Summary Circulating branched-chain amino acid (BCAA) levels are elevated in obesity/diabetes and are a sensitive predictor for type 2 diabetes. Here we show in rats that insulin dose-dependently lowers plasma BCAA levels through induction of hepatic protein expression and activity of branched-chain α keto-acid dehydrogenase (BCKDH), the rate-limiting enzyme in the BCAA degradation pathway. Selective induction of hypothalamic insulin signaling in rats and genetic modulation of brain insulin receptors in mice demonstrate that brain insulin signaling is a major regulator of BCAA metabolism by inducing hepatic BCKDH. Short-term overfeeding impairs the ability of brain insulin to lower BCAAs in rats. High-fat feeding in non-human primates and obesity and/or diabetes in humans is associated with reduced BCKDH protein in liver. These findings support the concept that decreased hepatic BCKDH is a major cause of increased plasma BCAAs, and that hypothalamic insulin resistance may account for impaired BCAA metabolism in obesity and diabetes.

Insulin is a key regulator of adipose tissue lipolysis, and impaired adipose tissue insulin action results in unrestrained lipolysis and lipotoxicity, which are hallmarks of the metabolic syndrome and diabetes. Insulin regulates adipose tissue metabolism through direct effects on adipocytes and through signaling in the central nervous system by dampening sympathetic outflow to the adipose tissue. Here we examined the role of insulin signaling in agouti-related protein (AgRP) and pro-opiomelanocortin (POMC) neurons in regulating hepatic and adipose tissue insulin action. Mice lacking the insulin receptor in AgRP neurons (AgRP IR KO) exhibited impaired hepatic insulin action because the ability of insulin to suppress hepatic glucose production (hGP) was reduced, but the ability of insulin to suppress lipolysis was unaltered. To the contrary, in POMC IR KO mice, insulin lowered hGP but failed to suppress adipose tissue lipolysis. High-fat diet equally worsened glucose tolerance in AgRP and POMC IR KO mice and their respective controls but increased hepatic triglyceride levels only in POMC IR KO mice, consistent with impaired lipolytic regulation resulting in fatty liver. These data suggest that although insulin signaling in AgRP neurons is important in regulating glucose metabolism, insulin signaling in POMC neurons controls adipose tissue lipolysis and prevents high-fat diet–induced hepatic steatosis.

Individuals with a history of binge drinking have an increased risk of developing the metabolic syndrome and type 2 diabetes. Whether binge drinking impairs glucose homeostasis and insulin action is unknown. To test this, we treated Sprague-Dawley rats daily with alcohol (3 g/kg) for three consecutive days to simulate human binge drinking and found that these rats developed and exhibited insulin resistance even after blood alcohol concentrations had become undetectable. The animals were resistant to insulin for up to 54 hours after the last dose of ethanol, chiefly a result of impaired hepatic and adipose tissue insulin action. Because insulin regulates hepatic glucose production and white adipose tissue lipolysis, in part through signaling in the central nervous system, we tested whether binge drinking impaired brain control of nutrient partitioning. Rats that had consumed alcohol exhibited impaired hypothalamic insulin action, defined as the ability of insulin infused into the mediobasal hypothalamus to suppress hepatic glucose production and white adipose tissue lipolysis. Insulin signaling in the hypothalamus, as assessed by insulin receptor and AKT phosphorylation, decreased after binge drinking. Quantitative polymerase chain reaction showed increased hypothalamic inflammation and expression of protein tyrosine phosphatase 1B (PTP1B), a negative regulator of insulin signaling. Intracerebroventricular infusion of CPT-157633, a small-molecule inhibitor of PTP1B, prevented binge drinking–induced glucose intolerance. These results show that, in rats, binge drinking induces systemic insulin resistance by impairing hypothalamic insulin action and that this effect can be prevented by inhibition of brain PTP1B.

Background: Insulin suppresses lipolysis through direct effects on adipocytes and indirectly through its neuronal receptors by reducing sympathetic outflow to adipose tissue. Results: Three-day voluntary overfeeding impairs the ability of brain insulin to suppress lipolysis in vivo. Conclusion: Unrestrained lipolysis that is commonly seen in obesity and diabetes can be caused by impaired brain insulin action. Significance: Enhancing brain insulin action potentially restores lipolytic control.

