DEVELOPMENT OF THE INSULIN SECRETORY DEFECT IN GENETICALLY DIABETIC (db/db) MOUSE

Berglund, O; Frankel, Barbara J.; Hellman, Bo

doi:10.1530/acta.0.0870543

Cited by 63 publications

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“…This is in line with earlier observations (Berglund et al 1978, Gustavsson et al 2005. The urinary glucose level was 17G2 mM (nZ33).…”

Section: Animalssupporting

confidence: 93%

“…In diabetic subjects, the b-cell response to sulfonylureas is less impaired than the response to glucose (Del Guerra et al 2005). db/db mice develop severe diabetes (Berglund et al 1978) and their b-cells show a defective Ca 2C response to glucose stimulation (Roe et al 1994). ob/ob mice are hyperglycemic, but their b-cells respond adequately in vitro to stimulators and inhibitors of insulin release (Hellman et al 1974, Idahl et al 1976).…”

Section: Introductionmentioning

confidence: 99%

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Cell specificity of the cytoplasmic Ca2+ response to tolbutamide is impaired in β-cells from hyperglycemic mice

Gustavsson¹,

Larsson-Nyrén²,

Lindström³

2006

Journal of Endocrinology

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We recently reported that the timing and magnitude of the nutrient-induced Ca 2C response are specific and reproducible for each isolated b-cell. We have now used tolbutamide and arginine to test if the cell specificity exists also for the response to non-nutrient stimulation of b-cells and if so, whether it is disturbed in b-cells from hyperglycemic ob/ob and db/db mice. Zn 2C outflow measurements were used to study the correlation between Ca 2C response and insulin secretion in individual b-cells. Tolbutamide and arginine induced cellspecific Ca 2C responses in lean mouse b-cells both with regard to lag times for [Ca 2C ] i rise and peak [Ca 2C ] i heights. b-Cells within intact islets also showed cell-specific timing of their Ca 2C responses to tolbutamide. However, in tolbutamide-and arginine-stimulated single b-cells from ob/ob and db/db mice only the magnitude of Ca 2C response was cell-specific, not the timing. The lag time of tolbutamideinduced insulin secretion was cell-specific in lean mouse b-cells but not in ob/ob mouse cells. Therefore, cell specificity seems to be a robust mechanism, and probably important for an adequate b-cell function. The loss of temporal cell specificity for the response to tolbutamide in single b-cells from hyperglycemic mice may be a sign of K ATP -or voltagedependent calcium channel dysfunction.

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“…This is in line with earlier observations (Berglund et al 1978, Gustavsson et al 2005. The urinary glucose level was 17G2 mM (nZ33).…”

Section: Animalssupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Cell specificity of the cytoplasmic Ca2+ response to tolbutamide is impaired in β-cells from hyperglycemic mice

Gustavsson¹,

Larsson-Nyrén²,

Lindström³

2006

Journal of Endocrinology

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“…In the dormouse, a constant insulin flow in the late phase was rapidly reached. Several animals present similar properties of insulin secretion as the dormouse: the non-diabetic Chinese hamster [14], the Syrian hamster [15] and the mouse [13,16,17] also failed to show a rising second phase. In the dormouse the glucose-stimulated insulin increase was much more discrete than in the rat.…”

Section: Comparison Of Insulin Secretion Of the Perfused Rat And Edibmentioning

confidence: 99%

Dynamics of insulin release by perfused edible dormouse (Glis glis) pancreas

Castex

1981

Diabetologia

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Summary.In order to characterize seasonal variations of beta cell function in the edible dormouse (Glis glis), the dynamics of insulin release were examined during perfusion of the isolated pancreas. The B cells exhibited biphasic insulin secretion; however, the dynamic response differed from that of the rat in that there was a steady-state second release phase. Glucose-induced insulin release changed according to the seasons. With 16.8 mmol/1 glucose, the average insulin release of the late phase was 30.8 + 12.6 ng/min in winter, 7.4 + 3.2 ng/min in spring, 13.1 + 3 ng/min in summer and 23.3 + 4.4 ng/min in autumn. The glucose-induced insulin release, expressed as percent of the insulin content of the pancreas, varied according to the season: it represented 2.23 + 0.31% in winter, 1.28 + 0.10% in spring, 1.56 + 0.15 in summer and 2.6 + 0.11 in autumn. It is suggested that in spring and summer, the edible dormouse B cell secretion mechanism is less sensitive to glucose than in the other seasons.Key words: Edible dormouse (Glis glis), hibernating mammal, dynamics of insulin release, insulin secretion, glucose-stimulated insulin secretion, perfused pancreas, B cell, seasonal variations.Glucose tolerance tests performed in the edible dormouse have shown seasonal variations in the plasma insulin response, associated with glucose tolerance changes [1]. In autumn and in winter, the glucoseinduced plasma insulin concentrations are increased and insulin regulates the high peripheral consumption of this hexose; at the beginning of spring, it decreases and glucose tolerance is impaired. In June plasma insulin levels are low and poor glucose tolerance persists.Glucose tolerance tests give useful information about glucose effects on B cell function. In vivo tests are limited however, in that insulin secretagogues could act through secondary effects rather than through a direct action on the B cell [2]. In order to circumvent this problem and to discover if seasonal variations of plasma insulin levels after glucose loading are due to variations of insulin secretion, we have studied insulin secretion of the perfused pancreas of the edible dormouse and compared values with those found in the rat. Material and Methods

