Cyclic AMP Signaling in Pancreatic Islets

Furman, Brian L.; Ong, Wee Kiat; Pyne, Nigel J.

doi:10.1007/978-90-481-3271-3_13

Cited by 91 publications

(71 citation statements)

References 184 publications

(231 reference statements)

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“…Cyclic AMP in the ␤-cell is elevated by numerous agonists, as just described, and also by glucose (23). Its effects are to potentiate insulin secretion and to stimulate and modify gene expression controlling multiple functions.…”

Section: Samols Et Al (100) In 1965mentioning

confidence: 97%

“…Its effects are to potentiate insulin secretion and to stimulate and modify gene expression controlling multiple functions. Prominent among these are insulin biosynthesis, replication, and apoptosis (23). Mediators of these effects are protein kinase A (PKA), the exchange proteins activated by cyclic AMP (Epac), and cyclic AMP response elements and other proteins in the nucleus.…”

Section: Samols Et Al (100) In 1965mentioning

confidence: 99%

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Evolving insights regarding mechanisms for the inhibition of insulin release by norepinephrine and heterotrimeric G proteins

Straub

Sharp

2012

American Journal of Physiology-Cell Physiology

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Straub SG, Sharp GW. Evolving insights regarding mechanisms for the inhibition of insulin release by norepinephrine and heterotrimeric G proteins. Am J Physiol Cell Physiol 302: C1687-C1698, 2012. First published April 4, 2012 doi:10.1152/ajpcell.00282.2011.-Norepinephrine has for many years been known to have three major effects on the pancreatic ␤-cell which lead to the inhibition of insulin release. These are activation of K ϩ channels to hyperpolarize the cell and prevent the gating of voltage-dependent Ca 2ϩ channels that increase intracellular Ca 2ϩ concentration ([Ca 2ϩ ]i) and trigger release; inhibition of adenylyl cyclases, thus preventing the augmentation of stimulated insulin release by cyclic AMP; and a "distal" effect that occurs downstream of increased [Ca 2ϩ ]i to inhibit exocytosis. All three are mediated by the pertussis toxin (PTX)-sensitive heterotrimeric Gi and Go proteins. The distal inhibitory effect on exocytosis is now known to be due to the binding of G protein ␤␥ subunits to the synaptosomal-associated protein of 25 kDa (SNAP-25) on the soluble NSF attachment protein receptor (SNARE) complex. Recent studies have uncovered two more actions of norepinephrine on the ␤-cell: 1) retardation of the refilling of the readily releasable granule pool after it has been discharged, an action that is mediated by G␣i 1 and/or G␣i2; and 2) inhibition of endocytosis that is mediated by Gz. Of importance also are new findings that G␣o regulates the number of docked granules in the ␤-cell, and that G␣o 2 maintains a tonic inhibitory influence on secretion. The latter provides another explanation as to why PTX, which blocks the effect of G␣o2, was initially called "islet activating protein." Finally, there is clear evidence that overexpression of ␣ 2A-adrenergic receptors in ␤-cells can cause type 2 diabetes. pancreatic ␤-cell; K ϩ channels; adenylyl cyclases; exocytosis; granule pools; endocytosis NOREPINEPHRINE IS RESPONSIBLE for multiple effects in the body as it acts as a hormone after its release from the adrenal medulla along with epinephrine, and as a neurotransmitter when released by the central and sympathetic nervous systems. It has important functions on the cardiovascular system, on muscle, liver, and adipose tissue, and in the control of whole body metabolism. This review, however, focuses on the effects of norepinephrine on the pancreatic ␤-cell and recent advances in our knowledge. Norepinephrine has three major effects on the ␤-cell that lead to the inhibition of insulin release (65,74,102,104). It activates K ϩ channels to hyperpolarize the cell. This prevents or reverses depolarization and the consequent gating of voltage-dependent Ca 2ϩ channels that increase intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) and trigger insulin release. It inhibits adenylyl cyclases, thus preventing the augmentation of stimulated insulin release, and it has a "distal" effect that occurs downstream of increased [Ca 2ϩ

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Section: Samols Et Al (100) In 1965mentioning

confidence: 97%

Section: Samols Et Al (100) In 1965mentioning

confidence: 99%

Evolving insights regarding mechanisms for the inhibition of insulin release by norepinephrine and heterotrimeric G proteins

Straub

Sharp

2012

American Journal of Physiology-Cell Physiology

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“…Thus, in response to food transit, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) (11) are released by enteroendocrine L and K cells, respectively, from where they augment GSIS to counteract the postprandial hyperglycemic spike (12)(13)(14)(15). This so-called "incretin effect" requires elevated glycemia, and GLP-1 and GIP receptor activation engages intracellular signaling mechanisms largely dependent on cyclic adenosine monophosphate (cAMP) generation (16)(17)(18) and activated Ca 2+ influx (19). Since incretins also stimulate antiapoptotic and prosurvival pathways in β cells (20), GLP-1 mimetics and dipeptidyl peptidase-4 (DPP-4) inhibitors have become first-line antihyperglycemic agents for the treatment of T2DM (21).…”

