Lindtner C, Scherer T, Zielinski E, Filatova N, Fasshauer M, Tonos N, et al. Binge drinking induces whole-body insulin resistance by impairing hypothalamic insulin action. Sci Transl Med 2013;5:170ra14. (Reprinted with permission.)
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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.
The uncontrolled indulgence of binge drinking may have far-reaching consequences other than getting inebriated. Drinking large quantities of alcohol in a short period of time is a popular custom, particularly among young people. While the immediate effects of binge drinking are intoxication and behavioral changes, it has been known that this practice of drinking is associated with the risk of developing metabolic syndrome and type-2 diabetes.1–3 Interestingly, this epidemiological association has been described even in individuals who binge drink only once a month, suggesting that binge drinking induces metabolic derangements that persist after alcohol has been metabolized and cleared from the blood. Acute and chronic alcohol consumption are known to cause functional insulin resistance, reflected as the inability of systemic insulin to stimulate glucose uptake and suppress lipolysis.4 However, the mechanisms underlying alcohol-mediated effects in insulin signaling are far from being understood and even paradoxical observations have been reported such as the ethanol-mediated enhancement of hepatic insulin receptor phosphorylation and downstrean signaling events including the phosphorylation of protein kinase B (AKT).5 Given the growing prevalence of binge drinking, especially in the young population, understanding the effects and mechanisms of this habit in the regulation of glucose homeostasis and insulin action is a major health concern due to the comorbidities associated with insulin resistance and type 2 diabetes.
In a recent study, Lindtner et al.6 set out to examine the impact of binge drinking on whole-body insulin resistance and the mechanisms involved. Female Sprague-Dawley rats were administered a dose of alcohol (3 g/kg, intraperitoneally) equivalent to 7 ounces for humans, or isocaloric glucose to control rats, every 24 hours for 3 consecutive days. Initial experiments in which ethanol was given intraperitoneally or orally via gavage indicated that the route of administration did not influence the effects of ethanol on glucose homeostasis and insulin resistance. In addition, because the experimental design of the study required placement of intravascular and intracerebroventricular catheters (see below) and to minimize potential confounding variables such as first-pass gastric ethanol metabolism, the authors chose the intraperitoneal route of ethanol administration for all subsequent experiments. Compared to control rats, ethanol administration increased blood glucose levels during a glucose tolerance test (GTT), suggesting that binge drinking reduced glucose tolerance. Plasma insulin concentrations were higher in the ethanol-treated group after fasting and throughout the GTT. Quite remarkably, these effects were observed in the absence of detectable blood alcohol levels following 8-10 hours fasting. Although the deleterious effects of binge drinking on blood glucose and GTT were confirmed in male rats, the outcome was more pronounced in females rats, consistent with clinical evidence indicating that females are more sensitive to the metabolic detrimental effects of binge drinking.2 To confirm insulin resistance, control or ethanol-treated rats were subjected to hyperinsulinemic euglycemic pancreatic clamp studies. The glucose infusion rate required to maintain euglycemia was significantly lower in the ethanol group, consistent with insulin resistance. Moreover, binge drinking impaired the ability of insulin to suppress hepatic glucose production during the clamp. These effects were still observed 30 hours after the last ethanol infusion dose, demonstrating that binge drinking leads to a long-lasting metabolic impairment. Liver extracts prepared at the end of the hyperinsulinemic clamp were used to examine whether ethanol impaired hepatic insulin signaling. Interestingly, insulin receptor subunitβ phosphorylation and the phosphorylation of the downstream signaling molecule AKT were not reduced in the ethanol-exposed rats, indicating that hepatic insulin signaling during the clamp was not disturbed by binge drinking. Moreover, glycerol appearance in response to systemic hyperinsulinemia, which is an estimation of lipolysis by white adipose tissue (WAT), was decreased in control but not ethanol-treated rats. Since increased lipolytic flux from WAT to the liver can drive hepatic gluconeogenesis, these findings suggest that excess lipolysis contributes to the inability of insulin to suppress hepatic glucose production in ethanol-treated rats.
To further explore the mechanisms whereby binge drinking impairs systemic glucose homeostasis despite intact hepatic insulin signaling, and since insulin receptors are widely expressed in the central nervous system and control autonomic nervous system outflow to the liver,7 the authors investigated the role of ethanol on hypothalamic insulin action, which is known to play a major role in the control of nutrient fluxes and glucose regulation.8, 9 This was of particular relevance, as the systemic hyperinsulinemic clamp approach does not distinguish between the peripheral or central action of insulin. To address this critical issue, the authors placed stereotactic cannula in the mediobasal hypothalamus (MBH) and vascular catheters in the carotid artery and jugular vein to test whether insulin delivered directly to the MBH suppressed hepatic glucose production and lipolysis during euglycemic pancreatic clamp. Insulin infusion to the MBH increased the average glucose infusion rate to maintain euglycemia compared to rats infused with artificial cerebrospinal fluid used as control vehicle. Moreover, MBH insulin infusion significantly reduced the hepatic glucose production and the rate of appearance of glycerol compared to control rats infused with vehicle in the MBH during baseline and clamp period. However, binge drinking for 3 days suppressed the ability of MBH insulin infusion in these events. In keeping with these findings and in contrast with the sparing of hepatic insulin signaling, binge drinking markedly blunted insulin-mediated autophosphorylation of the insulin receptorβ subunit in MBH extracts, suggesting impaired hypothalamic insulin signaling in the MBH.
