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  • 1
    ISSN: 1432-0428
    Keywords: Chinese hamster ; Cricetulus griseus ; spontaneous diabetes ; pancreatic islets ; islets of Langerhans ; beta cell mitosis ; beta cell hyperplasia ; autoradiography ; insulin ; diabetes remission ; adrenal glucocorticoid
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Light microscopic and autoradiographic studies were performed in normal genetic nondiabetic and diabetic Chinese hamsters after the administration of thymidine-3H and correlated with levels of blood glucose (BG) and plasma insulin (IRI). Pancreatic islets of normal hamsters contained well granulated beta cells; rare islet cells incorporated thymidine-3H and the IRI/BG ratio (I/G) was =1.91. Recent onset diabetics revealed hyperglycemia and hyperinsulinemia (I/G = 1.97), beta cell degranulation and increased islet cell labelling. With progression of diabetes, I/G ratios decreased (Non-ketotic animals: 1.08, Ketotic hamsters: 0.17), beta cell numbers declined and islet labelling was infrequent. Hamsters with spontaneous remission from diabetes showed normoglycemia, hyperinsulinemia (I/G = 2.84) and beta cell hyperplasia. Glucocorticoid administration to normal hamsters induced marked BG elevations, beta cell hyperplasia and increased thymidine-3H incorporation. The absence of increased beta cell labelling among most diabetics treated with glucocorticoids may be a manifestation of a genetically defined defect of beta cell replication that is in part responsible for the declining beta cell mass and insulin synthetic capacity of the diabetic Chinese hamsters.
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    Diabetologia 14 (1978), S. 199-207 
    ISSN: 1432-0428
    Keywords: Animal model ; spontaneous diabetes ; juvenile diabetes ; plasma glucose ; insulin ; glucagon ; ketones ; oral glucose tolerance tests ; chemical diabetes ; insulitis ; free fatty acids
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A longitudinal study of 51 weanlings from 5 litters of “BB” Wistar rats was undertaken to characterize the time course of the spontaneous diabetic syndrome. Nine rats developed overt diabetes. An abnormal glucose tolerance preceded the onset of the syndrome in 6 of these 9 rats. No other “clinical” or metabolic variable measured was predictive of the development of this syndrome. In these rats, the onset was remarkably abrupt, followed by rapid clinical deterioration with marked hyperglycaemia, glycosuria, ketonaemia and hypoinsulinaemia attained within 2 to 8 days. Pronounced insulitis was present in the early stages of the syndrome, resulting in complete B-cell destruction at the time of sacrifice at 7 to 40 days. Among the 42 littermates, 9 revealed sequential abnormalities in oral glucose tolerance tests performed at weekly intervals (to age 90–120 d) though remaining aglycosuric and maintaining normal fasting plasma glucose levels. In 7 of these rats, a milder form of the same islet inflammatory lesion seen in the overtly diabetic animals was present. Thus the new features identified are: 1) a time course of evolution from normoglycaemia to overt diabetes telescoped into a period of days, and 2) a “chemical” stage or form with an insulitis similar to that found in the early stages of overt diabetes.
