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1.
J Neurosci Res ; 66(5): 931-40, 2001 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-11746421

RESUMEN

The ketogenic diet has been utilized for many years as an adjunctive therapy in the management of epilepsy, especially in those children for whom antiepileptic drugs have not permitted complete relief. The biochemical basis of the dietary effect is unclear. One possibility is that the diet leads to alterations in the metabolism of brain amino acids, most importantly glutamic acid, the major excitatory neurotransmitter. In this review, we explore the theme. We present evidence that ketosis can lead to the following: 1) a diminution in the rate of glutamate transamination to aspartate that occurs because of reduced availability of oxaloacetate, the ketoacid precursor to aspartate; 2) enhanced conversion of glutamate to GABA; and 3) increased uptake of neutral amino acids into the brain. Transport of these compounds involves an uptake system that exchanges the neutral amino acid for glutamine. The result is increased release from the brain of glutamate, particularly glutamate that had been resident in the synaptic space, in the form of glutamine. These putative adaptations of amino acid metabolism occur as the system evolves from a glucose-based fuel economy to one that utilizes ketone bodies as metabolic substrates. We consider mechanisms by which such changes might lead to the antiepileptic effect.


Asunto(s)
Aminoácidos/metabolismo , Encéfalo/metabolismo , Metabolismo Energético/fisiología , Epilepsia/metabolismo , Epilepsia/terapia , Alimentos Formulados , Cuerpos Cetónicos/biosíntesis , Animales , Encéfalo/citología , Epilepsia/fisiopatología , Humanos , Transmisión Sináptica/genética
2.
J Neurosci Res ; 66(2): 272-81, 2001 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-11592124

RESUMEN

The relationship between ketosis and brain amino acid metabolism was studied in mice that consumed a ketogenic diet (>90% of calories as lipid). After 3 days on the diet the blood concentration of 3-OH-butyrate was approximately 5 mmol/l (control = 0.06-0.1 mmol/l). In forebrain and cerebellum the concentration of 3-OH-butyrate was approximately 10-fold higher than control. Brain [citrate] and [lactate] were greater in the ketotic animals. The concentration of whole brain free coenzyme A was lower in ketotic mice. Brain [aspartate] was reduced in forebrain and cerebellum, but [glutamate] and [glutamine] were unchanged. When [(15)N]leucine was administered to follow N metabolism, this labeled amino acid accumulated to a greater extent in the blood and brain of ketotic mice. Total brain aspartate ((14)N + (15)N) was reduced in the ketotic group. The [(15)N]aspartate/[(15)N]glutamate ratio was lower in ketotic animals, consistent with a shift in the equilibrium of the aspartate aminotransferase reaction away from aspartate. Label in [(15)N]GABA and total [(15)N]GABA was increased in ketotic animals. When the ketotic animals were injected with glucose, there was a partial blunting of ketoacidemia within 40 min as well as an increase of brain [aspartate], which was similar to control. When [U-(13)C(6)]glucose was injected, the (13)C label appeared rapidly in brain lactate and in amino acids. Label in brain [U-(13)C(3)]lactate was greater in the ketotic group. The ratio of brain (13)C-amino acid/(13)C-lactate, which reflects the fraction of amino acid carbon that is derived from glucose, was much lower in ketosis, indicating that another carbon source, i.e., ketone bodies, were precursor to aspartate, glutamate, glutamine and GABA.


Asunto(s)
Aminoácidos/metabolismo , Encéfalo/metabolismo , Grasas de la Dieta/farmacología , Cetosis/metabolismo , Animales , Ácido Aspártico/metabolismo , Barrera Hematoencefálica , Peso Corporal , Coenzima A/análisis , Grasas de la Dieta/administración & dosificación , Cromatografía de Gases y Espectrometría de Masas , Glucosa/farmacología , Ácido Glutámico/metabolismo , Cuerpos Cetónicos/metabolismo , Masculino , Ratones , Proteínas del Tejido Nervioso/análisis , Prosencéfalo/metabolismo , Ácido gamma-Aminobutírico/análisis
3.
J Biol Chem ; 276(34): 31876-82, 2001 Aug 24.
Artículo en Inglés | MEDLINE | ID: mdl-11423541

