# Mechanisms of cardiac remodeling triggered by gestational diabetes

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2020 · $425,355

## Abstract

ABSTRACT
Gestational diabetes mellitus (GDM) heightens the risk of developing cardiovascular disease in both mother
and offspring. A recent large population-based prospective study (CARDIA) found that GDM is independently
associated with cardiac hypertrophy and impaired heart function later in life. In agreement with this finding, our
preliminary data show cardiac hypertrophy and activation of Ca2+-dependent transcriptional signaling two
months after a GDM-complicated pregnancy in female rats. Although hyperglycemia is generally considered
the critical mediator, numerous studies reported that GDM has negative long term consequences even with
good glycemic control in the mother. Thus, additional mechanisms promote metabolic and cardiovascular
dysfunction in GDM. We previously demonstrated an essential role for amylin, a pancreatic hormone with
amyloidogenic properties and whose secretion increases in parallel with that of insulin, in the cardiac
remodeling and dysfunction induced by type-2 diabetes. Moreover, we found that amylin activates Ca2+-
dependent transcriptional signaling in cardiac myocytes. Our preliminary studies show higher amylin levels in
blood from female rats with GDM and their offspring. Based on these findings, we hypothesize that GDM
promotes pathological remodeling of maternal and offspring heart through activation of Ca2+-dependent
hypertrophy signaling that is triggered by systemic amylin dyshomeostasis. To test this overall hypothesis, we
will i) determine the molecular mechanisms underlying the GDM-induced pathological remodeling of the heart,
ii) probe the amylin-cardiac myocyte interaction in GDM, and iii) assess the effect of hyperamylinemia on
pregnancy-induced cardiac remodeling in the absence of other metabolic alterations associated with GDM.
Experiments will combine in vivo assessment of heart structure and function and pharmacological treatment
with measurements in explanted hearts and isolated cardiac myocytes in female rats with normal and GDM-
complicated pregnancies and their offspring as well as in pregnant amylin-KO females injected with
recombinant amylin. Thus, the project will provide unique insights into the complex mechanisms through which
GDM programs cardiac remodeling in mother and offspring. The study may be paradigm shifting by asserting
amylin dyshomeostasis as a key player in this pathology, which will help design new therapeutic strategies for
reducing the postpartum risk of heart disease in mothers with GDM and their offspring.

## Key facts

- **NIH application ID:** 9972589
- **Project number:** 1R01HL148443-01A1
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Sanda Despa
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $425,355
- **Award type:** 1
- **Project period:** 2020-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9972589

## Citation

> US National Institutes of Health, RePORTER application 9972589, Mechanisms of cardiac remodeling triggered by gestational diabetes (1R01HL148443-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9972589. Licensed CC0.

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