|
|
|
Cellular models |
|
|
Crespel et al. [32] |
Glucagon, GLP-1 (7–36), and exendin (9–39) |
Rat CA-77 C-cell line |
cAMP production and calcitonin secretion |
GLP-1 (7–36) and glucagon dose dependently stimulated cAMP production and calcitonin secretion. Exendin (9–39) abolished a further increase in cAMP formation at glucagon concentration over 10 nM and partially suppressed glucagon-induced calcitonin secretion. |
|
Lamari et al. [31] |
GLP-1 (7–37), and exendin (9–39) |
Rat CA-77 C-cell line |
cAMP production, calcitonin mRNA levels, and calcitonin secretion |
GLP-1 (7–37) increased cAMP formation in a dose-dependent manner. Exedin (9–39), an antagonist of GLP-1 receptor, blunted the stimulation of cAMP production induced by GLP-1 (7–37). Gene expression and peptide secretion of calcitonin were increased after incubation of CA-77 cells with GLP-1 (7–37). |
|
Knudsen et al. [11] |
Liraglutide, exenatide, and GLP-1 (7–37) |
Human TT C-cell line, rat MTC 6–23 C-cell line, and rat CA-77 C-cell line |
GLP-1 receptor mRNA and protein expression; calcitonin release after GLP-1 receptor agonists |
Native GLP-1, liraglutide, and exenatide all stimulate calcitonin gene expression and calcitonin secretion via the GLP-1 receptor in a dose-dependent manner in rat C cells. The human TT cells express few GLP-1 receptors compared with rat MTC 6–23 and CA-77 and show a lack of functional response to GLP-1 and GLP-1 receptor agonists. |
|
|
|
|
Animal experiments |
|
|
(I) Rodents |
|
|
|
|
Knudsen et al. [11] |
Liraglutide versus vehicle control |
Sprague Dawley rats aged 6-7 weeks and CD-1 mice at the age of 5–10 weeks |
Plasma calcitonin and pathological examination to thyroid gland sections after dosing with liraglutide |
Calcitonin levels increase with time and dose with 104-week repeated dosing of liraglutide. The incidences of both C-cell hyperplasia and C-cell tumor formation at 104 weeks were increased in a dose-dependent manner and reached statistical significance. |
|
Madsen et al. [33] |
Liraglutide, exenatide, and vehicle control |
CD-1 wild-type mice aged 5-6 weeks and GLP-1-receptor knockout mice at the age of 4-5 weeks |
Plasma calcitonin, pathological examination to thyroid tissue sections, and immunohistochemical staining for phosphoproteins after 13-week treatment with liraglutide or exenatide |
GLP-1 agonists cause calcitonin release and C-cell hyperplasia in wild-type mice via a GLP-1-receptor-dependent mechanism. GLP-1 activates the mammalian target of rapamycin (mTOR) pathway by stimulating the production of cAMP. Activation of mTOR in turn results in downstream phosphorylation of ribosome S6. Liraglutide-induced C-cell hyperplasia in mice is not associated with RET activation. |
|
(II) Primates |
|
|
|
|
Knudsen et al. [11] |
Liraglutide versus vehicle control |
Cynomolgus monkeys aged 1-2 years |
Plasma calcitonin and pathological analysis to thyroid gland sections after dosing with liraglutide |
No increase in plasma calcitonin was seen in cynomolgus monkeys receiving a single dose of liraglutide or during 87-week daily dose. There was also no change in the thyroid gland sections, relative C-cell fraction of the thyroid gland, and proliferative index in the C cells after liraglutide for 52 weeks. |
|
|
|
|
Human studies |
|
|
Gier et al. [10] |
— |
Human thyroid glands |
Expression of GLP-1 receptors in tissue samples with C-cell abnormalities, papillary thyroid cancer, and normal thyroid |
GLP-1 receptor immunoreactivities were detected in 33%, >90%, and 18% of patients with normal C cells, C-cell pathologies, and PTC lesions, respectively. |
|
Hegedüs et al. [34] |
Liraglutide versus active comparators and placebo |
Nine clinical trials of 20–104-week duration |
Geometric mean levels of serum calcitonin and outlier analysis |
There was no significant difference in mean calcitonin levels between liraglutide and control groups. The proportions of subjects with calcitonin levels shifting to a higher category or above a clinically relevant cut-off value of 20 pg/mL were low and did not differ between treatment groups. |
|
Elashoff et al. [36] |
Exenatide versus rosiglitazone |
Adverse effect reporting system |
Overall thyroid cancer |
Odds ratio for thyroid cancer was 4.73; P = 4 × 10−3
|