The development of Type 2 diabetes (T2DM) in adults results from the gradual fall in p-cell function occurring on a background of insulin resistance. The inclusion of pediatric participants in studies envisioned by this RFA is critical because there are subtle but important differences in T2DM pathophysiology in adolescents, particularly with regard to changes in ?-cell function. Indeed, the deterioration in ?-cell functio in youth with T2DM is accelerated relative to than that observed in adults. Furthermore, in childhood, the ?-cell secretory burden to compensate for insulin resistance grows disproportionately larger when insulin resistance worsens during puberty. Diminished first-phase insulin secretion is an early marker of ?-cell dysfunction, appearing long before significant changes in absolute glucose concentrations are apparent in obese youth. Declining ?-cell function relative to insulin sensitivity in these obese youth is evident with increasing fasting glucose levels even in the non-diabetic normal range. The central theme of our proposal is that desensitization of the ?-cell to changes in glucose levels and ?-cell destruction due to glucolipotoxicity may contribute to alterations in insulin secretion. Early correction of glucotoxicity via early intensive insulin therapy, allowing ?-cell rest, may be a strategy to protet or produce sustained recovery of ?-cell function in youth with new onset T2DM. Therefore, we hypothesize that early intensive intravenous insulin infusion (IVII) plus metformin in youth with recently diagnosed T2DM, by tightly controlling fasting and postprandial hyperglycemia, will have favorable effects on short-term recovery and long-term maintenance of p-cell function (first phase insulin secretion) and long-term glycemic control compared with treatment with metformin alone. To address this hypothesis, we have brought together 3 centers of Pediatric Endocrinology/Metabolism and Diabetes Mellitus with expertise in adolescent T2DM to determine: whether a short course of early IVII plus metformin in obese adolescents with new onset T2DM, to rapidly attain fasting and post-parandial normoglyemia, can restore short-term insulin secretion, sustain the recovery of long-term insulin secretion, and promote extended and durable glycemic control relative to metformin therapy alone.

Public Health Relevance

T2DM is a common disease characterized by ?-cell failure and insulin resistance, shortening lifespan despite advances in blood sugar and cardiovascular disease (CVD) treatment. T2DM is increasingly prevalent in youth, forecasting early complications, including CVD and death. Improving ?-cell function may improve glycemic control and decrease later need for insulin, and could thereby decrease diabetes-associated complications. NOTE: The following critiques were prepared by the reviewers assigned to this application. These commentaries may not necessarily reflect the position of the reviewers at the close of the group discussion or the final majority opinion of the group, although the reviewers were asked to amend their critiques if their positions changed during the discussion. The resume and other initial sections of the summary statement are the authoritative representations of the final outcome of group discussion. If there is any discrepancy between the peer reviewers'commentaries and the numerical score on the face page of this summary statement, the numerical score should be considered the most accurate representation of the final outcome of the group discussion.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZDK1-GRB-7 (O1))
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Linder, Barbara
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University of Colorado Denver
Schools of Medicine
United States
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