# Regulation of Brain Glucose Metabolism in Type 1 Diabetes

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $502,500

## Abstract

Abstract:
Normalization of blood glucose levels via intensive insulin therapy reduces the incidence of diabetic
complications. Despite numerous technologic developments such as continuous glucose monitors and closed
loop insulin pumps, hypoglycemia unawareness and fear of hypoglycemia remain among the biggest obstacles
to achieving tight glycemic control in type 1 diabetic (T1DM) patients. Frequent bouts of hypoglycemia diminish
the brain’s capacity to detect hypoglycemia and to activate protective counterregulatory hormonal responses
(CRR). As a result hypoglycemia associated autonomic failure (HAAF) with reduced glucagon and epinephrine
release increases the risk of more severe hypoglycemic events with adverse consequences including cognitive
impairment, seizures and permanent brain injury. This issue is of particular concern in T1DM where recent
studies suggest that severe and recurrent hypoglycemia occurring early in a patient’s life can result in cognitive
impairment and lasting brain damage. Thus identification of the mechanisms driving counterregulatory failure
and central nervous system complications remain an important area of study with the hope of ultimately
devising preventive strategies. Previous paradigms have been focused on the contribution of alternate energy
substrates such as acetate and lactate to brain metabolism in the context of recurrent hypoglycemia (RH);
however in the light of more recent observations, their role appears only limited. Instead, the regulation of brain
glucose uptake at the blood brain barrier (BBB) and its neuronal oxidation in mitochondria have emerged as
more dominant regulatory steps in this area: We describe for the first time in T1DM how RH exposure limits
neuronal glucose utilization by reducing pyruvate dehydrogenase (PDH) activity, thereby providing a rationale
for higher lactate production rates. In a recent clinical pilot study we made the exciting observation that
pharmacologic re-activation of the PDH complex via the small molecule kinase inhibitor dichloroacetate (DCA)
in intensively treated T1DM patients reverses cognitive deficits associated with recurrent hypoglycemia
exposure. Under this proposal we will take advantage of a newly developed NRM-based deuterium metabolic
imaging (DMI) method that permits metabolism measurements across all areas of the brain simultaneously to
determine in a combination of preclinical and clinical studies the mechanism by which DCA affects glucose
uptake, oxidative metabolism and regional lactate production and how this ultimately leads to preserved brain
energetics, hormonal counterregulation and cognitive function under hypoglycemia. In the end these studies
will yield important new information to tailor our therapeutic approaches to protect the brain from hypoglycemic
injury, ultimately permitting tighter glycemic control in diabetes.

## Key facts

- **NIH application ID:** 9897264
- **Project number:** 2R01DK101984-06
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Raimund Ingo Herzog
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $502,500
- **Award type:** 2
- **Project period:** 2014-09-24 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9897264

## Citation

> US National Institutes of Health, RePORTER application 9897264, Regulation of Brain Glucose Metabolism in Type 1 Diabetes (2R01DK101984-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9897264. Licensed CC0.

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