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Insulin and nutrient actions in the FGR fetal liver

Award Number: R01DK108910
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: 01/17/2017
PERIOD OF PERFORMANCE END DATE: 11/30/2029

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Insulin and nutrient actions in the FGR fetal liver - PROJECT SUMMARY Individuals born with fetal growth restriction (FGR) have dysregulated hepatic glucose production (HGP) as neonates, and higher rates of hepatic insulin resistance and steatotic liver disease with higher hepatic fibrosis scores as children and adults. We discovered, using the same sheep models as in the current proposal, that the FGR fetus has an early activation of HGP and hepatic insulin resistance9, hallmark features of type 2 diabetes (T2D). We also discovered that fetal hypoxemia (HOX model) recapitulates hepatic insulin resistance. Our compelling new data demonstrates hepatic collagen deposition, a sign of fibrosis, in FGR and HOX fetal sheep. Thus, in utero hypoxemia during FGR injures the fetal liver initiating both hepatic insulin resistance and fibrosis. How hypoxemia produces these effects, and the cell-specific mechanisms remain poorly understood, thus limiting our ability to prevent fibrotic liver disease and T2D risk in the former FGR individual. The goal of this renewal is to demonstrate that lactate is more than a metabolic substrate and byproduct of hypoxemia and exerts regulatory control initiating hepatic insulin resistance and fibrosis in the FGR fetal liver. Lactate is abundant in normal mammalian fetuses with higher concentrations during FGR and hypoxemia. Our FGR and HOX fetal sheep also have increased systemic and hepatic lactate (i.e., lactate load). In addition to lactate's role as a precursor for HGP and oxidative substrate in adults and fetuses, emerging studies in adults and cancer cells demonstrate that lactate is a metabolite signal and driver of epigenomic regulation. Given these and our recent data, we propose a mechanism whereby increased lactate production and decreased lactate oxidation increase “lactate load” and enable lactate to be used for HGP; however, this redirection in lactate flux produces energetic and redox stress. In support, FGR and HOX fetal livers have JNK-FOXO1 stress kinase activation and oxidative stress, a major cause of insulin resistance and fibrosis in adults. Moreover, in FGR and HOX fetal sheep, collagen deposition co-localizes with higher lactate entering hepatic periportal regions. Thus, lactate may activate periportal hepatic stellate cells into collagen-producing cells. These findings form the premise for our central hypothesis that increased hepatic lactate load via its metabolic, signaling, and epigenomic effects initiates insulin resistance in hepatocytes and fibrogenic activation in stellate cells with intrinsic programming. Studies in Aim 1 will use our FGR fetal sheep model to demonstrate how lactate is metabolized in the normal and FGR fetal liver. We also will identify novel spatial and cell-specific intrinsic mechanisms to understand how fibrosis and IR develop in the FGR fetus. We propose that lactate-associated metabolism is largely responsible for these effects in the FGR liver. In Aims 2 and 3, we will directly test the role of lactate on insulin resistance and fibrosis by experimentally increasing or decreasing lactate load in fetal sheep. We will also perform in vitro studies using isolated primary fetal hepatocytes and stellate cells to test mechanisms and discern the direct versus indirect effects of lactate. Overall, our studies will delineate the physiologic and hepatocellular effects of lactate as a metabolite and regulatory signal in the fetal liver.


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: 2026 ( Subtotal = $669,407 )
2026	2026	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	12/3/2025	NON-COMPETING CONTINUATION	$669,407
														Subtotal = $669,407

Issue Date FY: 2025 ( Subtotal = $708,887 )
2025	2025	THE REGENTS OF THE UNIV. OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	12/18/2024	COMPETING CONTINUATION	$708,887
														Subtotal = $708,887

Issue Date FY: 2023 ( Subtotal = -$1,394 )
2023	2021	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	9/28/2023	NON-COMPETING CONTINUATION	-$1,394
														Subtotal = -$1,394

Issue Date FY: 2021 ( Subtotal = $577,321 )
2021	2021	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	2/12/2021	NON-COMPETING CONTINUATION	$57,732
2021	2021	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	12/15/2020	NON-COMPETING CONTINUATION	$519,589
														Subtotal = $577,321

Issue Date FY: 2020 ( Subtotal = $577,321 )
2020	2020	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	3/10/2020	NON-COMPETING CONTINUATION	$57,732
2020	2020	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	12/31/2019	NON-COMPETING CONTINUATION	$519,589
														Subtotal = $577,321

Issue Date FY: 2019 ( Subtotal = $577,321 )
2019	2019	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	1/4/2019	NON-COMPETING CONTINUATION	$577,321
														Subtotal = $577,321

Issue Date FY: 2018 ( Subtotal = $583,839 )
2018	2018	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	1/1/2018	NON-COMPETING CONTINUATION	$525,455
2018	2018	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	7/26/2018	NON-COMPETING CONTINUATION	$58,384
														Subtotal = $583,839

Issue Date FY: 2017 ( Subtotal = $584,678 )
2017	2017	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	1/16/2017	NEW	$584,678
														Subtotal = $584,678

Grand Total All Awards = $4,277,380

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Insulin and nutrient actions in the FGR fetal liver

Award Number: R01DK108910

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: 01/17/2017

PERIOD OF PERFORMANCE END DATE: 11/30/2029

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