ABSTRACT
Diabetes results from insufficient functional ß-cell mass to meet peripheral insulin demands. ß-cells rely upon
mitochondrial respiration to generate the energy necessary for insulin biosynthesis, processing, and secretion.
Indeed, defects in mitochondrial structure and function have been reported in the ß-cells of patients with type 2
diabetes (T2D). Defects in mitochondrial structure and function are characteristic of impairments in mitochondrial
dynamics, the balance of fusion and fission of mitochondrial networks. Mitochondrial fusion is governed by
several dynamin-like GTPases, including Mitofusins 1 and 2 (Mfn1 and 2). Expression of Mfn1 and/or Mfn2 are
reduced in human T2D islets, mouse models of T2D, and following the deposition of toxic islet amyloid
polypeptide oligomers. However, the functions of Mfn1 and Mfn2 in ß-cells in vivo, and their role in T2D
pathogenesis are unclear. Therefore, our goal is to dissect the mechanistic and physiologic regulation of
mitochondrial fusion in ß-cells to elucidate its contribution to diabetes pathogenesis. The central hypothesis to
be tested is that Mfn1 and 2 regulate insulin secretion and islet ß-cell connectivity through control of mitochondrial
DNA and network stability, and their dysregulation contribute to ß-cell failure in T2D. We will test this hypothesis
by the following approach: Specific Aim 1 will directly assess the mechanistic implications of loss of mitochondrial
fusion on control of mitochondrial DNA copy number. Specific Aim 2 will delineate the mechanisms by which
incretins restore insulin secretion following impairments in mitochondrial fusion. Specific Aim 3 will investigate
the importance of mitofusins within human ß-cells. We anticipate obtaining a clear understanding of the
importance and translational relevance of mitochondrial fusion in ß-cell function from an evaluation of the central
effectors crucial to the maintenance of mitochondrial structure. These results should advance the field of ß-cell
biology by defining the role of mitochondrial fusion in T2D pathogenesis and could open new horizons for
therapies for patients with diabetes.