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Neural Bases of Cephalic Phase Endocrine Responses

Award Number: R01DK118910
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/10/2019
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Neural Bases of Cephalic Phase Endocrine Responses - PROJECT SUMMARY Cephalic phase responses (CPRs) are autonomic and endocrine events triggered by stimulation of ‘head’ receptors, especially those of the gustatory system. These are widely considered as the first preparatory steps required for the optimal digestion, absorption, and utilization of nutrients. Although postoral mechanisms are clearly essential for this purpose, the significance of oral stimulation during eating for maintaining normal metabolic function should not be underestimated. One of the most extensively studied CPRs is the early rise in insulin that is stimulated by oral glucose. However, the insulin CPR literature is uneven, most likely because of methodological limitations and variations in blood sampling sites. To clarify how CPRs and their underlying neural mechanisms are organized we have developed a unique and sensitive rat preparation. It combines in a single animal intraoral and intragastric cannulae that precisely deliver test solutions, with a hepatic portal vein (HPV) sampling catheter. We have used this preparation in male rats to find strikingly early rises in HPV insulin and GLP-1 levels that are significantly greater after oral compared to gastric delivery of glucose. Responses to fructose or water showed no such oral/gastric differences. These insulin and GLP-1 increases were robust and rapid, reaching peak levels within 3 min of orally delivering 180 mg of glucose in less than 1 min. This is the first report of significant GLP-1 release triggered by oral stimulation with glucose. Impressively, its peak is substantially greater than that seen after a normal meal. Considering the rapidity of both the GLP-1 CPR and its subsequent degradation in blood, one hypothesis that we will test is whether oral glucose-driven GLP-1 release from enteroendocrine cells acts as an incretin that mediates the insulin CPR neurally through a vago-vagal reflex. Our design employs two experimental approaches organized in three Specific Aims to reveal the neural mechanisms and circuits responsible for these GLP-1 and insulin CPRs. One approach uses explicitly controlled intraoral or intragastric infusions of glucose, fructose, and control taste solutions followed by HPV measurements of plasma GLP-1, insulin, and glucose responses. It will test whether insulin and GLP-1 CPRs can be conditioned, and whether CPRs are recapitulated in females. The other approach will use transneuronal viral tracing techniques combined with state-of-the-art neuroinformatics methods to map the neural pathways through which gustatory signals control pancreatic and enteroendocrine secretions. Furthermore, both approaches use functional nerve transections to define the organization of the neural pathways driving GLP-1 and insulin CPRs. The project is a scientific alliance of highly experienced investigators who have complementary expertise. Its outcomes will provide new insights into the neural control of insulin and GLP-1 secretion. It will also define mechanisms that could be therapeutically targeted to facilitate treatment strategies for patients requiring enteral or parenteral nutrition, as well as promoting healthier eating and nutrient assimilation in the general population.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	8/6/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $595,857 )
2023	2023	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	8/21/2023	NON-COMPETING CONTINUATION	$595,857
														Subtotal = $595,857

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	7/18/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $607,797 )
2021	2021	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	7/6/2021	NON-COMPETING CONTINUATION	$607,797
														Subtotal = $607,797

Issue Date FY: 2020 ( Subtotal = $617,105 )
2020	2020	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	7/16/2020	NON-COMPETING CONTINUATION	$617,105
														Subtotal = $617,105

Issue Date FY: 2019 ( Subtotal = $643,900 )
2019	2019	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	6/11/2019	NEW	$643,900
														Subtotal = $643,900

Grand Total All Awards = $2,464,659

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Neural Bases of Cephalic Phase Endocrine Responses

Award Number: R01DK118910

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/10/2019

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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