced behavioral responses to non-noxious (monofilaments) and noxious (pinprick) stimuli. In addition, diabetic mice displayed a 50% reduction in NF-H-positive myelinated innervation of the dermal footpad compared with non-diabetic mice. To test whether two neurotrophins nerve growth factor (NGF) and/or neurotrophin-3 (NT-3) known to support myelinated cutaneous fibers could influence myelinated innervation, diabetic mice were treated intrathecally for 2 weeks with NGF, NT-3, NGF and NT-3. Neurotrophin-treated mice were then compared with diabetic mice treated with insulin for 2 weeks. NGF and insulin treatment both increased paw withdrawal to mechanical stimulation in diabetic mice, whereas NT-3 or a combination of NGF and NT-3 failed to alter paw withdrawal responses. Surprisingly, all treatments significantly increased myelinated innervation compared with control-treated diabetic mice, demonstrating that myelinated cutaneous fibers damaged by hyperglycemia respond to intrathecal administration of neurotrophins. Moreover, NT-3 treatment increased epidermal Merkel cell numbers associated with nerve fibers, consistent with increased numbers of NT-3-responsive slowly adapting A-fibers. These studies suggest that myelinated fiber loss may contribute as significantly as unmyelinated epidermal loss in diabetic neuropathy, and the contradiction between neurotrophin-induced increases in dermal innervation and behavior emphasizes the need for multiple approaches to accurately assess sensory improvements in diabetic neuropathy.
 ...
PMID:Neurotrophic modulation of myelinated cutaneous innervation and mechanical sensory loss in diabetic mice. 1722 73

Diabetic foot ulcers (DFUs) consist of an interaction of neuropathy, ischemia and infection. Neuropathy affects sensory, motor and autonomic pathways. Pathogenic factors for neuropathy include hyperglycemia, nonenzymatic glycosylation, oxidative stress, ischemic and hypoxic factors, nerve growth factor anomalies, activation of polyol pathway and immunologic abnormalities. All these factors are stated to contribute to microvascular disease and neural dysfunction. Peripheral neuropathy and ischemia combined with repetitive traumas can lead to diabetic foot ulceration. Fifteen percent of diabetic patients develop foot ulcers during their lifetime and nonhealing ulcers are responsible for 85% of nontraumatic lower extremity amputation. On the other hand, the treatment cost of foot disease in diabetic patients is estimated at $1 billion annually. When these conditions are considered, it is very important to design improved and novel strategies for treatment and prevention of diabetic foot disease. Lipid-lowering agents, such as statins, have been shown to prevent cardiovascular events in patients with diabetes. However, in addition, to preventing macrovascular diseases, statins may also be able to retard the progression of microvascular complications of diabetes. Statins alter the balance between vasodilatation and vasoconstriction in favor of vasodilatation by increasing nitric oxide (NO) synthesis, by downregulating endothelin 1 (ET-1) synthesis and reducing vascular response to angiotensin-2 (AT-2). These agents have been shown to augment cerebral blood flow by upregulating endothelial nitric oxide synthase (eNOs) and to reduce cerebral infarct size in a murine model of cerebral ischemia. In addition, recent in vivo and in vitro investigations have evidenced that statins have a favorable effect on diabetic peripheral neuropathy independent of its lipid-lowering effect by demonstrating restoration or preservation of microcirculation of the sciatic nerve. We hypothesized that statins can be useful for the prevention and treatment of diabetic foot. Possible mechanisms include the reduction of neuropathy and ischemia or through growth factors, the effectiveness of which has been shown for fracture healing in animal models.
 ...
PMID:Statins may be useful in diabetic foot ulceration treatment and prevention. 1749 47

A clearer understanding of the mechanisms underlying the development and progression of diabetic neuropathy is likely to indicate new directions for the treatment of this complication of diabetes. In the present study we investigated the expression of cannabinoid CB(1) receptors in models of diabetic neuropathy. PC12 cells were differentiated into a neuronal phenotype with nerve growth factor (NGF) (50 ng/ml) in varying concentrations of glucose (5.5-50 mM). CB(1) receptor expression was studied at the mRNA level by reverse transcriptase-polymerase chain reaction (RT-PCR) and at the protein level via immunohistochemical and Western blot analysis. CB(1) expression was also compared in dorsal root ganglia (DRG) removed from streptozotocin-induced diabetic rats versus control animals. Total neurite length induced by NGF was reduced in cells cultured in 20 to 50 mM glucose at day 6 (P < 0.01 versus 5.5 mM; n = 6). Cell viability assays conducted in parallel on day 6 confirmed that the total cell numbers were not significantly different among the various glucose concentrations (P = 0.86; n = 12). RT-PCR, immunohistochemical, and Western blot analysis all revealed down-regulation of the CB(1) receptor in cells treated with high glucose (P < 0.05; n = 4-5 for each), and in DRG removed from diabetic rats compared with controls (P < 0.01; n = 5 for immunohistochemistry, and n = 3 for Western blot). These results suggest that high glucose concentrations are associated with decreased expression of CB(1) receptors in nerve cells. Given the neuroprotective effect of cannabinoids, a decline in CB(1) receptor expression may contribute to the neurodegenerative process observed in diabetes.
 ...
PMID:Expression of cannabinoid CB1 receptors in models of diabetic neuropathy. 1770 1

