Bioenergetics and Type 2 Diabetes

Hyperglycemia of type 2 diabetes mellitus (T2DM) develops when pancreatic β-cells damaged by chronic exposure to elevated blood glucose and lipids (glucolipotoxicity) fail to synthesize and secrete sufficient quantities of insulin for maintaining plasma glucose level. Despite intensive studies in this field, the molecular mechanism by which fatty acids (FA) cause β-cell impairment is not well understood. It still remains unknown what are the lipid- or glucose-derived molecules directly responsible for the impairment of β-cell function? Our studies showed that in addition to impaired insulin secretion and loss of biphasicity, T2D islets exhibited altered cell bioenergetics as evidenced by decreased oxygen consumption rate as compared to those of the control islets. We also discovered that fuel overload (high level of FA and glucose leads to incomplete FA oxidation and results in accumulation of "toxic" long-chain 3-OH-fatty acids that could induce oxidative stress and disrupt mitochondrial function. Timedependent impairments of bioenergetics due to chronic exposure to elevated blood glucose and lipids would be the consequence leading to pancreatic β-cell failure