Siriporn C. Chattipakorn

PPARγ Agonist Improves Neuronal Insulin Receptor Function in Hippocampus and Brain Mitochondria Function in Rats with Insulin Resistance Induced by Long Term High-Fat Diets

We previously demonstrated that a high-fat diet (HFD) consumption can cause not only peripheral insulin resistance, but also neuronal insulin resistance. Moreover, the consumption of an HFD has been shown to cause mitochondrial dysfunction in both the skeletal muscle and liver. Rosiglitazone, a peroxizome proliferator-activated receptor-γ ligand, is a drug used to treat type 2 diabetes mellitus. Recent studies suggested that rosiglitazone can improve learning and memory in both human and animal models. However, the effects of rosiglitazone on neuronal insulin resistance and brain mitochondria after the HFD consumption have not yet been investigated. Therefore, we tested the hypothesis that rosiglitazone improves neuronal insulin resistance caused by a HFD via attenuating the dysfunction of neuronal insulin receptors and brain mitochondria. Rosiglitazone (5 mg/kg · d) was given for 14 d to rats that were fed with either a HFD or normal diet for 12 wk. After the 14(th) week, all animals were euthanized, and their brains were removed and examined for insulin-induced long-term depression, neuronal insulin signaling, and brain mitochondrial function. We found that rosiglitazone significantly improved peripheral insulin resistance and insulin-induced long-term depression and increased neuronal Akt/PKB-ser phosphorylation in response to insulin. Furthermore, rosiglitazone prevented brain mitochondrial conformational changes and attenuated brain mitochondrial swelling, brain mitochondrial membrane potential changes, and brain mitochondrial ROS production. Our data suggest that neuronal insulin resistance and the impairment of brain mitochondria caused by a 12-wk HFD consumption can be reversed by rosiglitazone.

Effects of high-fat diet on insulin receptor function in rat hippocampus and the level of neuronal corticosterone.

AIM Chronic consumption of a high-fat (HF) diet contributes to peripheral insulin resistance and elevated plasma corticosterone. However, the effect of HF consumption on the neurofunctional insulin receptors and neuronal corticosterone level is unclear. We tested the hypothesis that HF consumption can lead to peripheral insulin resistance, elevated neuronal corticosterone, and impaired neuronal responses to insulin. MAIN METHODS Male Wistar rats were fed with normal diet or HF diet for 4, 8 or 12weeks. At the end of each dietary period, plasma was collected for investigating peripheral insulin resistance parameters and corticosterone. Brains were then rapidly removed for studying the function of neuronal insulin receptors (IRs) by extracellular recording in CA1 hippocampus, neuronal IR signaling by immunoblot technique and neuronal corticosterone. KEY FINDINGS Elevated plasma corticosterone level was initially seen in 4-week HF-fed rats. Peripheral insulin resistance developed at 8-week HF-fed rats. However, the elevated neuronal corticosterone level was found at 12-week HF consumption. The neuronal IR response demonstrated by insulin-mediated long-term depression in CA1 hippocampus was diminished in 12-week HF-fed rats. The phosphorylation levels of neuronal IR, IR substrate 1 and Akt/PKB were decreased in 12-week HF-fed rats with no change in these proteins. There was a correlation among peripheral insulin resistance, neuronal stress (elevated neuronal corticosterone), and neuronal insulin resistance in HF group. SIGNIFICANCE Our findings suggest that HF consumption can lead to the elevation of corticosterone and peripheral insulin resistance, which could contribute to neuronal insulin resistance and neuronal stress.

DPP4-inhibitor improves neuronal insulin receptor function, Brain mitochondrial function and cognitive function in rats with insulin resistance induced by high-fat diet consumption

High‐fat diet (HFD) consumption has been demonstrated to cause peripheral and neuronal insulin resistance, and brain mitochondrial dysfunction in rats. Although the dipeptidyl peptidase‐4 inhibitor, vildagliptin, is known to improve peripheral insulin sensitivity, its effects on neuronal insulin resistance and brain mitochondrial dysfunction caused by a HFD are unknown. We tested the hypothesis that vildagliptin prevents neuronal insulin resistance, brain mitochondrial dysfunction, learning and memory deficit caused by HFD. Male rats were divided into two groups to receive either a HFD or normal diet (ND) for 12 weeks, after which rats in each group were fed with either vildagliptin (3 mg/kg/day) or vehicle for 21 days. The cognitive function was tested by the Morris Water Maze prior to brain removal for studying neuronal insulin receptor (IR) and brain mitochondrial function. In HFD rats, neuronal insulin resistance and brain mitochondrial dysfunction were demonstrated, with impaired learning and memory. Vildagliptin prevented neuronal insulin resistance by restoring insulin‐induced long‐term depression and neuronal IR phosphorylation, IRS‐1 phosphorylation and Akt/PKB‐ser phosphorylation. It also improved brain mitochondrial dysfunction and cognitive function. Vildagliptin effectively restored neuronal IR function, increased glucagon‐like‐peptide 1 levels and prevented brain mitochondrial dysfunction, thus attenuating the impaired cognitive function caused by HFD.

