# Effects of Nutritional Ketosis on Brain Response to Hypoglycemia in People with Type One Diabetes Mellitus

> **NIH NIH R03** · BOSTON CHILDREN'S HOSPITAL · 2021 · $131,803

## Abstract

PROJECT SUMMARY
The scientific goal of this application is to examine the effects of a ketogenic diet on hypoglycemia tolerance
and brain function in people with type 1 diabetes mellitus (T1D). Glycemic management of T1D is typified by
alternating periods of hyper- and hypoglycemia. Because brain metabolism under usual conditions depends on
glucose, acute hypoglycemia leads to immediate complications including impaired cognitive function and a
counter-regulatory hormone response. Recurrent hypoglycemia is associated with functional and structural
changes in the brain, and contributes to the cognitive decline observed in individuals with diabetes. The state
of nutritional ketosis (as distinct from diabetic ketoacidosis) may protect against these acute and chronic
complications by providing an alternative fuel for the brain. Studies during hypoglycemia have shown better
cognitive function and lower hypoglycemia symptoms in the setting of nutritional ketosis or ketone
administration. This physiological benefit may have special relevance for people with T1D who experience
hypoglycemia frequently. To date, no mechanistic studies have examined brain effects of nutritional ketosis in
T1D; nor have any trials explored the potential practical translation into a relevant clinical setting.
To examine the effects of a ketogenic diet on hypoglycemia tolerance and brain function in people with T1D, I
propose a randomized mechanistic study using insulin-clamping and neuroimaging. The study will leverage a
randomized controlled trial (RCT) concurrent with my K23 award. Thirty-two adolescents and young adults with
T1D will receive a very low-carbohydrate diet (5% carbohydrate, 20% protein, 75% fat, expected to cause
nutritional ketosis) vs a standard diet (50%, 20% protein, 30% fat). With this rigorously controlled design to
provide a strong contrast of brain physiology, I propose to conduct a euglycemic-hypoglycemic insulin clamp
and assess activation and connectivity of relevant brain areas by magnetic resonance imaging. Using
continuous imaging during a gradual glycemic descent from 90 mg/dl to 50 mg/dl, I will establish the glycemic
threshold at which the hypothalamus becomes activated (Aim 1). Using a combination of imaging modalities, I
will assess brain activation and connectivity changes during hypoglycemia vs euglycemia (Aim 2). Brain
findings will be integrated with physiologic (blood levels of glucose, ketones, free fatty acids, counter regulatory
hormones) and behavioral (reaction time, cognitive task performance, hypoglycemia symptoms scale)
parameters. Comparison will be made between the 2 diet arms.
As a result of these studies, I hope to elucidate whether nutritional ketosis increases, both neurological and
behavioral, hypoglycemia tolerance in people with T1D, and to clarify mechanisms linking diet to brain
physiology. The research findings will contribute to the understanding of brain metabolism, with direct potential
implications to the managem...

## Key facts

- **NIH application ID:** 10077285
- **Project number:** 5R03DK123541-02
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** BELINDA S LENNERZ
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $131,803
- **Award type:** 5
- **Project period:** 2020-01-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10077285

## Citation

> US National Institutes of Health, RePORTER application 10077285, Effects of Nutritional Ketosis on Brain Response to Hypoglycemia in People with Type One Diabetes Mellitus (5R03DK123541-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10077285. Licensed CC0.

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