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  • 3
    ISSN: 1432-0428
    Keywords: Key words GLUT 2 ; BB/Wor rats ; Kilham Rat Virus ; autoimmune diabetes mellitus ; beta cell ; islets of Langerhans ; parvoviridae infections.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Loss of GLUT 2, the glucose transporter isoform of pancreatic beta cells, has been reported to accompany the onset and perhaps contribute to the pathogenesis, of insulin-dependent and non-insulin-dependent diabetes mellitus in BB/Wor and Zucker fatty rats. In this study we investigated the effect of Kilham Rat Virus infection on GLUT 2 expression in diabetes-resistant BB/Wor rats. Viral antibody-free diabetes-resistant rats do not develop spontaneous diabetes, but inoculation with Kilham Rat Virus induces autoimmune beta-cell destruction and hyperglycaemia. Pancreas sections from normoglycaemic diabetes-resistant BB/Wor rats were obtained 5, 7 and 25 days after inoculation with Kilham Rat Virus and stained for GLUT 2 using a rabbit polyclonal antibody. At all time points, beta cells displayed GLUT 2 expression comparable to uninfected diabetes-resistant controls. Immunostained insulin content of the beta cells also remained unchanged. Sections were also examined from Kilham Rat Virus inoculated diabetes-resistant rats with lymphocytic insulitis or diabetes. GLUT 2 and insulin immunostaining were unchanged in non-diabetic rats with early insulitis. GLUT 2 beta-cell staining was variably reduced in diabetic rats with established insulitis and reduced beta-cell insulin immunostaining. Hence, the initial stages of Kilham Rat Virus-induced diabetes in diabetes-resistant rats are not accompanied by a significant reduction in GLUT 2 expression. These results suggest that the loss of GLUT 2 does not play a significant role in the aetiology of diabetes in the Kilham Rat Virus-infected diabetes-resistant BB/Wor rat. [Diabetologia (1994) 37: 1186–1194]
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  • 4
    Electronic Resource
    Electronic Resource
    Springer
    Diabetologia 43 (2000), S. 890-898 
    ISSN: 1432-0428
    Keywords: Keywords Autoimmunity, BB rat, MHC Class II, adhesion molecules.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aims/hypothesis. We did experiments to explore the pathways putatively leading to Type I (insulin-dependent) diabetes mellitus, and their association with the MHC locus, the major genetic determinant of disease susceptibility.¶Methods. Normal MHC congenic rat strains that do not spontaneously develop diabetes or any other autoimmune syndrome were injected with the interferon-alpha inducer polyinosinic-polycytidylic acid (Poly IC).¶Results. Insulitis and diabetes developed only in strains expressing Class IIu genes and was independent of the Class I haplotype. Poly IC induced islet cell Class I hyperexpression, up regulation of pancreatic endothelial intercellular adhesion molecule-1 and vascular adhesion molecule-1 and a T-cell and macrophage infiltration of the pancreatic interstitium in all rat strains studied, including diabetes-resistant strains. Poly IC also induced the generation of diabetes-transferring spleen cells in most Class IIu haplotype rats, including the diabetes-resistant WF rat.¶Conclusion/Interpretation. The minimum requirements for autoimmune diabetes development in the rat include: RT1 Class IIu genes, a T-cell repertoire containing beta-cell autoreactive T cells and a triggering event which breaks tolerance by the local up regulation of pancreatic endothelial adhesion receptors. Even when all of the minimum requirements have, however, been met, most Class IIu rats do not develop diabetes in response to autoimmune stimuli. It is clear, nonetheless, that susceptibility to diabetes is widely distributed in the RT1 u rat. [Diabetologia (2000) 43: 890–898]
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  • 5
    Electronic Resource
    Electronic Resource
    Springer
    Diabetologia 36 (1993), S. 912-919 
    ISSN: 1432-0428
    Keywords: BBZ/Wor ; obesity ; autoimmune diabetes mellitus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The BBZ/Wor rat is a model of obesity and autoimmune diabetes mellitus developed by crossing the BB/Wor and Zucker rats. We studied circulating glucose and insulin levels, islet morphology and lymphocyte subsets in lean and obese BBZ/Wor rats before and after the onset of diabetes, and studied the clinical course of diabetes in animals after interruption of exogenous insulin therapy. Lean BBZ/Wor rats developed insulin-dependent diabetes and died in ketoacidosis within 1 week after cessation of insulin injections. Diabetes also developed in obese rats, but these animals were not insulin-dependent and survived for months without insulin therapy. The islets of the lean diabetic rats revealed complete destruction of pancreatic beta cells and plasma insulin levels were virtually undetectable. In contrast, the islets of the obese rats revealed insulitis and substantial beta-cell loss, however autoimmune bete-cell destruction was incomplete, and residual beta cells were presumably responsible for the presence of measurable levels of plasma insulin and the long-term survival of obese diabetics without insulin therapy. Obese rats were hyperinsulinaemic, developed diabetes significantly earlier, and with a greater incidence than lean rats, suggesting a possible relationship between enhanced beta-cell metabolic activity and immune destruction. Obese males became diabetic more frequently and at an earlier age than obese females and lean rats of both sexes, suggesting a role for gender in the pathogenesis of diabetes. We conclude that the BBZ/Wor rat is a unique animal model for investigating the interaction of obesity, beta-cell metabolism, autoimmune insulitis and genetic predisposition to diabetes.
