RESUMO
Dosage-dependent release of 45Ca was observed from prelabeled mouse calvarial bones after treatment with two thiazolidinediones, troglitazone and ciglitazone. Release of 45Ca by ciglitazone was decreased by the osteoclast inhibitors acetazolamide, calcitonin, 3-amino-1-hydroxypropylidene-1,1-bisphosphonate, and IL-4, but not affected by the peroxisome proliferator-activated receptor gamma antagonist, GW 9662, the mitotic inhibitor, hydroxyurea, or indomethacin. Enhanced expression of receptor activator of nuclear factor-kappaB ligand (RANKL) mRNA and protein and decreased osteoprotegerin (OPG) mRNA and protein were noted after ciglitazone treatment of calvariae. Ciglitazone and RANKL each caused increased mRNA expression of osteoclast markers: calcitonin receptor, tartrate-resistant acid phosphatase, cathepsin K, matrix metalloproteinase-9, integrin beta3, and nuclear factor of activated T cells 2. OPG inhibited mRNA expression of RANKL stimulated by ciglitazone, mRNA expression of osteoclast markers stimulated by ciglitazone and RANKL, and 45Ca release stimulated by troglitazone and ciglitazone. Increased expression of IL-1alpha mRNA by ciglitazone was not linked to resorption stimulated by the thiazolidinedione. Ciglitazone did not increase adipogenic gene expression but enhanced osteocalcin mRNA in calvariae. In addition to exhibiting sensitivity to OPG, data indicate that stimulation of osteoclast differentiation and activity by thiazolidinediones may occur by a nonperoxisome proliferator-activated receptor gamma-dependent pathway that does not require cell proliferation, prostaglandins, or IL-1alpha but is characterized by an increased RANKL to OPG ratio.
Assuntos
Reabsorção Óssea/induzido quimicamente , Crânio/fisiologia , Tiazolidinedionas/farmacologia , Animais , Sequência de Bases , Cálcio/metabolismo , Proteínas de Transporte/genética , Catepsina K , Catepsinas/genética , Células Cultivadas , Primers do DNA , Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Integrina beta3/genética , Metaloproteinase 9 da Matriz/genética , Glicoproteínas de Membrana/genética , Camundongos , Fatores de Transcrição NFATC , Proteínas Nucleares/genética , Técnicas de Cultura de Órgãos , Ligante RANK , RNA Mensageiro/genética , Receptor Ativador de Fator Nuclear kappa-B , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Crânio/efeitos dos fármacos , Fatores de Transcrição/genéticaRESUMO
Interleukin-11 (IL-11) is a stromal cell-derived cytokine that can enhance osteoclast formation and stimulate bone resorption. In the present study, the characteristics of the resorptive effect of IL-11 in mouse calvarial bones were investigated. Both recombinant mouse IL-11 and human IL-11 caused concentration- and time-dependent stimulations of (45)Ca release from prelabeled mouse calvariae. Half-maximal responses were obtained at 0.7 ng/mL (approximately 40 pmol/L). Mouse and human IL-11 also stimulated release of (3)H from [(3)H]-proline-labeled bones. The magnitude of the (45)Ca and (3)H release (1.4-1.6-fold) caused by a maximally effective concentration of IL-11 was less than the stimulation (2.5-4.0-fold) elicited by a maximum concentration of parathyroid hormone (PTH). Release of (45)Ca by IL-11 was unaffected by the mitotic inhibitors, hydroxyurea and aphidicolin. In addition to resorption of bone, IL-11 caused a small (1.5-2.0-fold) enhancement of prostaglandin E(2) (PGE(2)) biosynthesis in calvariae, but had no effect on the mRNA expression of cyclooxygenase-1 and -2, or cytosolic phospholipase A(2). Indomethacin and flurbiprofen abolished the formation of PGE(2) and partially reduced (45)Ca release stimulated by IL-11. When either mouse interleukin-4 (IL-4) or interleukin-13 (IL-13) was added to calvariae treated with IL-11, (45)Ca release was inhibited. Resorption caused by IL-11 was also inhibited by both anti-mouse glycoprotein 130 (gp130) and an antibody neutralizing IL-11, but these agents had no effect on (45)Ca release caused by PTH or 1,25(OH)(2)vitamin D(3) (D(3)). Real-time, quantitative polymerase chain reaction (PCR) analysis (TaqMan PCR) and semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) demonstrated that IL-11 caused concentration-dependent enhancements of receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoprotegerin (OPG) mRNA, without affecting the mRNA expression of RANK. Mouse RANKL stimulated (45)Ca release in the calvarial bones. The stimulatory effects of RANKL and IL-11 were inhibited by mouse OPG. These data demonstrate that IL-11 stimulates osteoclastic resorption in mouse calvariae by mechanisms that are independent of cell proliferation; partially dependent on prostaglandin biosynthesis; sensitive to inhibition by IL-4, IL-13, and OPG; and associated with enhanced expression of RANKL and OPG. In addition, IL-11 was not found to play an essential role in resorption stimulated by other calciotropic agents in calvariae.
