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PubMed1999

Identification of two novel mutations in the hypoglycemic phenotype of very long chain acyl-CoA dehydrogenase deficiency.

Very long chain acyl-CoA dehydrogenase (VLCAD) catalyzes the initial step of long chain fatty acid oxidation in the mitochondria. Patients with VLCAD deficiency have recently been observed with two clinical phenotypes. The cardiac form presents with an early onset cardiomyopathy and a high incidence of infant death, while the hypoglycemic form resembles medium chain acyl-CoA dehydrogenase (MCAD) manifesting with hypoketotic hypoglycemia. In our investigation on the molecular basis for these phenotypes, we identified two novel mutations in one VLCAD patient with the hypoglycemic form, a C953T (Pro318Leu) mutation in exon 10 resulting in a substitution of proline 318 by leucine on one allele, and a C1194A (Tyr398Stop) mutation in exon 12 which created a premature stop codon TAA on another allele. The Tyr398Stop mutation may result in a truncated protein or instable messenger RNA.

Acyl-CoA Dehydrogenase, Long-Chain↗
PubMed1988

Mechanisms of hypoglycemic brain damage. Evidence against a significant role of the noradrenergic locus coeruleus system.

Selective lesions of the noradrenergic locus coeruleus (LC) system have recently been shown to aggravate both ischemic and epileptic brain damage. This study explores the possibility that the LC system also influences hypoglycemic brain injury. Bilateral 6-hydroxydopamine lesions of the LC projection to the forebrain were found to cause no change in the degree of neuronal necrosis in the neocortex, hippocampal formation and caudate-putamen following 30 min of reversible insulin-induced hypoglycemic coma. We propose that selective neuronal necrosis in ischemia and status epilepticus is due to the action of excitatory amino acids at synaptic sites, which can be partly counteracted by noradrenaline release from inhibitory LC terminals. In hypoglycemia, excitatory amino acids probably cause brain damage via a local and more diffuse toxic effect which is not significantly influenced by the activation of the LC system.

Animals↗
PubMed1985

The temporal evolution of hypoglycemic brain damage. I. Light- and electron-microscopic findings in the rat cerebral cortex.

In the course of a study on the pathogenesis of neuronal necrosis in severe hypoglycemia, the morphological characteristics reflecting reversible and irreversible neuronal lesions were examined as a function of time following normalization of blood glucose. To that end, closely spaced time intervals were studied in the rat cerebral cortex before, during, and up to 1 year after standardized pure hypoglycemic insults of 30 and 60 min of cerebral isoelectricity. Both the superficial and deep layers of the cerebral cortex showed dark and light neurons during and several hours after the insult. By electron microscopy (EM) the dark neurons were characterized by marked condensation of both karyoplasm and cytoplasm, with discernible, tightly packed cytoplasmic organelles. The light neurons displayed clustering of normal organelles around the nucleus with clearing of the peripheral cytoplasm. Some cells, both dark neurons and neurons of normal electron density, contained swollen mitochondria with fractured cristae. Light neurons disappeared from the cerebral cortex by 4 h of recovery. Some dark neurons in the superficial cortex and almost all in the deep cortex evolved through transitional forms into normal neurons by 6 h recovery. Another portion of the dark neurons in the superficial cortex became acidophilic between 4 and 12 h, and by EM they demonstrated karyorrhexis with stippled electron-dense chromatin. The plasma membrane was disrupted, the cytoplasm was composed of amorphous granular debris, and the mitochondria contained flocculent densities. These definitive indices of irreversible neuronal damage were seen as early as 4-8 h recovery. Subsequently, the acidophilic neurons were removed from the tissue, and gliosis ensued. Thus, even markedly hyperchromatic "dark" neurons are compatible with survival of the cell, as are neurons with conspicuous mitochondrial swelling. Definite nerve cell death is verified as the appearance of acidophilic neurons at which stage extensive damage to mitochondria is already seen in the form of flocculent densities, and cell membranes are ruptured. Our previous results have shown that hypoglycemic neocortical damage affects the superficial laminae, chiefly layer 2. The present results demonstrate that, following the primary insult, this damage evolves relatively rapidly within the first 4-12 h. We have obtained no evidence that additional necrotic neurons are recruited after longer recovery periods.

