# Effects of Advanced Glycation Endproducts on Type 2 Diabetes and Fragility Fractures

> **NIH NIH R01** · RENSSELAER POLYTECHNIC INSTITUTE · 2024 · $55,928

## Abstract

Abstract
 Bone fractures, due to aging and disease, contribute significantly to healthcare cost
affecting the quality of life of 32.6 million adults in the US. Clinically, fracture risk can be
predicted by dual x-ray absorptiometry (DXA) or the fracture risk assessment (FRAX) tool.
Because type 2 diabetes (T2D) patients exhibit high bone mineral density, both of these tools
fail to correctly predict fracture risk, leading to a significant increase of fragility fractures in
diabetic subjects. Therefore, there is a need to investigate how modifications in collagen and
other organic components in bone can forecast diabetic fractures. Pentosidine (PEN), a
fluorescent Advanced Glycation Endproduct (AGE) that forms in bone by reaction between
sugars and proteins, is the only established marker of bone fragility. However, it does not
consistently predict T2D and fragility fractures. Here, for the first time in bone, we demonstrate
the formation of carboxymethyl-lysine (CML), a non-fluorescent AGE associated with
glycoxidative damage and hyperglycemia. We further show that it forms in abundance in bone
and is highly correlated to loss of bone toughness. Preliminary data presented in the proposal
demonstrate that, in contrast to other AGEs, CML is upregulated >60% in T2D human bone
compared to their age-matched controls. We then provide evidence that CML promotes
formation and growth of additional hydroxyapatite (HA) crystals, similar to human T2D condition,
and forms a ‘molecular link’ between the organic and inorganic components of bone (collagen-
HA interface) impairing bone quality. CML could therefore be a ‘new and relevant’ biomarker
of T2D fracture that captures the effects of hyperglycemia and oxidative stress in bone
and explains why diabetic bone is susceptible to fracture during overt T2D. Using an
obese and a non-obese mouse model of T2D, that mimic both causality and impact of human
T2D on bone, we provide evidence that T2D increases AGEs, with CML explaining bone
fragility. Similarly, we show that higher serum CML levels are associated with increased risk of
incident clinical and prevalent vertebral fractures in T2D, independent of BMD. Thus, our overall
goal is to establish CML as a new and relevant biomarker of bone fragility and determine how it
contributes to bone fragility in T2D. Using a combination of in vitro, ex vivo and in vivo models
we will pursue the following three aims: Aim 1: Evaluate CML as a putative new biomarker of
bone fragility and determine the mechanism(s) by which it reduces energy dissipation in bone;
Aim 2: Determine the contribution of CML and other AGEs to alterations in bone matrix and
energy dissipation in human T2D vertebrae and cortical and cancellous bone from hip fracture
patients.; Aim 3: Validate CML as a biomarker of T2D bone fragility using obese and non-obese
mouse models of T2D and data from the Health, Aging and Body Composition (ABC) study. Our
findings will provide a new understanding of the mechan...

## Key facts

- **NIH application ID:** 10884002
- **Project number:** 3R01AG075654-02S1
- **Recipient organization:** RENSSELAER POLYTECHNIC INSTITUTE
- **Principal Investigator:** Deepak Vashishth
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $55,928
- **Award type:** 3
- **Project period:** 2022-08-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10884002

## Citation

> US National Institutes of Health, RePORTER application 10884002, Effects of Advanced Glycation Endproducts on Type 2 Diabetes and Fragility Fractures (3R01AG075654-02S1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10884002. Licensed CC0.

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