# Skeletal Health in Type 1 Diabetes and the Role of Diabetic Kidney Disease

> **NIH NIH R01** · NORTHERN CALIFORNIA INSTITUTE/RES/EDU · 2022 · $666,170

## Abstract

PROJECT SUMMARY/ABSTRACT
 Type 1 diabetes (T1D) is associated with increased risk of fracture throughout the lifespan. As
individuals with T1D now live to older ages, when morbidity and mortality from fracture are greatest, it is crucial
to understand this skeletal fragility and identify strategies to mitigate fracture risk. Bone mineral density is
reduced, but fracture is elevated out of proportion to this reduction, indicating that other factors—“bone
quality”—also contribute to the skeletal fragility. These may include low bone turnover and compromised bone
geometry and microstructure. The presence of a diabetes microvascular complication is associated with
particular skeletal fragility, but studies to date have been unable to disentangle specific contributions of each
complication, nor to determine whether associations are independent of glycemic control. Of the microvascular
complications, diabetic kidney disease may be especially detrimental, as other skeletal effects of T1D may be
compounded by bone and mineral derangements of chronic kidney disease, including abnormal bone turnover
and vitamin D metabolism. Our central hypothesis is that diabetic kidney disease particularly affects the
already vulnerable T1D skeleton and plays a key role in the pathophysiology of diabetic skeletal fragility.
 The PERL trial presents a unique opportunity to understand the overlapping impact of these effects, as
it has extensively characterized the kidney function of adult participants with T1D and diabetic kidney disease
of varied severity. This 3-year trial of the effects of allopurinol vs. placebo on kidney function has ended, and
participants are enrolled in an observational post-trial cohort study. In the 148 participants at 7 PERL centers,
we propose an ancillary study that will add skeletal imaging for bone density (with dual-energy X-ray
absorptiometry) and bone microstructure and estimated strength (with high-resolution peripheral quantitative
computed tomography). We will also add analyses on stored serum specimens from 3 time points during
PERL. A subset of participants (N=25) will undergo tetracycline-labeled bone biopsy. We will estimate
relationships of gold-standard iohexol GFR and albuminuria—measured longitudinally—with skeletal
parameters (Aim 1a). Then, we will determine if those relationships vary across a wider spectrum of kidney
function, by combining data from PERL with consistently-acquired skeletal imaging data from 220 adults in the
EDIC study, many of whom have normal GFR and no albuminuria (Aim 1b). We will next determine if glycemic
control is independently associated with skeletal parameters in PERL (Aim 2). Finally, we will examine whether
high or low parathyroid hormone and bone turnover marker levels are associated with skeletal parameters, and
whether altered vitamin D metabolites partially explain the kidney-bone relationship (Aim 3). In the biopsy
subset, we will explore whether PTH and bone turnover markers correlate wit...

## Key facts

- **NIH application ID:** 10459481
- **Project number:** 5R01DK125646-03
- **Recipient organization:** NORTHERN CALIFORNIA INSTITUTE/RES/EDU
- **Principal Investigator:** ANN V SCHWARTZ
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $666,170
- **Award type:** 5
- **Project period:** 2020-09-10 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10459481

## Citation

> US National Institutes of Health, RePORTER application 10459481, Skeletal Health in Type 1 Diabetes and the Role of Diabetic Kidney Disease (5R01DK125646-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10459481. Licensed CC0.

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