RESUMEN

We have utilized [(15)N]alanine or (15)NH(3) as metabolic tracers in order to identify sources of nitrogen for hepatic ureagenesis in a liver perfusion system. Studies were done in the presence and absence of physiologic concentrations of portal venous ammonia in order to test the hypothesis that, when the NH(4)(+):aspartate ratio is >1, increased hepatic proteolysis provides cytoplasmic aspartate in order to support ureagenesis. When 1 mm [(15)N]alanine was the sole nitrogen source, the amino group was incorporated into both nitrogens of urea and both nitrogens of glutamine. However, when studies were done with 1 mm alanine and 0.3 mm NH(4)Cl, alanine failed to provide aspartate at a rate that would have detoxified all administered ammonia. Under these circumstances, the presence of ammonia at a physiologic concentration stimulated hepatic proteolysis. In perfusions with alanine alone, approximately 400 nmol of nitrogen/min/g liver was needed to satisfy the balance between nitrogen intake and nitrogen output. When the model included alanine and NH(4)Cl, 1000 nmol of nitrogen/min/g liver were formed from an intra-hepatic source, presumably proteolysis. In this manner, the internal pool provided the cytoplasmic aspartate that allowed the liver to dispose of mitochondrial carbamyl phosphate that was rapidly produced from external ammonia. This information may be relevant to those clinical situations (renal failure, cirrhosis, starvation, low protein diet, and malignancy) when portal venous NH(4)(+) greatly exceeds the concentration of aspartate. Under these circumstances, the liver must summon internal pools of protein in order to accommodate the ammonia burden.


Asunto(s)
Alanina/metabolismo , Hígado/metabolismo , Amoníaco/metabolismo , Animales , Hidrólisis , Masculino , Isótopos de Nitrógeno , Perfusión , Ratas , Ratas Sprague-Dawley
4.
Am J Physiol ; 233(1): E19-27, 1977 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-327831

RESUMEN

The uptake of injected radioactive amino acids by the isolated islet and other tissues of the toadfish has been examined. The islet and most other tissues appear to actively transport most amino acids and, of the tissues studied, the islet is one of the most active in this regard. Most tissues accumulated the dicarboxylic acids to the greatest extent, with the basic amino acids and the neutral amino acids with unbranched side chains also being taken up well. However, each tissue showed a unique pattern of uptake of the different amino acids, and islet was distinguished by its high uptake of glycine 15 min after injection. The pattern of uptake of amino acids by toadfish islet does not appear to be related to their relative ability to stimulate insulin release from islets of other species or to their relative rates of metabolism, but does correlate well with the content of free amino acids in mouse islets and with the sum of the amino acid contents of anglerfish proinsulin and proglucagon.


Asunto(s)
Aminoácidos/metabolismo , Islotes Pancreáticos/metabolismo , Aminoácidos/sangre , Animales , Encéfalo/metabolismo , Peces , Branquias/metabolismo , Riñón/metabolismo , Hígado/metabolismo , Miocardio/metabolismo , Especificidad de Órganos , Factores de Tiempo
5.
Anat Rec ; 185(2): 209-21, 1976 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-776036

RESUMEN

When pancreases from fetal rats were transplanted beneath the kidney capsule of isologous normal adult recipients, continued growth and differentiation of the endocrine portion of the pancreas occurred. While limited amounts of acinar tissues were identifiable in the early transplant period (7 days), such cells were absent in long term transplants (14 and 21 days). In contrast, while few definitive islet beta cells were present at the time of transplantation, following 21 days at the kidney site large circumscribed islets comprised of heavily granulated beta cells in association with duct epithelial cells predominated. Mitotic figures were seen in both these cell populations. Total islet mass had increased over 20-fold during the transplantation period. Similar results were observed if fetal pancreases were grown in organ culture for ten days prior to transplantation. Continued islet and duct cell growth, as evidenced by mitotic figures and an increase in absolute islet cell mass was obtained in such cultured explants when transplanted to either isogenic or allogenic recipients. These observations support the hypothesis that fetal pancreas may be the best source of donor material for transplantation to diabetic recipients, in part due to the continued growth and differentiation of the islet tissue during the transplantation period.


