Project Update

I am happy to inform you that this project has been funded and I began working on it on 04/01/2020. We postulate that muscle wasting and poor muscle function in children with T1D is associated with, and may be predicted by, changes in levels of branched-chain amino acids (BCAA) and their breakdown products. In the first stage of this project, we will compare muscle mass in children with and without T1D; and identify biomarkers that associate with muscle wasting and poor glycemic control in children with T1D. To that end we will use a unique, comprehensive suite of assays in the Metabolomics Core Laboratory at Duke University to measure BCAA and breakdown products. We will evaluate muscle health by a novel D3-creatine dilution method. Our collaborators at UC Berkeley spearheaded the development of this method and demonstrated in humans that it is a noninvasive, reliable technique. A third-party supplier, Cambridge Isotope Laboratories, Inc. will be contracted to prepare and individually-package the D3Cr doses and ship them (in anhydrous form) directly to me. We will order all necessary supplies including custom-designed, filter paper-containing, retractable urine sticks, plastic pipettes and refrigerator; and we will create a RedCap Database. Once all necessary supplies are obtained, we will start subject recruitment. Participants in this study will have a blood sample and a urine sample collected after taking a single dose of a nontoxic chemical called D3-creatine. Their body composition will be measured by a scale-like device. Parents of participating children will also be asked to complete a food and activity questionnaire. In the next part of the project, we will determine if those biomarkers of muscle wasting predict changes in muscle health and glycemic control over time. To that end, participants will be followed for 12 months. This pilot study has the potential to identify novel biomarkers of skeletal muscle health in T1D, and targets for T1D treatment focused on improving skeletal muscle health. These will address our goals of delaying/preventing the development of future diabetic complications and premature death and enhancing patient evaluation and care.

Project Description

Type 1 diabetes (T1D) causes breakdown of skeletal muscle and impairs muscle function. Given the critical importance of skeletal muscle in glucose metabolism and insulin action, the loss of skeletal muscle leads to high blood glucose, high lipid levels, and insulin resistance. These in turn promote development and progression of long-term complications such as blindness, kidney failure, and cardiovascular disease. Thus, keeping skeletal muscle healthy is essential for management of T1D and preventing future complications. However, assessing muscle health in children is difficult and often impractical. Current methods, such as muscle biopsy, are invasive and risky. To that end we need new reliable and non-invasive methods/markers that associate with, or predict, muscle health in children with T1D.

My colleagues and I will measure muscle mass and function in children with Type 1 diabetes using a novel, noninvasive D3-creatine dilution method. We will correlate the measures of muscle mass and function with variations in blood sugar as assessed using continuous glucose monitors and with the levels of blood metabolites of fat, protein, and carbohydrate. This will allow us to identify novel biomarkers that associate with muscle wasting and poor glycemic control in children with type 1 diabetes.

This project has the potential to: 1) characterize a novel, noninvasive technique for measurement of muscle health in children with T1D; 2) identify novel biomarkers of skeletal muscle health in T1D; and 3) identify targets for T1D treatment focused on improving skeletal muscle health. These will address our goals of delaying/preventing the development of future diabetic complications and premature death.