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

Rats with streptozotocin-induced diabetes of 4 to 6 weeks duration showed a depletion of both substance P (P < 0.01) and calcitonin gene-related peptide (P < 0.01) in the sciatic nerve. Since expression of both peptides is sensitive to nerve growth factor (NGF) in vitro we examined the effect of treatment of diabetic rats with NGF, which significantly increased the levels of both peptides in treated diabetic animals (P < 0.01 for both). Treatment of non-diabetic rats with a similar NGF regime raised the mean peptide levels to a value similar to that seen in treated diabetic rats but the change was not statistically significant. In vehicle-treated diabetic rats the depletions of sciatic nerve neuropeptides were accompanied by a significant (P < 0.05) reduction in the level of CGRP mRNA in the 4th and 5th lumbar dorsal root ganglia, this was accompanied by an analogous reduction in the mRNA for gamma-preprotachykinin A (gamma-PPT), which did not attain statistical significance. Treatment of diabetic rats with NGF also prevented the deficits in the levels of CGRP and gamma-PPT mRNA in the lumbar dorsal root ganglia (P < 0.05). Treatment of other diabetic rats with the related neurotrophin, brain-derived neurotrophic factor (BDNF), had no effect on the levels of substance P and calcitonin gene-related peptide in the sciatic nerve.
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PMID:Expression of neuropeptides in experimental diabetes; effects of treatment with nerve growth factor or brain-derived neurotrophic factor. 751 41

The levels of neurotrophin mRNA in sensory ganglia, sciatic nerve, and skeletal muscle were measured in the streptozotocin-diabetic rat using northern blotting. Periods of diabetes of 4, 6, and 12 weeks significantly elevated brain-derived neurotrophic factor (BDNF) mRNA levels in soleus muscle compared with age-matched controls, the increase being highest at 6 weeks. At all time periods studied, the levels of nerve growth factor (NGF) mRNA in soleus muscle were decreased by 21-47%. Following 12 weeks of diabetes, BDNF mRNA levels were increased approximately two- to threefold in L4 and L5 dorsal root ganglia (DRG), and in sciatic nerve, NGF mRNA levels were raised 1.65-fold. Intensive insulin treatment of diabetic rats for the final 4 weeks of the 12-week period of diabetes reversed the up-regulation of BDNF mRNA in DRG and muscle and NGF mRNA in sciatic nerve. All diabetes-induced changes in neurotrophin mRNA were not paralleled by similar alterations in the levels of beta-actin mRNA in muscle and nerve, or of GAP-43 mRNA in DRG and nerve. It is proposed that the up-regulation of neurotrophin mRNA is an endogenous protective and/or repair mechanism induced by insult and, as such, appears as an early marker of peripheral nerve and muscle damage in experimental diabetes.
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PMID:Altered neurotrophin mRNA levels in peripheral nerve and skeletal muscle of experimentally diabetic rats. 786 Nov 56

The levels of neurotrophins and their receptor mRNAs were measured in rat sciatic nerve, after 6 or 12 weeks of streptozotocin-induced diabetes. Expression of neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4) was decreased by 50 and 29%, respectively, compared with age-matched controls after 12 weeks of diabetes. Expression of brain-derived neurotrophic factor (BDNF) was not detected. In addition, diabetes induced a reduction in the expression levels of the neurotrophin receptors: trkB mRNA decreased by 50% after 6 weeks of diabetes, but returned to control levels after 12 weeks; meanwhile the trkC and p75LNGFR transcripts were reduced by 20% of control at both times studied. trkA expression was below detection limits. Thus, these data suggest that a reduction in neurotrophin and neurotrophin receptors could contribute to the development and maintenance of diabetic neuropathy.
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PMID:Expression of neurotrophins and their receptors in sciatic nerve of experimentally diabetic rats. 858 61