Animals↗
PubMed1991

Chronic effects of methylmercury on the urinary excretion of catecholamines and their responses to hypoglycemic stress.

Five male Wistar rats were treated with methylmercury chloride (MMC) and compared with five age-matched control rats. A dose of 10 mg/kg was given three times. The chronic effects of the MMC administration on the urinary output of catecholamines [norepinephrine (NE), epinephrine (E) and dopamine (DA)] were measured for 50 days. On the 69th day after MMC administration, the rats were examined for insulin-induced hypoglycemic stress. On the 90th day, the animals were decapitated and various organs were weighed and serum thyroid hormones [thyroid stimulating hormone (TSH) and total and free thyroxine (T4)] were measured. Decreases in DA excretion and DA response to stress were observed in the MMC-treated group. Inflammation of the kidney was also found, suggesting MMC-induced damage to the renal tubular region, the apparent site of renal DA synthesis. The MMC group and the control group showed differential NE and E response patterns. The lowered baseline excretion of NE appeared to continue even 70 days after MMC administration, while the difference in E excretion between the two groups disappeared 1 month after MMC administration. Both NE and E showed normal responsiveness to hypoglycemic stress induced by insulin. All serum TSH and total and free T4 baseline levels showed slight increases, and the thyroid gland weights in the MMC group were slightly heavier. These findings suggest a rather hyperthyroid state after the initial acute phase suppression, as suggested by the previous examinations. Thus, these findings suggest long-lasting effects of methylmercury administration, especially on renal DA synthesis. Baseline urinary excretion of NE and thyroid function could also be affected for a long time.

Animals↗
PubMedDate not supplied

Hypoglycemic therapy and hemostasis in maturity- onset diabetes mellitus: existence of an early prethrombotic state.

We studied 115 patients with uncomplicated maturity-onset diabetes mellitus, 55 males and 60 females; patients were divided into 7 groups according to the hypoglycemic therapy (diet alone, tolbutamide, glibenclamide, phenformin, combination of the last two drugs, insulin, combination of insulin and phenformin). All patients were tested for a prethrombotic state by the simultaneous determination of the following parameters: ADP-induced platelet aggregation, Factor VIII as antigen and procoagulant activity and the plasma levels of fibrinogen and antithrobin III. Our results show that these parameters were markedly altered in diabetic patients when compared to apparently normal subjects of the same age; on the contrary, differences between groups of diabetic patients were very slight and hardly ever statistically significant. These results suggest that the prethrombotic alterations of hemostatic system are very similar in all groups of diabetic patients; this is true also for patients submitted to diet alone, i.e. with slight and usually recent-onset diabetes mellitus. In conclusion, our study suggests the opportunity, at least from the theoretical point of view, of systematic antiaggregant and/or anticoagulant treatment(s) in maturity-onset diabetes mellitus, whose severe and precocious prethrombotic alterations seem to be independent of the hypoglycemic treatment applied.

Adenosine Diphosphate↗
PubMed1992

Human insulin-specific immunoglobulin G antibody and hypoglycemic attacks after the injection of gold thioglucose.

A 56-year-old woman with granulomas of gold thioglucose in her hips exhibited recurrent bouts of hypoglycemic attacks. The first attack occurred 2 years after the last injection of gold thioglucose, when large amounts of extractable insulin and human insulin-specific antibody were noted in her serum. Histological examination of the resected granulomas showed marked infiltration of lymphocytes, plasma cells, and macrophages containing yellowish-brown granules, which proved to be gold by electron microscopy using X-ray microanalysis. After resection of the granuloma, however, the frequency of the hypoglycemic attacks decreased remarkably as well as the levels of both extractable insulin and human insulin-specific antibody.

Antibody Specificity↗
PubMed2007

Site-specific habituation of insulin-induced hypoglycemic induction of fos immunoreactivity in glucocorticoid receptor: immunopositive neurons in the male rat brain.

