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Acutely Induced Insulin Resistance by Antipsychotic Medication in Healthy Volunteers: Impact of Skeletal Muscle Epigenomic and Proteomic Mechanisms

Award Number: K23DK118199
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

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PROJECT SUMMARY/ABSTRACT This K23 Patient-Oriented Mentored Research Award builds on the candidate’s expertise in pharmacology and epigenetics to provide the support necessary to complete training in responsible conduct of research and three other needs: 1) clinical research design and execution, 2) in vivo insulin sensitivity measurement, 3) design and execution proteomics experiments. This training will be accomplished through a combination of expert mentor- ship, didactic (short courses and certificate program) and hands-on experiences (human insulin sensitivity meas- urements and proteomics). The career development activities and research will be mentored by Dr. Zhengping Yi (Primary) and Dr. Renu Kowluru, and supplemented by a physician key collaborator (Dr. Berhane Seyoum), consultants and a yearly, external scientific advisory committee. The candidate’s transition to independence will be aided by an R01 grant writing program, presentation of findings at national conferences and publication of results in high-impact journals. The research plan will provide a platform for training and address a gap in the understanding of how atypical antipsychotics cause insulin resistance. The long-term goal of the proposed work is to establish and sustain an independent career focused on the impact of molecular factors and mechanisms in medication outcomes. The objective is to determine the causal relationship between the observed skeletal muscle epigenetic and protein changes in response to atypical antipsychotics, and the development of insulin resistance using a randomized, placebo-controlled, 7-day trial of olanzapine in healthy volunteers. The central hypothesis, based on preliminary data, is that obesity- and mental illness-independent atypical antipsychotic- induced insulin resistance is caused by DNA hypermethylation and altered protein abundance and regulation in the skeletal muscle. The rationale for this work is that it will establish the molecular mechanisms that underlie atypical antipsychotic-induced insulin resistance, while providing the training and expertise for a research pro- gram to develop precise, tractable targets for future interventions to alleviate epigenetic and/or protein-based dysregulations. The central hypothesis will be tested by obtaining baseline and endpoint basal and insulin-stim- ulated skeletal muscle samples from the 7-day trial in the following specific aims: 1) Identify the relevant genes affected by the hypermethylation seen with atypical antipsychotic-induced insulin resistance and 2) Determine the relevant protein changes underlying obesity-independent atypical antipsychotic-induced insulin resistance. The approach is innovative, in the candidate’s opinion, because it seeks to change the status quo of assessing molecular changes in psychiatric populations already using antipsychotics and because it seeks to assess these changes in a tissue-specific manner using powerful epigenomic and proteomic approaches. The proposed work is significant because it is expected to have a positive impact both on the field, and in positioning the candidate for independence. This work will provide the basis for targeting the molecular dysregulations caused by antipsy- chotics and preventing mortality from insulin resistance and diabetes.


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 = -$12,987 )
2024	2021	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	2/13/2024	NON-COMPETING CONTINUATION	-$12,987
														Subtotal = -$12,987

Issue Date FY: 2021 ( Subtotal = $168,120 )
2021	2021	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	7/20/2021	NON-COMPETING CONTINUATION	$168,120
														Subtotal = $168,120

Issue Date FY: 2020 ( Subtotal = $222,439 )
2020	2020	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	7/21/2020	NON-COMPETING CONTINUATION	$168,552
2020	2020	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	8/13/2020	SUPPLEMENT FOR EXPANSION	$53,887
														Subtotal = $222,439

Issue Date FY: 2019 ( Subtotal = $168,444 )
2019	2019	WAYNE STATE UNIVERSITY	5057 WOODWARD 13 FLOOR	DETROIT	MI	48202	WAYNE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	7/16/2019	NON-COMPETING CONTINUATION	$168,444
														Subtotal = $168,444

Issue Date FY: 2018 ( Subtotal = $170,052 )
2018	2018	WAYNE STATE UNIVERSITY	5057 WOODWARD 13 FLOOR	DETROIT	MI	48202	WAYNE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/24/2018	NEW	$170,052
														Subtotal = $170,052

Grand Total All Awards = $716,068

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Acutely Induced Insulin Resistance by Antipsychotic Medication in Healthy Volunteers: Impact of Skeletal Muscle Epigenomic and Proteomic Mechanisms

Award Number: K23DK118199

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

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