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Palmitoylation and Diabetes

Award Number: R01DK139956
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: 07/01/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2031

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Palmitoylation and Diabetes - Project Summary/Abstract Type 2 diabetes (T2D) is a lethal disease associated with complications that decrease quality of life. T2D usually occurs due to b cell dysfunction in the setting of insulin resistance. The mechanisms underlying b cell dysfunction in T2D are unclear. Insulin hypersecretion occurs commonly in early forms of T2D. We discovered that protein S-palmitoylation is involved in b cell dysfunction in T2D. Palmitoylation forms a thioester bond between the ubiquitous fatty acid palmitate and a cysteine residue in a protein. This modification is reversible mostly through the activity of acyl-protein thioesterase 1 (APT1). APT1 erases the fatty acid from modified proteins, an event important for intracellular trafficking and signaling. Human islet APT1 activity is decreased by hyperglycemia, and APT1 knockdown in human b cells causes insulin hypersecretion. Chow fed APT1 knockout mice have insulin hypersecretion mediated downstream of depolarization-dependent calcium influx and insulin biosynthesis at the level of insulin granule fusion. Scamp1 (secretory carrier membrane protein 1) was shown to be an APT1 substrate, Scamp1 knockdown mimicked APT1 deficiency in insulin secreting cells, and a palmitoylation-deficient Scamp1 expressed in APT1-deficient cells reversed insulin hypersecretion and apoptosis. High fat diet-fed mice with APT1 deficiency have impaired glucose tolerance, decreased insulin levels following glucose challenge, and b cell loss. High fat diet-fed mice with APT1 overexpression have a metabolic phenotype opposite to that of APT1 deficiency: improved glucose tolerance, increased insulin levels after glucose challenge, and preservation of b cell mass. Chow fed Scamp1 knockout mice phenocopy chow fed APT1 deficient mice: improved glucose tolerance and increased insulin levels. Thus, APT1 appears to affect b cell function through the vesicle protein Scamp1. We propose to test the hypothesis that the depalmitoylation enzyme APT1 mediates b cell function through Scamp1. Our specific aims are: 1) To identify mechanisms underlying improved b cell function in mice with islet specific APT1 overexpression. 2) To establish a physiologic link between APT1 and Scamp1 by studying human islets, Scamp1 knockout mice with high fat feeding (to determine if they develop b cell failure like APT1 knockout mice), and islet specific APT1 overexpression in Scamp1 knockouts. 3) To determine if islet specific overexpression of a mutant Scamp1 incapable of palmitoylation improves b cell function, and identify proteins interacting with Scamp1 implicated in b cell function. Achieving these aims has the potential to establish a strategy for preserving b cell function, which could prevent diabetes progression and improve quality of life.


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 = $537,032 )
2026	2026	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	6/25/2026	NEW	$537,032
														Subtotal = $537,032

Grand Total All Awards = $537,032

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Palmitoylation and Diabetes

Award Number: R01DK139956

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: 07/01/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2031

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