# Glucoregulatory Hormone Interactions in Diabetes

> **NIH NIH R01** · YALE UNIVERSITY · 2021 · $845,452

## Abstract

Project Summary/Abstract
Hypoglycemia and its adverse effects on brain function remain the major factor limiting the use of intensified
insulin therapy that has been shown to prevent or delay the long-term complications in type 1 diabetes (T1DM).
Higher cognitive functions (e.g. working memory) that involve the prefrontal cortex are particularly sensitive to
neuroglycopenia. This proposal seeks continued support of a long-term RO-1 grant with the long-term goal of
documenting the health benefits of insulin delivery strategies that minimize the risk of frequent bouts of
hypoglycemia in T1DM patients. The specific aims of the current project outlined below use functional
magnetic resonance imaging (fMRI) and magnetic resonance spectroscopy (MRS) techniques to assess the
changes in brain function and fuel metabolism caused by acute hypoglycemia and acute hyperglycemia in
T1DM patients with hypoglycemia unawareness (versus hypoglycemia-aware T1DM patients and healthy
controls) as well as the potential beneficial impact of employing closed-loop insulin delivery systems to improve
brain function in hypoglycemia unaware T1DM individuals. The protocols rely heavily on human investigation
involving non-diabetic as well as hypoglycemia aware and unaware T1DM subjects exposed to experimental
mild and moderate hypoglycemia and acute hyperglycemia using the glucose clamp technique while
undergoing brain imaging. However, we also take advantage of the power of rodent diabetic models to test
specific mechanistic hypotheses. The primary hypothesis of this proposal is that hypoglycemia unaware T1DM
patients not only have impaired hormonal and symptomatic responses, but also lack another key hypoglycemia
defense mechanism, namely the capacity of the brain to activate motivation/reward circuits due to adaptive
increases in brain glucose transport and metabolism as well as stimulation of the polyol pathway. The specific
aims are to determine: 1) If T1DM patients with hypoglycemia unawareness (vs. T1DM and non-diabetic
controls) lose the capacity to elicit brain responses to visual food cues as well as functional connectivity in
striatal and a variety of other brain regions in response to food cues during mild and moderate hypoglycemia
using the glucose clamp technique; 2) If patients with T1DM and hypoglycemia unawareness display adaptive
changes causing excessive increases in brain glucose transport and metabolism in response to acute
hyperglycemia that induce adverse neurocognitive effects within the pre-frontal cortex, a key brain region for
cognitive function not previously examined in humans using magnetic resonance spectroscopy (MRS). In
addition, mechanistic studies will be conducted in diabetic rats exposed to recurrent hypoglycemia to define the
molecular mechanisms driving the changes in brain fuel metabolism induced by intensive insulin treatment;
and 3) if reducing glycemic variability with a closed loop insulin delivery system in patients with hypoglyce...

## Key facts

- **NIH application ID:** 10220945
- **Project number:** 5R01DK020495-45
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Janice Jin Hwang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $845,452
- **Award type:** 5
- **Project period:** 1977-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10220945

## Citation

> US National Institutes of Health, RePORTER application 10220945, Glucoregulatory Hormone Interactions in Diabetes (5R01DK020495-45). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10220945. Licensed CC0.

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