Monday, June 30, 2025 6/30/2025

Novel Molecular Determinants of Insulin Clearance

Award Number: R01DK129877
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: 04/25/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Novel Molecular Determinants of Insulin Clearance - Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Type 2 diabetes (T2D) is associated with elevated risk of cardiovascular disease and a major cause of blindness, limb amputation and kidney failure. It has reached epidemic proportions worldwide with a prevalence exceeding 10% in the US. The pathophysiology of T2D involves defects in insulin homeostasis including insufficient insulin secretion from the pancreas, impaired insulin action in muscle, liver and adipose tissues (insulin resistance), and reduced insulin removal from the circulation (insulin clearance) predominantly by the liver. Understanding the cellular and molecular mechanisms of insulin secretion and insulin resistance has been a major focus of investigations for decades, which has resulted in successful antidiabetic therapeutic strategies. In contrast, insulin clearance has been a relatively understudied area in diabetes research. Its molecular determinants are incompletely understood and its role in the etiology of T2D remains unclear. Reduced insulin clearance may represent a beneficial metabolic adaptation to insulin resistance that promotes compensatory hyperinsulinemia to limit the burden on -cells and likely protect against T2D. Conversely, it has been proposed that impaired insulin clearance may exacerbate insulin resistance by driving hyperinsulinemia- mediated downregulation of insulin receptors. It has also been hypothesized that genetically reduced hepatic insulin clearance constitute a primary causal factor in the development of T2D. Clearly, the mechanisms and physiological correlates of insulin clearance deserve further attention. A limitation of experimental investigations of insulin clearance is the relative dearth of known molecular determinants that regulate this process. In previous studies, we identified CEACAM1 as a critical factor in hepatic insulin clearance. While the role of CEACAM1 in receptor-mediated insulin internalization, an initial step in cellular insulin clearance, and metabolic homeostasis is now well established, the molecular mechanisms and mediators of subsequent steps in cellular insulin trafficking are less well understood. Thus, the overall objective of the present proposal is to extend our understanding of this process through the discovery of novel molecular determinants and characterization of their role in systemic insulin/glucose homeostasis. Motivated by the high heritability of insulin clearance observed in humans, we embarked on a hypothesis-free genetic approach. Using a collection of ~100 inbred mouse strains in the Hybrid Mouse Diversity Panel, we performed transcriptome and genome-wide association studies (GWAS) to identify genes and molecular pathways associated with steady-state C-peptide/insulin (C/I) molar ratio, a surrogate measure of insulin clearance. Our preliminary results provide several novel insights. First, they implicate the AMPK pathway in the regulation of cellular insulin clearance and identify this process as a previously unrecognized metabolic target of AMPK signaling. Moreover, we identified Tmem175 as a novel genetic determinant of insulin clearance in the mouse. While Tmem175 has not previously been characterized in the context of insulin metabolism, it has been implicated in endosomal pH regulation, a key process in the degradation and intracellular trafficking of insulin and the insulin receptor (INSR). Furthermore, the TMEM175 chromosomal region is associated with T2D in human populations, which lends support to the hypothesis that variation in TMEM175 activity may affect diabetes risk and highlights the potential translational relevance of this project. We will follow up on our preliminary results as described below: Specific Aim 1: To investigate the role of AMPK pathway in insulin clearance. We will use primary hepatocytes to investigate the cellular mechanisms responsible for the regulation of insuli


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: 2025 ( Subtotal = $477,742 )
2025	2025	WESTERN UNIVERSITY OF HEALTH SCIENCES	309 E 2ND ST	POMONA	CA	91766	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	2/26/2025	NON-COMPETING CONTINUATION	$429,968
2025	2025	WESTERN UNIVERSITY OF HEALTH SCIENCES	309 E 2ND ST	POMONA	CA	91766	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	6/13/2025	NON-COMPETING CONTINUATION	$47,774
														Subtotal = $477,742

Issue Date FY: 2024 ( Subtotal = $458,632 )
2024	2024	WESTERN UNIVERSITY OF HEALTH SCIENCES	309 E 2ND ST	POMONA	CA	91766	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	5/20/2024	NON-COMPETING CONTINUATION	$28,664
2024	2024	WESTERN UNIVERSITY OF HEALTH SCIENCES	309 E 2ND ST	POMONA	CA	91766	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	1/30/2024	NON-COMPETING CONTINUATION	$429,968
														Subtotal = $458,632

Issue Date FY: 2023 ( Subtotal = $477,742 )
2023	2023	WESTERN UNIVERSITY OF HEALTH SCIENCES	309 E 2ND ST	POMONA	CA	91766	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	1/30/2023	NON-COMPETING CONTINUATION	$477,742
														Subtotal = $477,742

Issue Date FY: 2022 ( Subtotal = $487,992 )
2022	2022	WESTERN UNIVERSITY OF HEALTH SCIENCES	309 E 2ND ST	POMONA	CA	91766	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	4/13/2022	NEW	$487,992
														Subtotal = $487,992

Grand Total All Awards = $1,902,108

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Novel Molecular Determinants of Insulin Clearance

Award Number: R01DK129877

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: 04/25/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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