Assuntos
Reabsorção Óssea/metabolismo , Interleucina-11/farmacologia , Crânio/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Cálcio/metabolismo , Relação Dose-Resposta a Droga , Humanos , Interleucina-11/fisiologia , Camundongos , Técnicas de Cultura de Órgãos , RNA Mensageiro/biossíntese , Crânio/metabolismoRESUMO
The thyroid hormones, thyroxine (T4) and triiodothyronine (T3), were found to enhance both neonatal mouse calvarial bone resorption and pit formation on bovine slices by isolated rat osteoclasts. Dosage-dependent release of 45Ca from mouse calvarial bones was observed after 120 hr of culture with 10(-6)-10(-8) MT4 and 10(-6)-10(-10) M T3. Maximum treatment/control ratios of 45Ca release were recorded for 10(-7) M T4 and 10(-8) MT3. Inhibition of 45Ca release stimulated by 10(-8) M T3 was observed in the presence of 30 nM salmon calcitonin at 48 hr and 120 hr of culture with no indication of "escape" by T3-treated bones. In contrast, stimulation of 45Ca release from mouse calvarial bones by 10(-7) MT4 and 10(-8) MT3 was not inhibited by 10(-6) M indomethacin. Formation of PGE2 and PGI2 (evaluated by measuring 6-keto-PGF1alpha) by mouse calvariae was also not increased by 10(-8) MT3 after 120 hr of culture. Furthermore, no increases in cAMP formation were observed in calvarial bone cultures after either 10 min or 24 hr of exposure to 10(-8) MT3. However, significant inhibition of 45Ca release stimulated by 10(-8) M T3 was found at 120 hr in the presence of 10(-3) M hydroxyurea. When isolated rat osteoclasts were cultured in the presence of 10(-7) MT3, a 1.4-fold stimulation of pit number was observed. Pit formation was not affected by addition of 10(-6) M indomethacin to either the control or T3-treated cultures. These data suggest that the stimulation of bone resorption in neonatal mouse calvariae and activation of isolated rat osteoclasts by the thyroid hormones is not related to either prostaglandin or cAMP formation. In mouse calvariae, the effect on bone resorption of the thyroid hormones is dependent on increased cellular replication, perhaps of osteoclast precursors, or other bone cells involved in the resorptive process.
