Role of hypothalamic Prolyl endopeptidase in glucose homeostasis
General Research Subject: Type 2 Diabetes
Focus: Integrated Physiology\Regulation of Food Intake, Integrated Physiology\Regulation of Glucose Kinetics, Other
Type of Grant: Basic Science
Project Start Date: July 1, 2011
Project End Date: June 30, 2014
We have discovered a new role for a protein called Prolyl endopeptidase (PREP) in the regulation of glucose metabolism. We believe that the lack of this protein in the hypothalamus, the brain center for glucose regulation, induced an increase of glucose in the blood (diabetes) possibly due to its role in regulating insulin secretion in the pancreas from the hypothalamus. Our studies will shed light on the novel role of this protein as critical player in the regulation of glucose homeostasis and will offer previously unsuspected strategies to combat diabetes and its complications.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
My research project aims to study the role of hypothalamic Propyl endopeptidase in glucose homeostasis. We have discovered that brain Prolyl endopeptidase (Prep) plays an important role in sensing changes in glucose levels and in regulating glucose homeostasis and rebound feeding. Prep cleaves short peptides containing an internal proline residue, including alpha-melanocyte stimulating hormone (alpha-MSH), a potent hypothalamic promoter of satiety. Analysis of Prep expression in the hypothalamus showed that Prep-expressing neurons are mainly localized in the hypothalamic ventromedial nucleus (VMN). Knockdown of Prep (Prepgt/gt) in mice diminished glucose-induced neuronal responses in the VMN, suppressed hypothalamic vesicular glutamate transporter 2 mRNA expression levels and decreased excitatory postsynaptic currents of POMC neurons. In agreement with an altered neuronal substrate of glucose homeostasis regulation, Prep knockdown, Prepgt/gt mice exhibited glucose intolerance, insulin sensitivity, decreased fasting insulin levels, decreased fasting POMC mRNA and peptide levels and increased rebound feeding compared to wild type controls. These observations unmasked the importance of central Prep in the hypothalamic regulation of glucose metabolism and rebound feeding most likely by affecting the excitability of POMC neurons. Thus, by further deciphering the molecular underpinning of Prep’s involvement in the modulation of peripheral glucose metabolism will shed light on a novel mechanism in the regulation of glucose homeostasis and will offer a previously unsuspected pharmacological target to combat diabetes and its complications.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
To study the mechanism by which the brain senses changes in glucose levels in the circulation is of great importance for understanding metabolic diseases such as diabetes, and to develop drugs that may help to prevent or cure these disorders.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
From a very personal point of view, diabetes research is of great importance because of the lives affected by this disorder in my family. The possibility to do something that could help to prevent or cure diabetes and improve the lives of diabetic patients is my driving force to continue to pursue research in this field.
In what direction do you see the future of diabetes research going?
1) To understand how the brain senses changes in the levels of nutrients such as glucose.
2) To understand the molecular mechanisms responsible for insulin and leptin resistance.
3) To understand the mechanism by which the brain controls peripheral organs such as pancreas, liver and muscle.
4) The relationship between diabetes and aging.
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