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Defective secretion of islet hormones in chromogranin-B deficient mice.

Obermüller S, Calegari F, King A, Lindqvist A, Lundquist I, Salehi A, Francolini M, Rosa P, Rorsman P, Huttner WB, Barg S - PLoS ONE (2010)

Bottom Line: Stimulated release of glucagon and somatostatin was reduced as well.Consequentially CgB-ko animals display some, but not all, hallmarks of human type-2 diabetes.However, the molecular mechanisms underlying this defect remain to be determined.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Sciences-Malmö, Lund University, Malmö, Sweden.

ABSTRACT
Granins are major constituents of dense-core secretory granules in neuroendocrine cells, but their function is still a matter of debate. Work in cell lines has suggested that the most abundant and ubiquitously expressed granins, chromogranin A and B (CgA and CgB), are involved in granulogenesis and protein sorting. Here we report the generation and characterization of mice lacking chromogranin B (CgB-ko), which were viable and fertile. Unlike neuroendocrine tissues, pancreatic islets of these animals lacked compensatory changes in other granins and were therefore analyzed in detail. Stimulated secretion of insulin, glucagon and somatostatin was reduced in CgB-ko islets, in parallel with somewhat impaired glucose clearance and reduced insulin release, but normal insulin sensitivity in vivo. CgB-ko islets lacked specifically the rapid initial phase of stimulated secretion, had elevated basal insulin release, and stored and released twice as much proinsulin as wildtype (wt) islets. Stimulated release of glucagon and somatostatin was reduced as well. Surprisingly, biogenesis, morphology and function of insulin granules were normal, and no differences were found with regard to beta-cell stimulus-secretion coupling. We conclude that CgB is not required for normal insulin granule biogenesis or maintenance in vivo, but is essential for adequate secretion of islet hormones. Consequentially CgB-ko animals display some, but not all, hallmarks of human type-2 diabetes. However, the molecular mechanisms underlying this defect remain to be determined.

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In vivo measurements of insulin secretion, glucose tolerance and insulin sensitivity.Time course of (A) plasma insulin concentration (pM), and (B) plasma glucose (mM) in response to i.p. glucose injection (3 g/kg) at time 0; wt (black squares, n = 12) and CgB-ko (white squares, n = 16). (C) plasma glucose (mM) in response to i.p. insulin injection (0.8U/kg). **P<0.01;*P<0.05.
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pone-0008936-g004: In vivo measurements of insulin secretion, glucose tolerance and insulin sensitivity.Time course of (A) plasma insulin concentration (pM), and (B) plasma glucose (mM) in response to i.p. glucose injection (3 g/kg) at time 0; wt (black squares, n = 12) and CgB-ko (white squares, n = 16). (C) plasma glucose (mM) in response to i.p. insulin injection (0.8U/kg). **P<0.01;*P<0.05.

Mentions: We tested how the defects observed in islets might affect glucose tolerance of the mice. A bolus of glucose was injected intraperitoneally (i.p.), followed by analysis of blood samples (Fig 4). The initial plasma insulin concentration was similar in wt and CgB-ko mice (100±22 pM vs. 93±21 pM; Fig 4). All mice responded to the glucose challenge with a transient increase in plasma insulin, which then declined to baseline with a half-time of ∼10 min. The peak in plasma insulin was higher in the wt (332±46 pM), compared with CgB-ko (200±38 pM) (Fig 4A). Correspondingly, the wt mice were somewhat more resistant to the glucose challenge and plasma glucose reached peaks of 33.9±1.1 mM in wt and 38.3±0.9 mM in CgB-ko (Fig 4B). Lack of CgB might affect peripheral glucose uptake, as was recently shown for CgA [29]. We therefore tested whether insulin sensitivity was likewise affected in the CgB-ko animals. This was not the case since a single i.p. injection of insulin (0.8 U/kg body weight) caused near identical reductions in blood glucose over time in both wt and CgB-ko animals (Fig 4C).


