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)

gamma-Aminobutyric acid (GABA) has been proposed to function as a paracrine signaling molecule in islets of Langerhans. We have shown that rat beta-cells release GABA by Ca(2+)-dependent exocytosis of synaptic-like microvesicles. Here we demonstrate that GABA thus released can diffuse over sufficient distances within the islet interstitium to activate GABA(A) receptors in neighboring cells. Confocal immunocytochemistry revealed the presence of GABA(A) receptors in glucagon-secreting alpha-cells but not in beta- and delta-cells. RT-PCR analysis detected transcripts of alpha(1) and alpha(4) as well as beta(1-3) GABA(A) receptor subunits in purified alpha-cells but not in beta-cells. In whole-cell voltage-clamp recordings, exogenous application of GABA activated Cl(-) currents in alpha-cells. The GABA(A) receptor antagonist SR95531 was used to investigate the effects of endogenous GABA (released from beta-cells) on pancreatic islet hormone secretion. The antagonist increased glucagon secretion at 1 mmol/l glucose twofold and completely abolished the inhibitory action of 20 mmol/l glucose on glucagon release. Basal and glucose-stimulated secretion of insulin and somatostatin were unaffected by SR95531. The L-type Ca(2+) channel blocker isradipine evoked a paradoxical stimulation of glucagon secretion. This effect was not observed in the presence of SR95531, and we therefore conclude that isradipine stimulates glucagon secretion by inhibition of GABA release.
Diabetes 2004 Apr
PMID:Glucose inhibition of glucagon secretion from rat alpha-cells is mediated by GABA released from neighboring beta-cells. 1504 19

The aim of this work was to investigate the interrelated effects of glucose, nitric oxide (NO) and erythropoietin on neuronal survival in retinal cultures, thereby exploring the mechanism of neuronal death in the diabetic retina. Rat retinal cells were cultured in low (5 mM) or high (15 mM) glucose concentrations. After 9 days, cell viability was assessed by (3,4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and NO production was determined by the Griess reaction. Immunohistochemistry was used to quantify GABA-labelled neurones and cells staining for DNA breakdown. High or low glucose concentrations had no effect on basal NO production or the survival of neurones in culture, but treatment with N-nitro-L-arginine methyl ester reduced extracellular levels of NO and increased neuronal survival at both concentrations of glucose. Erythropoietin decreased cell death and NO levels, but only in cultures grown in low concentrations of glucose. It is concluded that erythropoietin's neurotrophic function in the retina is attenuated at glucose concentrations similar to those which occur in diabetes.
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PMID:Neuronal death in primary retinal cultures is related to nitric oxide production, and is inhibited by erythropoietin in a glucose-sensitive manner. 1565 19

The purpose of the present study was to determine the effect of treatment with leptin on gonadotrophin secretion and hypothalamic GnRH, excitatory and inhibitory amino acids release, in prepubertal (15 days old) and peripubertal (30 days old) male rats. Rats of both ages received a single (ip) injection of 30 microg/kg leptin 60 minutes previous to sacrifice. Serum LH was determined, and the hypothalamus dissected and incubated in Earle's medium. GnRH and amino acids release were determined in the media. LH and GnRH were measured by RIA. Amino acids were assessed by HPLC-UV detection. In the two prepubertal stages, (prepubertal and peripubertal, 15 and 30 days of age respectively) leptin increased plasmatic LH levels (p < 0.01) and hypothalamic GnRH release (p < 0.01). Glutamate (GLU) release showed an increment in leptin-treated rats (p < 0.01) at both ages, while only the 30 days old rats showed an increment of the aspartate (ASP) release. GABA secretion was not modified by leptin treatment. In conclusion, the results demonstrated that leptin stimulates the LH-GnRH axis during sexual development in male rats, increasing the secretion of both hormones. The hypothalamic excitatory amino acid neurotransmitter system appears to be involved in this change.
Exp Clin Endocrinol Diabetes 2005 Mar
PMID:Leptin stimulates the reproductive male axis in rats during sexual maturation by acting on hypothalamic excitatory amino acids. 1578 71

In addition to its well-recognized function as a cerebral inhibitory transmitter, less well established is the role of GABA in peripheral nervous and endocrine systems. We summarize current evidence that GABA serves as a neurotransmitter or neuromodulator in the autonomic nervous system and as a hormone or trophic factor in non-neuronal peripheral tissue as well. GABA is widely distributed in endocrine tissues including the pituitary, pancreas, adrenal glands, uterus, ovaries, placenta and testis. Moreover, GABA is involved in the pathophysiology of endocrine disorders such as diabetes mellitus, diseases of adrenal glands and reproductive tracts. Current literature indicates that the peripheral GABA system in the autonomic nervous system, endocrine and immune systems is as yet nearly an unexplored target for diagnosis and drug treatment.
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PMID:The peripheral GABAergic system as a target in endocrine disorders. 1633 74

