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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Diabetologia 19 (1980), S. 58-65 
    ISSN: 1432-0428
    Keywords: Diabetes mice ; pancreatic islets ; glucagon ; insulin ; A-cell ; B-cell ; acinar cell necrosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A spontaneous recessive mutation appearing in strain 129/J mice at the diabetes (db) locus on Chromosome 4 has been characterized. The new allele, designated db 3J,produced hyperphagia and severe obesity. Mutants weighed in excess of 70 g by 6 months of age, compared to 22–28 g for lean littermates. Although the disease was similar to the mild hyperglycaemia-severe obesity syndrome exhibited by db gene presentation on the C57BL/6J inbred background, the syndrome in 129/J mice reduced lifespan, with mutants exhibiting sudden weight loss, hypoglycaemia, and a 67% mortality between 6 and 14 months of age. Mutant males, but not females, were transiently hyperglycaemic between 2 to 4 months of age, attaining a maximum mean blood sugar of 196±27 (SEM) mg/dl. Thereafter glucose levels declined to normoglycaemic values (80–100 mg/dl), and with increasing age, mutants of both sexes became hypoglycaemic (60 mg/dl at 9 months). Mutants of both sexes were extremely hyperinsulinaemic at the earlier ages, with mean plasma insulin at month 5 reflecting 30-fold elevations above normal for males and 18-fold for females. These levels diminished with age, the decline being more marked in males. Plasma glucagon levels were 3-fold elevated in the younger mutants of both sexes (86 pg/ ml versus 28 pg/ml in normal mice), mean levels increasing to almost 5-fold above mean control values in the older age group (198 pg/ml versus 41 pg/ ml in normal mice). Histopathological findings were limited to pancreas. Increasing necrosis of the exocrine, but not endocrine, pancreas was noted in aging mutants. Aldehyde fuchsin staining of the mutant pancreas revealed hyperplastic islets filled with heavily granulated B-cells. B-cell hyperplasia was accompanied by a 30-fold increase over controls in pancreatic insulin content in the 8 month old mutants, whereas pancreatic glucagon content was only doubled. Morphometric analysis showed less than a 2-fold increase in the mean number of A-cells per islet. Thus, an interesting feature of expression of the diabetes gene in the 129/J strain is the persisting hyperglucagonaemia in the face of moderating hyperinsulinaemia.
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    Diabetologia 10 (1974), S. 607-610 
    ISSN: 1432-0428
    Keywords: Diabetes mice ; pre-clinical diabetes ; hyperinsulinemia ; insulin resistance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Two new strains of diabetes mice (C57BL/ KsJ-m db and C57BL/6J-m db) have been developed with diabetes (db) and the closely linked misty (m) gene coupled on the same chromosome. This permits identification of diabetes mice (m db/m db) by their gray coat color and white feet as early as age 4 days, well before obesity or signs of diabetes are visible. Hyperinsulinemia was evident in diabetes mice of both strains at 10 days of age and the severity increased progressively with age. These elevated concentrations of plasma insulin were associated with mild hypoglycemia. No significant differences were observed with respect to the degrees of hyperinsulinemia or hypoglycemia between diabetes mice of the two strains. The mild hypoglycemia observed in diabetes mice in the presence of a pronounced hyperinsulinemia suggests that insulin resistance occurs as early as age 10 days and may itself be a factor in causing hyperinsulinemia. The sequence of early events occurring in diabetes mice appears to be hyperinsulinemia leading to mild hypoglycemia, followed by compensatory hyperphagia which in turn results in enhanced insulin secretion and obesity.
