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SGK1 is a regulator of islet beta cell mass and secretory function

Award Number: R01DK123183
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: 07/01/2020
PERIOD OF PERFORMANCE END DATE: 10/31/2025

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SGK1 is a regulator of islet beta cell mass and secretory function - Pancreatic beta-cell mass expansion occurs in the early stages of obesity and insulin resistance. Conversely, humans with diabetes have reduced numbers and diminished function of pancreatic beta-cells, indicating that islet beta-cell expansion and loss are dynamic processes subject to signal-induced regulation. Using external cues that signal demand for insulin, or that produce insulin resistance, we queried changes in gene expression in rodent and human beta-cells for inducible genes linked with growth and proliferation pathways. This approach yielded the serum and glucocorticoid inducible kinase 1 (SGK1), which is rapidly upregulated after exposure to cytokines, glucose, glucocorticoids, and lipids. Thus, we created mice lacking SGK1 in pancreatic beta-cells to address the fundamentally important question: does inhibition of SGK1 in islet beta-cells block their ability to expand during states of caloric overload and insulin resistance? Our preliminary data shows that SGK1 deletion in beta-cells restricts islet mass expansion during high-fat feeding. Intriguingly, SGK1 inhibition in beta-cells augmented insulin secretion in vitro and in vivo, resulting in improved whole-body glucose tolerance. Based on these preliminary data, we hypothesize that restricting beta-cell proliferation has the added benefit of improving stimulus-secretion coupling to promote insulin secretion. To test this overarching hypothesis, the following aims are proposed. Specific Aim 1 will investigate how SGK1 regulates beta-cell mass in response to signals that create a demand for insulin. Using in vivo approaches that build on our preliminary data using mice with beta- cell deletion of SGK1, we will investigate the early changes in beta-cell proliferation using two established experimental paradigms: high-fat feeding and continuous glucose infusion. Specific Aim 2 will investigate the mechanisms underlying enhanced proliferation and alterations in insulin secretion. In this aim, we propose several ex vivo comprehensive analyses to address key pathways supporting proliferation versus insulin secretion by coupling RNA sequencing techniques with stable isotope tracer-based metabolomics analyses. These studies, in combination with additional mechanistic approaches, are designed to reveal how substrate usage is altered by caloric excess to drive beta-cell mass expansion and importantly, how SGK1 inhibition limits this response to improve metabolic outcomes. Completing these Aims will reveal the critical SGK1-dependent molecular events responsible for regulating islet beta-cell changes in growth and secretory function during caloric overload, obesity, and insulin resistance. Collectively, the results of these studies are expected to inform the future design of therapies targeting cellular growth mechanisms important for diagnosing and treating metabolic diseases.


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: 2024 ( Subtotal = $355,200 )
2024	2024	LSU PENNINGTON	6400 PERKINS RD	BATON ROUGE	LA	70808	EAST BATON ROUGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	5/9/2024	NON-COMPETING CONTINUATION	$355,200
														Subtotal = $355,200

Issue Date FY: 2023 ( Subtotal = $370,000 )
2023	2023	LOUISIANA STATE UNIVERSITY SYSTEM	6400 PERKINS RD	BATON ROUGE	LA	70808	EAST BATON ROUGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	4/4/2023	NON-COMPETING CONTINUATION	$370,000
														Subtotal = $370,000

Issue Date FY: 2022 ( Subtotal = $360,901 )
2022	2022	LOUISIANA STATE UNIVERSITY SYSTEM	6400 PERKINS RD	BATON ROUGE	LA	70808	EAST BATON ROUGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	4/12/2022	NON-COMPETING CONTINUATION	$360,901
														Subtotal = $360,901

Issue Date FY: 2021 ( Subtotal = $352,713 )
2021	2021	LOUISIANA STATE UNIVERSITY SYSTEM	6400 PERKINS RD	BATON ROUGE	LA	70808	EAST BATON ROUGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	3/30/2021	NON-COMPETING CONTINUATION	$352,713
														Subtotal = $352,713

Issue Date FY: 2020 ( Subtotal = $370,000 )
2020	2020	LOUISIANA STATE UNIVERSITY SYSTEM	6400 PERKINS RD	BATON ROUGE	LA	70808	EAST BATON ROUGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	6/1/2020	NEW	$370,000
														Subtotal = $370,000

Grand Total All Awards = $1,808,814

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SGK1 is a regulator of islet beta cell mass and secretory function

Award Number: R01DK123183

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: 07/01/2020

PERIOD OF PERFORMANCE END DATE: 10/31/2025

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