Assuntos
Reabsorção Óssea , Osteoclastos/efeitos dos fármacos , Prostaglandinas/fisiologia , Tiroxina/farmacologia , Tri-Iodotironina/farmacologia , 6-Cetoprostaglandina F1 alfa/metabolismo , Acetilglucosaminidase/metabolismo , Animais , Matriz Óssea/metabolismo , Calcitonina/farmacologia , Cálcio/metabolismo , AMP Cíclico/metabolismo , Dinoprostona/metabolismo , Hidroxiureia/farmacologia , Técnicas In Vitro , Indometacina/farmacologia , Camundongos , Hormônio Paratireóideo/farmacologia , Fosfatos/metabolismo , Ratos , Crânio/efeitos dos fármacosRESUMO
Differential effects on in vitro bone resorption were observed when the glucocorticoids, hydrocortisone and dexamethasone, were added to neonatal mouse calvariae treated with either parathyroid hormone (PTH), 1,25(OH)2-vitamin D3, all trans-retinoic acid (t-RA), or prostaglandin E2 (PGE2). Bone resorption was assessed by analyzing either the release of 45Ca from [45Ca]CaCl2 prelabeled calvarial bones or the release of 3H from [3H]proline prelabeled calvariae. At PGE2 concentrations of 3 x 10(-8) and 3 x 10(-7) mol/l, co-treatment with either 10(-6) mol/l dexamethasone or 10(-6) mol/l hydrocortisone caused additive 45Ca release from neonatal mouse calvariae. In contrast, synergistic release from mouse calvarial bones of both 45Ca and 3H was found after either 10(-6) mol/l hydrocortisone or 10(-6) mol/l dexamethasone was combined with 3 x 10(-11) mol/l PTH treatment for 120 h. Dose-response studies indicated that the synergistic stimulation of 45Ca release from neonatal mouse calvariae by glucocorticoids and PTH could be elicited at glucocorticoid concentrations of 10(-8) to 10(-6) mol/l and at PTH concentrations of 10(-11) to 10(-9) mol/l. Progesterone and RU 38486 (a derivative of 19-nortestosterone with antiglucocorticoid activity) blocked the synergism noted with glucocorticoid and PTH co-treatment, suggesting that interaction between the steroids and PTH was dependent on glucocorticoid receptor interaction. Addition of either 10(-6) mol/l hydrocortisone or 10(-6) mol/l dexamethasone to neonatal mouse calvariae treated with 1,25(OH)2-vitamin D3 (10(-11) and 10(-10) mol/l) also resulted in synergistic stimulation of 45Ca release. In contrast to these observations, the stimulatory effect of t-RA (10(-8) mol/l) on 45Ca release from calvarial bones was abolished in the presence of 10(-6) mol/l dexamethasone. These results suggest that an important role of glucocorticoids may be to synergistically potentiate bone resorption stimulated by PTH and 1,25(OH)2-vitamin D3, but indicate an opposing interaction between the glucocorticoids and bone resorptive retinoids.
Assuntos
Reabsorção Óssea , Calcitriol/farmacologia , Dinoprostona/farmacologia , Glucocorticoides/farmacologia , Hormônio Paratireóideo/farmacologia , Tretinoína/farmacologia , Animais , Animais Recém-Nascidos , Cálcio/metabolismo , Técnicas de Cultura , Dexametasona/farmacologia , Sinergismo Farmacológico , Hidrocortisona/farmacologia , Camundongos , Camundongos Endogâmicos , Prolina/metabolismo , Crânio , Estimulação Química , Trítio/metabolismoRESUMO
In vitro stimulation of bone resorption was observed with the glucocorticoids hydrocortisone and dexamethasone. Dosage-dependent release of 45Ca from neonatal mouse calvarial bones was found for both steroids, with half-maximal responses for hydrocortisone and dexamethasone of 0.3 and 0.08 microM, respectively. Significant release of stable calcium (Ca2+), inorganic phosphate (Pi), and the lysosomal enzyme beta-N-acetylglucosaminidase was noted following treatment of mouse calvariae with either 1 microM hydrocortisone or 1 microM dexamethasone. Additionally, both 1 microM hydrocortisone and 1 microM dexamethasone elicited release of 3H from calvarial bones prelabeled with [3H]proline. The stimulation of bone resorption by the glucocorticoids, as assessed by 45Ca release, was sustained over 120 h of culture. Inhibition of 45Ca release from calvariae treated with either 1 microM hydrocortisone or 0.1 microM dexamethasone was observed with 0.01-30 nM salmon calcitonin (sCT), 0.1 mM acetazolamide, and 0.1 mM of the bisphosphonate AHPrBP. Inhibition of glucocorticoid-induced bone resorption by sCT occurred without "escape from calcitonin-induced inhibition." The 45Ca release stimulated by 1 microM hydrocortisone and 0.1 microM dexamethasone was also inhibited by 10 microM progesterone in a competitive manner and by 1 microM of the antiglucocorticoid RU38486, both of which are modulators of glucocorticoid binding. Prostaglandin E2 (PGE2) formation by 10 nM parathyroid hormone (PTH) in neonatal mouse calvarial bones was inhibited by both 1 microM hydrocortisone and 1 microM dexamethasone, but neither compound altered basal PGE2 formation. Exposure of calvarial bones to the mitotic inhibitors hydroxyurea and mitomycin C inhibited 45Ca release stimulated by 1 microM hydrocortisone and 1 microM dexamethasone. In contrast, addition of 1 ng/ml of recombinant murine granulocyte macrophage colony stimulating factor (rmGM-CSF) had no effect on 45Ca release elicited by the glucocorticoids. These results suggest that hydrocortisone and dexamethasone stimulate osteoclastic resorption in neonatal mouse calvariae by a receptor-mediated mechanism that is dependent on cellular replication.