Current studies show that type II glucocorticoid receptor (GR) stimulation during recurring insulin-induced hypoglycemia (RIIH) results in diminished hypoglycemic activation of neurons in discrete CNS metabolic structures, namely the lateral hypothalamic area (LHA), hypothalamic paraventricular (PVH) and dorsomedial (DMH) nuclei, and nucleus of the solitary tract (NTS). The present work utilized immunofluorescence histochemistry to evaluate the reactivity of GR-expressing neurons in characterized hypothalamic, thalamic, and hindbrain metabolic structures to glucoprivation, and to determine if antecedent hypoglycemic stimulation of central GR decreases Fos protein expression by these neurons. Groups of adult male rats were injected subcutaneously with one or four doses of the intermediate-acting insulin, Humulin NPH, on as many days, while controls received diluent only. Rats injected with four doses of insulin were pretreated by intracerebroventricular administration of the selective GR antagonist, CP-475222, or vehicle alone prior to insulin doses 1-3. All animals were sacrificed by trancardial perfusion 2 h after injections on day four of the study. Mean numbers of GR-immunoreactive (-ir) neurons did not differ between groups injected with diluent versus one dose of insulin in each structure evaluated, but were significantly elevated above baseline on the fourth day of RIIH in the LHA and DMH, but not the PVH, VMH, ARC, thalamic paraventricular (PVT), or NTS. Counts of GR-ir-positive neurons in each site were similar between groups treated with CP-475222 or vehicle icv during RIIH. While mean numbers of GR-plus Fos-ir neurons in the PVH, DMH, LHA, and NTS, but not the PVT were significantly elevated after one dose of NPH, this increase was abolished in each site by RIIH. Pharmacological antagonism of central GR during antecedent hypoglycemia prevented RIIH-associated habituation of Fos colabeling of GR-expressing neurons in the PVH, DMH, and LHA. These data show that RIIH increases nuclear immunolabeling for GR in discrete CNS metabolic structures, evidence that recurring metabolic stress may amplify receptor-mediated genomic regulatory function in local neurons. The results also demonstrate that GR-containing neurons in the LHA, DMH, PVH, and NTS react to hypoglycemia by induction of the Fos stimulus-transcription cascade, and that precedent stimulation of central GR is critical for RIIH-associated habituation of this functional response in the former three sites.

Animals↗
PubMed2006

Reversible splenial abnormality in hypoglycemic encephalopathy.

INTRODUCTION: Lesions involving the splenium of the corpus callosum (SCC) have been rarely reported in cases of hypoglycemic brain injury. METHODS: We identified signal abnormalities in the SCC in three adult patients with hypoglycemic encephalopathy by using diffusion-weighted imaging (DWI) on a 1.5-T MR scanner. Repeat DWI was performed in all patients following a marked clinical improvement, and MR angiography and routine MRI were also performed. We examined each patient's detailed medical history and blood laboratory tests in order to exclude other conditions causing similar SCC abnormalities. RESULTS: Initial DWI was performed during which each patient showed altered mental status that was attributed to profound hypoglycemia. We observed an identical pattern of DWI abnormality characterized by high signals in the SCC with apparent diffusion coefficient reductions that were reversed completely within several days following appropriate correction of hypoglycemia. T2-weighted or FLAIR images also showed no residual lesion in the SCC and MR angiography was normal in all patients. CONCLUSION: These case reports suggest that the SCC should be added to the list of selective vulnerability to hypoglycemia and that hypoglycemia, in turn, be included in the differential diagnosis of reversible SCC abnormalities.

Adult↗
PubMed2003

Cysteine-induced hypoglycemic brain damage: an alternative mechanism to excitotoxicity.

