The future of incretin‐based therapy: novel avenues—novel targets

Åhrén, Bo

doi:10.1111/j.1463-1326.2011.01457.x

Cited by 55 publications

(39 citation statements)

References 74 publications

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“…Treatment with 25 nmol/kg (pGlu-Gln)-CCK-8 twice daily did not appear to have a negative impact on islet structure, and circulating amylase and lipase concentrations were not significantly different between control and (pGlu-Gln)-CCK-8-treated mice. This highlights an important facet of (pGlu-Gln)-CCK-8 action in terms of therapeutic potential, which appears no worse in terms of acute pancreatitis than either exenatide or liraglutide [37]. Indeed, alanine aminotransferase, aspartate aminotransferase and creatinine kinase tended to be lower, suggesting improved kidney and liver function after (pGlu-Gln)-CCK-8.…”

Section: Discussionmentioning

confidence: 87%

Beneficial effects of the novel cholecystokinin agonist (pGlu-Gln)-CCK-8 in mouse models of obesity/diabetes

et al. 2012

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Aims/hypothesis Cholecystokinin (CCK) is a rapidly degraded gastrointestinal peptide that stimulates satiety and insulin secretion. We aimed to investigate the beneficial weight-lowering and metabolic effects of the novel N-terminally modified CCK analogue, (pGlu-Gln)-CCK-8. Methods The biological actions of (pGlu-Gln)-CCK-8 were comprehensively evaluated in pancreatic clonal BRIN BD11 cells and in vivo in high-fat-fed and ob/ob mice. Results (pGlu-Gln)-CCK-8 was completely resistant to enzymatic degradation and its satiating effects were significantly (p<0.05 to p<0.001) more potent than CCK-8. In BRIN-BD11 cells, (pGlu-Gln)-CCK-8 exhibited enhanced (p<0.01 to p<0.001) insulinotropic actions compared with CCK-8. When administered acutely to high-fat-fed or ob/ob mice, (pGlu-Gln)-CCK-8 improved glucose homeostasis. Sub-chronic twice daily injections of (pGlu-Gln)-CCK-8 in high-fat-fed mice for 28 days significantly decreased body weight (p<0.05 to p<0.001), accumulated food intake (p< 0.05 to p<0.001), non-fasting glucose (p<0.05) and triacylglycerol deposition in pancreatic (p<0.01), adipose (p< 0.05) and liver (p<0.001) tissue, and improved oral (p< 0.05) and i.p. (p<0.05) glucose tolerance and insulin sensitivity (p<0.001). Similar observations were noted in ob/ob mice given twice daily injections of (pGlu-Gln)-CCK-8. In addition, these beneficial effects were not reproduced by simple dietary restriction and were not associated with changes in energy expenditure. There was no evidence for development of tolerance to (pGlu-Gln)-CCK-8, and analysis of histology or blood-borne markers for pancreatic, liver and renal function in mice treated with (pGlu-Gln)-CCK-8 suggested little abnormal pathology. Conclusions/interpretation These studies emphasise the potential of (pGlu-Gln)-CCK-8 for the alleviation of obesity and insulin resistance.

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Section: Discussionmentioning

confidence: 87%

Beneficial effects of the novel cholecystokinin agonist (pGlu-Gln)-CCK-8 in mouse models of obesity/diabetes

et al. 2012

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“…The effects of these peptides to potentiate stimulated insulin secretion is blocked or reduced by the effect of norepinephrine to inhibit adenylyl cyclases. The importance of these peptides is emphasized by the fact that knowledge of the effects of GLP-1 has been transformed into therapy for type 2 diabetes by the development of long-acting GLP-1 analogs and slow-release formulations, and by inhibitors of dipeptidyl peptidase 4 (DPP-4), the enzyme that rapidly breaks down GLP-1 in the body (2,24).…”

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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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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“…diabetes [1][2][3]. The pancreatic islets are vital regulators of glucose homeostasis, and islet dysfunction is a primary cause of type 2 diabetes [4].…”

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confidence: 99%

CART is overexpressed in human type 2 diabetic islets and inhibits glucagon secretion and increases insulin secretion

et al. 2016

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CART is overexpressed in human type 2 diabetic islets and inhibits glucagon secretion and increases insulin secretionAbels, Mia; Riva, Matteo; Bennet, Hedvig; Ahlqvist, Emma; Dyachok, Oleg; Nagaraj, Vini; Shcherbina, Liliya; Fred, Rikard G.; Poon, Wenny; Sörhede-Winzell, Maria; Fadista, Joao; Lindqvist, Andreas; Kask, Lena; Sathanoori, Ramasri; Dekker-Nitert, Marloes; Kuhar, Michael J.; Ahrén, Bo; Wollheim, Claes B.; Hansson, Ola; Tengholm, Anders; Fex, Malin; Renström, Erik; Groop, Leif; Lyssenko, Valeriya; Wierup, Nils Link to publication Citation for published version (APA): Abels, M., Riva, M., Bennet, H., Ahlqvist, E., Dyachok, O., Nagaraj, V., ... Wierup, N. (2016). CART is overexpressed in human type 2 diabetic islets and inhibits glucagon secretion and increases insulin secretion. Diabetologia, 59(9), 1928Diabetologia, 59(9), -1937Diabetologia, 59(9), . https://doi.org/10.1007 General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. and if CART affects insulin-and glucagon secretion in vitro in humans and in vivo in mice.Methods CART expression was assessed in human type 2 diabetic and non-diabetic control pancreases and diabetic rodent models. Insulin-and glucagon secretion was examined in isolated islets and in vivo in mice. Ca 2+ oscillation patterns and exocytosis was studied in mouse islets.

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The future of incretin‐based therapy: novel avenues—novel targets

Cited by 55 publications

References 74 publications

Beneficial effects of the novel cholecystokinin agonist (pGlu-Gln)-CCK-8 in mouse models of obesity/diabetes

Beneficial effects of the novel cholecystokinin agonist (pGlu-Gln)-CCK-8 in mouse models of obesity/diabetes

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

CART is overexpressed in human type 2 diabetic islets and inhibits glucagon secretion and increases insulin secretion

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