Assuntos
Anti-Inflamatórios/toxicidade , Reabsorção Óssea/induzido quimicamente , Cálcio/metabolismo , Dexametasona/toxicidade , Hidrocortisona/toxicidade , Osso Parietal/efeitos dos fármacos , Acetazolamida/administração & dosagem , Acetazolamida/farmacologia , Acetilglucosaminidase/metabolismo , Animais , Animais Recém-Nascidos , Calcitonina/administração & dosagem , Calcitonina/farmacologia , Dinoprostona/antagonistas & inibidores , Difosfonatos/administração & dosagem , Difosfonatos/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Antagonistas de Hormônios/farmacologia , Hidroxiureia/farmacologia , Lisossomos/metabolismo , Camundongos , Mifepristona/farmacologia , Mitomicina/farmacologia , Hormônio Paratireóideo/farmacologia , Osso Parietal/citologia , Fosfatos/metabolismo , Progesterona/administração & dosagem , Progesterona/farmacologia , Prolina/metabolismoRESUMO
The present investigation was undertaken to determine if an interaction affecting 45Ca release from prelabeled fetal rat long bones could be elicited by the Ca2+ ionophore, A-23187, and the phorbol ester, 12-myristate 13-acetate (PMA). Treatment with either A-23187 at a concentration of 0.3 microM or PMA at concentrations of 10(-6) M, 10(-7) M, and 10(-8) M produced significant 45Ca mobilization. When A-23187 and PMA were combined, enhanced 45Ca release was observed on days 1 and 2 of culture. The stimulation of calcium mobilization noted on day 1 occurred when neither ionophore nor 10(-6) M PMA treatments alone produced significant 45Ca release. On day 2, cumulative 45Ca release elicited by the combination of A-23187 plus 10(-6) M PMA was slightly more than additive (15.9% for combination treatment vs. 13.7% for the sum of the individual treatments). Moreover, when A-23187 was combined with 10(-7) M PMA on day 2, an enhancement of 45Ca release was observed which was clearly more than additive (14.5% for combination treatment vs. 8.8% for the individual treatments), suggesting the possibility of a synergistic interaction between the two agents. These results were in marked contrast to those obtained with the inactive phorbol ester analog, phorbol 13-monoacetate. No stimulation of 45Ca release was observed with 10(-6) M and 10(-7) M phorbol 13-monoacetate alone nor was enhanced 45Ca release noted when the analog was combined with 0.3 microM A-23187.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Reabsorção Óssea/efeitos dos fármacos , Osso e Ossos/embriologia , Calcimicina/farmacologia , Feto/metabolismo , Ésteres de Forbol/farmacologia , Animais , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Cálcio/farmacocinética , Células Cultivadas , Feto/citologia , Ratos , Fatores de TempoRESUMO
Release of previously incorporated 45Ca from fetal rat long bones was determined with the diterpene forskolin, both in the absence and presence of parathyroid hormone (PTH) and calcitonin (CT). In the absence of hormone, increased bone resorption was observed with 10(-7)M forskolin, but biphasic responses, consisting of initial decreases in 45Ca release that were followed by increased calcium mobilization, were produced with 10(-6)M and 10(-5)M forskolin. Inhibition of 45Ca release was pronounced and delayed more with 10(-5)M forskolin while the greatest stimulation of bone resorption was elicited by 10(-6)M forskolin, a response that was inhibited by 100 mU/ml CT. In the presence of 250 ng/ml PTH, a synergistic enhancement of 45Ca release occurred with 10(-7)M forskolin treatment while, in contrast, calcium mobilization was inhibited by 10(-6)M and 10(-5)M forskolin. Inhibition by 10(-6)M forskolin was characterized by "escape" while that of 10(-5)M forskolin was continuous over a 5 day interval. Inhibition throughout the experimental period also was noted when 10(-5)M forskolin was combined with 2.5 ng/ml PTH, but no effect on calcium mobilization was observed upon addition of 10(-7)M forskolin and, rather than inhibition, an enhancement of 45Ca release occurred when 10(-6)M forskolin was combined with 2.5 ng/ml PTH. Inhibition of 250 ng/ml PTH, but lack of inhibition of 2.5 ng/ml PTH by 10(-6)M forskolin suggests a 10(-6)M forskolin-sensitive portion of PTH-mediated calcium efflux. Absence of "escape" when 10(-5) M forskolin is combined with 250 ng/ml PTH suggests that heterologous desensitization may not play a major role in the "escape" which occurs with 10(-6) M forskolin.
