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Circulating miRNAs and prediction of beta-cell treatment response: The Restoring Insulin Secretion Study

Award Number: R01DK132355
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: 04/20/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Circulating miRNAs and prediction of beta-cell treatment response: The Restoring Insulin Secretion Study - Abstract Despite treatment, a significant proportion of patients with type 2 diabetes (T2D) do not experience clinical improvement (i.e., lack treatment response). In analyses of data from the Restoring Insulin Secretion (RISE) Study, a randomized controlled trial testing the potential of medical and surgical therapies to improve and maintain β-cell function, members of our team have demonstrated substantial heterogeneity in treatment response at the level of the β cell using gold standard measures from hyperglycemic clamps. We know little, however, about contributing factors to heterogeneity of T2D treatment response and lack tools to prospectively identify treatment responders and non-responders. A major reason for this is lack of circulating biomarkers that predict or reflect treatment response at the level of the β cell. Epigenetic regulation of genes important in glucose and insulin metabolism by short non-coding RNAs such as microRNAs (miRNAs) may mediate improvement or preservation of β-cell function with treatment, and circulating miRNAs may be predictive biomarkers of treatment response. In the β cell, regulation of gene expression by miRNAs is crucial to both insulin secretion and cell turnover. In addition, miRNAs secreted into the circulation may reflect tissue-level differences in expression and/or participate actively in inter-organ crosstalk. While miRNAs in a variety of tissues and in the circulation have been shown to be altered by exposure to the RISE interventions in humans or in vitro models, effects of most of these miRNAs in the β cell are not yet described. Using data and samples from the RISE Pediatric Medication Study (n=49; R03DK122100; PI Wander), we identified 9 plasma miRNAs that are prospectively related to treatment response in youth aged 10–19 years including two novel miRNAs, miR-4468 and miR-6727, which are predicted to regulate islet apoptosis via Bcl-2 like 1 and islet amyloid polypeptide. Our objective is to characterize miRNAs that are related to preservation or improvement in β-cell function among adult RISE participants, defined by clamp-derived measures of β-cell response paired with insulin sensitivity, after treatment with medications or gastric banding. To achieve this goal, we propose a two-part study. In Aim 1, we will assay circulating miRNAs using next-generation sequencing at baseline and after treatment in a nested case-control sample of treatment responders vs. non-responders in RISE. In Aim 2, we will examine effects of miR-4468, miR- 6727, and miRNAs identified in Aim 1 on β-cell function, survival, and de-differentiation in gain-of-function in vitro experiments using locked nucleic acid-based miRNA mimics in human islets. Our overarching hypothesis is that circulating miRNAs contribute to treatment heterogeneity via effects on insulin secretion and β-cell survival. To our knowledge, this project will be the first to directly test the role of treatment-related miRNAs in mediating or reflecting treatment response. Better understanding of miRNAs as biomarkers of treatment heterogeneity will facilitate T2D precision medicine by prospectively identifying subgroups likely to benefit from specific treatments and promote development of targeted interventions to prevent or delay the progression of T2D.


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 = $0 )
2026	2025	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY	SEATTLE	WA	98108	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	11/3/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $461,835 )
2025	2025	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY	SEATTLE	WA	98108	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	2/26/2025	NON-COMPETING CONTINUATION	$461,835
														Subtotal = $461,835

Issue Date FY: 2024 ( Subtotal = $461,837 )
2024	2024	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY	SEATTLE	WA	98108	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	2/12/2024	NON-COMPETING CONTINUATION	$432,974
2024	2024	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY	SEATTLE	WA	98108	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	5/15/2024	NON-COMPETING CONTINUATION	$28,863
														Subtotal = $461,837

Issue Date FY: 2023 ( Subtotal = $481,081 )
2023	2023	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY # 151F	SEATTLE	WA	98108	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/8/2023	NON-COMPETING CONTINUATION	$481,081
														Subtotal = $481,081

Issue Date FY: 2022 ( Subtotal = $494,920 )
2022	2022	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY # 151F	SEATTLE	WA	98108	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	4/19/2022	NEW	$494,920
														Subtotal = $494,920

Grand Total All Awards = $1,899,673

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Circulating miRNAs and prediction of beta-cell treatment response: The Restoring Insulin Secretion Study

Award Number: R01DK132355

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: 04/20/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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