Asunto(s)
Islotes Pancreáticos/crecimiento & desarrollo , Trasplante de Páncreas , Animales , Feto , Técnicas de Cultivo de Órganos , Páncreas/anatomía & histología , Ratas , Trasplante Isogénico
6.
Am J Anat ; 146(2): 133-49, 1976 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-941846

RESUMEN

Fetal rat pancreas (ages 16 to 22 days postcoitum) and neonatal pancreas (4 days postnatal) were grown in organ culture for four days. The medium consisted of chick embryo extract and rooster serum either with or without the addition of corticosterone (3 X 10(-5) M). Acinar cell differentiation was assessed using quantitative light microscopic linear scanning of tissue sections and enzymatic analysis of amylase in the culture media and in the explants. In the younger fetal tissue of 16 and 18 days postcoitum exocrine differentiation continued in vitro. The effect of corticosterone was an enhancement of the degree of in vitro differentiation. Even with corticosterone, however, the degree of differentiation in vitro was less than that observed during a similar period in vivo. In differentiated pancreas (20- and 22-day fetal neonatal) the acinar pancreas degenerated under control conditions and a selective growth of the endocrine pancreas was observed. The addition of corticosterone to the media resulted in a maintenance of the differentiated state of the acini except in 22-day fetal tissue in which the acini were not preserved. The differences between these results and the work of other investigators and the possible in vivo role of adrenocorticosteroids in exocrine pancreatic differentiation is discussed.


Asunto(s)
Diferenciación Celular , Corticosterona/farmacología , Páncreas/citología , Factores de Edad , Amilasas/metabolismo , Animales , Feto , Técnicas de Cultivo de Órganos , Ratas
7.
Differentiation ; 6(1): 17-26, 1976 Mar 16.
Artículo en Inglés | MEDLINE | ID: mdl-976649

RESUMEN

Foetal rat pancreatic explants (20-day postcoitum) were grown in organ culture on medium enriched with serum and embryo extract containing various concentrations of corticosterone. Normal pancreatic exocrine morphology was preserved. In addition, media amylase concentration remained high and media insulin was suppressed. This is in sharp contrast to explants incubated on control medium without addition of steroid in which a rapid dissappearance of the acinar component and a selective proliferation of the islet cells was noted. The magnitude of these effects was related to the concentration of the steroid. Corticosterone was effective in preserving pancreatic acinar cells through 8-10 days in vitro. Removal of high levels of corticosterone from the incubation medium after 4 days of culture resulted in a decrease in media amylase and a fall in explant acinar cell mass. The media insulin returned to control levels during the following 4 days of culture. Addition of corticosterone to the media following 4 days of control culture resulted in no increase in media amylase and no statistically significant differences in explant acinar cell mass. Media insulin was decreased from control levels following the additional 4 days of incubation. However, corticosterone, even at a concentration of 10.0 mug/ml, was not effective in depressing insulin secretion as was foetal adrenal co-culture. It is proposed that adrenal corticosteroids are responsible for the maintenance of differentiated acinar cells previously observed in pancreatic adrenal co-culture. This suggests that corticosteroids may play an important role in in vivo pancreatic morphogenesis and cytodifferentiation. In addition, adrenal corticosteroids directly inhibit insulin release from the explant beta cells in vitro.


