Short-term administration of the GLP-1 analog liraglutide decreases circulating leptin and increases GIP levels and these changes are associated with alterations in CNS responses to food cues: A randomized, placebo-controlled, crossover study.
BACKGROUND
GLP-1 agonists, including liraglutide, have emerged as effective therapies for type 2 diabetes (DM) and obesity. Here, we attempted to delineate how liraglutide, at doses approved for DM, may impact circulating hormones influencing energy homeostasis in diabetics.


METHODS
Using a randomized, placebo-controlled, double-blind, cross-over trial of 20 patients with type 2 diabetes, we examined the effects of liraglutide as compared to placebo on fasting levels of circulating hormones important to energy homeostasis, including leptin, ghrelin, PYY, and GIP. After 17days (0.6mg for 7days, 1.2mg for 7days and 1.8mg for 3days) of treatment, we also studied changes in fMRI responses to food cues.


RESULTS
By design, to avoid any confounding by weight changes, subjects were studied for 17days, i.e. before body weight changed. Participants on liraglutide had significantly increased GLP-1 levels (p<0.001), decreased percent change in leptin levels (p<0.01) and increased GIP levels (p<0.03) in comparison to placebo treated subjects. Whole brain regressions of functional activity in response to food cues reveal that increased GIP levels were associated with deactivation of the attention- and reward-related insula. Decreases in leptin levels were associated with activations in the reward-related midbrain, precuneus, and dorsolateral prefrontal cortex (DLPFC), and sensorimotor-related motor cortex and with deactivations in the attention-related parietal cortex and the cognitive control-related thalamus and pre-SMA.


CONCLUSIONS
We demonstrate herein short-term changes to circulating levels of GIP and leptin in response to GLP-1 agonist liraglutide therapy. These findings suggest that liraglutide may alter the circulating levels of hormones important in energy homeostasis that, in turn, influence CNS perception of food cues. This could possibly lead to compensatory changes in energy homeostasis that could over time limit the efficacy of liraglutide to decrease body weight. These novel findings, which, pointing to the potential advantages of combination therapies, may have therapeutic implications, will need to be confirmed by larger and longer-term trials.
Division of Endocrinology, Beth-Israel Deaconess Medical Center/Harvard Medical School, Boston, MA 02215. Electronic address: ofarr@bidmc.harvard.edu.
Olivia M
OM
Farr
Division of Endocrinology, Beth-Israel Deaconess Medical Center/Harvard Medical School, Boston, MA 02215.
Michael A
MA
Tsoukas
Division of Endocrinology, Beth-Israel Deaconess Medical Center/Harvard Medical School, Boston, MA 02215.
Georgios
G
Triantafyllou
Division of Endocrinology, Beth-Israel Deaconess Medical Center/Harvard Medical School, Boston, MA 02215.
Fadime
F
Dincer
Division of Endocrinology, Beth-Israel Deaconess Medical Center/Harvard Medical School, Boston, MA 02215.
Andreas
A
Filippaios
Division of Endocrinology, Beth-Israel Deaconess Medical Center/Harvard Medical School, Boston, MA 02215.
Byung-Joon
BJ
Ko
Division of Endocrinology, Beth-Israel Deaconess Medical Center/Harvard Medical School, Boston, MA 02215.
Christos S
CS
Mantzoros
D001288:Attention / Q000502:physiology*; D001921:Brain / Q000000981:diagnostic imaging*; D018592:Cross-Over Studies; D003463:Cues; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000000981:diagnostic imaging; D004311:Double-Blind Method; D005260:Female; D059907:Functional Neuroimaging; D005749:Gastric Inhibitory Polypeptide / Q000097:blood*; D054439:Ghrelin / Q000097:blood; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007091:Image Processing, Computer-Assisted; D020738:Leptin / Q000097:blood*; D000069450:Liraglutide / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D019894:Peptide YY / Q000378:metabolism; D012201:Reward
D054439:Ghrelin; D007004:Hypoglycemic Agents; D020738:Leptin; D019894:Peptide YY; D005749:Gastric Inhibitory Polypeptide; D000069450:Liraglutide
Diabetes; GLP-1; Leptin; Liraglutide; Obesity; fMRI