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

> **NIH NIH R01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2024 · $648,358

## Abstract

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 a...

## Key facts

- **NIH application ID:** 10804917
- **Project number:** 1R01DK138471-01
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Joana Almaca
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $648,358
- **Award type:** 1
- **Project period:** 2024-01-12 → 2028-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10804917

## Citation

> US National Institutes of Health, RePORTER application 10804917, Loss of insulin signaling across functional pancreas compartments as a major pathogenic mechanism underlying diabetic exocrine pancreatopathy (1R01DK138471-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10804917. Licensed CC0.

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