This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A recent consensus workshop evaluated potential surrogate markers such as immune responses to islet cells, HbA1c, and rates of complicatons or hypoglycemia. Each of these potential markers was determined to have limitations. Measures of anti-ilset immune responses have not been shown to correlate with clinical measures. HbA1c is not only an insensitive measure of beta cell secretion, the currently accepted clinical treatment standard for 'tight' glucose control confounds the use of HbA1c as an endpoint in clinical trials. In addition, use of rates of complications or hypoglycemia as a primary endpoint would require many years or decades of study. In contrast, direct assessment of residual beta cell function is an appropriate endpoint, as retention of beta cell function in patients with T1D is known to result in improved glycemic control and reduced hypoglycemia, retinopathy, and nephropathy. Endogenous beta cell function or insulin secretion is best measured by determination of C-peptide (which is co-secreted with insulin in a 1:1 molar ratio). Intervention studies over the past few decades have usually used measurement of C-peptide in response to a liquid mixed meal (mixed meal tolerance test; MMTT) or an introvenous bolus of glucagon as indicative of residual beta cell function. However, the relationship between these or other measures of beta cell funtion has not been well studied. In addition, the relative advantages of one measure over another in terms of variability, sensitivity and burden to the subject is unknown. The overall goal of this proposal therefore is to select the metabolic test that would be best to use for intervention studies in subjects with T1D. In addition, the optimal conditions for the conduct of the test need to be determined. Important considerations for these choices include knowing the variability of the test and how sensitive the test is to detect changes in beta cell function. Equally important is selecting the test that is practical to conduct in the context of a large clinical trial. In summary, the TrialNet Metabolic Assessment Study comparing the reliabilty of MMTT and IV Glucagon Stimulation Tests in T1D will greatly facilitate the optimal design and implementation of future TrialNet prevention trials. Moreover, the kind and quantity of data that will be derived from the extensive study network will enhance research into the prevention of T1D beyond the realm of TrialNet.
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