Central neural damage caused by L-cysteine (L-Cys) was first reported more than 30 years ago. Nevertheless, the exact mechanisms of L-Cys-mediated neurotoxicity are still unclear. Preliminary study in mice demonstrated that, following L-Cys injection, animals developed tachypnea, tremor, convulsions, and death in conjunction with documented hypoglycemia. The aim of the present study was to further investigate the mechanism of L-Cys-mediated hypoglycemic effect and neural damage. Neonatal ICR mice (n=6) were injected with L-Cys (0.5-1.5 mg/g body weight [BW]), and their blood glucose and insulin levels were determined up to 90 min following the injection. Experiments were repeated in chemically (streptozotocin [STZ]) pancreatectomized animals. Brain histology was assessed. Mice injected with L-Cys exhibited dose-dependent neurotoxicity and higher mortality as compared with controls. L-Cys (1.2-1.5 mg/g BW) caused severe hypoglycemia (glucose<42 mg/dl) ( P<0.001). In STZ-treated (diabetic) animals, L-Cys (1.5 mg/g BW) increased plasma insulin levels 2.3-fold and decreased serum glucose levels by 50% ( P<0.01). Brain histology revealed destruction of as much as 51% of hippocampal neurons in the L-Cys-treated mice but not in the glucose-resuscitated animals. These findings suggest that L-Cys injection can cause pronounced hypoglycemia and central neural damage which is glucose reversible. Since L-Cys is chemically different from the other excitatory amino acids (glutamate and aspartate), L-Cys-mediated neurotoxicity may be connected to its hypoglycemic effect.

Animals↗
PubMed1992

Reactive hypoglycemic coma due to insulin autoimmune syndrome: case report and literature review.

Recurrent episodes of postprandial hypoglycemic symptoms culminated in hypoglycemic coma in a hypertensive but otherwise healthy man while he was taking hydralazine. The patient was found to have an extreme elevation in the immunoreactive insulin level, leading to the discovery of insulin antibodies in the absence of prior exposure to exogenous insulin. Negative results of an anatomic study of the pancreas and an inability to reproduce hypoglycemia during a prolonged fast helped to exclude insulinoma. In contrast, symptomatic hypoglycemia developed in response to oral glucose loading and was associated with an elevation in total and free insulin as well as C-peptide levels. The patient was diagnosed with insulin autoimmune syndrome, which, although a common source of hypoglycemia in Japan, has been well documented in only 15 cases from other countries. HLA typing revealed the patient to be positive for groups Cw4 and DR4, a combination that has been preliminarily associated with insulin autoimmune syndrome in Japan. Unlike the majority of cases previously reported, this patient had no clinical or serologic evidence of an underlying autoimmune disorder and had not been exposed to drugs containing sulfhydryl groups. This case adds to the world literature on insulin autoimmune syndrome, lends support to a postulated HLA association, and documents the presence of insulin autoantibodies in the absence of another underlying autoimmune disorder.

Adult↗
PubMed1993

Embryopathic effects of the oral hypoglycemic agent chlorpropamide in cultured mouse embryos.

OBJECTIVES: The oral hypoglycemic agent chlorpropamide was evaluated for embryopathic effects in the mouse embryo model. STUDY DESIGN: Mouse embryos (n = 10 to 31 per group) were exposed in whole embryo culture to serum from chlorpropamide-treated rats or chlorpropamide-supplemented control rat serum. Hypoglycemic serum from chlorpropamide-treated rats was supplemented with glucose to control for effects of hypoglycemia. Differences in malformation rates were evaluated by Fisher's exact test and numerical differences by analysis of variance. RESULTS: Mouse embryos were malformed by > or = 24 micrograms/ml of chlorpropamide, embryonic protein content and somites were decreased by > or = 130 micrograms/ml of chlorpropamide, and visceral yolk sac protein was reduced by > 500 micrograms/ml of chlorpropamide. Similar development occurred in serum from chlorpropamide-treated rats and chlorpropamide-supplemented control serum, and growth was not improved by adding glucose. CONCLUSIONS: Chlorpropamide produces malformations and growth retardation in mouse embryos in vitro at concentrations overlapping therapeutic levels in humans. Chlorpropamide-induced defects are not mediated by hypoglycemia or by products of chlorpropamide metabolism.

Animals↗
PubMed1995

Protective effects of BDNF and NT-3 but not PDGF against hypoglycemic injury to cultured striatal neurons.

Brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and platelet-derived growth factor (PDGF) exert trophic effects on striatal neurons in vitro, which raises the possibility that these growth factors might also counteract neuronal death provoked by various insults. We have found that BDNF and NT-3, but neither PDGF-AA nor -BB, added 24 h before the insult ameliorated hypoglycemic neuronal damage induced by 15 or 24 h of glucose deprivation in rat striatal cell cultures. BDNF and NT-3 afforded neuronal protection even when administered 8 or 4 h, respectively, after the onset of hypoglycemia. In normoglycemic striatal cultures exposed to these neurotrophins for several days, there was a slight, nonsignificant increase of the number of surviving microtubule-associated protein-2-positive cells (20-30%) compared to untreated control cultures, but no change of glial cells. Exposure of the cultures to BDNF or NT-3 produced a significant increase in the number of neurons expressing detectable levels of the calcium-binding protein, calbindin, suggesting that a stabilization of calcium homeostasis might be implicated in the neuroprotection. Immunocytochemical analysis revealed that the majority (70-80%) of neurons in the striatal cultures expressed TrkB and TrkC, the functional receptors for BDNF and NT-3, respectively, implying that the effects of the neurotrophins are most likely direct. These data indicate that BDNF and NT-3 can protect striatal neurons against hypoglycemia in vitro and raise the possibility that these neurotrophins could counteract striatal neuronal death induced by hypoglycemic and ischemic insults in vivo.

Animals↗
PubMed1980

Alternation in both insulin release and its hypoglycemic effects in atopic bronchial asthma.

In 31 patients with atopic bronchial asthma in clinical remission and in 21 healthy sex- and age-matched subjects, the responses to intravenous tolbutamide (1.0 gm) and insulin (0.1 U/kg) were studied over a period of 2 hr. In response to tolbutamide, asthmatics released significantly less insulin, but their blood glucose levels did not differ from those of controls. Asthmatics also reacted to tolbutamide-induced hypoglycemia with significantly greater output of growth hormone to blood. Following intravenous injection of insulin, the recovery of the blood glucose concentrations was significantly reduced in asthmatic patients. More economical use of insulin and increased responsiveness to its hypoglycemic action, together with the well-known reduction in hypoglycemic effects of catecholamines in bronchial asthma, might explain why asthmatics rarely develop diabetes mellitus.

Adolescent↗
PubMed1987

Monosodium L-glutamate lesions reduce susceptibility to hypoglycemic feeding and convulsions.

Lesions of the circumventricular regions of the brain induced by neonatal administration of monosodium L-glutamate (MSG) are associated with chronic hypophagia and deficits in response to a variety of feeding challenges. These deficits occur despite the fact that, at least at high doses, MSG can produce obesity. The cause of the feeding deficits in MSG-treated animals is unknown. However, the circumventricular regions that are damaged by MSG contain high concentrations of insulin binding sites. In order to determine whether the MSG lesion alters responsiveness to circulating insulin, we have investigated the response of non-obese MSG-treated mice to doses of exogenous insulin designed either to stimulate feeding or to induce hypoglycemic convulsions. We report that MSG produces a dose-related decrease in hypoglycemic convulsions and glucoprivic feeding, suggesting that a loss in sensitivity to insulin may contribute to the MSG syndrome.

Animals↗
PubMed1989

Diabetic and hypoglycemic neuropathy--a comparison in the BB rat.

Functional and structural neuropathy was examined in hyperglycemic (diabetic) BB rats maintained on small maintenance doses of insulin, hyperglycemic BB rats receiving no insulin, and BB rats in whom hypoglycemia was induced by the administration of excessive insulin doses. The data were compared with those of non-diabetic age- and sex-matched BB rats. Functional deficits and structural abnormalities were comparable in diabetic rats with and without insulin supplementation, suggesting that the generally necessary insulin dosing in this model does not per se account for the neuropathy. Hypoglycemic neuropathy was characterized by slowing of nerve conduction velocity, marked loss of anterior horn motoneurons and Wallerian degeneration, as well as loss of large myelinated fibers, suggesting a neuropathy involving predominantly motoneurons. Diabetic neuropathy was not associated with nerve cell loss but showed marked axonal atrophy involving predominantly sensory fibers. Thus, diabetic and hypoglycemic neuropathies are two distinguishable entities under strict experimental conditions, but may overlap in human diabetic subjects in whom tight insulin control is desirable.