Asunto(s)
Corticosterona/farmacología , Técnicas de Cultivo de Órganos , Páncreas/embriología , Glándulas Suprarrenales/fisiología , Amilasas/metabolismo , Animales , Diferenciación Celular/efectos de los fármacos , Corticosterona/metabolismo , Relación Dosis-Respuesta a Droga , Insulina/metabolismo , Páncreas/efectos de los fármacos , Páncreas/metabolismo , Ratas
8.
Diabetes ; 25(3): 180-9, 1976 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-767184

RESUMEN

Pancreases from neonatal rats four to 16 days postpartum were grown in organ culture for from two to nine days. Approximately 10-20 explants, each measuring 1 mm.3 (1 mg.), were grown on a single Millipore filter placed at the gas-liquid interface of a medium consisting of 50 per cent horse serum and 50 per cent chick embryo extract. Following organ culture, an estimated 9-20 mg. of cultured islet tissue were dissociated with collagenase and isotransplanted into the peritoneal cavity of alloxan-diabetic recipients. In seven of eight recipients the diabetes was reversed between 11 and 53 days of posttransplantation. Animals receiving 12-16 mg. of cultured islet attained normoglycemia in 11-20 days; animals receiving 9-10 mg. of cultured islet tissue recovered between 45 and 53 days. These animals have remained symptom-free for over six months. Biopsies of grafts taken from the peritoneal cavity following reversal of diabetes contained well-vascularized islets compared primarily of heavily granulated beta cells. Quantitative analysis of host pancreases by the linear scanning method (biopsied at one to two weeks and four to five months following reversal of the diabetes) demonstrated that the total beta-cell mass was 3 per cent and the total insulin content was 6 per cent of the normal values. Little or no evidence of regeneration of host beta cells was observed. These studies show that a period of organ culture prior to isotransplantation does not impair the ability of islet tissue to reverse alloxan diabetes in the rat.


Asunto(s)
Diabetes Mellitus Experimental/terapia , Trasplante de Páncreas , Animales , Animales Recién Nacidos , Glucemia/metabolismo , Diabetes Mellitus Experimental/metabolismo , Técnicas de Cultivo de Órganos , Páncreas/patología , Cavidad Peritoneal , Ratas , Factores de Tiempo , Trasplante Isogénico
9.
Artículo en Inglés | MEDLINE | ID: mdl-826063

RESUMEN

Long term reversal of alloxan diabetes has been accomplished by intraperitoneal isotransplantation of enzymatically dispersed neonatal pancreas. In contrast, allotransplanted recipients showed only a transient recovery from the alloxan diabetes followed by a return to the diabetic state at the time of the homograft rejection. These data strongly suggest that the reversal of the diabetic state was a consequence of the transplanted islets. This conclusion is further supported by quantitative analysis of biopsied pancreases from successfully reversed recipients which reveals only 3% of the normal beta cell mass. By comparison, recovery of transplanted islets composed primarily of aldehyde fuchsin positive beta cells was routinely accomplished in these recipients. Utilization of the more specific unlabeled immunoperoxidase method has revealed that some of the transplanted islets are composed of cells positive for glucagon and somatostatin, as well as insulin. Other recovered transplanted islets (generally smaller in size) are composed primarily of one cell type or the other. The presence of insulin, glucagon, somatostatin, and delete pancreatic polypeptide positive cells in the islets of normal rat pancreas has been confirmed. In addition, cells reacting positively for these hormones have been observed in the alloxan diabetic rat pancreatic islets and in islets from reversed recipients. The time required for the disappearance of glycosuria and hyperglycemia (usually occurring from one to eleven weeks posttransplantation) appeared to be related to the amount and age of the donor islet tissue transplanted. Fetal islet tissue was more effective on a per milligram basis in reversing the diabetic state. In addition, while reversal was obtained by transplantation of as little as 5 mg of neonatal islet tissue, relatively large amounts (20 mg) were required before successfully reversed recipients responded normally to glucose tolerance test. By comparison, a similar reversal of diabetes with normal response to glucose load was attained by transplanting only 3 mg of fetal islet tissue. Quantitative morphological evidence of large increases in absolute islet mass, obtained in fetal transplants at the renal subcapsular site suggests that the superiority of fetal islet donor tissue may by in its high growth potential. No adverse effects of an in vitro organ culture period, prior to transplantation, were observed with regard to the ability of neonatal tissue to reverse the diabetic state or for fetal islet tissue to continue to survive at the renal subcapsular site. Likewise, no advantage in regard to amelioration of the homograft rejection response was observed in cultured islet tissue; allotransplants of which were rejected at the kidney site.