In a previous study the levels of brain-derived neurotrophic factor (BDNF) mRNA were shown to be elevated in skeletal muscle of the diabetic rat compared with age-matched control animals. It was proposed that diabetes-induced changes in nerve function may initiate changes in nerve/muscle contact akin to those following denervation of target skeletal muscle. In this study hindlimb skeletal muscles were denervated by sciatic nerve crush or transection and the effect on BDNF mRNA levels in control and diabetic rats was observed using Northern blotting. Contralateral to the side of nerve injury, the levels of BDNF mRNA in soleus muscle of diabetic rats were higher than in controls (three- to sevenfold), as has been seen previously in diabetic rats without any axotomy. Sciatic nerve crush or transection, of 1 week or of 3 weeks duration, lowered the levels of BDNF mRNA by 50% in ipsilateral soleus muscle of diabetic rats. BDNF mRNA levels in contralateral gastrocnemius muscle were not similarly raised in diabetic rats compared with controls and nerve injury had no effect. In control animals, ipsilaterally, the BDNF mRNA levels of soleus muscle were raised approximately twofold at 1 week and were lowered by approximately 50% at 3 weeks following nerve injury. Neurotrophin-3 mRNA levels were reduced approximately 50% in soleus muscle of diabetic rats compared with control rats, and nerve injury had no significant effect. The specific up-regulation of BDNF mRNA in soleus muscle of diabetic rats is discussed in terms of a proposed diabetes-induced ischemia within hindlimb skeletal muscle, with a protective role for BDNF in muscle and/or nerve being introduced.
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PMID:Brain-derived neurotrophic factor mRNA levels are up-regulated in hindlimb skeletal muscle of diabetic rats: effect of denervation. 881 63

There is enthusiasm for the application of knowledge concerning neurotrophins and other growth factors to human neurologic disease. New neurotrophins and other growth factors or inflammatory mediators that influence neurons and axons have been recently identified. Diabetic neuropathy may be an ideal testing ground for these substances because specific neurotrophins and growth factors could theoretically prevent loss of diabetic dorsal root ganglion (DRG) cells or enhance regeneration of diabetic nerves. Several of the neurotrophins support DRG cells in culture or prevent their loss during neonatal development, and a few help prevent retrograde loss of adult DRG cells after axotomy. Early Phase I trials suggest that nerve growth factor, brain-derived neurotrophic factor, and neurotrophin-3 are reasonably safe agents as administered in short-term trials to humans, but there are lingering experimental doubts. For example, it has not been established whether DRG cells are targeted by diabetes. Additional work suggests that simultaneous and sequential cocktails of trophins are required to support and rescue neurons and that the use of single agents may not be sufficient. Finally, it in uncertain whether trophins might act as a general tonic for DRG cells to prevent diabetes-related injury or whether they are actually deficient in human diabetic patients.
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PMID:Neurotrophins and other growth factors in diabetic neuropathy. 898 29

Recent evidence from animal models of diabetes and human diabetic subjects suggests that the reduced availability of neurotrophic factors may contribute to the pathogenesis of diabetic peripheral neuropathy (DPN). Of these proteins, nerve growth factor (NGF), brain-derived neurotrophic factor, neurotrophin (NT-3) and NT-4/5 appear to be important for the development and maintenance of peripheral neurons, but others, including insulin-like growth factors (IGFs), may also be involved. Studies with NGF, NT-3, IGF-I and IGF-II both in vitro and in animal models of neuropathies (including DPN) suggest that these factors ameliorate nerve degeneration. Recombinant human NGF is the first neurotrophic factor to enter clinical trials for DPN and is currently being tested in two phase III studies.
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PMID:Neurotrophic factors and diabetic peripheral neuropathy. 1002 26

Systemic administration of brain-derived neurotrophic factor (BDNF) decreases nonfasted blood glucose in obese, non-insulin-dependent diabetic C57BLKS-Lepr(db)/lepr(db) (db/db) mice, with a concomitant decrease in body weight. By measuring percent HbA1c in BDNF-treated and pair-fed animals, we show that the effects of BDNF on nonfasted blood glucose levels are not caused by decreased food intake but reflect a significant improvement in blood glucose control. Furthermore, once established, this effect can persist for weeks after cessation of BDNF treatment. Oral glucose tolerance tests were performed to examine the effects of BDNF on blood glucose control in the fasted state and after an oral glucose challenge. BDNF treatment normalized fasting blood glucose from initially hyperglycemic levels and also showed evidence for beneficial, although less marked, effects on the ability to remove exogenous glucose from blood. One means to lower fasting blood glucose is to reduce the glucose output of peripheral tissues that normally play a part in the maintenance of fasting hyperglycemia. Because the liver is the major endogenous source of glucose in blood during fasting, and because hepatic weight and glucose output are increased in type 2 diabetes, we evaluated the effects of BDNF on liver tissue. BDNF reduced the hepatomegaly present in db/db mice, in association with reduced liver glycogen and reduced liver enzyme activity in serum, supporting the possible involvement of liver tissue in the mechanism of action for BDNF.
Diabetes 1999 Mar
PMID:Brain-derived neurotrophic factor improves blood glucose control and alleviates fasting hyperglycemia in C57BLKS-Lepr(db)/lepr(db) mice. 1007 61

