Insulin resistance and neurodegeneration: roles of obesity, type 2 diabetes mellitus and non-alcoholic steatohepatitis.
Recent studies have linked obesity, type 2 diabetes mellitus (T2DM) or non-alcoholic steatohepatitis (NASH) to insulin resistance in the brain, cognitive impairment and neurodegeneration. Insulin resistance compromises cell survival, metabolism and neuronal plasticity, and increases oxidative stress, cytokine activation and apoptosis. T2DM/NASH has been demonstrated to be associated with increased ceramide generation, suggesting a mechanistic link between peripheral insulin resistance and neurodegeneration because ceramides mediate insulin resistance and can cross the blood-brain barrier (BBB). Peripheral insulin resistance diseases may potentially cause brain insulin resistance via a liver-brain axis of neurodegeneration as a result of the trafficking of ceramides across the BBB. Therapy that includes insulin-sensitizing agents may help prevent brain insulin resistance-mediated cognitive impairment.
de la Monte
Suzanne M
SM
Warren Alpert Medical School of Brown University, Providence, RI 02912, USA. suzanne_delamonte_MD@brown.edu
Longato
Lisa
L
Tong
Ming
M
Wands
Jack R
JR
D000544:Alzheimer Disease / Q000209:etiology / Q000503:physiopathology; D000818:Animals; D001921:Brain / Q000473:pathology; D002518:Ceramides / Q000378:metabolism; D003072:Cognition Disorders / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000503:physiopathology; D005234:Fatty Liver / Q000150:complications / Q000503:physiopathology; D006801:Humans; D007333:Insulin Resistance; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology*; D009765:Obesity / Q000150:complications / Q000503:physiopathology
D002518:Ceramides