(1) The first-line treatment for partial epilepsy is carbamazepine monotherapy; gabapentin monotherapy is an alternative, given its lower risk of drug-drug interactions. (2) The standard treatment for neuropathic pain associated with diabetes or post-herpetic neuralgia is a tricyclic antidepressant, with gabapentin as an alternative. Few drugs are available in this setting, and their efficacy is often modest. (3) Pregabalin is a GABA analogue closely related to gabapentin. Both drugs are marketed by Pfizer. Pregabalin has been approved for use in two indications: refractory partial epilepsy and neuropathic pain. (4) In patients with partial epilepsy inadequately controlled by a combination of two or possibly three antiepileptics, three placebo-controlled double-blind trials lasting 12 weeks suggest that adjunctive pregabalin treatment, at a dose of 600 mg/day divided in two or three doses, at least halves the frequency of seizures in 50% of patients. Pregabalin has not been compared with other second-line antiepileptics. (5) In neuropathic pain, there are 12 double-blind placebo-controlled trials involving patients with diabetes or post-herpetic neuralgia. Depending on the trial, between one-third and one-half of patients treated with pregabalin at a dose of 600 mg/day given in two or three doses had at least a 50% reduction in their pain score. In the only trial that included a group treated with amitriptyline (75 mg/day), the latter was significantly more effective than placebo, while pregabalin was not. (6) There are no comparative trials of pregabalin after amitriptyline and gabapentin failure. (7) The adverse effects profile of pregabalin is similar to that of gabapentin, and includes mainly neuropsychological reactions (dizziness and drowsiness). (8) Pregabalin, like gabapentin, can lead to weight gain and peripheral oedema especially in elderly patients. (9) Cases of visual field restriction have been reported with pregabalin in clinical trials. Animal studies suggest a possible risk of haemangiosarcoma, although no human cases have yet been described. (10) Pregabalin, like gabapentin, is eliminated unchanged in urine, implying a limited risk of interactions involving cytochrome P450, and suggesting that the dose should be reduced in patients with even moderate renal failure (creatinine clearance below 60 ml/min). (11) In practice, pregabalin offers nothing new for patients with partial epilepsy, for whom several other antiepileptics are available. The few available treatments for neuropathic pain have limited efficacy, and pregabalin may therefore be tried when both tricyclics and gabapentin fail. However, it is in no way certain that pregabalin is effective in such patients, and comparative trials are lacking.
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PMID:Pregabalin: new drug. Very similar to gabapentin. 1639 76

To investigate mechanisms by which diabetes alters sensory processing, we measured levels of amino acid neurotransmitters in spinal dialysates from awake, unrestrained control and diabetic rats under resting conditions and following hind paw formalin injection. Under resting conditions, glutamate concentrations in spinal dialysates were significantly (P<0.05) decreased in diabetic rats compared to those of control rats whereas aspartate, taurine, glycine and citrulline remained unchanged and GABA was significantly (P<0.05) increased. Noxious stimulation of the hind paw by subcutaneous injection of 0.5% formalin into the dorsum caused a defined flinching behavior in the afflicted paw, and the amount of flinching was significantly (P<0.05) greater in diabetic rats than in controls. Paw formalin injection significantly (P<0.05) increased dialysate levels of glutamate, aspartate, taurine, glycine and citrulline by 3- to 4-fold above basal in both control and diabetic rats. The concentration of glutamate in dialysate samples collected immediately after paw formalin injection remained significantly (P<0.05) lower in diabetic rats compared to those in controls. Formalin injection did not alter dialysate GABA concentrations in control rats, whereas in diabetic rats there was an increase of 151+/-15% above basal levels. These findings indicate that the selective depression of basal and stimulus-evoked glutamate levels in the spinal cord of diabetic rats occurs in parallel with elevated spinal GABA levels. Because increased pain-associated behavior is accompanied by an attenuated spinal glutamate spike following paw formalin injection, hyperalgesia in diabetic rats does not appear to be secondary to enhanced glutamatergic input to the spinal cord.
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PMID:Impaired formalin-evoked changes of spinal amino acid levels in diabetic rats. 1692 81

