Wednesday, December 4, 2024 12/4/2024

Mechanisms of Insulin Resistance in Man

Award Number: R01DK029953
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY Mechanisms of Insulin Resistance in Man Almost ~ 100 million people in the US have type 2 diabetes (T2D) or pre-diabetes that accounts for 1 in 5 health care dollars. The prevalence of these metabolic disorders is increasing exponentially. Understanding the pathogenesis of and developing better and rational therapies based on the causal factors for these conditions is a very high priority. We have previously evaluated nighttime regulation of glucose and effects of counter- regulatory hormones (glucagon, cortisol) on nocturnal endogenous glucose production (EGP) in T2D. We observed that rates of EGP remained high all night (at 1AM vs. 4 AM vs. 7 AM) in T2D. However, we did not determine whether the higher nighttime EGP was due to higher EGP rates all day i.e. post breakfast, post lunch and post dinner. We also did not determine the daytime temporal profiles of EGP, insulin action and secretion. Therefore, the mechanism of daytime regulation and diurnal pattern of EGP in T2D remains poorly understood i.e. when do rates of EGP increase - are they higher throughout the day as they are during the night; why is EGP higher – is it due to abnormalities in hepatic glycogen content? How can we control the higher rates of EGP? We have designed a set of experiments to test hypotheses related to various specific aims that address these fundamental questions. In Specific Aim 1A we will determine the diurnal pattern of EGP using a stable label triple tracer approach and in Specific aim 1B concurrently estimate insulin action and beta cell responsivity during the day in T2D. We will study the role of hepatic glycogen on nocturnal EGP in T2D with glycogen loading vs. non-glycogen loading using NMR to measure hepatic glycogen content and deuterium labeled water to measure gluconeogenesis as part of Specific Aim 2. We have designed a mechanistic clinical trial in Specific Aim 3 to test the effects of modulators of gluconeogenesis (metformin), glycogenolysis (insulin-glargine) and glucokinase activity (novel glucokinase activator drug: dorzagliatin) on EGP in T2D. We have assembled a multi-disciplinary team of investigators (endocrinologists, mathematical modelers, radiologist, biostatistician) to design the various specific aims in adult subjects with T2D using state of the art imaging (NMRS of liver to estimate glycogen content), isotopic, glucose clamp techniques and glucose/hormonal modeling coupled with CGM data for innovative and comprehensive assessments which will be easily translatable to clinical practice. Taken together, we believe our approach will answer vital questions regarding the regulation of daytime and nighttime glucose production on fasting and post-prandial hyperglycemia in subjects with T2D. The planned research will fill knowledge gaps in regulation of endogenous glucose production, glycogenolysis, and gluconeogenesis in people with T2D and provide insights into future innovative therapies for this condition.


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 = $559,553 )
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	004	42	8/14/2024	NON-COMPETING CONTINUATION	$597,690
2024	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	41	12/8/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$653,522
2024	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	40	12/7/2023	NON-COMPETING CONTINUATION	-$691,659
2024	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	41	1/10/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$485,995
2024	2021	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	39	1/10/2024	NON-COMPETING CONTINUATION	-$485,995
														Subtotal = $559,553

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	40	7/26/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $691,659 )
2022	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	40	8/29/2022	NON-COMPETING CONTINUATION	$691,659
														Subtotal = $691,659

Issue Date FY: 2021 ( Subtotal = $655,665 )
2021	2021	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	004	39	7/9/2021	NON-COMPETING CONTINUATION	$655,665
2021	2020	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	38	4/13/2021	NON-COMPETING CONTINUATION	$0
2021	2020	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	38	3/4/2021	NON-COMPETING CONTINUATION	$0
2021	2019	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	37	3/11/2021	COMPETING CONTINUATION	$10,571
2021	2017	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	36	3/11/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$10,571
														Subtotal = $655,665

Issue Date FY: 2020 ( Subtotal = $683,211 )
2020	2020	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	012	38	7/27/2020	NON-COMPETING CONTINUATION	$683,211
2020	2019	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	009	37	6/3/2020	COMPETING CONTINUATION	$125
2020	2019	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	007	37	6/1/2020	COMPETING CONTINUATION	$181,214
2020	2019	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	011	37	6/4/2020	COMPETING CONTINUATION	-$181,214
2020	2019	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	37	3/11/2020	COMPETING CONTINUATION	$181,214
2020	2017	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	008	36	6/3/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$181,214
2020	2017	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	010	36	6/4/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2020	2017	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	006	36	6/1/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$181,339
2020	2017	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	36	2/5/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$181,214
2020	2010	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Trans-NIH Recovery Act Research Support	004	28	5/6/2020	SUPPLEMENT FOR EXPANSION	$181,214
2020	2010	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Trans-NIH Recovery Act Research Support	005	28	5/6/2020	SUPPLEMENT FOR EXPANSION	-$181,214
2020	2010	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Trans-NIH Recovery Act Research Support	002	28	3/11/2020	SUPPLEMENT FOR EXPANSION	-$181,214
2020	2010	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Trans-NIH Recovery Act Research Support	000	28	2/5/2020	SUPPLEMENT FOR EXPANSION	$181,214
														Subtotal = $683,211

Issue Date FY: 2019 ( Subtotal = $726,860 )
2019	2019	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	37	7/31/2019	COMPETING CONTINUATION	$726,860
														Subtotal = $726,860

Issue Date FY: 2018 ( Subtotal = $0 )
2018	2017	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	36	1/5/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$306,556
2018	2016	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	35	1/5/2018	NON-COMPETING CONTINUATION	-$306,556
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $636,854 )
2017	2017	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	36	8/30/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$636,854
														Subtotal = $636,854

Issue Date FY: 2016 ( Subtotal = $614,135 )
2016	2016	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	35	6/22/2016	NON-COMPETING CONTINUATION	$614,135
														Subtotal = $614,135

Issue Date FY: 2015 ( Subtotal = $614,135 )
2015	2015	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	34	7/28/2015	NON-COMPETING CONTINUATION	$614,135
														Subtotal = $614,135

Issue Date FY: 2014 ( Subtotal = $627,850 )
2014	2014	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	33	6/23/2014	COMPETING CONTINUATION	$627,850
														Subtotal = $627,850

Issue Date FY: 2013 ( Subtotal = $553,065 )
2013	2013	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	32	8/23/2013	NON-COMPETING CONTINUATION	$553,065
														Subtotal = $553,065

Issue Date FY: 2012 ( Subtotal = $574,150 )
2012	2012	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	31	9/6/2012	NON-COMPETING CONTINUATION	$574,150
														Subtotal = $574,150

Issue Date FY: 2011 ( Subtotal = $575,505 )
2011	2011	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	30	7/29/2011	NON-COMPETING CONTINUATION	$575,505
														Subtotal = $575,505

Issue Date FY: 2010 ( Subtotal = $729,492 ) (Continued on the next page)
Grand Total All Awards = $11,518,410

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Mechanisms of Insulin Resistance in Man

Award Number: R01DK029953

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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