Dipeptidyl-peptidase-4 (DDP-IV) inhibitors restore the impairment of cognition and brain mitochondrial function of obese insulin resistant rats

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 142-166-Hypothalamus-Pituitary Development & Biology
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-148
Siriporn C Chattipakorn*, Hiranya Pintana, Nattayaporn Apaijai and Nipon Chattipakorn
Chiang Mai University, Chiang Mai, Thailand
Our previous study demonstrated that long-term high-fat diet (HFD) consumption caused not only peripheral insulin resistance, but also brain mitochondrial dysfunction and cognitive impairment.1  Both vildagliptin and sitagliptin  are recently developed anti-diabetic drugs in the dipeptidyl peptidase-4 (DDP-IV) inhibitor class that have been shown to be effective in glycemic control via prolonged levels of endogenous active GLP-1. Although GLP-1 has been demonstrated to positively affect learning and memory, the effects of vildagliptin and sitagliptin on metabolic parameters, cognitive behaviors, and brain mitochondrial function in HFD induced insulin resistant condition have never been investigated.  In the present study, we hypothesized that vildagliptin and sitagliptin can improve cognitive behaviors and brain mitochondrial function which are impaired in insulin resistant rats induced by long-term HFD consumption. Thirty-six male rats were equally divided into 2 groups to receive either normal diet or HFD for 12 weeks.  Then, rats in each group were further divided into 3 treatment groups (n=6/group) to additionally receive either vehicle, vildagliptin (3 mg/kg/day) or sitagliptin (30 mg/kg/day) for another 21 days.  The cognitive behaviors were tested using the Morris Water Maze test (MWM).  Blood samples were collected to determine metabolic parameters (glucose, insulin, cholesterol) and plasma malondialdehyde (MDA) for oxidative stress.  Upon completion of the study, animals were euthanized and brains were removed to investigate the brain mitochondrial function and oxidative stress levels.  We demonstrated that rats in the HFD exhibited (1) insulin resistance as indicated by increased plasma insulin, cholesterol and HOMA index with euglycemia, (2) impaired cognition as shown by MWM, and (3) brain mitochondrial dysfunction indicated by increased reactive oxygen species (ROS) production, mitochondrial depolarization, and mitochondrial swelling.  Both vildagliptin and sitagliptin significantly improved metabolic parameters by decreased HOMA index, plasma insulin levels, and plasma cholesterol levels as well as increased plasma HDL levels. They also decreased circulating and brain MDA levels in these obese insulin resistant rats.  In addition, both drugs completely restored brain mitochondrial function by decreasing mitochondrial ROS production, preventing mitochondrial membrane depolarization, and preventing brain mitochondrial swelling.  HFD rats treated with both drugs also had improved learning and memory behaviors.  Our findings suggest that the inhibition of DDP-IV in obese insulin resistant rats not only increases peripheral insulin sensitivity, but also decreases brain and circulation oxidative stress, and restores brain mitochondrial function, thus leading to a prevention of learning and memory impairment in these obese insulin resistant rats. 

1 Pintana H, Apaijai N, Pratchayasakul W, Chattipakorn N, Chattipakorn SC. Effects of metformin on learning and memory behaviors and brain mitochondrial functions in high fat diet induced insulin resistant rats. Life Sci. 2012 91(11-12):409-14

Nothing to Disclose: SCC, HP, NA, NC

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Thailand Research Fund grant: TRF-BRG5480003 (SC) and TRF-RTA 5580006 (NC)