One important complication of diabetes is damage to the peripheral nervous system. However, in spite of the number of studies on human and experimental diabetic neuropathy, the current therapeutic arsenal is meagre. Consequently, the search for substances to protect the nervous system from the degenerative effects of diabetes has high priority in biomedical research. Neuroactive steroids might be interesting since they have been recently identified as promising neuroprotective agents in several models of neurodegeneration. We have assessed whether chronic treatment with progesterone (P), dihydroprogesterone (DHP) or tetrahydroprogesterone (THP) had neuroprotective effects against streptozotocin (STZ)-induced diabetic neuropathy at the neurophysiological, functional, biochemical and neuropathological levels. Using gas chromatography coupled to mass-spectrometry, we found that three months of diabetes markedly lowered P plasma levels in male rats, and chronic treatment with P restored them, with protective effects on peripheral nerves. In the model of STZ-induced of diabetic neuropathy, chronic treatment for 1 month with P, or with its derivatives, DHP and THP, counteracted the impairment of nerve conduction velocity (NCV) and thermal threshold, restored skin innervation density, and improved Na(+),K(+)-ATPase activity and mRNA levels of myelin proteins, such as glycoprotein zero and peripheral myelin protein 22, suggesting that these neuroactive steroids, might be useful protective agents in diabetic neuropathy. Interestingly, different receptors seem to be involved in these effects. Thus, while the expression of myelin proteins and Na(+),K(+)-ATPase activity are only stimulated by P and DHP (i.e. two neuroactive steroids interacting with P receptor, PR), NCV, thermal nociceptive threshold and intra-epidermal nerve fiber (IENF) density are also affected by THP, which interacts with GABA-A receptor. Because, a therapeutic approach with specific synthetic receptor ligands could avoid the typical side effects of steroids, future experiments will be devoted to evaluating the role of PR and GABA-A receptor in these protective effects.
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PMID:Progesterone and its derivatives are neuroprotective agents in experimental diabetic neuropathy: a multimodal analysis. 1718 35

OBJECTIVE-To determine whether alterations in counterregulatory responses to hypoglycemia through the modulation of ATP-sensitive K(+) channels (K(ATP) channels) in the ventromedial hypothalamus (VMH) are mediated by changes in GABAergic inhibitory tone in the VMH, we examined whether opening and closing K(ATP) channels in the VMH alter local GABA levels and whether the effects of modulating K(ATP) channel activity within the VMH can be reversed by local modulation of GABA receptors. RESEARCH DESIGN AND METHODS-Rats were cannulated and bilateral guide cannulas inserted to the level of the VMH. Eight days later, the rats received a VMH microinjection of either 1) vehicle, 2) the K(ATP) channel opener diazoxide, 3) the K(ATP) channel closer glybenclamide, 4) diazoxide plus the GABA(A) receptor agonist muscimol, or 5) glybenclamide plus the GABA(A) receptor antagonist bicuculline methiodide (BIC) before performance of a hypoglycemic clamp. Throughout, VMH GABA levels were measured using microdialysis. RESULTS-As expected, diazoxide suppressed glucose infusion rates and increased glucagon and epinephrine responses, whereas glybenclamide raised glucose infusion rates in conjunction with reduced glucagon and epinephrine responses. These effects of K(ATP) modulators were reversed by GABA(A) receptor agonism and antagonism, respectively. Microdialysis revealed that VMH GABA levels decreased 22% with the onset of hypoglycemia in controls. Diazoxide caused a twofold greater decrease in GABA levels, and glybenclamide increased VMH GABA levels by 57%. CONCLUSIONS-Our data suggests that K(ATP) channels within the VMH may modulate the magnitude of counterregulatory responses by altering release of GABA within that region.
Diabetes 2007 Apr
PMID:ATP-sensitive K(+) channels regulate the release of GABA in the ventromedial hypothalamus during hypoglycemia. 1725 Dec 73

Gamma-aminobutyric acid (GABA) is synthesized by two isoforms of the pyridoxal 5'-phosphate-dependent enzyme glutamic acid decarboxylase (GAD65 and GAD67). GAD67 is constitutively active and is responsible for basal GABA production. In contrast, GAD65, an autoantigen in type I diabetes, is transiently activated in response to the demand for extra GABA in neurotransmission, and cycles between an active holo form and an inactive apo form. We have determined the crystal structures of N-terminal truncations of both GAD isoforms. The structure of GAD67 shows a tethered loop covering the active site, providing a catalytic environment that sustains GABA production. In contrast, the same catalytic loop is inherently mobile in GAD65. Kinetic studies suggest that mobility in the catalytic loop promotes a side reaction that results in cofactor release and GAD65 autoinactivation. These data reveal the molecular basis for regulation of GABA homeostasis.
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PMID:GABA production by glutamic acid decarboxylase is regulated by a dynamic catalytic loop. 1738 44

Burning mouth syndrome (BMS) is characterized by oral dysesthesia, xerostomia and dysgeusia without visible alterations of oral mucosa. While secondary BMS results from an underlying general condition such as diabetes or iron deficiency, no causal disorder can be identified in primary BMS. The estimated prevalence is 1 - 2%, postmenopausal women are substantially more frequently affected than men. Current etiologic concepts assume a focal peripheral and central neuropathy. Only few controlled drug trials have yet been conducted. Thioctic acid appears the medical treatment of choice due to its comparatively good evidence for efficacy and low incidence of adverse reaction. Gabapentin and pregabalin are modern GABA-analogue anticonvulsants, which are also efficient in the treatment of peripheral neuropathies. Also conceptually appropriate for BMS treatment, current evidence for efficacy in BMS is insufficient. In two trials, local oral treatment with clonazepam has been beneficial in BMS. The efficacy of antidepressants is equivocal.
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PMID:[Burning mouth syndrome]. 1754


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