Animals↗
PubMedDate not supplied

Unchanged hypothalamic neuropeptide Y concentrations in hyperphagic, hypoglycemic rats: evidence for specific metabolic regulation of hypothalamic NPY.

Hypothalamic concentrations of neuropeptide Y (NPY), a potent central appetite stimulant, increase dramatically in food-restricted and insulin-deficient diabetic rats. This suggest that NPY may drive hyperphagia in these conditions, which are characterized by weight loss and insulin deficiency. To test the hypothesis that insulin deficiency and weight loss are specific stimuli to hypothalamic NPY, we measured NPY concentrations in individual hypothalamic regions in rats with hyperphagia caused by insulin-induced hypoglycemia. Groups of 8 male Wistar rats were injected with ultralente insulin (20-60 U/kg) to induce either acute hypoglycemia (7 h after a single injection) or chronic hypoglycemia (8 days with daily injections). In hypoglycemic rats, plasma insulin concentrations were increased 6- to 7-fold compared with saline-injected controls; food intake was significantly increased with acute and chronic hypoglycemia and weight gain was significantly increased in the chronically hypoglycemic group. NPY concentrations were measured by radioimmunoassay in 8 hypothalamic regions microdissected from fresh brain slices. NPY concentrations were not increased in any region in either acute or chronic hypoglycemia. NPY therefore seems unlikely to mediate hyperphagia in hyperinsulinemia-induced hypoglycemia, supporting the hypothesis that weight loss is a specific stimulus to hypothalamic NPY and that insulin deficiency may be the metabolic signal responsible.

Animals↗
PubMed1990

Hypoglycemic neurotoxicity in vitro: involvement of excitatory amino acid receptors and attenuation by monosialoganglioside GM1.

Rat cerebellar granule cells, when subjected to a glucose-free environment for 4 h, developed extensive degeneration of neuronal cell bodies and their associated neurite network over the following 24 h. This neuronal damage was quantitated with a colorimetric assay using the metabolic dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide. Hypoglycemic neuronal injury could be markedly reduced by the presence of both competitive (3-(+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid) and non-competitive (phencyclidine) N-methyl-D-aspartate receptor antagonists, but not by kainate/quisqualate preferring antagonists 6-cyano-7-nitroquinoxaline-2,3-dione and 6,7-dinitroquinoxaline-2,3-dione. Glucose deprivation neuronal injury was also reduced by adding glutamate-degrading enzymes to the incubation medium. Monosialoganglioside GM1, but not its asialo derivative (lacking sialic acid), was also effective in protecting against hypoglycemic neurodegeneration when included during the period of glucose deprivation. These results suggest that the neuronal injury to cerebellar granule cells resulting from glucose deprivation is mediated predominantly by activation of the N-methyl-D-aspartate type of excitatory amino acid receptor, perhaps through the action of endogenously released glutamate. Furthermore, the monosialoganglioside GM1, a member of a class of naturally occurring sialoglycosphingolipids, is able to attenuate this neuronal injury--as already observed for glutamate neurotoxicity and anoxic neuronal death in cerebellar granule cells. Gangliosides may thus prove to be of therapeutic utility in excitatory amino acid-associated neuropathologies.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMedDate not supplied

Hypoglycemic hemiplegia in an adolescent with insulin-dependent diabetes mellitus: a case report and a review of the literature.

A case of hypoglycemic hemiparesis in a fifteen-year-old girl with insulin dependent diabetes mellitus (IDDM) is described. The initial presentation included left facial paresis and muscular weakness of the left upper and lower extremities, associated with a blood glucose level of 31 mg/dL. The patient recovered completely after a glucose infusion. Her neurological examination became normal within 24 hours and remained so for a follow-up period of 6 months. Hypoglycemic hemiparesis is rarely described in children and adolescents.

Adolescent↗