Asunto(s)
Diabetes Mellitus Experimental/terapia , Trasplante de Islotes Pancreáticos , Factores de Edad , Animales , Animales Recién Nacidos , Glucemia/análisis , Diabetes Mellitus Experimental/patología , Prueba de Tolerancia a la Glucosa , Rechazo de Injerto , Insulina/sangre , Islotes Pancreáticos/embriología , Islotes Pancreáticos/patología , Ratas , Ratas Endogámicas , Donantes de Tejidos , Trasplante Homólogo , Trasplante Isogénico
10.
Differentiation ; 3(1-3): 69-77, 1975 Aug 11.
Artículo en Inglés | MEDLINE | ID: mdl-1102373

RESUMEN

The differentiation and growth of the foetal rat pancreas (20 days postcoitum) was studied in parabiotic organ culture with foetal adrenal tissue. In such co-cultures, characteristic pancreatic morphology was preserved and further acinar cell differentiation was fostered. Acinar cells contiunued to represent about 65% of the total explant volume following short-term incubation. The selective islet cell proliferation, previously observed in control pancreatic explants cultured alone, did not occur when adrenals were co-cultured. In addition, the amylase content of the incubation media and of the explanted pancreatic tissue remained high with adrenal co-culture, while the insulin content of the media and of the explanted tissue was markedly suppressed when compared to control pancreatic explants cultured alone. The effects of the adrenal in maintaining the differentiated acinar component of the pancreas and suppressing media insulin concentration diminished over extended incubation. The addition of adrenals to culture of foetal pancreatic explants after 6 days of control culture (at a time when differentiated acinar cells were not identifiable in the explant) did not result in redifferentiation of the acinar component, but did markedly depress media insulin content. Removal of adrenals after 4 days of co-culture resulted in an immediate rise in media insulin concentration and a rapid decline in pancreatic acinar mass. An adrenal-exocrine pancreatic axis is proposed and it is suggested that foetal adrenal secretions may play an important role in the development of the exocrine pancreas in vivo as well as in vitro.


Asunto(s)
Glándulas Suprarrenales/embriología , Técnicas de Cultivo de Órganos , Páncreas/embriología , Parabiosis , Corticoesteroides/fisiología , Amilasas/análisis , Animales , Diferenciación Celular/efectos de los fármacos , Supervivencia Celular , Medios de Cultivo/análisis , Femenino , Insulina/análisis , Islotes Pancreáticos/análisis , Páncreas/citología , Páncreas/efectos de los fármacos , Ratas , Esteroides/análisis
11.
Proc Soc Exp Biol Med ; 148(1): 75-9, 1975 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-1093188

RESUMEN

Pancreases of 18-day fetal and 3-day neonatal rat were grown in organ culture in both standard glucose (150 mg/100 ml) and high glucose (500 mg/100 ml) media. Insulin content of medium was measured by radioimmunoassay at time of transfer. In fetal cultures, standard and high glucose media contained a similar level of insulin through 6 days of culture. In neonatal cultures, high glucose medium contained 40-60% more insulin than did standard medium. However, after 8 days of organ culture fetal pancreas developed responsiveness to high glucose; a greater amount of insulin was present in the high glucose medium (50% by 10 days and 70% by 12 days) than in standard glucose medium. The time at which this responsiveness develops in vitro approximates the chronologic age which corresponds to 3-5 days postnatal period. The maturation of this responsiveness appears to be inherent to the pancreas and is independent of other organ systems. When neonatal explants, grown in standard medium for 8 days, were transferred to high glucose medium, 80-160% more insulin was detected in the high glucose medium than in standard medium during the next 4 days of culture. These results indicate that once glucose responsiveness had developed, it is maintained in organ culture for at least 12 days.


Asunto(s)
Glucosa/farmacología , Islotes Pancreáticos/embriología , Animales , Animales Recién Nacidos , Edad Gestacional , Islotes Pancreáticos/metabolismo , Técnicas de Cultivo de Órganos , Radioinmunoensayo , Factores de Tiempo
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