Assuntos
Reabsorção Óssea/efeitos dos fármacos , Calcitonina/farmacologia , Colforsina/farmacologia , Hormônio Paratireóideo/farmacologia , Animais , Osso e Ossos/embriologia , Osso e Ossos/metabolismo , Radioisótopos de Cálcio/metabolismo , Interações Medicamentosas , RatosRESUMO
Prostaglandins have been shown to stimulate osteoclastic bone resorption in organ culture but morphologic studies of isolated osteoclasts have shown a transient calcitonin-like inhibiting effect of these agents. We looked for a dual effect on bone resorption by comparing the early and late effects of prostaglandin E1 (PGE1), prostacyclin (PGI2), 6 alpha-carbaprostaglandin I2 (C-PGI2), a carbon substituted analog of PGI2, and salmon calcitonin (CT) on the release of previously incorporated 45Ca from fetal rat long bones cultured in the presence of an inhibitor of cyclooxygenase, RO-20-5720. Experiments were performed in both the presence and absence of PTH (400 ng/ml), which was administered 24 hours before addition of prostaglandins or CT. In control cultures not stimulated by PTH, CT (100 mU/ml) produced significant decreases in 45Ca release at 48, 72, and 96 hours while PGE1 (10(-6) M), PGI2 (10(-5)), and C-PGI2 (10(-6) M) each produced significant increases in resorption at 24 through 96 hours. PGE1 at 10(-5) M, but not 10(-6) M, caused a significant decrease in medium 45Ca of 21% at 1 and 2 hours. Medium calcium measurements suggest that the change in 45Ca was due to inhibition of release and not to increased uptake. PGI2 (10(-5) M) and C-PGI2 (10(-6) M) caused no significant inhibitory effect. In cultures stimulated by PTH, CT produced significant inhibition of bone resorption of 6 through 96 hours, but no inhibition of bone resorption was noted at either early or late time points with PGE1, PGI2, or C-PGI2.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Alprostadil/farmacologia , Reabsorção Óssea/efeitos dos fármacos , Epoprostenol/farmacologia , Hormônio Paratireóideo/farmacologia , Animais , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Calcitonina/farmacologia , Cálcio/metabolismo , Carbazóis/farmacologia , Feto , Técnicas de Cultura de Órgãos , Ratos , Fatores de TempoRESUMO
Glucose, somatostatin-like immunoreactivity (SLI), and glucagon were measured in the portal vein during a glucose infusion (0.5 mg/kg) in 9 diabetic and 7 normal rabbits. The diabetic animals were from a colony of New Zealand white rabbits which develop spontaneous hyperglycemia characterized by low basal and stimulated serum insulin levels and lack of obesity. SLI and insulin were also extracted from pancreatic islets isolated from the diabetic and normal animals. The concentrations of SLI and glucagon, although quite variable, were similar in the portal and peripheral plasma in diabetic and control animals. The insulin content/islet was moderately decreased in the diabetic rabbits, however the content of insulin/microgram protein was similar to the controls. In contrast, SLI content/islet was no different than controls, but was increased when expressed/microgram of protein. Thus, this rabbit colony develops diabetes characterized by some decrease in beta cell mass. The remaining beta cells appear to have a severe defect in the release of insulin.