Defective secretion of islet hormones in chromogranin-B deficient mice.

Obermüller S, Calegari F, King A, Lindqvist A, Lundquist I, Salehi A, Francolini M, Rosa P, Rorsman P, Huttner WB, Barg S - PLoS ONE (2010)

In vivo measurements of insulin secretion, glucose tolerance and insulin sensitivity.Time course of (A) plasma insulin concentration (pM), and (B) plasma glucose (mM) in response to i.p. glucose injection (3 g/kg) at time 0; wt (black squares, n = 12) and CgB-ko (white squares, n = 16). (C) plasma glucose (mM) in response to i.p. insulin injection (0.8U/kg). **P<0.01;*P<0.05.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2812483&req=5

pone-0008936-g004: In vivo measurements of insulin secretion, glucose tolerance and insulin sensitivity.Time course of (A) plasma insulin concentration (pM), and (B) plasma glucose (mM) in response to i.p. glucose injection (3 g/kg) at time 0; wt (black squares, n = 12) and CgB-ko (white squares, n = 16). (C) plasma glucose (mM) in response to i.p. insulin injection (0.8U/kg). **P<0.01;*P<0.05.
Mentions: We tested how the defects observed in islets might affect glucose tolerance of the mice. A bolus of glucose was injected intraperitoneally (i.p.), followed by analysis of blood samples (Fig 4). The initial plasma insulin concentration was similar in wt and CgB-ko mice (100±22 pM vs. 93±21 pM; Fig 4). All mice responded to the glucose challenge with a transient increase in plasma insulin, which then declined to baseline with a half-time of ∼10 min. The peak in plasma insulin was higher in the wt (332±46 pM), compared with CgB-ko (200±38 pM) (Fig 4A). Correspondingly, the wt mice were somewhat more resistant to the glucose challenge and plasma glucose reached peaks of 33.9±1.1 mM in wt and 38.3±0.9 mM in CgB-ko (Fig 4B). Lack of CgB might affect peripheral glucose uptake, as was recently shown for CgA [29]. We therefore tested whether insulin sensitivity was likewise affected in the CgB-ko animals. This was not the case since a single i.p. injection of insulin (0.8 U/kg body weight) caused near identical reductions in blood glucose over time in both wt and CgB-ko animals (Fig 4C).

Bottom Line: Stimulated release of glucagon and somatostatin was reduced as well.Consequentially CgB-ko animals display some, but not all, hallmarks of human type-2 diabetes.However, the molecular mechanisms underlying this defect remain to be determined.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Sciences-Malmö, Lund University, Malmö, Sweden.

ABSTRACT
Granins are major constituents of dense-core secretory granules in neuroendocrine cells, but their function is still a matter of debate. Work in cell lines has suggested that the most abundant and ubiquitously expressed granins, chromogranin A and B (CgA and CgB), are involved in granulogenesis and protein sorting. Here we report the generation and characterization of mice lacking chromogranin B (CgB-ko), which were viable and fertile. Unlike neuroendocrine tissues, pancreatic islets of these animals lacked compensatory changes in other granins and were therefore analyzed in detail. Stimulated secretion of insulin, glucagon and somatostatin was reduced in CgB-ko islets, in parallel with somewhat impaired glucose clearance and reduced insulin release, but normal insulin sensitivity in vivo. CgB-ko islets lacked specifically the rapid initial phase of stimulated secretion, had elevated basal insulin release, and stored and released twice as much proinsulin as wildtype (wt) islets. Stimulated release of glucagon and somatostatin was reduced as well. Surprisingly, biogenesis, morphology and function of insulin granules were normal, and no differences were found with regard to beta-cell stimulus-secretion coupling. We conclude that CgB is not required for normal insulin granule biogenesis or maintenance in vivo, but is essential for adequate secretion of islet hormones. Consequentially CgB-ko animals display some, but not all, hallmarks of human type-2 diabetes. However, the molecular mechanisms underlying this defect remain to be determined.

Show MeSH
Related in: MedlinePlus