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Loss of insulin signaling across functional pancreas compartments as a major pathogenic mechanism underlying diabetic exocrine pancreatopathy

Award Number: R01DK138471
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: 01/12/2024
PERIOD OF PERFORMANCE END DATE: 12/31/2028

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Loss of insulin signaling across functional pancreas compartments as a major pathogenic mechanism underlying diabetic exocrine pancreatopathy - PROJECT SUMMARY ABSTRACT The exocrine pancreas of patients with type 1 diabetes is smaller than the pancreas of healthy subjects and shows histological anomalies such as fibrosis, fatty degeneration, inflammatory cell infiltration and atherosclerosis. The histological features associated with diabetes are so specific that they have been defined as a distinct entity called diabetic exocrine pancreatopathy, which can be readily distinguished from chronic pancreatitis. The prevalence is high: 35 to 77% of adult patients with type 1 diabetes present with pancreatic exocrine dysfunction. Multiple etiological factors have been proposed, but it is inescapable that type 1 diabetes is defined by the autoimmune attack destroying the beta cells. Our goals are (a) to understand how the beta cell coordinates pancreas function and (b) to determine how the progressive demise of the beta cell impacts this coordination. In preliminary studies, we found that local insulin signaling affects the function of the acinar tissue and the islet microvasculature. We thus propose that locally delivered insulin orchestrates pancreas function by acting on three functional effectors: (1) adjacent acinar tissues, (2) vascular units comprised of pericytes and endothelial cells, and (3) intrapancreatic neurons that provide local cholinergic input. We hypothesize that beta cell control of these effectors deteriorates during the progression of T1D, leading to inadequate coordination of pancreas activity. The long term loss of this coordination produces pathological sequelae across compartments. The rationale for the proposed research is that if we want to develop therapies it is imperative to elucidate the mutual interactions and mechanism that promote the disease state. The proposed research is therefore relevant to the mission of the NIH that pertains to the pursuit of fundamental knowledge about beta cell function and its demise in diabetes. Guided by strong preliminary data, our hypothesis will be tested by pursuing three specific aims (1) Determine the impact of insulin on exocrine tissue function during diabetes development, (2) Determine the impact of insulin on the pancreatic microvasculature, and (3) Determine how insulin impacts neural coordination of pancreas function. We will determine the trophic role of insulin by manipulating insulin signaling and measuring the structural and functional consequences in exocrine, vascular, and neural compartments. The manipulation will be performed in the mouse in vivo, using genetic tools or in diabetes models. We will study the healthy and the diseased state in the human pancreas by using living pancreas slices provided by the network of pancreatic organ donors. The proposed research is significant because it could generate mechanistic insight into how beta cells influence surrounding tissues to coordinate activity across pancreas compartments. By identifying the effectors and principles governing this local regulation, we will be able to understand how the progressive loss of beta cell function produces pathological changes across pancreas compartments in people with type 1 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: 2026 ( Subtotal = $662,173 )
2026	2026	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	12/18/2025	NON-COMPETING CONTINUATION	$662,173
														Subtotal = $662,173

Issue Date FY: 2025 ( Subtotal = $663,708 )
2025	2025	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	12/19/2024	NON-COMPETING CONTINUATION	$663,708
2025	2024	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	12/18/2024	NEW	$0
														Subtotal = $663,708

Issue Date FY: 2024 ( Subtotal = $648,358 )
2024	2024	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	1/12/2024	NEW	$648,358
														Subtotal = $648,358

Grand Total All Awards = $1,974,239

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Loss of insulin signaling across functional pancreas compartments as a major pathogenic mechanism underlying diabetic exocrine pancreatopathy

Award Number: R01DK138471

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: 01/12/2024

PERIOD OF PERFORMANCE END DATE: 12/31/2028

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