# Role of lipid droplet proteins in islet function in diabetes and obesity

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2024 · $479,190

## Abstract

Type 2 diabetes (T2D) is the major health problem in the US that imposes significant physical, financial, and
emotional tolls. Thus, there is a strong and urgent need for an effective and widely applicable therapy.
Excessive accumulation of lipids in beta cells is considered to contribute to the development of T2D. At the
same time, lipids supports insulin secretion. We aim to understand how an intracellular organelle termed lipid
droplets (LDs) in beta cells regulate a double-edged sword action of lipids. Our work to date has shown that
lipid droplet protein perilipin 2 and 5 (PLIN2 and 5) each has a unique role in beta cells to support insulin
secretion and protects beta cells from nutritional stress. PLIN5 interacts with adipose triglycerides lipase
(ATGL) and supports insulin secretion. PLIN2 sequestrates lipids as an inert pool and protects beta cells from
lipid overload. However, beta cells cannot continue to accumulate lipids indefinitely. Thus, a pathway of LD
clearance is important to maintain beta cell health under nutritional stress. Lipophagy is self-digestion of LDs at
lysosome and known to play a role in LD clearance in a wide range of cells. Importantly, dysregulation of
lipophagy has been associated with obese adipocytes and fatty liver. However, little is known regarding a role
of lipophagy in beta cells. Our preliminary data showed that lipophagy is constitutively active in beta cells
without nutrient deprivation. Interestingly, chronic suppression of LIPA in INS1 cells, rat islets, and human non-
diabetic islets impairs insulin secretion. Therefore, we hypothesize that lysosomal degradation of LDs is critical
for LD homeostasis and insulin secretion in beta cells, and that the impairment in lipophagy accelerates beta
cell demise in T2D. The following three aims will test our hypothesis.
Specific Aim 1: Determine how LIPA regulates LD catabolism and lipid metabolism in beta cells under
regular and glucolipotoxic conditions: Our preliminary data indicates that LIPA and ATGL each has a
distinct role in mobilization of LDs in beta cells. We will clarify how LIPA and ATGL confer the spatial and
temporal regulation of lipid metabolism at LDs using beta cells in which LIPA and ATGL are down-regulated.
Specific Aim 2: Determine a role of LIPA in the maintenance of beta cell function and health: Our
preliminary data indicates that prolonged suppression of lipophagy negatively affects insulin secretion. We will
address how LIPA deficiency affect beta cell health and function at regular and glucolipotoxic conditions.
Specific Aim 3: Determine whether lipophagy dysfunction contributes to beta cell failure in T2D. It has
been proposed that lysosome becomes dysfunctional in beta cells during the development of T2D. This could
create functional deficiency of LIPA that requires the acidity of lysosome. In addition, nutritional stress may
increase demand for clearance of LDs by lipophagy during the development of T2D. Here, we will test the
rel...

## Key facts

- **NIH application ID:** 10852002
- **Project number:** 5R01DK090490-13
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Yumi Imai
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $479,190
- **Award type:** 5
- **Project period:** 2011-02-15 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10852002

## Citation

> US National Institutes of Health, RePORTER application 10852002, Role of lipid droplet proteins in islet function in diabetes and obesity (5R01DK090490-13). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10852002. Licensed CC0.

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