Oral salmon calcitonin enhances insulin action and glucose metabolism in diet-induced obese streptozotocin-diabetic rats

Feigh, Michael; Hjuler, Sara Toftegaard; Andreassen, Kim Vietz; Gydesen, Sofie; Ottosen, Ida; Henriksen, Jan Erik; Beck‐Nielsen, Henning; Christiansen, Claus; Karsdal, Morten A.; Henriksen, Kim

doi:10.1016/j.ejphar.2014.05.016

Cited by 16 publications

(59 citation statements)

References 27 publications

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“…findings clearly indicate an improvement in insulin sensitivity which was also confirmed by HOMA-IR and tested directly in the IPITTFeigh et al, 2014).…”

supporting

confidence: 68%

KBP-042 improves bodyweight and glucose homeostasis with indices of increased insulin sensitivity irrespective of route of administration

Hjuler¹,

Andreassen²,

Gydesen³

et al. 2015

European Journal of Pharmacology

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“…findings clearly indicate an improvement in insulin sensitivity which was also confirmed by HOMA-IR and tested directly in the IPITTFeigh et al, 2014).…”

supporting

confidence: 68%

KBP-042 improves bodyweight and glucose homeostasis with indices of increased insulin sensitivity irrespective of route of administration

Hjuler¹,

Andreassen²,

Gydesen³

et al. 2015

European Journal of Pharmacology

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“…Given its clinical usage, it is unsurprising that salmon CT has been explored as a treatment for other disorders. Numerous studies have suggested that salmon CT could treat metabolic disorders by lowering body weight, elevating energy expenditure, limiting food intake and improving glucose handling in rats (Lutz et al, ; Eiden et al, ; Wielinga et al, ; Feigh et al, ; ). Recently, a number of CT mimetics, known by ‘KBP’ codes, for example, KBP‐042, KBP‐088 and KBP‐089, have been described (Patent WO 2015/071229).…”

Section: Developments With Agonistsmentioning

confidence: 99%

Update on the pharmacology of calcitonin/CGRP family of peptides: IUPHAR Review 25

Hay

Garelja

Poyner

et al. 2017

British J Pharmacology

295

441

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The calcitonin/CGRP family of peptides includes calcitonin, α and β CGRP, amylin, adrenomedullin (AM) and adrenomedullin 2/intermedin (AM2/IMD). Their receptors consist of one of two GPCRs, the calcitonin receptor (CTR) or the calcitonin receptor-like receptor (CLR). Further diversity arises from heterodimerization of these GPCRs with one of three receptor activity-modifying proteins (RAMPs). This gives the CGRP receptor (CLR/RAMP1), the AM and AM receptors (CLR/RAMP2 or RAMP3) and the AMY AMY and AMY receptors (CTR/RAMPs1-3 complexes, respectively). Apart from the CGRP receptor, there are only peptide antagonists widely available for these receptors, and these have limited selectivity, thus defining the function of each receptor in vivo remains challenging. Further challenges arise from the probable co-expression of CTR with the CTR/RAMP complexes and species-dependent splice variants of the CTR (CT and CT ). Furthermore, the AMY receptor is activated equally well by both amylin and CGRP, and the preferred receptor for AM2/IMD has been unclear. However, there are clear therapeutic rationales for developing agents against the various receptors for these peptides. For example, many agents targeting the CGRP system are in clinical trials, and pramlintide, an amylin analogue, is an approved therapy for insulin-requiring diabetes. This review provides an update on the pharmacology of the calcitonin family of peptides by members of the corresponding subcommittee of the International Union of Basic and Clinical Pharmacology and colleagues.

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“…In this study we utilized our recently established mouse model lacking the CTR [23], which does not exhibit the previously reported embryonic lethality of that respective CTR-deficiency model [33,34]. While several recent studies relying on pharmacological approaches demonstrated a beneficial effect of oral salmon CT on body weight, fasting glycaemia and glucose tolerance in rats [12,13,14], our results confirm a potential physiological role of CT in glucose metabolism, as obese CTR-deficient animals displayed features of enhanced NASH, impaired glucose tolerance and hyperinsulinemia in vivo . However, while apparently CTR-deficiency did not influence the rate of body weight gain, a more prominent finding was dyslipidemia due to increased cholesterol and triglyceride concentrations, supporting the concept that signaling through the CTR regulates plasma lipid homeostasis independent of weight gain in DIO.…”

Section: Discussionmentioning

confidence: 99%

“…Whereas the CTR mediates the biological effects of CT and Amylin (AMY), a peptide co-secreted with insulin and involved in glucose handling, αCGRP and PCT have been shown to exert their biological effects through the CTRL, displaying high levels of expression in the lung and the gastrointestinal tract [10,11]. Despite their pleiotropic effects within the organism, Calca -derived peptides have recently been linked to glucose, fat and lipid metabolism: First, salmon CT, exhibiting a much higher pharmacologic potency than mammalian CT, was reported to decrease cholesterol and triglyceride levels, improve energy and glucose homeostasis and attenuate diabetic progression in obese rats [12,13,14]. Second, αCGRP-deficient mice were reported to display increased energy expenditure [15], which is supported by clinical findings showing circulating αCGRP levels to positively correlate with obesity [16,17].…”

Section: Introductionmentioning

confidence: 99%

Differential effects of Calca-derived peptides in male mice with diet-induced obesity

et al. 2017

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Key metabolic hormones, such as insulin, leptin, and adiponectin, have been studied extensively in obesity, however the pathophysiologic relevance of the calcitonin family of peptides remains unclear. This family includes calcitonin (CT), its precursor procalcitonin (PCT), and alpha calcitonin-gene related peptide (αCGRP), which are all encoded by the gene Calca. Here, we studied the role of Calca-derived peptides in diet-induced obesity (DIO) by challenging Calcr−/− (encoding the calcitonin receptor, CTR), Calca−/−, and αCGRP−/− mice and their respective littermates with high-fat diet (HFD) feeding for 16 weeks. HFD-induced pathologies were assessed by glucose tolerance, plasma cytokine and lipid markers, expression studies and histology. We found that DIO in mice lacking the CTR resulted in impaired glucose tolerance, features of enhanced nonalcoholic steatohepatitis (NASH) and adipose tissue inflammation compared to wildtype littermates. Furthermore, CTR-deficient mice were characterized by dyslipidemia and elevated HDL levels. In contrast, mice lacking Calca were protected from DIO, NASH and adipose tissue inflammation, and displayed improved glucose tolerance. Mice exclusively lacking αCGRP displayed a significantly less improved DIO phenotype compared to Calca-deficient mice. In summary, we demonstrate that the CT/CTR axis is involved in regulating plasma cholesterol levels while Calca, presumably through PCT, seems to have a detrimental effect in the context of metabolic disease. Our study provides the first comparative analyses of the roles of Calca-derived peptides and the CTR in metabolic disease.

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Oral salmon calcitonin enhances insulin action and glucose metabolism in diet-induced obese streptozotocin-diabetic rats

Cited by 16 publications

References 27 publications

KBP-042 improves bodyweight and glucose homeostasis with indices of increased insulin sensitivity irrespective of route of administration

KBP-042 improves bodyweight and glucose homeostasis with indices of increased insulin sensitivity irrespective of route of administration

Update on the pharmacology of calcitonin/CGRP family of peptides: IUPHAR Review 25

Differential effects of Calca-derived peptides in male mice with diet-induced obesity

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