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  • 6
    ISSN: 1432-0428
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1432-0428
    Keywords: DBM mouse ; diabetic mutant mouse ; genotype: C57BL/Ks-db/db ; inherited diabetes ; diabetic heterozygote ; glucose tolerance ; serum insulin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Résumé Des souris homozygotes et hétérozygotes porteurs du gène du diabète (db) ont été étudiées dans le but de déterminer: 1. si une intolérance latente aux hydrates de carbone existe chez la jeune sourisdbdb normoglycémique, 2. si la sourisdbdb normoglycémique ayant une alimentation réduite présente une intolérance aux hydrates de carbone, et 3. si la souris hétérozygote pour le gènedb (db/+) montre des anomalies de la tolérance au glucose, des taux d'IRI sériques et du poids corporel. Les taux de glucose sanguin ont été mesurés 0, 30, 60, 120 et 180 min après l'injection intrapéritoneale de 2 mg glucose/ gramme de poids corporel. Les souris normales (+/+) et diabétiques (db/db) ont des courbes de tolérance au glucose semblables au cours des 2 premières semaines de leur vie. Il apparaît pourtant qu'elles manifestent une intolérance marquée au glucose si on les compare avec la souris normale adulte. Un petit nombre de sourisdb/db âgées de 3 semaines présentent des glycémies plus élevées que celles observées chez les souris normales à la 180ème minute du test. A 4 semaines, la glycémie moyenne avant la charge glucosée (0 min) est significativement plus élevée (P〈 0.02) chez les animaux diabétiquesdb/db (144 mg glucose %) que chez la souris normale +/+ (124 mg glucose %). Bien que la réduction de nourriture diminue la glycémie à 0 min, l'intolérance au glucose est clairement manifeste après administration du glucose. Chez les animaux hétérozygotes (db/+) âgés de 3 à 16 mois, les anomalies de la tolérance au glucose sont surtout décélables chez les mâles qui montrent une élévation modérée mais statistiquement significative des taux de glucose sanguins à 0 min et après l'administration du glucose. 40% des mâles hétérozygotes ont des taux d'IRI sériques plus élevés que ceux mesurés chez les animaux mâles normaux. Le poids corporel des mâles hétérozygotes est significativement plus élevé (P〈0.01) que celui des mâles normaux du même âge.
    Abstract: Zusammenfassung In den vorliegenden Studien an homozygoten (db/db) und heterozygoten (db +) Mäusen des Diabetes-Stammes wurde untersucht: 1. ob bei den jungen, noch normoglykämischen homozygoten Tieren bereits eine Glucosetoleranz nachzuweisen sei; 2. ob Calorieneinschränkung die Glucosetoleranz homozygoter Tiere beeinflusse; und 3. ob bei heterozygoten Anomalien des Zuckerstoffwechsels nachweisbar seien. Bis zum Alter von zwei Wochen war die Glucosetoleranz homozygot diabetischer Tiere (db/db) derjenigen homozygot normaler Tiere (+/+) vergleichbar. In beiden Fällen war sie aber deutlich schlechter als bei normalen erwachsenen Mäusen. Ab der dritten Woche zeigten einige der künftig diabetischen Tiere gegenüber der Norm erhöhte 3-Stundenwerte. Im Alter von 4 Wochen war bei den diabetischen Tieren der Nullwert signifikant erhöht. Kalorienrestriktion beeinflußte die Glucosetoleranz nicht, obwohl die Blutzuckerkonzentration vor Belastung deutlich niedriger war als bei normal ernährten Tieren. Hétérozygote (db/+) Weibchen (3–16 Monate alt) waren völlig normal, während bei Männchen vor und nach Glucosebelastung signifikant erhöhte Blutzuckerkonzentrationen und, in 40% der Fälle, auch erhöhte Serum-IRI-Konzentrationen gemessen wurden. Das Körpergewicht männlicher Heterozygote war signifikant höher als dasjenige gleichaltriger Normaltiere.
