Insulin Detemir in Obesity Management

Together with obesity, diabetes is epidemic in the US (20) and worldwide (21). Increased body weight is both a risk factor for diabetes (22) and a consequence of initiation and intensification of insulin therapy, as illustrated in landmark diabetes control trials (1-3). Weight gain can worsen insulin resistance leading to higher insulin requirements, and, thus perpetuates a vicious cycle (36), the ultimate effect of which may be to further enhance metabolic risk (15, 35). For example, an analysis of the diabetes control and complications trial (DCCT) revealed that the highest quartile of weight gain in the intensive treatment led to hyperlipidemia and increased blood pressure; i.e. metabolic syndrome (35). Thus, while glycemic control is clearly a critical metabolic target in diabetes outcomes, additional considerations, including body weight (adiposity) and weight gain, are of fundamental importance in the clinical management of a complex disease such as diabetes. Of course, overweight and obesity are clearly a critical risk factor for the development of type II diabetes in the first place (10), and further weight gain generates significant negative "biofeedback" to the patient and physician struggling to achieve control(33).

Mechanisms involved in weight gain on insulin therapy are incompletely understood: hypoglycemia is potent stimulus to feed (11), improving glycemic control reverses the negative energy balance associated with glycosuria (loss of energy as glucose through the urine), and insulin is clearly a potent anabolic hormone in peripheral tissues (37). In contrast to ample evidence associating insulin therapy with weight gain, a distinct body of evidence indicates that insulin functions as an adiposity negative feedback signal to the brain (23) and limits food intake and weight gain. It is now generally accepted that insulin plays an important role in the neural control of energy homeostasis (matching of caloric intake to energy expenditure to maintain body weight) as well as glucose homeostasis via such neural effects (23). Of course, as will be further discussed, insulin has numerous effects in the CNS ranging from modulation of reward (12), cognition (31), and mood (32). Indeed, the overarching hypothesis of this study is that insulin modulates brain function in a manner that is beneficial.

Food reward can loosely be described as the processes involved in liking, wanting, and learning to acquire food and each of these aspects represent separate but overlapping neuropsychological substrates. To put it even more simply, reward is the sense of satisfaction or pleasure derived from eating. Food reward has sensory, integrative, and motor components, all of which contribute to consummatory behaviors (38). Relevant to the focus of this particular study, is the monoamine neurotransmitter dopamine, which is heavily involved in the generation of food reward. Insulin, a signal generated in response to food intake, functions to decrease, or control food reward(12).