Insulin Signaling in the Pancreatic β-Cell

Leibiger, Ingo B.; Leibiger, Barbara; Berggren, Per Olof

doi:10.1146/annurev.nutr.28.061807.155530

Cited by 195 publications

(183 citation statements)

References 125 publications

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“…8E and F). ] i signal involves both Ca 2+ influx through Ca 2+ channels in the plasma membrane and Ca 2+ mobilization from intracellular stores (30)(31)(32), and is critically dependent on intact glucose metabolism (i.e., mitochondrial function). We now demonstrate an example of a diabetic phenotype that follows upon aging and that is associated with a defect in [Ca 2+ ] i dynamics.…”

Section: Aging Impairs In Vivo Glucose Homeostasismentioning

confidence: 99%

Defects in β-Cell Ca2+ Dynamics in Age-Induced Diabetes

Trifunović

Köhler

et al. 2014

Diabetes

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Little is known about the molecular mechanisms underlying age-dependent deterioration in β-cell function. We now demonstrate that age-dependent impairment in insulin release, and thereby glucose homeostasis, is associated with subtle changes in Ca2+ dynamics in mouse β-cells. We show that these changes are likely to be accounted for by impaired mitochondrial function and to involve phospholipase C/inositol 1,4,5-trisphosphate–mediated Ca2+ mobilization from intracellular stores as well as decreased β-cell Ca2+ influx over the plasma membrane. We use three mouse models, namely, a premature aging phenotype, a mature aging phenotype, and an aging-resistant phenotype. Premature aging is studied in a genetically modified mouse model with an age-dependent accumulation of mitochondrial DNA mutations. Mature aging is studied in the C57BL/6 mouse, whereas the 129 mouse represents a model that is more resistant to age-induced deterioration. Our data suggest that aging is associated with a progressive decline in β-cell mitochondrial function that negatively impacts on the fine tuning of Ca2+ dynamics. This is conceptually important since it emphasizes that even relatively modest changes in β-cell signal transduction over time lead to compromised insulin release and a diabetic phenotype.

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Section: Aging Impairs In Vivo Glucose Homeostasismentioning

confidence: 99%

Defects in β-Cell Ca2+ Dynamics in Age-Induced Diabetes

Trifunović

Köhler

et al. 2014

Diabetes

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“…Although the peripheral metabolic tissues are the main targets of insulin, mounting evidence from animal and human studies suggests that the β cell itself also possesses an insulin signaling system, which plays a critical role in regulating β-cell mass, survival, insulin biosynthesis, and secretion (3). β-cell-specific inactivation of several components involved in insulin signaling, including insulin receptor (IR), insulin receptor substrate (IRS)-2, class IA phosphatidylinositol 3-kinase (PI3K), and Akt, leads to impaired insulin secretion and/or decreased β-cell mass (4)(5)(6)(7).…”

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confidence: 99%

APPL1 potentiates insulin secretion in pancreatic β cells by enhancing protein kinase Akt-dependent expression of SNARE proteins in mice

Cheng¹,

Lam²,

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Insulin resistance and defective insulin secretion are the two major features of type 2 diabetes. The adapter protein APPL1 is an obligatory molecule in regulating peripheral insulin sensitivity, but its role in insulin secretion remains elusive. Here, we show that APPL1 expression in pancreatic β cells is markedly decreased in several mouse models of obesity and diabetes. APPL1 knockout mice exhibit glucose intolerance and impaired glucose-stimulated insulin secretion (GSIS), whereas transgenic expression of APPL1 prevents high-fat diet (HFD)-induced glucose intolerance partly by enhancing GSIS. In both pancreatic islets and rat β cells, APPL1 deficiency causes a marked reduction in expression of the exocytotic machinery SNARE proteins (syntaxin-1, synaptosomal-associated protein 25, and vesicle-associated membrane protein 2) and an obvious decrease in the number of exocytotic events. Such changes are accompanied by diminished insulin-stimulated Akt activation. Furthermore, the defective GSIS and reduced expression of SNARE proteins in APPL1-deficient β cells can be rescued by adenovirusmediated expression of APPL1 or constitutively active Akt. These findings demonstrate that APPL1 couples insulin-stimulated Akt activation to GSIS by promoting the expression of the core exocytotic machinery involved in exocytosis and also suggest that reduced APPL1 expression in pancreatic islets may serve as a pathological link that couples insulin resistance to β-cell dysfunction in type 2 diabetes.

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“…A simple but efficient way to provide such regulation is through an autocrine feedback mechanism in which the secreted hormone is "sensed" by its respective receptor and initiates synthesis at the level of transcription and/or translation. We and others have described such an autocrine feedback mechanism for the peptide hormone insulin in both rodent and human pancreatic β cells (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). After exocytosis of insulin, a portion of the secreted insulin binds to A-type insulin receptors and, by signaling via PI3 kinase, up-regulates (prepro)insulin gene transcription, which contributes to increased translation.…”

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confidence: 99%

Glucagon regulates its own synthesis by autocrine signaling

Leibiger

Moede

Muhandiramlage

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Peptide hormones are powerful regulators of various biological processes. To guarantee continuous availability and function, peptide hormone secretion must be tightly coupled to its biosynthesis. A simple but efficient way to provide such regulation is through an autocrine feedback mechanism in which the secreted hormone is "sensed" by its respective receptor and initiates synthesis at the level of transcription and/or translation. Such a secretion-biosynthesis coupling has been demonstrated for insulin; however, because of insulin's unique role as the sole blood glucose-decreasing peptide hormone, this coupling is considered an exception rather than a more generally used mechanism. Here we provide evidence of a secretion-biosynthesis coupling for glucagon, one of several peptide hormones that increase blood glucose levels. We show that glucagon, secreted by the pancreatic α cell, up-regulates the expression of its own gene by signaling through the glucagon receptor, PKC, and PKA, supporting the more general applicability of an autocrine feedback mechanism in regulation of peptide hormone synthesis.gene expression | signal transduction

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Insulin Signaling in the Pancreatic β-Cell

Cited by 195 publications

References 125 publications

Defects in β-Cell Ca2+ Dynamics in Age-Induced Diabetes

Defects in β-Cell Ca2+ Dynamics in Age-Induced Diabetes

APPL1 potentiates insulin secretion in pancreatic β cells by enhancing protein kinase Akt-dependent expression of SNARE proteins in mice

Glucagon regulates its own synthesis by autocrine signaling

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