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      GLP-1 receptors exist in the parietal cortex, hypothalamus and medulla of human brains and the GLP-1 analogue liraglutide alters brain activity related to highly desirable food cues in individuals with diabetes: a crossover, randomised, placebo-controlled trial

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          Abstract

          Aims/hypothesis

          Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue that has been demonstrated to successfully treat diabetes and promote weight loss. The mechanisms by which liraglutide confers weight loss remain to be fully clarified. Thus, we investigated whether GLP-1 receptors are expressed in human brains and whether liraglutide administration affects neural responses to food cues in diabetic individuals (primary outcome).

          Methods

          In 22 consecutively studied human brains, expression of GLP-1 receptors in the hypothalamus, medulla oblongata and parietal cortex was examined using immunohistochemistry. In a randomised (assigned by the pharmacy using a randomisation enrollment table), placebo-controlled, double-blind, crossover trial, 21 individuals with type 2 diabetes (18 included in analysis due to lack or poor quality of data) were treated with placebo and liraglutide for a total of 17 days each (0.6 mg for 7 days, 1.2 mg for 7 days and 1.8 mg for 3 days). Participants were eligible if they had type 2 diabetes and were currently being treated with lifestyle changes or metformin. Participants, caregivers, people doing measurements and/or examinations, and people assessing the outcomes were blinded to the medication assignment. We studied metabolic changes as well as neurocognitive and neuroimaging (fMRI) of responses to food cues at the clinical research centre of Beth Israel Deaconess Medical Center.

          Results

          Immunohistochemical analysis revealed the presence of GLP-1 receptors on neurons in the human hypothalamus, medulla and parietal cortex. Liraglutide decreased activation of the parietal cortex in response to highly desirable (vs less desirable) food images ( p < 0.001; effect size: placebo 0.53 ± 0.24, liraglutide −0.47 ± 0.18). No significant adverse effects were noted. In a secondary analysis, we observed decreased activation in the insula and putamen, areas involved in the reward system. Furthermore, we showed that increased ratings of hunger and appetite correlated with increased brain activation in response to highly desirable food cues while on liraglutide, while ratings of nausea correlated with decreased brain activation.

          Conclusions/interpretation

          For the first time, we demonstrate the presence of GLP-1 receptors in human brains. We also observe that liraglutide alters brain activity related to highly desirable food cues. Our data point to a central mechanism contributing to, or underlying, the effects of liraglutide on metabolism and weight loss. Future studies will be needed to confirm and extend these findings in larger samples of diabetic individuals and/or with the higher doses of liraglutide (3 mg) recently approved for obesity.

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          Most cited references29

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          Lifetime risk for diabetes mellitus in the United States.

          Although diabetes mellitus is one of the most prevalent and costly chronic diseases in the United States, no estimates have been published of individuals' average lifetime risk of developing diabetes. To estimate age-, sex-, and race/ethnicity-specific lifetime risk of diabetes in the cohort born in 2000 in the United States. Data from the National Health Interview Survey (1984-2000) were used to estimate age-, sex-, and race/ethnicity-specific prevalence and incidence in 2000. US Census Bureau data and data from a previous study of diabetes as a cause of death were used to estimate age-, sex-, and race/ethnicity-specific mortality rates for diabetic and nondiabetic populations. Residual (remaining) lifetime risk of diabetes (from birth to 80 years in 1-year intervals), duration with diabetes, and life-years and quality-adjusted life-years lost from diabetes. The estimated lifetime risk of developing diabetes for individuals born in 2000 is 32.8% for males and 38.5% for females. Females have higher residual lifetime risks at all ages. The highest estimated lifetime risk for diabetes is among Hispanics (males, 45.4% and females, 52.5%). Individuals diagnosed as having diabetes have large reductions in life expectancy. For example, we estimate that if an individual is diagnosed at age 40 years, men will lose 11.6 life-years and 18.6 quality-adjusted life-years and women will lose 14.3 life-years and 22.0 quality-adjusted life-years. For individuals born in the United States in 2000, the lifetime probability of being diagnosed with diabetes mellitus is substantial. Primary prevention of diabetes and its complications are important public health priorities.
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            When the brain loses its self: prefrontal inactivation during sensorimotor processing.

            A common theme in theories of subjective awareness poses a self-related "observer" function, or a homunculus, as a critical element without which awareness can not emerge. Here, we examined this question using fMRI. In our study, we compared brain activity patterns produced by a demanding sensory categorization paradigm to those engaged during self-reflective introspection, using similar sensory stimuli. Our results show a complete segregation between the two patterns of activity. Furthermore, regions that showed enhanced activity during introspection underwent a robust inhibition during the demanding perceptual task. The results support the notion that self-related processes are not necessarily engaged during sensory perception and can be actually suppressed.
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              Emotional arousal and activation of the visual cortex: an fMRI analysis.

              Functional activity in the visual cortex was assessed using functional magnetic resonance imaging technology while participants viewed a series of pleasant, neutral, or unpleasant pictures. Coronal images at four different locations in the occipital cortex were acquired during each of eight 12-s picture presentation periods (on) and 12-s interpicture interval (off). The extent of functional activation was larger in the right than the left hemisphere and larger in the occipital than in the occipitoparietal regions during processing of all picture contents compared with the interpicture intervals. More importantly, functional activity was significantly greater in all sampled brain regions when processing emotional (pleasant or unpleasant) pictures than when processing neutral stimuli. In Experiment 2, a hypothesis that these differences were an artifact of differential eye movements was ruled out. Whereas both emotional and neutral pictures produced activity centered on the calcarine fissure (Area 17), only emotional pictures also produced sizable clusters bilaterally in the occipital gyrus, in the right fusiform gyrus, and in the right inferior and superior parietal lobules.
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                Author and article information

                Journal
                0006777
                3399
                Diabetologia
                Diabetologia
                Diabetologia
                0012-186X
                1432-0428
                6 February 2016
                01 February 2016
                May 2016
                01 May 2017
                : 59
                : 5
                : 954-965
                Affiliations
                [1 ] Division of Endocrinology, Beth Israel Deaconess Medical Center/Harvard Medical School, 330 Brookline Ave, Stoneman 820, Boston, MA 02215, USA
                [2 ] Department of Pathology, St Savvas Anticancer-Oncology Hospital, Athens, Greece
                [3 ] Total Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
                [4 ] First Department of Pathology, University of Athens, Medical School, Athens, Greece
                Author notes
                Corresponding author O. M. Farr, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Stoneman 820, Boston, MA 02215, USA, ofarr@ 123456bidmc.harvard.edu
                Article
                PMC4826792 PMC4826792 4826792 nihpa756722
                10.1007/s00125-016-3874-y
                4826792
                26831302
                a89a3f70-3e9d-4d55-b353-6ec4c0f68110
                History
                Categories
                Article

                Immunohistochemistry,Brain,Diabetes,fMRI,GLP-1,Liraglutide,MRI
                Immunohistochemistry, Brain, Diabetes, fMRI, GLP-1, Liraglutide, MRI

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