Assuntos
Diabetes Mellitus Experimental/metabolismo , Somatostatina/metabolismo , Animais , Glicemia/análise , Glucagon/sangue , Insulina/análise , Ilhotas Pancreáticas/análise , Coelhos , Somatostatina/sangueRESUMO
Leprechaunism is a congenital syndrome with characteristic habitus and facies, with fasting hypoglycemia and hyperinsulinism. In response to a glucose challenge there is prolonged severe hyperglycemia with an increased hyperinsulinemia. Our studies on such a patient showed a normal response of the serum glucose to glucagon stimulation in the fed state but no response in the postabsorptive state. Ultrastructural studies on the hepatocytes demonstrated that a lack of hepatic glycogen was not responsible for the biochemical features, since there was abundant normal beta-glycogen in both the fed and fasting state, the granules being smaller in the fasted state. We speculate that carbohydrate intolerance in leprechaunism may be due to a relative insulin resistance of cell receptors in the fed state. Reactive hyperinsulinemia persisting into the postabsorptive phase appears to antagonize the usual glycogenolytic response to glucagon during fasting, resulting in hypoglycemia despite the presence of large hepatic glycogen stores.
Assuntos
Nanismo/patologia , Hiperinsulinismo/patologia , Fígado/ultraestrutura , Pré-Escolar , Jejum , Feminino , Humanos , Hipoglicemia/patologia , Glicogênio Hepático/análise , Microscopia Eletrônica , SíndromeRESUMO
Elevated glycosylated haemoglobin values have been observed in overtly diabetic animals from a colony of spontaneously diabetic rabbits. Chemically diabetic and normal animals did not show elevated levels. Overtly diabetic animals averaged 12.2% glycosylated haemoglobin versus 4.3% for chemically diabetic and 3.9% for normal animals. Increased levels did not correlate with plasma glucose concentration. Some chemically diabetic and normal animals progressed with time to a more severe diabetic classification. Glycosylated haemoglobin levels at the high end of the range of values for normal animals are predictive of this progression especially in certain litters.
Assuntos
Diabetes Mellitus Experimental/sangue , Diabetes Mellitus/veterinária , Glicosídeos/análise , Hemoglobina A/análogos & derivados , Animais , Glicemia/análise , Diabetes Mellitus/sangue , Hemoglobina A/análise , Coelhos , Valores de ReferênciaRESUMO
Spontaneous diabetes mellitus has been observed in a female New Zealand white rabbit. By inbreeding of this individual and her offspring, 39 litters comprising 157 animals have been studied and a closed colony of diabetic rabbits established. Three groups of animals can be identified. Twenty-nine (19%) have overt diabetes characterized by fasting hyperglycemia and depressed intravenous glucose stimulated serum insulin levels. This abnormality is seen between 1 and 3 yr of life. Forty-three of the animals (27%) have developed abnormal glucose disposal with normal or slight elevations in fasting serum glucose levels. Glucose stimulated insulin levels are also significantly lower in the rabbits with abnormal glucose disposal. The remaining 85 animals (54%) exhibit no apparent abnormalities of glucose metabolism. All animals with overt diabetes pass through a stage in which glucose disposal as measured by k values is less than 1.0, a value not observed in normal animals. Fasting and arginine stimulated glucagon levels were no different in 4 diabetic animals and 7 normal colony rabbits. Insulin therapy corrected the hyperglycemia in the diabetic rabbits. Insulin was withheld in 5 diabetic rabbits and serum and urinary glucose and ketones were measured for 9 days. Despite marked increases in serum and urinary glucose, only mild ketonemia was observed. The relatively late onset of diabetic symptoms, lack of obesity, severe hyperglycemia, and depressed insulin secretion without ketoacidosis make this a model with many of the characteristics of insulin responsive diabetes as seen in nonobese human adults.