Anterograde and retrograde trafficking of brain-derived neurotrophic factor (BDNF) was examined in streptozotocin-diabetic and galactose-fed rats by measuring accumulation of endogenous neurotrophin proximal and distal to two constricting sciatic nerve ligatures and by direct injection of radiolabeled neurotrophin into the sciatic nerve. Compared to controls, accumulation of endogenous BDNF proximal and distal to the ligatures as well as basal levels in non-ligated nerve segments were decreased in streptozotocin-diabetic and galactose-fed rats. Neither streptozotocin diabetes nor galactose intoxication affected the amount of 125I-labeled BDNF retrogradely transported to the DRG after injection into the sciatic nerve. These results suggest that reduced anterograde and retrograde accumulations of BDNF in experimental diabetes are not a result of impaired capacity for receptor-mediated transport.
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PMID:Decreased accumulation of endogenous brain-derived neurotrophic factor against constricting sciatic nerve ligatures in streptozotocin-diabetic and galactose-fed rats. 1021 57

Diabetes-induced embryo malformations and growth retardation are correlated with a variety of biochemical changes including oxidative stress. In this study, we show that the morphological alterations are correlated with progressive and selective changes of mRNA expression in specific neurotrophic factors. At embryological stage E-17, diabetes affected both embryo growth and NGF mRNA expression, which was reduced by as much as 90 and 56% in target tissues of sensory system such as tongue and intestine, respectively. The reduction in retina and heart was around 50%. Conversely, the mRNA expression of low-affinity neurotrophin receptor p75 was increased. At birth, BDNF mRNA expression was affected with a significant generalized reduction,while in vibrissae we observed a reduction of BDNF and p75 mRNAs and an increase of NGF. At postnatal day 14, pups from diabetic mothers showed reduced muscle levels of IGF-I, while we observed a partial impairment of substance P axonal transport at postnatal day 28. Treatment of diabetic mothers with silybin, a flavonoid with antioxidant properties, prevented most of the changes in neurotrophic factor expression and substance P axonal transport with no effects on hyperglycemia and embryo growth retardation. These results indicate that oxidative stress may influence neurotrophic factor synthesis in target territories during development. In addition, these data suggest that nervous system abnormalities observed in diabetic embryopathy may also derive by insufficient neurotrophic factor biosynthesis involving sequentially NGF in the embryo and BDNF and IGF-I in the early postnatal days. Insulin treatment of diabetic mothers normalized hyperglycemia and body growth, with consequent regular embryonic and postnatal development.
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PMID:Progressive and selective changes in neurotrophic factor expression and substance p axonal transport induced by perinatal diabetes: protective action of antioxidant treatment. 1044 Sep 1

A large number of neurotrophic factors that exert effects on specific neuronal populations in the peripheral nervous system have been discovered. Some of these factors may prove useful for the treatment of diabetic peripheral neuropathy. Among the most promising are members of the neurotrophin gene family (nerve growth factor [NGF], brain-derived neurotrophic factor, neurotrophin [NT]-3, and NT-4/5), insulin-like growth factor (IGF)-I and IGF-II, and glial cell-derived neurotrophic factor. Of these, NGF and the IGFs have been tested most extensively in animal models of diabetic neuropathy, with encouraging results. Recombinant human nerve growth factor (rhNGF) has been tested in phase II clinical trials for treatment of patients with diabetes, and the results have been encouraging. Phase III trials of rhNGF have been completed, and clinical trials of other neurotrophic factors are likely to be conducted in the next few years.
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PMID:Neurotrophic factors in the therapy of diabetic neuropathy. 1048 43


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