title: Progression from obesity to type 2 diabetes: lipotoxicity, glucotoxicity, and implications for management.
abstract: OBJECTIVE
  To examine the roles of lipotoxicity and glucotoxicity as critical pathogenic foundations in the development of type 2 diabetes and the potential benefits of TZDs in ameliorating these processes.
  
  
  CONCLUSIONS
  Type 2 diabetes represents the failure of the pancreas to maintain adequate insulin secretion in response to insulin resistance, which causes impedance to glucose membrane transport. The lipotoxicity, seen in insulin resistance and the metabolic syndrome and characterized by ectopic fat storage in skeletal muscle, the pancreas, and the liver, can cause adverse effects on the endothelium and thus lead to cardiovascular disease, independent of conversion to diabetes. Once diabetes develops, the resultant hyperglycemia leads to glucotoxicity, which in concert with lipotoxicity accounts for the microvascular and macrovascular complications seen in type 2 diabetes. Accumulating evidence suggests that thiazolidinediones may blunt the lipotoxicity and glucotoxicity that underlie insulin resistance and type 2 diabetes and that early treatment may provide important therapeutic benefits.
  
  
  CONCLUSIONS
  The lipotoxicity of insulin resistance and the glucotoxicity resulting from pancreatic beta-cell failure act synergistically to effect the clinical manifestations and complications of type 2 diabetes. Early treatment with agents that dampen both of these deleterious processes may delay or prevent the onset of type 2 diabetes in high-risk individuals and reduce the risks for microvascular and macrovascular complications in those already diagnosed with type 2 diabetes.
authors.affiliation: Cardiology Wellness Center, 5651 First Blvd., Suite 207, Hermitage, TN 37076, USA. cardiowellness@bellsouth.net
authors.forename: Hal M
authors.initials: HM
authors.lastname: Roseman
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000209:etiology* / Q000517:prevention & control; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy / Q000209:etiology; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D000078790:Insulin Secretion; D008055:Lipids; D009765:Obesity / Q000150:complications*; D012307:Risk Factors; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D008055:Lipids; D045162:Thiazolidinediones