The effects on anterior pituitary hormone secretion of salmon calcitonin in healthy volunteers

Dual amylin and calcitonin receptor agonists (DACRAs) are novel candidates for treatment of T2D and obesity due to their beneficial effects on body weight, blood glucose and insulin sensitivity as well as improved food preference, at least short-term. DACRAs activate the receptors for a prolonged time period resulting in metabolic effects superior to those of amylin. Due to the prolonged receptor activation, different dosing intervals and hence less frequent receptor activation might change the efficacy of DACRA treatment in terms of weight loss and food preference. In this study, we compared daily dosing (q.d.) to dosing every other day (q.a.d.) with the aim of understanding the optimal balance between efficacy and tolerability. Obese and lean male Sprague-Dawley rats were treated with the DACRA, KBP-088, applying two different dosing intervals: 1.5 nmol/kg q.d. and 3 nmol/kg q.a.d, in order to assess the effects on body weight, food intake, glucose tolerance as well as food preference when given the choice between chow (13% fat) and high fat diet (60% fat). Treatment with KBP-088 induced a significant weight loss, reduction in adiposity, improvement in glucose control and altered food preference towards less calorie-dense food. KBP-088 dosed q.a.d. (3 nmol/kg) was superior to KBP-088 q.d. (1.5 nmol/kg) in terms of weight loss and improvement of food preference. The beneficial effects were evident in both lean and obese rats. Hence, dosing KBP-088 q.a.d. positively affects overall efficacy on metabolic parameters regardless of the lean/obese state, suggesting that less frequent dosing with KBP-088 could be feasible. Significance statement Here we show that food preference can be altered chronically towards less calorie-dense choices by pharmacological treatment. Further, pharmacological dosing regimens affects the efficacy differently, as dosing every other day improved body weight loss and alterations in food preference 4 This article has not been copyedited and formatted. The final version may differ from this version.

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Dose Frequency Optimization of the Dual Amylin and Calcitonin Receptor Agonist KBP-088: Long-Lasting Improvement in Food Preference and Body Weight Loss

Larsen

Sonne

Andreassen

et al. 2020

The Journal of Pharmacology and Experimental Therapeutics

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Expression of a novel receptor for the calcitonin peptide family and a salmon calcitonin-like peptide in the alpha-thyrotropin thyrotroph cell line.

et al. 1995

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We have previously shown an increased incidence of alpha-subunit-producing thyrotroph tumors after salmon calcitonin (sCT) injection into rats. However, it is not clear whether the effects of CT are direct or indirect. Our hypothesis was that for sCT to act directly, it must have a binding site on thyrotrophs. The alpha TSH cell line was used as a model for thyrotrophs. Receptor binding studies using alpha TSH membranes revealed a high affinity binding site for sCT [IC50 = 0.97 +/- 0.18 nM (n = 4); Kd = 5.45 +/- 0.43 nM (n = 3); binding capacity = 6.6 pmol/mg protein (n = 3)]. Rat CT did not compete with binding at this site. Receptor screening for other CT peptide family members revealed high specific binding for CT gene-related peptide (CGRP; IC50 = 0.25 +/- 0.08 nM; n = 3) and islet amyloid polypeptide (IC50 = 4.36 +/- 1.1 nM; n = 3). This together with the absence of rat CT binding excluded a conventional CT-binding site, and we propose a site similar to the CGRP subtype III receptor described in the rat nucleus accumbens. Guanosine 5'O-(3-thiotriphosphate) (GTP gamma S) (20 microM), reduced [125I]CGRP binding to 38% of maximal, indicating that this site is G-protein coupled. Immunocytochemically, all of the cells displayed intense sCT-like immunoreactivity, which was totally abolished by preabsorption of the antibody with sCT. The presence of this receptor supports the hypothesis that sCT mediates tumorigenesis via a direct pituitary action and, together with the coexistence of a sCT-like peptide in these cells, provides evidence for a possible autocrine role of this peptide in the control of thyrotroph function.

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Intranasal Salcatonin (Salmon Calcitonin)

Plosker¹,

McTavish²

1996

Drugs & Aging

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Osteoporosis is a common problem among postmenopausal women and is associated with significant morbidity, mortality and costs primarily resulting from osteoporotic fractures. Salcatonin (salmon calcitonin) inhibits osteoclastic bone resorption and is approximately 40 to 50 times more potent than human calcitonin. In most randomised trials in which intranasal salcatonin (usually 50 to 200 IU/day plus oral calcium supplements) was administered for 1 to 5 years to postmenopausal women for prevention of osteoporosis, bone mineral density or content of the lumbar spine increased by approximately 1 to 3% from baseline. In contrast, postmenopausal women receiving only oral calcium supplements typically had reductions in bone mineral density or content of about 3 to 6%. The difference between treatment groups was statistically significant in essentially all studies. Although changes in bone mineral density or content were broadly similar in studies of postmenopausal women with established osteoporosis to those in postmenopausal women receiving therapy for prevention of the disease, studies in women with established osteoporosis did not usually demonstrate statistically significant differences between treatment groups. Also in postmenopausal women with established osteoporosis, intranasal salcatonin reduced pain and/or analgesic consumption in some trials and, in a limited number of studies of relatively short duration (i.e. < or = 2 years), the incidence of osteoporotic fractures. A large multicentre 5-year study with adequate statistical power to confirm the effect of intranasal salcatonin on reducing osteoporotic fracture rates in postmenopausal women is currently under way. The intranasal formulation of salcatonin offers a more convenient and better tolerated alternative to the parenteral formulation of the drug which is administered by regular subcutaneous or intramuscular injections. Adverse events associated with the intranasal formulation are generally mild and transient, usually involving local reactions such as nasal discomfort, rhinorrhoea or rhinitis. Thus, for postmenopausal women unable or unwilling to tolerate long term hormone replacement therapy, intranasal salcatonin is an attractive alternative for the management of osteoporosis.

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The effects on anterior pituitary hormone secretion of salmon calcitonin in healthy volunteers

Cited by 4 publications

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Dose Frequency Optimization of the Dual Amylin and Calcitonin Receptor Agonist KBP-088: Long-Lasting Improvement in Food Preference and Body Weight Loss

Dose Frequency Optimization of the Dual Amylin and Calcitonin Receptor Agonist KBP-088: Long-Lasting Improvement in Food Preference and Body Weight Loss

Expression of a novel receptor for the calcitonin peptide family and a salmon calcitonin-like peptide in the alpha-thyrotropin thyrotroph cell line.

Intranasal Salcatonin (Salmon Calcitonin)

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