Effects of metformin on learning and memory behaviors and brain mitochondrial functions in high fat diet induced insulin resistant rats

AIM Metformin is a first line drug for the treatment of type 2 diabetes mellitus (T2DM). Our previous study reported that high-fat diet (HFD) consumption caused not only peripheral and neuronal insulin resistance, but also induced brain mitochondrial dysfunction as well as learning impairment. However, the effects of metformin on learning behavior and brain mitochondrial functions in HFD-induced insulin resistant rats have never been investigated. MAIN METHODS Thirty-two male Wistar rats were divided into two groups to receive either a normal diet (ND) or a high-fat diet (HFD) for 12weeks. Then, rats in each group were divided into two treatment groups to receive either vehicle or metformin (15mg/kg BW twice daily) for 21days. All rats were tested for cognitive behaviors using the Morris water maze (MWM) test, and blood samples were collected for the determination of glucose, insulin, and malondialdehyde. At the end of the study, animals were euthanized and the brain was removed for studying brain mitochondrial function and brain oxidative stress. KEY FINDINGS We found that in the HFD group, metformin significantly attenuated the insulin resistant condition by improving metabolic parameters, decreasing peripheral and brain oxidative stress levels, and improving learning behavior, compared to the vehicle-treated group. Furthermore, metformin completely prevented brain mitochondrial dysfunction caused by long-term HFD consumption. SIGNIFICANCE Our findings suggest that metformin effectively improves peripheral insulin sensitivity, prevents brain mitochondrial dysfunction, and completely restores learning behavior, which were all impaired by long-term HFD consumption.

Cardioprotective effect of dipeptidyl peptidase-4 inhibitor during ischemia-reperfusion injury.

BACKGROUND Dipeptidyl peptidase-4 (DPP-4) inhibitor is a new anti-diabetic drug for type-2 diabetes mellitus patients. Despite its benefits on glycemic control, the effects of DPP-4 inhibitor on the heart during ischemia-reperfusion (I/R) periods are not known. We investigated the effect of DPP-4 inhibitor on cardiac electrophysiology and infarct size in a clinically relevant I/R model in swine and its underlying cardioprotective mechanism. METHODS Fourteen pigs were randomized to receive either DPP-4 inhibitor (vildagliptin) 50mg or normal saline intravenously prior to a 90-min left anterior descending artery occlusion, followed by a 120-min reperfusion period. The hemodynamic, cardiac electrophysiological and arrhythmic parameters, and the infarct size were determined before and during I/R. Rat cardiac mitochondria were used to study the protective effects of DPP-4 inhibitor on cardiac mitochondrial dysfunction caused by severe oxidative stress induced by H2O2 to mimic the I/R condition. RESULTS Compared to the saline group, DPP-4 inhibitor attenuated the shortening of the effective refractory period (ERP), decreased the number of PVCs, increased the ventricular fibrillation threshold (VFT) during the ischemic period, and also decreased the infarct size. In cardiac mitochondria, DPP-4 inhibitor decreased the reactive oxygen species (ROS) production and prevented cardiac mitochondrial depolarization caused by severe oxidative stress. CONCLUSIONS During I/R, DPP-4 inhibitor stabilized the cardiac electrophysiology by preventing the ERP shortening, decreasing the number of PVCs, increasing the VFT, and decreasing the infarct size. This cardioprotective effect could be due to its prevention of cardiac mitochondrial dysfunction caused by severe oxidative stress during I/R.

DPP-4 inhibitors improve cognition and brain mitochondrial function of insulin-resistant rats

Recent evidence has demonstrated that insulin resistance is related to the development of type 2 diabetes mellitus. Our previous study found that high-fat diet (HFD) consumption caused not only peripheral and brain insulin resistance but also brain mitochondrial dysfunction and cognitive impairment. Vildagliptin and sitagliptin, dipeptidyl-peptidase-4 inhibitors, are recently developed anti-diabetic drugs. However, the effects of both drugs on cognitive behaviors and brain mitochondrial function in HFD-induced insulin-resistant rats have not yet been investigated. Sixty male Wistar rats were divided into two groups to receive either normal diet or HFD for 12 weeks. Rats in each group were then further divided into three treatment groups to receive either vehicle, vildagliptin (3 mg/kg per day), or sitagliptin (30 mg/kg per day) for 21 days. The cognitive behaviors of the rats were tested using the Morris Water Maze test. Blood samples were collected to determine metabolic parameters and plasma oxidative stress levels. Upon completion of the study, the animals were killed and the brains were removed to investigate brain and hippocampal mitochondrial function as well as to determine oxidative stress levels. We demonstrated that both drugs significantly improved the metabolic parameters and decreased circulating and brain oxidative stress levels in HFD-induced insulin-resistant rats. In addition, both drugs completely prevented brain and hippocampal mitochondrial dysfunction and equally improved the learning behaviors impaired by the HFD. Our findings suggest that the inhibition of dipeptidyl-peptidase-4 enzymes with vildagliptin or sitagliptin in insulin-resistant rats not only increases peripheral insulin sensitivity but also decreases brain dysfunction.

