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Type 1 Diabetes in Acute Pancreatitis Consortium, Pacific Northwest Clinical Center: Immune Pathogenesis of Post-Pancreatitis T1D

Award Number: U01DK127404
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary / Abstract This application brings together the clinical strengths and large acute pancreatitis patient population of Virginia Mason Medical Center's Digestive Disease Institute and Benaroya Research Institute's expertise in autoimmunity and type 1 diabetes to understand the incidence, clinical course, and potential mechanisms of autoimmune mediated diabetes after acute pancreatitis. The underlying theme of this application is that knowledge gained from studying autoimmune diabetes after pancreatitis will provide key insights as to mechanisms of disease in typical type 1 diabetes. Review and meta-analysis data suggest that almost 40% of individuals will eventually develop diabetes or pre- diabetes post-acute pancreatitis. There is, however, inconsistency as to populations included, definitions of endpoints, and duration of follow-up across studies evaluating acute pancreatitis and diabetes. Thus, the true incidence and natural history of diabetes post-pancreatitis is not clear. Moreover, while generally considered to be a consequence of necrosis resulting in beta cell injury or destruction, the relationship between acute pancreatitis necrosis and incidence of diabetes has recently been questioned and there is limited mechanistic data from either animal or human studies. Thus, the etiopathology of diabetes post-acute pancreatitis is not well understood. In contrast, the natural history of typical type 1 diabetes is well described; autoantibodies are seen in genetically at-risk individuals, some of whom over time develop beta cell death leading to asymptomatic, followed by symptomatic dysglycemia eventually requiring exogenous insulin therapy. Evidence for the clear role of the adaptive immune system in this process include the strong genetic association with class II HLA type, the presence of cellular infiltrates in cadaver specimens, and the ability of adaptive immune therapy to alter disease course. What is not clear in typical type 1 diabetes is what underlies the initial triggering of the adaptive immune system. The increasing incidence of disease over time suggests gene-environment interactions leading to beta cell injury, yet it remains challenging to identify specific triggers. Since pancreatic damage and innate activation are known components of acute pancreatitis, the development of diabetes in this setting can allow for investigation as to how acute tissue injury results in autoimmunity and thus serves as a model system to understand mechanisms resulting in typical type 1 diabetes. In this proposal, we will determine the incidence and describe the natural history of diabetes and autoimmunity in individuals after acute pancreatitis (Aim 1), test the hypothesis that acute pancreatitis resolves to an altered immune state in a subset of individuals that predisposes them to develop islet autoimmunity (Aim 2), and determine if acute pancreatitis associated autoimmunity results in immune phenotypes similar to that seen in typical type 1 diabetes (Aim 3).


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: 2023 ( Subtotal = $215,625 )
2023	2023	BENAROYA RESEARCH INSTITUTE AT VIRGINIA MASON	1201 9TH AVE	SEATTLE	WA	98101	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	8/2/2023	NON-COMPETING CONTINUATION	$215,625
2023	2022	BENAROYA RESEARCH INSTITUTE AT VIRGINIA MASON	1201 9TH AVE	SEATTLE	WA	98101	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	5/9/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $215,625

Issue Date FY: 2022 ( Subtotal = $215,625 )
2022	2022	BENAROYA RESEARCH INSTITUTE AT VIRGINIA MASON	1201 9TH AVE	SEATTLE	WA	98101	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	7/22/2022	NON-COMPETING CONTINUATION	$215,625
2022	2021	BENAROYA RESEARCH INSTITUTE AT VIRGINIA MASON	1201 9TH AVE	SEATTLE	WA	98101	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	10/15/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $215,625

Issue Date FY: 2021 ( Subtotal = $215,625 )
2021	2021	BENAROYA RESEARCH INSTITUTE AT VIRGINIA MASON	1201 9TH AVE	SEATTLE	WA	98101	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	7/28/2021	NON-COMPETING CONTINUATION	$215,625
														Subtotal = $215,625

Issue Date FY: 2020 ( Subtotal = $217,625 )
2020	2020	BENAROYA RESEARCH INSTITUTE AT VIRGINIA MASON	1201 9TH AVE	SEATTLE	WA	98101	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/16/2020	NEW	$217,625
														Subtotal = $217,625

Grand Total All Awards = $864,500

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Type 1 Diabetes in Acute Pancreatitis Consortium, Pacific Northwest Clinical Center: Immune Pathogenesis of Post-Pancreatitis T1D

Award Number: U01DK127404

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

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