    Notes: Summary Mice homozygous and heterozygous for the diabetes (db) gene were studied to determine: 1. whether latent carbohydrate intolerance is present in young normoglycemic diabetic mutants (db/db); 2. whether normoglycemic food restricted diabetic mutants are carbohydrate intolerant; and 3. whether mice heterozygous for thedb gene (db/+) manifest abnormalities in glucose tolerance, serum IRI levels or body weights. Blood glucose levels were determined 0, 1/2, 1, 2 and 3 h following intraperitoneal administration of 2 mg glucose/g body weight. Normals (+/+) and diabetics (db/db) showed similar glucose tolerance curves during the first two weeks of life; however, both were markedly glucose intolerant compared to normal adult mice. At 3 weeks a small number of mutants had higher 3 h levels than any achieved in normal mice. By 4 weeks the average value for diabetics prior to glucose loading (0 time) was significantly (P 〈 0.02) elevated (db/db — 144 mg glucose/100 ml, +/+ = 124 mg glucose/100 ml). Although food restriction reduced blood glucose concentration at 0 time, persistence of carbohydrate intolerance was readily demonstrable following glucose loading. — Abnormalities in heterozygotes (db/+), 3 to 16 months of age, were primarily restricted to male mice, which showed moderate, but statistically significant elevations in blood glucose both at 0 time and following glucose administration. Forty percent of male heterozygotes had higher serum IRI levels than any observed in normal control males. Body weights of male heterozygotes were significantly greater (P〈0.01) than those in agematched normals.
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  • 8
    ISSN: 1432-0428
    Keywords: GLUT 2 ; BB/Wor rats ; Kilham Rat Virus ; autoimmune diabetes mellitus ; beta cell ; islets of Langerhans ; parvoviridae infections
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Loss of GLUT 2, the glucose transporter isoform of pancreatic beta cells, has been reported to accompany the onset and perhaps contribute to the pathogenesis, of insulin-dependent and non-insulin-dependent diabetes mellitus in BB/Wor and Zucker fatty rats. In this study we investigated the effect of Kilham Rat Virus infection on GLUT 2 expression in diabetes-resistant BB/Wor rats. Viral antibodyfree diabetes-resistant rats do not develop spontaneous diabetes, but inoculation with Kilham Rat Virus induces autoimmune beta-cell destruction and hyperglycaemia. Pancreas sections from normoglycaemic diabetes-resistant BB/Wor rats were obtained 5, 7 and 25 days after inoculation with Kilham Rat Virus and stained for GLUT 2 using a rabbit polyclonal antibody. At all time points, beta cells displayed GLUT 2 expression comparable to uninfected diabetes-resistant controls. Immunostained insulin content of the beta cells also remained unchanged. Sections were also examined from Kilham Rat Virus inoculated diabetes-resistant rats with lymphocytic insulitis or diabetes. GLUT 2 and insulin immunostaining were unchanged in non-diabetic rats with early insulitis. GLUT 2 beta-cell staining was variably reduced in diabetic rats with established insulitis and reduced beta-cell insulin immunostaining. Hence, the initial stages of Kilham Rat Virus-induced diabetes in diabetes-resistant rats are not accompanied by a significant reduction in GLUT 2 expression. These results suggest that the loss of GLUT 2 does not play a significant role in the aetiology of diabetes in the Kilham Rat Virus-infected diabetes-resistant BB/Wor rat.
