University of California Irvine, (UCI)

Molecular Mechanisms Associated with Type 2 Diabetes in Down's Syndrome

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Down’s syndrome (DS) is a genetic disorder that affects approximately 400,000 individuals in the USA. DS individual suffer mental retardation, obesity, diabetes, heart defects and Alzheimer’s disease. Previous research indicates that defects in energy production in mitochondria (defined as the powerhouse of the cell), is a general feature of DS. On the other hand, a number of studies show that alterations in mitochondrial fuction may be central during the process that leads to pancreatic ß-cells failure in diabetes type 2. Our working hypothesis is that mitochondrial dysfunction plays a central role in different clinical aspects associated with Down’s syndrome, including diabetes. To test this hypothesis we propose the following specific aims:

1) To determine the functional consequences of energy deficits in DS human pancreatic endocrine precursor cells.
2) To determine the effectiveness of energy buffers (creatine) to revert the reduced metabolism and to preserve and or restore the endocrine function in DS pancreatic cultures.

This research plan will help us to understand the effect of reduced energy production in endocrine cell function, namely insulin secretion, and on the intracellular accumulation of islet-amyloid polypeptide (IAPP), which has been linked to ß-cell death in the diabetic pancreas. I will also test the usefulness of mitochondrial energy buffers to prevent defects in insulin secretion, accumulation of IAPP and loss of viability in fetal DS endocrine precursor cells in culture. These experiments will provide important insight relevant to the molecular changes that lead to failure of ß-cell function in diabetes type 2.