In addressing the molecular link between ethanol and the disruption of hypothalamic insulin signaling, the authors focused on the expression of inflammatory cytokines and phosphatases, which are critical in the control of insulin signaling.10, 11 Binge drinking increased the messenger RNA (mRNA) levels of tumor necrosis factor-α (TNF) and interleukin-6 (IL-6), which are regulated at the transcriptional level by the IκB kinase (IKKβ) / nuclear factor kappa B (NF-κB) pathway. Moreover, among the different protein phosphatases analyzed, binge drinking significantly stimulated the mRNA levels for PTPN1 by about 3-fold without an effect on PTPRA and PTPRF. Finally, to examine the causal role of IKKβ/NF-κB and PTPN1 induction by ethanol on MBH insulin signaling impairment, small molecule inhibitors of both pathways, PS1145 and CTP-157633, respectively, were continuously infused into the lateral ventricle using osmotic minipumps. Forty-eight hours after pump implantation, rats were subjected to binge drinking and GTT was performed at 8, 30, and 54 hours after the last dose of ethanol. As expected, ethanol impaired glucose tolerance, and this effect persisted even up to 54 hours after the last ethanol dose. In contrast to the IKKβ inhibitor, pharmacological inhibition of central PTP1B improved glucose tolerance in ethanol-exposed rats at all timepoints examined, despite both inhibitors alleviated the hypothalamic inflammation induced by binge drinking.
These findings represent an important step forward to understand the deleterious effects of binge drinking on systemic insulin resistance and uncover a novel mechanism of action whereby ethanol impairs hypothalamic but not liver insulin signaling (Fig. 1). However, the study has several limitations and weaknesses. First of all, ethanol was given intraperitoneally. The rationale for intraperitoneal ethanol administration based on the first-pass gastric metabolism was unclear, especially given the relatively minor contribution of this process to overall ethanol metabolism. Moreover, as people abuse alcohol exclusively by oral intake the relevance of the “intraperitoneal binge drinking” effect on glucose homeostasis to the human situation is uncertain and deserves further investigation. In addition, the effect of binge drinking in increasing the PTPN1 mRNA level in MBH seems very modest (about 3-fold). Surprisingly, the authors did not show whether the transcriptional up-regulation of PTPN1 translated at the protein level, and, most important, if it resulted in enhanced PTPB1 activity. No evidence was provided that the efficacy of CPT-157633 in preventing ethanol-mediated impairment in insulin signaling in the MBH was associated with reduced PTPB1 activity. Of relevance, the possibility that CPT-157633 may have exerted off-target effects was not addressed by genetic targeting hypothalamic PTP1B (e.g., intracerebroventricular infusion of small interfering RNA [siRNA] into MBH). Moreover, the mechanisms whereby ethanol increased PTP1B expression were not addressed. In this regard, since ethanol is known to cause hepatic endoplasmic reticulum (ER) stress12 and in light of recent findings indicating that ER stress stimulates PTP1B expression,13 it is conceivable that binge drinking may have caused ER stress in the MBH, which may open up other therapeutic avenues to prevent the sequelae of ER stress, including PTP1B upregulation. The investigation of insulin signaling events in the MBH was restricted to the autophosphorylation of the insulin receptorβ subunit. These limitations raise potential alternative players (Fig. 1). For instance, the phosphatase PP2A mediates insulin resistance by antagonizing AKT phosphorylation.14 Ethanol has been shown to increase ceramide levels in brain cells,15 and PP2A is one of the myriad signaling targets of ceramide action.16 Finally, the notion that binge drinking spared liver insulin signaling was examined in liver extracts, and not confirmed in isolated hepatocytes, raising the possibility of masking impaired insulin signaling in parenchymal cells by the presence of nonparenchymal cells.
Despite these limitations, the findings by Lindtner et al. are of potential relevance with important clinical implications. Insulin resistance is a cardinal feature of the metabolic syndrome and type 2 diabetes, and hence the findings define binge drinking as an important risk habit for the development of diabetes, mediated by defective insulin signaling in the central nervous system. In addition to the role of insulin resistance in hypertension and dislipidemia, obesity is associated with fatty liver disease and both engage in a vicious cycle.17 Moreover, considering the key role of brain insulin in feeding behavior, reward pathways and cognitive functions,18–20 the disturbance of brain insulin signaling by binge drinking may pave the way for neuropsychiatric and neurodegenerative disorders. Given these nefarious implications and risks for developing metabolic and neurologic disorders, the study of Lindtner et al. may help partying people to make the right choice in deciding whether to binge or not to binge.