Section: Introductionmentioning

confidence: 99%

Lipotoxicity disrupts incretin-regulated human β cell connectivity

Hodson¹,

Mitchell²,

Bellomo³

et al. 2013

J. Clin. Invest.

208

312

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Pancreatic β cell dysfunction is pathognomonic of type 2 diabetes mellitus (T2DM) and is driven by environmental and genetic factors. β cell responses to glucose and to incretins such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are altered in the disease state. While rodent β cells act as a coordinated syncytium to drive insulin release, this property is unexplored in human islets. In situ imaging approaches were therefore used to monitor in real time the islet dynamics underlying hormone release. We found that GLP-1 and GIP recruit a highly coordinated subnetwork of β cells that are targeted by lipotoxicity to suppress insulin secretion. Donor BMI was negatively correlated with subpopulation responses to GLP-1, suggesting that this action of incretin contributes to functional β cell mass in vivo. Conversely, exposure of mice to a high-fat diet unveiled a role for incretin in maintaining coordinated islet activity, supporting the existence of species-specific strategies to maintain normoglycemia. These findings demonstrate that β cell connectedness is an inherent property of human islets that is likely to influence incretin-potentiated insulin secretion and may be perturbed by diabetogenic insults to disrupt glucose homeostasis in humans.

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“…Increased b-cell cAMP potentiates glucosestimulated insulin secretion and protects b-cell mass. 23 However, both sulfonylureas and incretin therapies have raised concerns of whether the added demands they place upon the insulin secretory capacity leads to b-cell exhaustion. Sulfonylureas are thought to exhaust b-cells, most likely through their sustained depolarization of the plasma membrane, the alteration of calcium fluxes and the lack of coupling between insulin release and insulin synthesis.…”

Section: Introductionmentioning

confidence: 99%

“…26 Furthermore, the rise in cAMP is protective of b-cell mass through improved survival in response to factors associated with the metabolic syndrome. 23 Beyond effects at the b-cells, GLP-1 receptor agonists induce satiety, reduce gastric emptying, and lower inappropriately elevated glucagon levels that contribute to the hyperglycemia. 27,28 The effects of incretins to decrease gastric emptying and satiety have been shown to reduce body weight and they are currently approved for the management of obesity.…”

Section: Introductionmentioning

confidence: 99%

Long-term activation of PKA inβ-cells provides sustained improvement to glucose control, insulin sensitivity and body weight

Levine

Kaihara

Layden

et al. 2016

Islets

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(2016) Long-term activation of PKA in β-cells provides sustained improvement to glucose control, insulin sensitivity and body weight, Islets, 8:5, 125-134, DOI: 10.1080/19382014.2016 To link to this article: https://doi.org/10. 1080/19382014.2016 ABSTRACTType 2 diabetes is associated with obesity, insulin resistance and b-cell failure. Therapeutic aims are to reduce adiposity, improve insulin sensitivity and enhance b-cell function. However, it has been proposed that chronically increasing insulin release leads to b-cell exhaustion and failure. We previously developed mice to have increased activity of the cAMP-dependent protein kinase (PKA), specifically in b-cells (b-caPKA mice). b-caPKA mice have enhanced acute phase insulin release, which is the primary determinant of the efficacy of glucose clearance. Here these mice were used to determine the sustainability of enhanced insulin secretion, and to characterize peripheral effects of enhanced b-cell function. Increased PKA activity was induced by tamoxifen administration at 10 weeks of age. Male mice were aged to 12 months of age and female mice to 16 months. Glucose control in both male and female b-caPKA mice was significantly improved relative to littermate controls with ad libitum feeding, upon refeeding after fasting, and in glucose tolerance tests. In female mice insulin release was both greater and more rapid than in controls. Female mice were more insulin sensitive than controls. Male and female b-caPKA mice had lower body weights than controls. DEXA analysis of male mice revealed that this was due to reduced adiposity and not due to changes in lean body mass. This study indicates that targeting b-cells to enhance insulin release is sustainable, maintains insulin sensitivity and reduces body weight. These data identify b-cell PKA activity as a novel target for obesity therapies.

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Cyclic AMP Signaling in Pancreatic Islets

Cited by 91 publications

References 184 publications

Evolving insights regarding mechanisms for the inhibition of insulin release by norepinephrine and heterotrimeric G proteins

Evolving insights regarding mechanisms for the inhibition of insulin release by norepinephrine and heterotrimeric G proteins

Lipotoxicity disrupts incretin-regulated human β cell connectivity

Long-term activation of PKA inβ-cells provides sustained improvement to glucose control, insulin sensitivity and body weight

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