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“…At 13-18 weeks the db/db mice showed significant differences in glucose tolerance tests (GTTs) indicative of the development of diabetes (Figure 3.1B and C, n=38 mice, one-way ANOVA p<0.0001). These changes in the db/db animals are due to both peripheral insulin resistance (Berglund, Frankel et al 1978) and deficit in insulin secretion of the islets (Boquist, Hellman et al 1974;Berglund, Frankel et al 1978). Insulin secretion is reduced in db/db islets Islets were isolated from WT and db/db mice, cultured for 2 days and tested for glucose-dependent insulin secretion.…”

Section: Resultsmentioning

confidence: 99%

“…The animals gain weight, develop insulin intolerance and reduced insulin secretion (Berglund, Frankel et al 1978). The explanation for this reduction in secretion, as in T2D, is still not clear, but may include: loss of islets, loss of beta-cells (Baetens, Stefan et al 1978), loss of insulin content (Boquist, Hellman et al 1974;Berglund, Frankel et al 1978;Ishida, Takizawa et al 2004) or reduced exocytic capacity. Direct comparison shows the proportionate loss of secretion parallels the loss of insulin content; ~4.5 to 6 fold for both (Boquist, Hellman et al 1974;Ishida, Takizawa et al 2004).…”

Section: Introductionmentioning

confidence: 99%

Structural and functional changes of pancreatic beta-cells during the progression of disease in the Leprdb model of type 2 diabetes

Hoang¹

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It is well established that changes in insulin secretion play an important role in the pathogenesis of type 2 diabetes. However, the underlying mechanisms of secretory changes occurring at the pancreatic beta-cell level are not fully elucidated. Therefore, this thesis focuses on the modulation of beta-cell function, particularly insulin granule exocytosis, during the progression of type 2 diabetes using the BKS.Cg-Dock7m+/+Lepr db /J (Lepr db mice) as a model of disease.I applied a variety of in vivo and in vitro methods to this project and further refined a livecell two-photon assay which I used to measure the numbers and kinetics of granule fusion events within intact islets.Using this latter technique, in the first part of the project I aimed to test a prevalent hypothesis that granule fusion behaviour changes in disease. Three indices of the post-fusion granule behaviour were compared between islets from animals with overt diabetes (db/db) and wild type. There was no difference in two indices of the fusion-granule behaviour; lifetime of granule fusion and post-fusion fluorescence intensity. The only change was a small increase in the percentage of recaptured granules (or "kiss-and-run" exocytosis) in db/db islets. In contrast to this minor change in granule fusion kinetics, further work showed that the main secretory deficit of frank diabetes, in db/db islets, is due to the loss of responding beta-cells and a reduction in the numbers of exocytic fusing granules in the remaining responsive cells.In the second part of the project I studied disease progression in the Lepr db model. Based on the area under the curve of the glucose tolerance tests, each db/db mouse was classified into one of four stages of disease, ranging from pre-diabetes (stage 1) to severe diabetes (stage 4). The results indicated that changes in islet size and insulin content occurred across all stages of disease severity.At stage 1, there was an increase in islet insulin content due to both an increased number of betacells and increased insulin content in each cell, whereas at stages 2-4, there was a progressive loss of islet insulin content that is a reflection of loss of content from individual beta-cells.Finally, in terms of beta-cell function, the data revealed that modulation of function characterised all stages of disease severity in db/db mice. In stage 1 there was an upregulation in the number of fusion of insulin-containing granules as well as the prevalence of compound exocytosis.At later disease stages there was a loss of glucose-induced insulin-granule fusion which my data indicated was due to impairment in glucose sensing. This work demonstrates that beta-cell function is intimately associated with pre-diabetes and progression to diabetes and adds weight to clinical strategies for therapeutic intervention as early as possible. Page | iiIn summary, the results show that the major factors in the disease phenotype are changes in the numbers of responding beta-cells and the numbers of fusing granules rather than the kinetic...

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DEVELOPMENT OF THE INSULIN SECRETORY DEFECT IN GENETICALLY DIABETIC (db/db) MOUSE

Cited by 63 publications

References 0 publications

Cell specificity of the cytoplasmic Ca2+ response to tolbutamide is impaired in β-cells from hyperglycemic mice

Cell specificity of the cytoplasmic Ca2+ response to tolbutamide is impaired in β-cells from hyperglycemic mice

Dynamics of insulin release by perfused edible dormouse (Glis glis) pancreas

Structural and functional changes of pancreatic beta-cells during the progression of disease in the Leprdb model of type 2 diabetes

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