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Hypoadiponectinemia and Gestational Diabetes

Award Number: R01DK113007
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: 12/01/2017
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Hypoadiponectinemia and Gestational Diabetes - SUMMARY Obesity is a key risk factor for Gestational diabetes mellitus (GDM). Due to the obesity epidemic, the prevalence of GDM has reached an alarming level. Most importantly, GDM has many adverse effects on pregnancy outcomes and postpartum maternal and offspring health. Therefore, it is urgent to elucidate the pathological mechanisms of GDM. Adiponectin is an adipocyte-secreted hormone that improves glucose and lipid metabolism. Hypoadiponectinemia before pregnancy and during the first and second trimesters strongly predicts GDM. Our studies from the previous funding period have demonstrated that adiponectin deficiency causes hyperglycemia and other metabolic abnormalities in pregnant mice. Interestingly, our studies revealed that adiponectin controls maternal metabolic adaptation by indirectly increasing β-cell proliferation and insulin production via placental lactogen (PL). However, decreased insulin secretion rates were still observed in size- matched islets from adiponectin gene knockout (Adipoq-/-) dams indicating additional mechanisms are involved besides β-cell proliferation. Extracellular vesicles (EVs) are well-conserved for intercellular and intra-organ communication. Pregnancy robustly increases EV levels in maternal circulation, partially attributed to placental- derived small EVs (psEVs). Consistent with other reports, our preliminary studies observed a stimulative effect of adiponectin on psEVs production. Importantly, psEVs enhanced glucose-induced insulin secretion of cultured islets. These data suggest that adiponectin, psEVs, and PL provide a pathway for fat/placenta/islet intra-organ crosstalk. During the last funding period, our study also identified a crucial role of pancreatic α-cells in maternal metabolic adaptation. Our study demonstrated that pregnancy increases glucagon-like peptide-1 (GLP-1) production from α-cells and then enhances maternal insulin secretion. A significant reduction of pancreatic GLP-1 was detected in Adipoq-/- dams. Notably, conditionally knocking out the adiponectin receptor 1 (AdipoR1) gene in α-cells significantly reduced GLP-1 production and glucose tolerance during pregnancy. Therefore, we hypothesize that adiponectin regulates islet adaptation to pregnancy through both fat/placenta/islet intra-organ crosstalk and intraislet paracrine. We will use genetic mouse models and human placenta and islets to 1) define the role of psEVs in adiponectin-regulated islet adaptation to pregnancy; 2) determine how adiponectin augments maternal insulin production through α-cells. The anticipated success of this project will have a significant impact on the research of maternal metabolic adaptation.


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 = $486,228 )
2026	2026	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	4/17/2026	NON-COMPETING CONTINUATION	$486,228
														Subtotal = $486,228

Issue Date FY: 2025 ( Subtotal = $486,228 )
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	4/29/2025	NON-COMPETING CONTINUATION	$486,228
														Subtotal = $486,228

Issue Date FY: 2024 ( Subtotal = $466,779 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	5/15/2024	NON-COMPETING CONTINUATION	$466,779
														Subtotal = $466,779

Issue Date FY: 2023 ( Subtotal = $486,228 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	8/9/2023	COMPETING CONTINUATION	$486,228
2023	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	6/6/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $486,228

Issue Date FY: 2021 ( Subtotal = $387,500 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	2/11/2021	NON-COMPETING CONTINUATION	$38,750
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	11/13/2020	NON-COMPETING CONTINUATION	$348,750
														Subtotal = $387,500

Issue Date FY: 2020 ( Subtotal = $387,500 )
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	11/27/2019	NON-COMPETING CONTINUATION	$348,750
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	2/19/2020	NON-COMPETING CONTINUATION	$38,750
														Subtotal = $387,500

Issue Date FY: 2019 ( Subtotal = $387,500 )
2019	2019	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	11/28/2018	NON-COMPETING CONTINUATION	$387,500
														Subtotal = $387,500

Issue Date FY: 2018 ( Subtotal = $387,500 )
2018	2018	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	11/27/2017	NEW	$387,500
														Subtotal = $387,500

Grand Total All Awards = $3,475,463

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Hypoadiponectinemia and Gestational Diabetes

Award Number: R01DK113007

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: 12/01/2017

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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