# Mitochondrial ADP privation: A unifying model for glucose-induced insulin secretion.

> **NIH NIH R01** · YALE UNIVERSITY · 2022 · $684,708

## Abstract

The most widely-accepted description of the β-cells glucose sensing mechanism involves the mitochondrial oxidation of glucose carbons to raise the ATP/ADP ratio, close KATP channels, and activate Ca2+ influx, which triggers insulin exocytosis. While there is no dispute that oxidative phosphorylation (OxPhos) contributes to function and increased ATP biosynthetic capacity in β-cells, several lines of genetic, biophysical and experimental evidence challenge one key component of the canonical mechanism – the exclusivity of coupling OxPhos to KATP channel closure. Importantly, the expansion mitochondrial metabolites (anaplerosis) through pyruvate carboxylase (PC) is more strongly correlated with insulin secretion than oxidative flux through pyruvate
dehydrogenase (PDH). Glucose carbons that transit PC generate 40% of the cytosolic  phosphoenolpyruvate (PEP) through the cataplerotic mitochondrial PEP carboxykinase (PCK2) reaction. This ‘PEP cycle’ provides a mechanism distinct from OxPhos for cytosolic ATP/ADP generation via pyruvate kinase (PK). Here, we propose a unified model that reconciles canonical OxPhos with anaplerosis by invoking an oscillatory, two-state model where PK itself initiates KATP channel closure. In the first phase, termed ‘MitoSynth,’ cytosolic ADP lowering by PK deprives mitochondria of ADP (termed ‘ADP privation’) that 1) turns off OxPhos to accelerate the PEP cycle, 2) PEP then leaves the mitochondria where 3) its hydrolysis by PK locally triggers KATP channel closure. Following depolarization, the second phase, termed ‘MitoOx,’ sustains membrane depolarization and insulin secretion via OxPhos. This revised model has profound implications for β-cell function, pharmacotherapy and health. This proposal will determine if PK can outcompete mitochondria for ADP, if such ADP privation turns off OxPhos and induces mitochondrial PEP synthesis, and if targeting MitoSynth can improve islet function and health in vivo. AIM 1: To assess how PK-mediated ADP privation induces the high-voltage, low-current MitoSynth state. This aim asks the question, can PK steal ADP from mitochondria as part of the signal to stimulate insulin
secretion? Such ADP privation induces KATP triggering and mitochondrial hyperpolarization at the end of the electrically-silent phase. AIM 2: To determine the regulation of anaplerotic and cataplerotic metabolism by mitochondrial ADP privation during MitoSynth. The hypothesis is that mitochondrial ADP privation activates PEP cycling through the generation of allosteric intermediates. This aim assesses the mechanistic, functional and biochemical characterization of the MitoSynth state. Aim 3: To determine the physiological and pharmacological significance MitoSynth and MitoOx phases of β-cell glucose sensing in vivo. In the two-state model, there are at least two targetable mechanisms to augment insulin secretion: lengthening MitoOx, or shortening the time for MitoSynth to trigger depolarization. We will determine if M...

## Key facts

- **NIH application ID:** 10366083
- **Project number:** 5R01DK127637-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Richard G Kibbey
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $684,708
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10366083

## Citation

> US National Institutes of Health, RePORTER application 10366083, Mitochondrial ADP privation: A unifying model for glucose-induced insulin secretion. (5R01DK127637-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10366083. Licensed CC0.

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