# Elucidating the pathophysiology and molecular mechanisms of renal insulin resistance

> **NIH NIH F30** · YALE UNIVERSITY · 2022 · $31,637

## Abstract

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.

## Key facts

- **NIH application ID:** 10465627
- **Project number:** 1F30DK131846-01A1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Brandon Hubbard
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $31,637
- **Award type:** 1
- **Project period:** 2022-03-16 → 2026-03-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10465627

## Citation

> US National Institutes of Health, RePORTER application 10465627, Elucidating the pathophysiology and molecular mechanisms of renal insulin resistance (1F30DK131846-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10465627. Licensed CC0.

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