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    Diabetologia 14 (1978), S. 141-148 
    ISSN: 1432-0428
    Keywords: Diabetes ; obesity ; hyperphagia ; hyperinsulinaemia ; mice ; genetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The diabetes syndromes produced by the two single gene mutations, obese (ob), and diabetes (db) are identical when both genes are expressed on the same inbred background, whereas on different backgrounds the syndrome changes from a severeobesity, moderate-diabetes to a severe life-shortening diabetes. The same initial sequence of events occurs in both conditions. Increased secretion of insulin and hyperphagia is followed by moderate hyperglycaemia with a further compensatory increase in insulin secretion followed by an expansion of the beta-cell mass. On the BL/6 inbred background, hypertrophy and hyperplasia of the beta cells continues until hyperglycaemia is controlled, whereas on the BL/Ks background, beta cell expansion fails and islet atrophy occurs causing insulinopenia, marked hyperglycaemia, and severe diabetes. The data presented here suggest that hyperphagia, hyperinsulinaemia, or both, early in development trigger the abnormal sequence of metabolic events leading to the obesity-diabetes state. These primary events interact with unknown genetic modifiers to produce either a juvenile or maturity-onset type of diabetes. An understanding of the mode of action of these background modifiers influencing the severity of diabetes in mice should lead to a better understanding of the ways in which unknown genetic and environmental factors contribute to human diabetes.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-0428
    Keywords: Diabetes mice ; pancreatic islets ; D cell ; somatostatin ; B cell ; A cell ; PP cell ; electron microscopy ; morphometric analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary An ultrastructural and immunocytochemical study was undertaken to elucidate the temporal and quantitative aspects of the changes occurring in the delta cells in the pancreatic islets of C57BL/KsJdb/db (diabetes) mice. Electron microscopy revealed that prior to the major topographical redistribution of delta cells from their peripheral location to the islet interior, long delta cell filopodial extensions penetrated into the islet, greatly increasing the area of surface contact between delta cells and hypersecretory beta cells. Coincident with delta cell redistribution in islets of 8 to 10 week diabetes mice, the mean number of delta cells per islet had increased significantly. In contrast, their volume density had decreased, indicating incomplete compensation for beta cell hyperplasia which had commenced approximately 4 weeks earlier. In the 14 week mutants, numbers of delta cells per islet and islet volume reached maximum values while delta cell volume density had been restored to a control level. Delta cell volume density exhibited a 2-fold increase in the mutants at 20 weeks that coincided with massive beta cell necrosis. However, a decline in the number of delta cells per islet (173.6±20.9 at 14 weeks versus 91.2±9.5 at 20 weeks) suggests that islet degeneration in terminal stages of the syndrome also includes some loss of these cells.
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    Springer
    Diabetologia 22 (1982), S. 205-211 
    ISSN: 1432-0428
    Keywords: Metabolic efficiency ; obesity ; ob/ob mice ; db/db mice ; non-shivering thermogenesis ; cold adaptation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The two mouse mutants, obese (ob) and diabetes (db), cause similar diabetes-obesity syndromes that are characterized by a marked increase in apparent metabolic efficiency with regard to utilization of energy. A failure to thermoregulate in a normal fashion would save energy which could then be diverted to other functions and be reflected as increased metabolic efficiency. This study assesses the contribution of a defect in thermogenesis to the increased metabolic efficiency. Thermogenesis in obese (ob) and diabetes (db) mutant mice was quantified at various environmental temperatures. Both mutants maintained body temperatures near normal when maintained at ambient temperatures (23 °C), and if exposed to cold at 10 °C for a brief period, became cold-adapted and would survive indefinitely at 4°C. Rectal temperatures of mutants maintained at 4 °C were only 1 °–2 °C less than those seen in normal mice. This maintenance of nearly normal body temperature at temperatures less than thermoneutral was reflected by increased food consumption in all mice maintained in the cold. The data presented suggest that the defect in thermogenesis in both mutants is not a major cause of the increased metabolic efficiency. Hyperinsulinaemia, a consistent feature of both mutants, might by increasing anabolic processes (synthesis) and decreasing degradation spare energy normally used for tissue turnover and account for some of this increased metabolic efficiency.
    Type of Medium: Electronic Resource
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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
    Electronic Resource
    Electronic Resource
    Springer
    Diabetologia 9 (1973), S. 287-293 
    ISSN: 1432-0428
    Keywords: Diabetes ; obesity ; modifying genes ; genetics ; hyperglycemia ; islet changes ; mice
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A new congenic strain of obese mice, C57BK/KsJ-ob, has been developed for comparison with the C57BL/6J-ob congenic strain. While obese mice of both strains are characterized by obesity, hyperphagia, and hyperglycemia, the C57BL/Ks obese mice have severe diabetes, marked hyperglycemia, temporarily elevated plasma insulin concentrations, and typical degenerative changes in the islets of Langerhans. In contrast, the C57BL/6J obese mice have mild hyperglycemia and marked hyperinsulinemia coupled with hypertrophy and hyperplasia of the islets of Langerhans. The severe diabetic condition produced by obese (ob) on the C57BL/KsJ background is similar, if not identical, to that produced by the diabetes (db) gene on the same background. The metabolic disorder produced by these mutations is associated with the capacity of the islets to respond to an increased demand for insulin. The islet response, whether atrophy or hypertrophy, appears to be due to the interaction of the obese and diabetes genes with modifiers in the genetic background rather than the specific consequences of the particular gene. The markedly different diabetic syndromes that result when the obese mutation is on different genetic backgrounds emphasize the importance of strict genetic control in studies with obese-hyperglycemic mutants.
