# Cardiometabolic Benefit of Reducing Iatrogenic Hyperinsulinemia Using Insulin Adjunctive Therapy in Type 1 Diabetes

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2024 · $340,747

## Abstract

PROJECT SUMMARY/ABSTRACT
Cardiovascular disease (CVD) is a major cause of death in individuals with type 1 diabetes (T1DM), but the
underlying mechanisms are not well understood. Despite efforts to control blood glucose levels, patients with
T1DM who meet glycemic targets (i.e., HbA1c ≤ 6.9%) are still at a 3-fold increased risk of CVD death. By
contrast, studies of a different type of diabetes called glucokinase maturity onset diabetes of the young (GCK-
MODY) have found that these individuals do not have an increased risk of CVD, despite having a similar level
of long-term high blood glucose.
Our previous research suggested that one important difference in CVD risk is that people with T1DM have
insulin resistance and those with GCK-MODY do not. Our data suggested that the presence of iatrogenic
hyperinsulinemia in T1DM—not hyperglycemia—was the principal factor contributing to the decreased insulin
sensitivity. This iatrogenic hyperinsulinemia occurs because patients with T1DM must deliver insulin into the
peripheral circulation rather than more physiologically into the hepatic portal circulation. Because this delivery
route bypasses first-pass hepatic clearance, people with T1DM have 2½-fold higher peripheral insulin levels
than people who have normal insulin secretion. These studies imply that reducing iatrogenic hyperinsulinemia
can improve insulin sensitivity and possibly other aspects of cardiometabolic risk. Insulin adjunctive therapies
may facilitate the needed reduction in hyperinsulinemia.
We will conduct paired experiments to investigate the effects of modifying iatrogenic hyperinsulinemia on three
markers of cardiometabolic risk: nitric oxide bioavailability (Aim 1), insulin sensitivity (Aim 2), and thrombotic
potential (Aim 3). We will compare the effect of lowering iatrogenic hyperinsulinemia in T1DM to the effect of
raising insulinemia by the same amount in individuals at low risk for cardiometabolic disease: those with GCK-
MODY and those without diabetes (control).
We will compare the three cardiometabolic risk markers in T1DM patients (n=13), GCK-MODY patients (n=7),
and those without diabetes (n=7) under conditions of high insulin levels (Hi-Ins, 20-25 μU/mL as seen in
T1DM) and normal insulin levels (Eu-Ins, 5-10 μU/mL, as seen in CGK-MODY and control). To allow T1DM
participants to acutely lower peripheral insulinemia to normal levels without consequent hyperglycemia, we will
use a sodium-glucose cotransporter-2 inhibitor (SGLT2i) as a research tool.
Overall, our goal is to determine how much reducing iatrogenic hyperinsulinemia using insulin adjunctive
therapy can improve CVD outcomes, and to understand the underlying mechanisms behind this effect. This
small, mechanistic pilot study will provide needed data to inform the development of larger trials of insulin
adjunctive insulin therapy in T1DM.

## Key facts

- **NIH application ID:** 10980044
- **Project number:** 1R01DK137997-01A1
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Justin Gregory
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $340,747
- **Award type:** 1
- **Project period:** 2024-09-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10980044

## Citation

> US National Institutes of Health, RePORTER application 10980044, Cardiometabolic Benefit of Reducing Iatrogenic Hyperinsulinemia Using Insulin Adjunctive Therapy in Type 1 Diabetes (1R01DK137997-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10980044. Licensed CC0.

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