IMPROVING METABOLIC ASSESSMENTS IN TYPE-1 DIABETES MELLITUS CLINICAL TRIALS

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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. The purpose of this study is to select the metabolic test that will be best to use for intervention studies in subjects with Type-1 Diabetes and to determine the optimal conditions for the conduct of the test. Important considerations for these choices include knowing the variability of the test and how sensitive the test is to detect changes in ¿-cell function. Equally important is selecting the test that is practical to conduct in the context of a large clinical trial. The choice of what measure of ¿-cell function should be used as a primary outcome in clinical trials of Type-1 Diabetes depends upon balancing the need for scientific validity with the practical realities of performing the tests in a clinical trial setting. While fasting C-peptide tests alone are easy to perform and may correlate well with stimulated C-peptide results, this may be insufficient to detect subtle effects of therapy. For post-clinical diagnosis, most studies involve a stimulated C-peptide response to non-glucose secretagogues. Europeans have most often used intravenous (IV) glucagon-stimulated testing. This has the advantage of being a short test (6 minutes), but the disadvantage of causing transient nausea. Others have used C-peptide responses to a liquid mixed meal (Sustacal/Boost). Though this does not induce nausea, it does require more time (most studies have used a two-hour testing period and some have advocated four hours). Recent data suggests that the rate of fall of glucagon stimulated C-peptide among subjects receiving intensive insulin treatment is very slow. Whether this is due to insensitivity of the glucagon stimulation test because of supraphysiological stimulation or to a changing natural history of the disease with intensive treatment is not known. C-peptide responses to mixed meal tests also seem to fall less rapidly in studies conducted after the advent of intensive therapy as compared with older investigations. Direct assessment of residual ¿-cell function is an appropriate endpoint, as retention of function in patients with Type-1 Diabetes is known to result in improved glycemic control and reduced hypoglycemia, retinopathy, and nephropathy. Endogenous ¿-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 IV bolus of glucagon as indicative of residual ¿-cell function. However, the relationship between these or other measures of ¿-cell function 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. This study will compare the reliability of measures of stimulated C-peptide response derived from the 2-hour MMTT and the glucagon stimulation test (GST). Experimental Design: The study is a multicenter, two-arm, randomized clinical trial. Comparisons are made between the two groups, with the primary objective of assessing the difference in reliability of the MMTT versus the IV glucagon infusion test. Each participant undergoes four tests within a limited period according to the test sequence assignment. The tests randomly start with either MMTT or GST. At each visit, participants undergo measurement of blood ketones, and either an MMTT or GST. In addition, at the first visit, participants have measurements of islet autoantibodies and HbA1c. Each visit is separated by 3-10 days.