Preventative Biomarkers and Potential Pharmacotherapies for Nicotine Use and Diabetes

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ABSTRACT Diabetes and nicotine use are significant public health problems that produce compounded health consequences, particularly in women. The proposed team of neuroscientists employ rodent models to provide a better understanding of the underlying factors that promote nicotine use in persons with metabolic disorders, such as diabetes. Our prior pre-clinical work has established that the rewarding effects of nicotine are greater in rodents that display a disruption in insulin signaling, the primary mediator of diabetes. This work has raised important additional questions regarding whether the development of insulin resistance (IR) or other indices of metabolic syndrome coincide with or predict greater nicotine dependence in females versus males. Also, the effects of nicotine exposure on the emergence of various biomarkers of metabolic syndrome are unclear. Importantly, there is also a lack of information on the efficacy of medications that reduce IR or serve as nicotine cessation agents on the development of nicotine dependence in rodent models of Type 1 or Type 2 diabetes. To address these issues, Aim 1 will assess sex- and time-dependent changes in IR, plasma biomarkers of metabolic syndrome, and behavioral indices of nicotine dependence that include escalation of nicotine self-administration and withdrawal severity. Aim 1 will use a procedure that will examine the natural emergence of IR following chronic access to a high fat diet (HFD). We will also include HFD-fed rats that receive a pharmacological intervention that accelerates the induction of IR. Aim 2 will assess the efficacy of various pharmacotherapies for diabetes (insulin, exenatide, glucophage, and bromocriptine) or smoking cessation (bupropion and varenicline) on the same measures collected in Aim 1 using rodent models of Type 1 and Type 2 diabetes. The scientific premise is that the development of IR will coincide with the escalation of nicotine intake and greater withdrawal severity in both types of diabetic rats. We anticipate that diabetic females will display the greatest escalation of nicotine intake and more intense withdrawal symptoms than males. Also, pharmacological interventions that treat IR will suppress the development of nicotine dependence in diabetic rats. These studies are rigorous because they incorporate rodent models of Type 1 and Type 2 diabetes and will assess time-dependent changes in nicotine dependence and various biomarkers of metabolic syndrome. The proposed work is significant because the results will advance our understanding of the relationship between various biomarkers of metabolic syndrome and the development of nicotine dependence. Our work will also inform how nicotine exposure alters various biomarkers of metabolic syndrome that lead to diabetes. Lastly, our results will inform the effectiveness of clinically approved pharmacotherapies in reducing the risk of nicotine use in persons with diabetes. This is in line with the mission of NIH to improve the lives of persons suffering from debilitating diseases, particularly in patients inflicted by compounded health consequences produced by diabetes and nicotine use.