Decreased Hypothalamic Glucagon-Like Peptide-1 Receptor Expression in Type 2 Diabetes Patients

Dec 18, 2015The Journal of clinical endocrinology and metabolism

Lower Levels of Glucagon-Like Peptide-1 Receptors in the Brain's Hunger Control Area in Type 2 Diabetes Patients

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Abstract

GLP-1R mRNA was expressed in several hypothalamic nuclei, with decreased expression observed in T2DM patients compared to controls.

GLP-1 receptors are found in key regions of the human hypothalamus that regulate energy metabolism.
Specific hypothalamic nuclei studied include the paraventricular nucleus (PVN) and the infundibular nucleus (IFN).
Sporadic colocalization of GLP-1R was noted with neuropeptide Y, agouti-related peptide, and proopiomelanocortin transcripts in the IFN.
T2DM patients exhibited decreased GLP-1R mRNA expression in both the PVN and IFN compared to control subjects.
The reduction in GLP-1R expression in T2DM may be associated with altered feeding behavior and glucose regulation.

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CONTEXT: Glucagon-like peptide-1 (GLP-1) and GLP-1 receptor agonist treatment in type 2 diabetes (T2DM) reduce blood glucose and food intake. It has been suggested that these effects are partly mediated through central GLP-1 receptors (GLP-1Rs). The rodent and nonhuman primate hypothalamus show clear GLP-1R expression. However, a detailed description of GLP-1R expression in the human hypothalamus is lacking, and it is unknown whether this expression is altered in T2DM patients.

OBJECTIVE: The objective of the study was to investigate the GLP-1R distribution in the human postmortem hypothalamus and to determine whether hypothalamic GLP-1R expression is altered in T2DM patients.

DESIGN: We investigated the distribution of GLP-1R expression throughout the human hypothalamus by means of in situ hybridization. We also performed quantifications of GLP-1R mRNA expression in two hypothalamic nuclei (ie, the paraventricular nucleus [PVN] and infundibular nucleus [IFN]), comparing patients with T2DM and control subjects.

RESULTS: We found that GLP-1R mRNA was expressed in a number of hypothalamic nuclei including the PVN and the IFN, both involved in the regulation of energy metabolism. We observed sporadic colocalization of the GLP-1R in the IFN with the orgexigenic neuropeptide Y, agouti-related peptide, or proopiomelanocortin transcripts. Comparison of GLP-1R mRNA in the PVN and IFN between T2DM patients and control subjects revealed a decreased expression in T2DM patients.

CONCLUSIONS: Our studies show that GLP-1R is widely expressed throughout the human hypothalamus. The decreased expression of GLP-1R in the PVN and IFN of T2DM patients may be related to the dysregulation of feeding behavior and glucose homeostasis in T2DM.

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Decreased Hypothalamic Glucagon-Like Peptide-1 Receptor Expression in Type 2 Diabetes Patients

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