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    Springer
    Diabetologia 9 (1973), S. 294-298 
    ISSN: 1432-0428
    Keywords: Parabiosis ; obese mice ; diabetes mice ; satiety factor ; satiety center
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Parabiosis of obese (ob/ob) with diabetes (db 2J/db2J) mice caused the obese partner to become hypoglycemic, to lose weight and to die of starvation, while no abnormal changes were observed in the diabetes partner. The striking similarity of this response to that observed in normal mice in parabiosis with diabetes mice suggests that obese mice are like normal mice in having normal satiety centers sensitive to the satiety factor produced by the diabetes partner. In contrast, parabiosis of obese with normal mice is a fully viable combination suggesting that the obese partner does not produce sufficient satiety factor to turn off the normal partner's eating drive. However, obese mice in parabiosis with normal mice gain weight less rapidly and eat less than obese mice in parabiosis with obese mice. These observations suggest that some humoral factor is provided by the normal partner that regulates food consumption in the obese partner. To explain the identical obese-hyperglycemic syndromes produced by these two unrelated and separate genes when on identical genetic backgrounds, it is postulated that the obese mouse is unable to produce sufficient satiety factor to regulate its food consumption, whereas the diabetes mouse produces satiety factor, but cannot respond to it because of a defective satiety center.
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Springer
    Diabetologia 6 (1970), S. 263-267 
    ISSN: 1432-0428
    Keywords: Hereditary diabetes ; mouse ; lesions ; ventromedial nucleus ; satiety center ; hypothalamus ; gold thioglucose
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Résumé Le noyau médioventral de la région hypothalamique de souris présentant un diabète génétique (db/db) et de souris normales (+/+) a été lésé par l'administration d'aurothioglucose ou par électrocautérisation. Les souris normales répondent de façon typique à l'un ou lautre de ces traitements en devenant hyperphagiques, obèses, et en montrant une élévation modérée de l'insulinémie tout en gardant des taux de glucose sanguins voisins de la normale. La destruction du noyau médioventral chez la souris diabétique empêche le développement d'une hyperglycémie sévère et a un effet thérapeutique chez les souris modérément hyperglycémiques. L'hyperphagie et l'accumulation rapide de tissu adipeux continuent à une cadence soutenue, comme prévu. La regranulation des cellulesβ du pancréas endocrine est accompagnée de taux de glucose sanguin normaux. L'amélioration prononcée des symptomes diabétiques dans ce syndrome chez la souris renforce l'hypothèse suivant laquelle le défaut primaire chez la souris diabétique implique une insuffisance hypothalamique, en particulier dans la région des centres de la satiété.
    Abstract: Zusammenfassung Bei hereditär diabetischen (db/db) und normalen (+/+) Mäusen wurde der ventromediale Kern des Hypothalamus entweder durch Goldthioglucose-injektion oder durch Elektrokauterisierung zerstört. Auf diese Behandlung reagierten normale Mäuse wie erwartet mit Hyperphagie, wurden fettsüchtig und zeigten bei normalen Blutzuckerkonzentrationen erhöhte Plasma-insulinkonzentrationen. Bei den diabetischen Tieren verhinderte der Eingriff den weitern Anstieg der Blutzuckerkonzentration und hatte bei mäßig hyperglykämischen Tieren eine Senkung des Blutzuckerspiegels zur Folge. Gleichzeitig blieb die für diedb/db Mäuse charakteristische Hyperphagie bestehen und führte wie bei unbehandeltendb/db Tieren zur Fettsucht. Im Pankreas wurde nach Setzen der hypothalamischen Läsionen eine Regranulation der B-Zellen beobachtet. Die deutliche Verbesserung der diabetischen Stoffwechsellage durch Zerstörung der ventromedialen Kerne des Hypothalamus läßt den Schluß zu, daß der primäre zur Entwicklung des Syndroms führende Defekt diese Strukturen des Zentralnervensystems betrifft.
    Notes: Summary Genetically diabetic (db/db) and normal (+/+) mice were lesioned in the ventromedial nucleus by either gold thioglucose or electrocauterization. The normal mice responded typically to either of these treatments by becoming hyperphagic, obese, and by exhibiting moderately elevated plasma insulin concentrations coupled with near normal blood sugar concentrations. In diabetic mice, destruction of the ventromedial nucleus prevented the development of severe hyperglycemia and had a therapeutic effect in those mice with established, but moderate, hyperglycemia. Hyperphagia and rapid accumulation of adipose tissue continued unabated as expected. Regranulation of theβ-cells of the endocrine pancreas was associated with the maintenance of blood sugar at normal concentrations. The marked improvement of the diabetic aspects of this syndrome in mice lends support to the hypothesis that the primary defect in diabetic mice may involve a defective hypothalamus, particularly in the regions of the satiety centers.
    Type of Medium: Electronic Resource
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  • 10
    Electronic Resource
    Electronic Resource
    Springer
    Diabetologia 13 (1977), S. 25-26 
    ISSN: 1432-0428
    Keywords: Corticosterone ; diabetes ; obesity ; mutation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Plasma corticosterone concentrations in diabetic (db) mice maintained on two different inbred backgrounds were found to be elevated significantly when compared to normal controls. These data are similar to that reported with the phenotypically similar obese (ob) mouse. These results suggest that the hyperadrenolcorticism is not related to the primary gene action of either gene but rather is a consequence of the development of the obesity-diabetes syndromes.
    Type of Medium: Electronic Resource
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