The CaMK4/CREB/IRS-2 Cascade Stimulates Proliferation and Inhibits Apoptosis of β-Cells

Liu, Bo; Barbosa-Sampaio, Helena Cristina; Jones, Peter M.; Persaud, Shanta J.; Müller, D.

doi:10.1371/journal.pone.0045711

Cited by 53 publications

(46 citation statements)

References 45 publications

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“…1). Therefore, as Camk4 promotes beta cell survival and proliferation [17,38], repressing Nupr1 expression via CaMK4 stimulation might be part of a transduction cascade regulating beta cell mass expansion.…”

Section: Discussionmentioning

confidence: 99%

Nupr1 deletion protects against glucose intolerance by increasing beta cell mass

et al. 2013

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Aims/hypothesis The stress-activated nuclear protein transcription regulator 1 (NUPR1) is induced in response to glucose and TNF-α, both of which are elevated in type 2 diabetes, and Nupr1 has been implicated in cell proliferation and apoptosis cascades. We used Nupr1 −/− mice to study the role of Nupr1 in glucose homeostasis under normal conditions and following maintenance on a high-fat diet (HFD). Methods Glucose homeostasis in vivo was determined by measuring glucose tolerance, insulin sensitivity and insulin secretion. Islet number, morphology and beta cell area were assessed by immunofluorescence and morphometric analysis, and islet cell proliferation was quantified by analysis of BrdU incorporation. Islet gene expression was measured by gene arrays and quantitative RT-PCR, and gene promoter activities were monitored by measuring luciferase activity. Results Nupr1 −/− mice had increased beta cell mass as a consequence of enhanced islet cell proliferation. Nupr1-dependent suppression of beta cell Ccna2 and Tcf19 promoter activities was identified as a mechanism through which Nupr1 may regulate beta cell cycle progression. Nupr1 −/− mice maintained on a normal diet were mildly insulin resistant, but were normoglycaemic with normal glucose tolerance because of compensatory increases in basal and glucose-induced insulin secretion. Nupr1 deletion was protective against HFD-induced obesity, insulin resistance and glucose intolerance. Conclusions/interpretation Inhibition of NUPR1 expression or activity has the potential to protect against the metabolic defects associated with obesity and type 2 diabetes.

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Section: Discussionmentioning

confidence: 99%

Nupr1 deletion protects against glucose intolerance by increasing beta cell mass

et al. 2013

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“…Transient transfection GPR75 was downregulated in MIN6 beta cells by transient transfection with siRNAs (150 nmol/l) directed against mouse GPR75 using previously described protocols for efficient gene knockdown [20,21]. MIN6 beta cells transfected with non-interfering RNAs (150 nmol/l) were used as controls.…”

Section: Methodsmentioning

confidence: 99%

The novel chemokine receptor, G-protein-coupled receptor 75, is expressed by islets and is coupled to stimulation of insulin secretion and improved glucose homeostasis

et al. 2013

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Aims/hypothesis Chemokine (C-C motif) ligand 5 (CCL5) acts at C-C chemokine receptors (CCRs) to promote immune cell recruitment to sites of inflammation, but is also an agonist at G-protein-coupled receptor 75 (GPR75), which has very limited homology with CCRs. GPR75 is coupled to Gq to elevate intracellular calcium, so we investigated whether islets express this receptor and whether its activation by CCL5 increases beta cell calcium levels and insulin secretion. Methods Islet CCL5 receptor mRNA expression was measured by quantitative RT-PCR and GPR75 was detected in islets by western blotting and immunohistochemistry. In some experiments GPR75 was downregulated by transient transfection with small interfering RNA. Real-time changes in intracellular calcium were determined by single-cell microfluorimetry. Dynamic insulin secretion from perifused islets was quantified by radioimmunoassay. Glucose homeostasis in lean and obese mice was determined by measuring glucose and insulin tolerance, and insulin secretion in vivo. Results Mouse and human islets express GPR75 and its ligand CCL5. Exogenous CCL5 reversibly increased intracellular calcium in beta cells via GPR75, this phenomenon being dependent on phospholipase C activation and calcium influx. CCL5 also stimulated insulin secretion from mouse and human islets in vitro, and improved glucose tolerance in lean mice and in a mouse model of hyperglycaemia and insulin resistance (ob/ob ). The improvement in glucose tolerance was associated with enhanced insulin secretion in vivo, without changes in insulin sensitivity. Conclusions/interpretation Although CCL5 is implicated in the pathogenesis of diabetes through activation of CCRs, it has beneficial effects on beta cells through GPR75 activation.

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“…38,39 To assess the effect of deglycosylation, the cells were incubated in the absence or presence of Peptide N-Glycosidase F and Endoglycosidase H.…”

Section: Insulin Secretionmentioning

confidence: 99%

Polycystic Kidney Disease with Hyperinsulinemic Hypoglycemia Caused by a Promoter Mutation in Phosphomannomutase 2

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Flanagan

Stanescu

et al. 2017

JASN

102

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General rightsThis document is made available in accordance with publisher policies. Please cite only the published version using the reference above. We propose that the promoter mutation alters tissue-specific chromatin loop formation with consequent organ-specific deficiency of PMM2 leading to the restricted phenotype of HIPKD. Our findings extend the spectrum of genetic 5 causes for both HI and PKD and provide insights into gene regulation and PMM2 pleiotropy.6

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The CaMK4/CREB/IRS-2 Cascade Stimulates Proliferation and Inhibits Apoptosis of β-Cells

Cited by 53 publications

References 45 publications

Nupr1 deletion protects against glucose intolerance by increasing beta cell mass

Nupr1 deletion protects against glucose intolerance by increasing beta cell mass

The novel chemokine receptor, G-protein-coupled receptor 75, is expressed by islets and is coupled to stimulation of insulin secretion and improved glucose homeostasis

Polycystic Kidney Disease with Hyperinsulinemic Hypoglycemia Caused by a Promoter Mutation in Phosphomannomutase 2

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