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  • 9
    ISSN: 1432-0428
    Keywords: Diabetic mutant mouse ; genotype: C 57-BL/Ks-db/db ; hereditary diabetes in mice ; mutation: diabetes ; pancreatic islets ; islets of Langerhans ; beta cell replication ; mitotic activity ; glucose ; insulin ; diet ; food restriction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Résumé La division des cellulesβ a été étudiée chez la souris normale (C 57 BL/Ks) et chez son mutant diabétique (C 57 BL/Ks-db/db) après administration de3H-thymidine. L'activité spécifique de l' ADN des îlots isolés (DPM/μg ADN) sert d'index de l'activité de prolifération et est corrélée avec le marquage décélé par autoradiographie. Bien que l'incorporation de3H- thymidine dans les îlots de sourisdb/db préhyperglycémiques âgées de 5 à 6 semaines soit assez faible, elle est cependant significativement plus élevée que chez la souris normale. L'augmentation des taux de glucose sanguin s'accompagne d'un accroissement très net de l'incorporation, qui est maximale pour les glycémies supérieures à 130 mg glucose %. Une hyperglycémie sévère et prolongée s'accompagne à la suite d'une diminution de la synthèse d'ADN dans les îlots. Une diminution de l'apport alimentaire au début de la manifestation du syndrome décroît l'hyperglycémie concomitante avec une incorporation faible de la substance marquée. Lorsque ces animaux peuvent de nouveau s'alimenter à volonté pendant 1, 2 ou 3 semaines, on constante une augmentation significative du marquage atteignant un taux maximum après une semaine de réalimentation. — L'examen autoradiographique combiné à la microscopie électronique des îlots démontre la présence de radioactivité dans les cellulesβ, mais pas dans les cellulesα. Ce résultat suggère que l'activité de prolifération est essentiellement confinée aux cellulesβ.
    Abstract: Zusammenfassung Mittels Messung der spezifischen Aktivität der DNA isolierter Langerhans'scher Inseln und radioautographischer Lokalisation der Radioaktivität nach Injektion von Thymidin-3H wurde die Vermehrung der B-Zellen im Pankreas normaler und hereditär diabetischer (db/db) Mäuse untersucht. Die Inkorporation von Radioaktivität war bei 5–6 Wochen altendb/db Tieren signifikant höher als bei den normalen Kontrolltieren. Mit Ansteigen der Blutzuckerkonzentration nahm die Inkorporation zu und erreichte bei Blutzuckerkonzentrationen über 130 mg/100 ml ihr Maximum. Anhaltend schwere Hyperglykämie war von einem progressiven Abfall der Inkorporation von Radioaktivität in die Insel-DNA begleitet. Kalorienrestriktion in einem Frühstadium des Syndroms verminderte sowohl die Hyperglykämie als auch die Inkorporation von Radioaktivität. Nach Normalisierung der Nahrungsaufnahme zeigte sich eine deutliche Erhöhung der Inkorporation, die nach einer Woche ihr Maximum erreichte. Elektronenmikroskopische Autoradiographie ergab, daß die Radioaktivität ausschließlich in den B-Zellen lokalisiert war. Markierte A-Zellen wurden nicht beobachtet. Dies weist darauf hin, daß sich die proliferative Aktivität praktisch ausschließ-lich auf die B-Zellen beschränkt.