Low-amplitude, left vagus nerve stimulation significantly attenuates ventricular dysfunction and infarct size through prevention of mitochondrial dysfunction during acute ischemia-reperfusion injury

BACKGROUND Right cervical vagus nerve stimulation (VNS) provides cardioprotective effects against acute ischemia-reperfusion injury in small animals. However, inconsistent findings have been reported. OBJECTIVE To determine whether low-amplitude, left cervical VNS applied either intermittently or continuously imparts cardioprotection against acute ischemia-reperfusion injury. METHODS Thirty-two isoflurane-anesthetized swine (25-30 kg) were randomized into 4 groups: control (sham operated, no VNS), continuous-VNS (C-VNS; 3.5 mA, 20 Hz), intermittent-VNS (I-VNS; continuously recurring cycles of 21-second ON, 30-second OFF), and I-VNS + atropine (1 mg/kg). Left cervical VNS was applied immediately after left anterior descending artery occlusion (60 minutes) and continued until the end of reperfusion (120 minutes). The ischemic and nonischemic myocardium was harvested for cardiac mitochondrial function assessment. RESULTS VNS significantly reduced infarct size, improved ventricular function, decreased ventricular fibrillation episodes, and attenuated cardiac mitochondrial reactive oxygen species production, depolarization, and swelling, compared with the control group. However, I-VNS produced the most profound cardioprotective effects, particularly infarct size reduction and decreased ventricular fibrillation episodes, compared to both I-VNS + atropine and C-VNS. These beneficial effects of VNS were abolished by atropine. CONCLUSIONS During ischemia-reperfusion injury, both C-VNS and I-VNS provide significant cardioprotective effects compared with I-VNS + atropine. These beneficial effects were abolished by muscarinic blockade, suggesting the importance of muscarinic receptor modulation during VNS. The protective effects of VNS could be due to its protection of mitochondrial function during ischemia-reperfusion.

T-type calcium channel blockade improves survival and cardiovascular function in thalassemic mice.

Objectives:  Iron‐overload cardiomyopathy is a major cause of morbidity and mortality in patients with thalassemia. However, the precise mechanisms of iron entry and sequestration in the heart are still unclear. Our previous study showed that Fe2+ uptake in thalassemic cardiomyocytes are mainly mediated by T‐type calcium channels (TTCC). Nevertheless, the role of TTCC as well as other transporters such as divalent metal transporter1 (DMT1) and L‐type calcium channels (LTCC) as possible portals for iron entry into the heart in in vivo thalassemic mice under an iron‐overload condition has not been investigated.

Effects of vildagliptin versus sitagliptin, on cardiac function, heart rate variability and mitochondrial function in obese insulin-resistant rats

Long‐term high‐fat diet (HFD) consumption has been shown to cause insulin resistance, which is characterized by hyperinsulinaemia with metabolic inflexibility. Insulin resistance is associated with cardiac sympathovagal imbalance, cardiac dysfunction and cardiac mitochondrial dysfunction. Dipeptidyl peptidase‐4 (DPP‐4) inhibitors, vildagliptin and sitagliptin, are oral anti‐diabetic drugs often prescribed in patients with cardiovascular disease. Therefore, in this study, we sought to determine the effects of vildagliptin and sitagliptin in a murine model of insulin resistance.

Cardioprotective Effects of Metformin and Vildagliptin in Adult Rats with Insulin Resistance Induced by a High-Fat Diet

Insulin resistance has been shown to be associated with cardiac sympathovagal imbalance, myocardial dysfunction, and cardiac mitochondrial dysfunction. Whereas metformin is a widely used antidiabetic drug to improve insulin resistance, vildagliptin is a novel oral antidiabetic drug in a group of dipeptidyl peptidase-4 inhibitors in which its cardiac effect is unclear. This study aimed to determine the cardiovascular effects of metformin and vildagliptin in rats with insulin resistance induced by high-fat diet. Male Wistar rats were fed with either a normal diet or high-fat diet (n =24 each) for 12 wk. Rats in each group were divided into three subgroups to receive the vehicle, metformin (30 mg/kg, twice daily), or vildagliptin (3 mg/kg, once daily) for another 21 d. Heart rate variability (HRV), cardiac function, and cardiac mitochondrial function were determined and compared among these treatment groups. Rats exposed to a high-fat diet developed increased body weight, visceral fat, plasma insulin, cholesterol, oxidative stress, depressed HRV, and cardiac mitochondrial dysfunction. Metformin and vildagliptin did not alter body weight and plasma glucose levels but decreased the plasma insulin, total cholesterol, and oxidative stress levels. Although both metformin and vildagliptin attenuated the depressed HRV, cardiac dysfunction, and cardiac mitochondrial dysfunction, vildagliptin was more effective in this prevention. Furthermore, only vildagliptin prevented cardiac mitochondrial membrane depolarization caused by consumption of a high-fat diet. We concluded that vildagliptin is more effective in preventing cardiac sympathovagal imbalance and cardiac dysfunction, as well as cardiac mitochondrial dysfunction, than metformin in rats with insulin resistance induced by high-fat diet.