Interplay between mitochondria, primary cilium, diabetes and its complications

Abstract

Diabetes is one of the major health problems of the 21st century. Dysfunction of the insulin secreting pancreatic β-cell together with insulin resistance is central to the pathogenesis of type 2 diabetes mellitus (T2DM). The cause of the disease and the underlying mechanisms linking hyperglycemia to diabetes complications are still unclear. This thesis is focused on two cellular organelles, the mitochondrion and the primary cilium, and their role in the pathophysiological mechanisms of diabetes and its complications.

In the first paper, we studied the effect of hyperglycemia on cell biology and energy metabolism in human primary fibroblasts and endothelial cells. Acute hyperglycemia triggered a metabolic switch from mitochondrial respiration to aerobic glycolysis, which was persistent after prolonged exposure together with reduced ATP/ADP ratio without increase in reactive oxygen species (ROS). An acute decrease in mitochondrial transmembrane potential and cellular proliferation with changes in cytoskeletal reorganization was linked to the increased osmotic pressure induced by hyperglycemia.

In the second and third papers we investigated the effect of hypoxia, a common feature in diabetes, and hyperoxia in pancreatic islets. Here, we found deleterious effects on mitochondrial content, respiration and glucose-stimulated insulin secretion. Preconditioning with the K+ATP channel opener diazoxide enhanced insulin release, HIF-1α and AMPK activation and improved β-cell survival in response to hypoxia.

In the fourth paper, a role for the β-cell primary cilium in diabetes was reported. We found reduced first phase insulin secretion in ciliary defective cells and islets, and impaired glucose tolerance in a ciliopathy mouse model. These results were linked to impaired recruitment of insulin receptor A to the cilium, necessary for proper insulin signaling. Mitochondrial respiration and glucose uptake was unaffected by cilia impairment. Additionally, in vivo evidence of ciliary morphology alteration in the GK rat, a model of T2DM, supported a relationship between ciliary defect and T2DM.

Preliminary results show that decreasing intracellular ATP and increasing mitochondrial ROS production impaired cilia morphology and/or number in two different cell types. Further, cilia were decreased in number with altered morphology in the kidneys of a mouse model of T2DM with diabetic nephropathy, characterized by increased ROS and altered mitochondrial metabolism. Finally, a reduction of 60-80% in mtDNA content (reported in diabetes) did not affect mitochondrial metabolism, respiration and energy production in two different cell types.

In summary, mitochondrial dysfunctions during diabetes and its complications are most probably due to a combination of hyperglycemia and other factors such as hypoxia, depending on the cells and tissues involved. A proper ciliary/basal body function is necessary for insulin release and signaling in β-cell. Cilia morphology and number can be affected by mitochondrial dysfunction/ROS and thus related to diabetic complications such as diabetic nephropathy.