title: Hyperglycemia-associated alterations in cellular signaling and dysregulated mitochondrial bioenergetics in human metabolic disorders.
abstract: OBJECTIVE
  The severity of untreated or refractory diabetes mellitus has been functionally linked to elevated concentrations of free plasma glucose, clinically defined as hyperglycemia. Operationally, the pathophysiological presentations of prolonged hyperglycemia may be categorized within insulin-dependent and insulin-independent, type 1 and type 2 diabetic phenotypes, respectively. Accordingly, major areas of empirical biomedical research have focused on the elucidation of underlying mechanisms driving key cellular signaling systems that are significantly altered in patients presenting with diabetes-associated chronic hyperglycemia.
  
  
  METHODS
  Presently, we provide a translationally oriented review of key studies evaluating the aberrant effects of hyperglycemia on two major signaling pathways linked to debilitating cellular and systemic effects via targeted disruption of mitochondrial bioenergetics: (1) advanced glycation end-products (AGEs)/and their cognate receptor for advanced glycation end-products (RAGEs), and (2) the hexosamine biosynthetic pathway (HBP).
  
  
  RESULTS
  In preclinical models, cultured vascular endothelial cells exposed to hyperglycemic glucose concentrations were observed to produce enhanced levels of reactive oxygen species (ROS) functionally linked to increased formation of AGEs and expression of their cognate RAGEs. Importantly, inhibitors of AGEs formation, mitochondrial complex II, or un-couplers of oxidative phosphorylation, were observed to significantly reduce the effects of hyperglycemia on ROS production and cellular damage, thereby establishing a critical linkage to multiple levels of mitochondrial functioning. Hyperglycemia-mediated enhancement of mitochondrial ROS/superoxide production in vascular endothelial cells has been functionally linked to the shunting of glucose into the HBP with resultant long-term activation of pro-inflammatory signaling processes. Additionally, exposure of cultured cells to hyperglycemic conditions resulted in enhanced HBP-mediated inhibition of protein subunits of mitochondrial respiratory complexes I, III, and IV, intimately associated with normative cellular bioenergetics and ATP production.
  
  
  CONCLUSIONS
  Convergent lines of evidence link chronic hyperglycemic conditions to aberrant expression of AGEs/RAGEs and HBP signaling pathways in relation to the pathophysiological formation of ROS and pro-inflammatory processes on the functional dysregulation of mitochondrial bioenergetics.
authors.affiliation: MitoGenetics LLC, 3 Bioscience Park Drive, Suite 307, Farmingdale, NY, 11735, USA. George.Stefano@MitoGenetics.com.
authors.forename: George B
authors.initials: GB
authors.lastname: Stefano
authors.affiliation: MitoGenetics LLC, 3 Bioscience Park Drive, Suite 307, Farmingdale, NY, 11735, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Challenger
authors.affiliation: MitoGenetics LLC, 3 Bioscience Park Drive, Suite 307, Farmingdale, NY, 11735, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Kream
mesh_terms: D002908:Chronic Disease; D003920:Diabetes Mellitus / Q000503:physiopathology; D004032:Diet; D004734:Energy Metabolism; D017127:Glycation End Products, Advanced / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000150:complications / Q000503:physiopathology*; D024821:Metabolic Syndrome / Q000150:complications / Q000503:physiopathology*; D008928:Mitochondria / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013481:Superoxides / Q000378:metabolism
chemical_list: D017127:Glycation End Products, Advanced; D017382:Reactive Oxygen Species; D000067759:Receptor for Advanced Glycation End Products; D013481:Superoxides
keywords: ATP; Advanced glycation end-products; Aerobic glycolysis; Diabetes; Glucose; Hexosamine biosynthetic pathway; Hyperglycemia; Mitochondria; Receptor for advanced glycation end-products