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Elucidating the pathophysiology and molecular mechanisms of renal insulin resistance

Award Number: F30DK131846
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 03/16/2022
PERIOD OF PERFORMANCE END DATE: 03/15/2026

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Elucidating the pathophysiology and molecular mechanisms of renal insulin resistance - Project Summary Type 2 diabetes (T2D) is one of the defining medical challenges of the 21st century, with one in three Americans born in 2000 estimated to develop diabetes in their lifetime. T2D is characterized by multi-organ insulin resistance and perturbed whole-body glucose homeostasis. Over the past three decades, there have been hints that the kidney plays a central pathophysiologic role in dysregulated whole-body glucose homeostasis in diabetes, with a seminal study suggesting renal glucose production to be increased 300%, climbing to 85% that of the liver. Notwithstanding, insulin resistance in the kidney has remained controversial and any potential mechanisms are unknown. It would be of great public health interest to crystallize the mechanisms and precise pathophysiology of insulin resistance in the kidney, as this may have myriad translational implications. In this proposal, we will build upon our strong preliminary evidence that the renal cortex does, indeed, become insulin resistant with high fat diet (HFD) feeding. In further preliminary data, we have observed both diacylglycerol (DAG) accumulation and Protein Kinase Cε (PKCε) translocation in the mouse renal cortex, raising the possibility that diet-induced renal insulin resistance may be mediated by a similar mechanism as in the liver, where high fat feeding leads to DAG accumulation, which activates PKCε. PKCε subsequently phosphorylates insulin receptor (IR) at Thr1160, causing abrogated insulin signaling. In this proposal, we will carefully assess the insulin signaling defects associated with renal insulin resistance and also further characterize if there is aberrant DAG-PKCe-IR axis activation. We will also use two novel 13C isotopic tracer strategies to understanding oxidative and gluconeogenic defects in the insulin resistant renal cortex. Further, we will directly test the hypothesis that the DAG-PKCe-IR axis causes renal insulin resistance by utilizing an already-generated mouse model where the critical Thr1160 residue of IR is mutated to an alanine, which cannot be phosphorylated by PKCε. We predict these mice will be protected from signaling and metabolic flux manifestations of renal insulin resistance when fed a HFD. This proposal represents an integrated scientific approach and new learning experiences that harness techniques of physiology, cell biology, and analytical chemistry to yield novel insights into the mechanisms and pathophysiology or renal insulin resistance.


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 = $54,538 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	6/9/2025	NON-COMPETING CONTINUATION	$564
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	3/4/2025	NON-COMPETING CONTINUATION	$53,974
														Subtotal = $54,538

Issue Date FY: 2024 ( Subtotal = $53,919 )
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	2/21/2024	NON-COMPETING CONTINUATION	$52,639
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	5/8/2024	NON-COMPETING CONTINUATION	$1,280
														Subtotal = $53,919

Issue Date FY: 2023 ( Subtotal = $32,579 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	3/8/2023	NON-COMPETING CONTINUATION	$32,579
														Subtotal = $32,579

Issue Date FY: 2022 ( Subtotal = $31,637 )
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/24/2022	NEW	$30,921
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	1	7/8/2022	NEW	$716
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	2/24/2022	NEW	$0
														Subtotal = $31,637

Grand Total All Awards = $172,673

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Elucidating the pathophysiology and molecular mechanisms of renal insulin resistance

Award Number: F30DK131846

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 03/16/2022

PERIOD OF PERFORMANCE END DATE: 03/15/2026

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