NOD (non-obese diabetic) mice develop type 1 diabetes mellitus spontaneously and with a strong similarity to the human disease. Differentiation and function of pancreas beta cells are regulated by a variety of hormones and growth factors, including the nerve growth factor (NGF). Gangliosides have multiple immunomodulatory activities with immunosuppressive properties, decreasing lymphoproliferative responses and modulating cytokine production. In the present study, serum, pancreas islets and spleen mononuclear cells from NOD mice treated with monosialic ganglioside GM1 (100 mg/kg/day) and the group control which received saline solution were isolated to investigate the proinflammatory cytokines (IL-1beta, IFN-gamma, IL-12, TNF-alpha), NGF and its high-affinity receptor TrkA, peri-islet Schwann cells components (GFAP, S100-beta) expression and the relationship with diabetes onset and morphological aspects. Our results suggest that GM1 administration to female NOD mice beginning at the 4th week of life is able to reduce the index of inflammatory infiltrate and consequently the expression of diabetes, modulating the expression of proinflammatory cytokines (IL-12, IFN-gamma, TNF-alpha and IL-1beta). Furthermore, GM1 increases GFAP, S-100beta and NGF in pancreas islets, factors involved in beta cell survival.
 ...
PMID:Ganglioside GM1 effects on the expression of nerve growth factor (NGF), Trk-A receptor, proinflammatory cytokines and on autoimmune diabetes onset in non-obese diabetic (NOD) mice. 1832 89

Stress is accompanied by metabolic alterations that could contribute to the etiology of diabetes mellitus, arteriosclerosis, and cardiovascular diseases; however, the mechanisms by which stress affects glucose and lipid metabolism remain to be resolved. Stress-induced effects on neurotransmission and interleukin-1 (IL-1) signaling rapidly produce hyperglycemia by increasing sympathetic outflow. Activation of the sympathetic nervous system can also rapidly stimulate lipolysis and hepatic triglyceride secretion. Furthermore, stress increases serum interleukin-6 (IL-6) and nerve growth factor (NGF) levels by activating neuroendocrine systems. IL-6 and NGF can rapidly increase lipolysis and hepatic triglyceride secretion without inducing hyperglycemia. The sympathetic nervous system does not mediate cytokine-induced hypertriglyceridemia. Thus, the central nervous system plays an important role in regulation of hepatic glucose and lipid metabolism via the sympathetic nervous system and cytokines. (Trends Endocrinol Metab 1997;8:192-197). (c) 1997, Elsevier Science Inc.
 ...
PMID:Stress, acute hyperglycemia, and hyperlipidemia role of the autonomic nervous system and cytokines. 1840 6

The role of hyperglycemia in perineural invasion in pancreatic cancer is not clear. Pancreatic cancer is characterized by extremely high frequency of perineural invasion (can be as high as 90%, even 100%), which has been associated with poorer survival. In previous epidemiologic, the prevalence of diabetes mellitus in pancreatic cancer is 34-40% and more than half of them are new-onset, which means the course of disease of diabetes mellitus is less than 24 months before cancer diagnosis. The association between diabetes mellitus and pancreatic cancer has long been recognized as that long-standing diabetes mellitus is thought to be an etiologic factor for pancreatic cancer and new-onset diabetes mellitus may be a manifestation of the cancer. Long-standing diabetes mellitus can cause peripheral neuropathy. The main morphological features of established neuropathy include a combination of demyelinization and axonal degeneration of myelinated fibers, degeneration with regeneration of unmyelinated fibers and endoneurial microangiopathy, with nerve fiber loss in its final stage. Diabetes mellitus can also induce the high expression of cytokines such as nerve growth factor to repair the damaged nerves. We present the hypothesis that hyperglycemia promotes the perineural invasion in pancreatic cancer through two mechanisms. One is that hyperglycemia enhances the proliferation of cancer cells, which subsequently increase the expression of cytokines such as nerve growth factor. The overexpression of nerve growth factor can enhance the interaction between nerve and cancer cell and neurotropism. The other is that hyperglycemia causes demyelinization and axonal degeneration of nerves, which can form defections to make cancer cells enter nerves with deeply invasion. The above two mechanisms can promote the perineural invasion in pancreatic cancer. Controlling hyperglycemia might reduce the perineural invasion in pancreatic cancer.
 ...
PMID:Hyperglycemia promotes the perineural invasion in pancreatic cancer. 1857 73


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