    Notes: Summary Beta cell replication was studied in normal (C 57 BL/Ks) and diabetic mutant (C 57 BL/Ks-db/db) mice following thymidine-3H administration. The specific activity of DNA of isolated islets (DPM/μg islet DNA) was used as an index of proliferative activity and correlated with labeling determined by radioautography. Although thymidine-3H incorporation in islets of prehyperglycemic 5 to 6 week old mutants was limited, it was significantly greater than that in normal mice. With the elevation of blood glucose values, incorporation rose sharply, reaching a maximum level above 130 mg glucose/100 ml blood. Sustained, severe hyperglycemia subsequently correlated with a decline in islet DNA synthesis. Food restriction early in the syndrome reduced hyperglycemia and resulted in low incorporation of label. Animals refed ad lib for periods of 1, 2, or 3 weeks showed significant increases in labeling, with maximal values after 1 week of refeeding. Electron microscopic radioautographs of the islets revealed labeled beta cells but no labeled alpha cells, suggesting that proliferative activity is predominantly restricted to the beta cell population.
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  • 10
    ISSN: 1432-0428
    Keywords: DBM mouse ; diabetic mutant mouse:genotype C 57 BL/Ks-db/db ; inherited diabetes ; pancreatic islets ; islets of Langerhans ; blood glucose ; serum insulin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Résumé Le poids corporel, les taux de glucose sanguin et d'insuline sérique ainsi que la morphologie des îlots sont étudiées chez la souris DBM, mutant diabétique modifié provenant du croisement d'animaux diabétiques noirs originaux (C 57 BL/Ks-db) avec des souris normales grisâtres (C 57 BL/6J-m). La souris DBM semble avoir une plus longue vie que la plus grande partie des animaux de souche originelle. Chez un animal sur 6, — âgés de 7 mois ou plus — on observe la diminution du poids corporel qui a lieu chez la plupart des mutants originaux pendant la période terminale de l'affection. Les taux de glucose sanguin mesurés chez les deux souches de mutants sont semblables, oscillant généralement entre 400 et 500 mg glucose %. Les taux moyens d'insuline circulante des mutants DBM plus âgés (18 semaines ou plus) sont significativement plus élevées que chez le mutant original. — Ces différences peuvent s'expliquer par l'incapacité des mutants DBM de développer une diminution marquée du nombre de cellules comme elle se produit chez les mutants plus âgés de la souche initiale.
    Abstract: Zusammenfassung Die Kreuzung von Tieren des ursprünglichen Diabetesstammes (db) mit normalen grauen Mäusen ergab die modifizierte Mutante DBM. DBM-Mäuse scheinen länger zu leben als die Großzahl der Tiere des ursprünglichendb-Stammes. Die beidb/db-Mäusen vom 7. Lebensmonat an regelmäßig beobachtete Gewichtsabnahme trat nur bei einem von 6 DBM-Tieren auf. Die Blutzuckerkonzentrationen beider Mutanten waren vergleichbar und schwankten zwischen 400 und 500 mg/100 ml. Bei älteren DBM-Mäusen (über 18 Wochen) waren deutlich höhere Insulinkonzentrationen festzustellen als beidb/db. Diese Unterschiede mögen mit der Tatsache zusammenhängen, daß die Zahl der B-Zellen des Pankreas bei älteren DBM-Tieren weniger stark absinkt als beidb/db-Mäusen.
    Notes: Summary Body weight, blood glucose, serum insulin and islet morphology were studied in DBM mice, modified diabetic mutants produced by crossing mice from the original black diabetic strain (C 57 BL/Ks-db) with normal misty colored mice (C 57 BL/6J-m). DBM mutants appeared to live longer than most mice from the original strain. Only 1 of 6 animals, 7 months of age or older, showed the fall in body weight observed in the majority of the original mutants during the terminal stage of the disease. Blood glucose levels in both types of mutants were similar, generally reaching levels of 400 to 500 mg glucose/100 ml blood. The mean insulin level in older (18 weeks or greater) DBM mutants was significantly greater than in the original mutants. These differences could be explained by the failure of DBM mutants to develop the marked decrease in numbers of beta cells seen in older mutants from the original strain.
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