Assuntos
Diabetes Mellitus/metabolismo , Modelos Animais de Doenças , Acetoacetatos/metabolismo , Animais , Arginina , Glicemia/metabolismo , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/genética , Feminino , Teste de Tolerância a Glucose , Hidroxibutiratos/metabolismo , Insulina/sangue , Insulina/uso terapêutico , Corpos Cetônicos/sangue , Masculino , CoelhosRESUMO
Electron microscopic studies on a closed colony of rabbits with an 18.5 per cent incidence of spontaneous onset insulin-dependent diabetes mellitus revealed that the beta-cells of the islets of Langerhans of the diabetic animals were hypergranulated. This finding contrasts with most other animal models of spontaneous diabetes mellitus which show degranulation of the beta-cells. There was no evidence of hyperplasia, insulitis, amyloid, or fibrosis of the islets by either light or electron microscopy. Correlation of our morphologic findings with physiologic data suggests a defect in insulin secretion. Rabbits with normal glucose metabolism showed a normal degree of granulation of their beta-cells. The alpha and delta cells were within normal limits in all animals. No other abnormalities associated with diabetes in humans or other animals were noted except for minimal fusion of the glomerular epithelial foot processes and mineralization of the proximal tubules and Bowman's capsules.
Assuntos
Diabetes Mellitus/veterinária , Coelhos/fisiologia , Animais , Diabetes Mellitus/genética , Diabetes Mellitus/patologia , Ilhotas Pancreáticas/patologia , Glomérulos Renais/patologia , Microscopia EletrônicaRESUMO
A colony of NZW rabbits was developed in which 18 of 126 members exhibited overt symptoms of diabetes mellitus. On the basis of total body weight measurements, obesity does not appear to play a primary role in the development or manifestation of the syndrome. The relatively high frequency of occurrence of spontaneous diabetes mellitus in this colony seems to suggest a unique genetic predisposition of these rabbits, yet analysis of glucose tolerance of colony animals indicates no clear genetic mode of transmittance of the trait. Rather, data suggest a possible interaction of as yet undefined genetic and/or environmental influences as being responsible for the disease state. Regressions of k-value on age indicate an early predetermination of glucose intolerance in the rabbits. In addition to a planned program of breeding, investigations of dietary intake and possible relationships of the diabetic condition to bacterial or viral infections appear to be initial areas indicative of further study.
Assuntos
Diabetes Mellitus/genética , Modelos Animais de Doenças , Coelhos/genética , Animais , Peso Corporal , Feminino , Teste de Tolerância a Glucose , Hiperglicemia/genética , Endogamia , Masculino , Obesidade/genética , Fenótipo , Coelhos/fisiologiaRESUMO
Rabbits were studied from a closed colony of NZW rabbits which exhibits a 19% occurrance of spontaneous diabetes mellitus. Six overtly diabetic rabbits and eight rabbits with normal glucose disposal were tested with intravenous glucose challenge (500 mg/kg), L-leucine administration (125 mg/kg), and 30 minute infusions with isoproterenol (10 microgram/kg/min.). These agents were shown to be ineffective insulin secretogogues in the overtly diabetic group when compared to the highly significant IRI response observed in colony rabbits with normal glucose disposal. The data indicate that the defect in IRI secretion observed in the spontaneously diabetic NZW rabbits is not confined to stimulation by glucose, but represents an abnormal IRI release mechanism which appears to lack secretogogue specificity.