Background: Cardiovascular diseases are the leading cause of death in the USA. Statin therapy reduces cardiovascular events significantly. Cognitive impairment has been reported with statin therapy but there is a lack of consensus. We analyzed the cognitive functions of adult patients who were on moderate-intensity statin therapy (MIST) or high-intensity statin therapy (HIST). Methods:A total of 213 patients underwent cognitive assessment testing. Cognitive function scores were correlated with the durations of statin therapy, age, and level of education by using Pearson correlation. Independent t-test was used to compare the mean cognitive function score to the gender, race, type of statin therapy, and comorbid conditions.Results: Mean age of all the patients was 55.4 years. Majority of the patients (66.2%) were on MIST while the rest (33.8%) were on HIST. Cognitive impairment was observed in 17.8% of the studied patients. A total of 41.7% of the patients in the HIST group and 5.7% in the MIST group had cognitive impairment (P < 0.001). There was no correlation between cognitive function score and age (r = -0.106), weakly positive correlation between the level of education and cognitive function score (r = 0.252), and weakly negative correlation between the duration of statin therapy and cognitive function score (r = -0.283). In the group of patients on HIST with cognitive impairment, the proportion of patients on atorvastatin 40 -80 mg was significantly higher than the proportion of patients on rosuvastatin 20 -40 mg (66.7% vs. 33.3%; P < 0.05). In the group of patients on MIST with cognitive impairment, atorvastatin 10 -20 mg was the most commonly used statin therapy (50%), followed by rosuvastatin 10 mg (25%), simvastatin 20 -40 mg (12.5%) and pravastatin 40 -80 mg (12.5%). Conclusions:We found a significantly higher association of cognitive impairment in patients who were on MIST or HIST compared to the general population. We found no correlation between cognitive function score and age, weakly positive correlation between the level of education and cognitive function score, and weakly negative correlation between the duration of statin therapy and cognitive function score. HIST was associated with a higher frequency of cognitive impairment compared to the MIST.

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A relationship of epilepsy and a used antiepileptic drug (AED) with the menstrual cycle, overweight, and reproductive disorders in women has been studied in recent years. In this connection,  topiramate engages attention as one of the AEDs that contribute to  weight loss, but not gain.Objective: to investigate the efficacy/tolerability of topiramate in reproductive-aged women with menstrual disorders.Patients and methods. An analysis was made in a group of 58 patients of fertile age (18–35 years) with a long history of focal epilepsy (FE) (n = 44) or idiopathic generalized epilepsy (IGE) (n =  14) who received mainly combined therapy with 2 AEDs. Different  degrees of overweight was observed in 82.8% of the patients;  51.7% had one or another menstrual cycle disorders; however, the  women had been followed up by a gynecologist in exceptional  cases. Switching from one of the parent AEDs to  topiramate or its incorporation into a treatment regimen as an  additional drug substantially improved the course of the disease:  remission at 12 months was achieved in 59.1% of the patients with  FE and in 78.6% of those with IGE.Results. 29.3% of the patients receiving dual therapy, the second medication of which was topiramate, were noted to have lost weight not only if those had a high baseline body mass index (BMI), but  also if those had normal BMI at baseline. 8.6% of all the patients  and 16.7% of those with menstrual cycle disorder achieved  normalization of menstrual function. Topiramate was discontinued  only in 1 (1.7%) patient because of critical weight loss (BMI<15).Discussion. The use of topiramate that has a wide spectrum of action in different types of seizures and forms of epilepsy in patients with a long history of the disease could achieve seizure remission in  59.1% of the patients with FE and in 78.6% of those with IGE for a  period of more than 12 months. One-third of all the cases were  observed to have lost 3–13 kg (median, 6 kg) of weight during  monotherapy or dual therapy with topiramate. The latter resulted in  the normalization of menstrual function in 5 patients, which was  8.6% of all the patients and 16.7% of those with menstrual cycle problems.Conclusion. In addition to a significant improvement in the disease course, the use of topiramate in monotherapy or dual therapy for FE or IGE can contribute to the normalization of body weight and the  menstrual cycle. The authors draw the attention of epileptologists to  the need to monitor menstrual function in women with epilepsy.