Insulin Detemir in Obesity Management
Insulin Detemir in Obesity Management
The purpose of this study is to evaluate the effects of the medication insulin detemir on
 weight, brain function and mood, and on blood vessel and other risk factors for heart
 disease. The study will compare how diet and insulin detemir affect areas of the brain that
 are involved in food intake and the sense of pleasure people get from eating.

 Participants will be randomized into one of 2 groups. Group 1 will follow a low calorie diet
 only. Group 2 will follow a low calorie diet and take insulin detemir.

 The study is 26 weeks in length and include outpatient visits, inpatient visits, phone and
 email contact, questionnaires, diary collection, blood draw and procedures involving MRI and
 PET scans. There are 4 inpatient visits at the Vanderbilt Clinical Research Center (CRC). The
 inpatient visits require a one night 2 day stay on the CRC at Weeks 2, 6, 16, 26. During the
 weekly and bi-weekly outpatient visits participants will meet with the study nurse and
 dietitian.
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).

 Reward, defined as the sense of satisfaction, or indeed, pleasure that results from feeding
 is an increasingly recognized and potentially potent influence over food intake that shares
 neuoranatomical and neurochemical correlates with substance abuse (although with clear
 differences as well). Although other neurotransmitters (in particular opioids and
 endocannabinoids) are involved in reward, the monoamine neurotransmitter, dopamine (DA) has
 been strongly implicated in mediating reward from food (and other stimuli). The midbrain is
 particularly rich in dopamine neurons, originating in the ventral tegmental area (VTA) that
 project to both ventral (nucleus accumbens, NAc) and dorsal (caudate and putamen) striatum,
 brain areas that integrate and subserve reward and food seeking behaviors. While the
 circuitry involved in feeding and reward is complex, these discreet brain areas (dorsal and
 ventral striatum) are heavily dopaminergic, implicated in reward, and are brain areas that
 our group has a great deal of expertise in studying.

 Dopamine is secreted into the synapse from pre-synaptic nerve terminals and either binds to
 and activates dopamine receptor signaling, or is cleared from the synaptic cleft by a
 specific transporter molecule. The dopamine receptor of interest for this study is the D2
 receptor, as it has been well studied and is the isoform involved in feeding. Similarly, the
 dopamine transporter has been well studied, plays a critical role in dopamine
 neurotransmission, and is regulated by insulin. In this study we will utilize PET
 radioligands to quantify expression of D2 receptors. We will additionally utilize functional
 brain imaging (functional magnetic resonance imaging (fMRI)) to quantify changes in dopamine
 circuits in response to food cues (visual images of obesogenic food) and in response to a
 probe of dopamine transporter function.

 Although weight-gain on insulin initiation or intensification is common, numerous reports in
 randomized, controlled human clinical trials describe attenuation of this effect with the
 basal insulin analogue, detemir ((17), reviewed in (18)). Intriguingly, the observed weight
 sparing effects of detemir appear to be amplified in the most obese (18), i.e. the effects of
 detemir are evident and even amplified in a situation in which insulin resistance is most
 severe. This scenario is entirely consistent with our overarching hypotheses described
 throughout. The current study will utilize insulin detemir as a tool to understand weight
 effects of insulin mediated by CNS effects and to identify the mechanisms involved in the
 observed weight sparing effect.

 Insulin detemir was approved by the FDA for the treatment of diabetes in 2005. Detemir is a
 long-acting, basal insulin analogue with unique pharmacological properties that we believe
 confers the capacity to regulate brain insulin sensitive processes. Compared to regular human
 insulin, detemir has one amino acid deleted, and a medium chain fatty acid conjugated to
 amino acid B29. Conjugation of this fatty acid confers prolonged absorption from the
 subcutaneous depot as it mediates polymerization and slow release. Additionally the fatty
 acid confers albumin binding in the plasma, further increasing the half-life, and providing a
 second buffering mechanism for prolongation of duration of action. We hypothesize that this
 fatty acid additionally confers enhanced transport into the CNS and/or, enhanced signaling
 through the insulin receptor in the context where insulin resistance is established. In the
 clinical development program, insulin detemir was noted to cause significantly less weight
 gain, and from a safety perspective is also associated with less hypoglycemia.

 Rationale for this study. Firstly, dopamine neurotransmission underlies reward. Several high
 visibility studies in humans provide proof-of-principle data supporting the hypothesis that
 defects in dopamine homeostasis contribute to the pathophysiology of obesity (40, 41). By PET
 imaging, dopamine D2 receptor availability (radioligand binding potential) was reduced in a
 BMI dependent fashion; i.e. with increased body mass, less dopamine D2 receptor is available
 in the brain for dopamine signaling (leading to reduced dopamine signaling;
 hypodopaminergia). Similarly, brain activation, as measured by functional MR imaging (using
 techniques similar to those utilized herein), was reduced in obese individual who possess
 polymorphisms in genes regulating dopamine signaling. This work, together with an ever
 expanding body of preclinical work indicates that obesity is a chronic state of reduced
 dopamine signaling, or hypodopaminergia; indeed this condition has been termed
 "hypodopaminergic reward deficiency syndrome." As our preliminary data supports dopamine
 neurotransmission is under regulatory influence by insulin; insulin regulates intracellular
 trafficking of the transporter (analogous to insulin regulation of glucose transporter
 trafficking), and this trafficking is required to maintain the fidelity of dopamine signaling
 via the D2 receptor
Inclusion criteria:

 1. Informed consent obtained before any trial-related activities

 2. Age at study entry is between 31-60 years of age

 3. Body Mass index (BMI) between 30-49 kg/m2 using measured height and weight

 4. Body weight <350lbs (MRI table limit)

 5. Stable body weight during the previous 3 months with a less than 5 pounds self
 -reported weight change

 6. Type 2 diabetes, insulin naïve (except for use during gestational diabetes) on either
 metformin, sitagliptin, or dipeptidyl-4 inhibitor (sitagliptin or saxagliptin), or a
 thiazolidines (rosiglitazone or pioglitazone)

 7. HbA1c level between ~6-8%

 8. Lives in a community dwelling and has a telephone

 9. Agrees to avoid alcohol and exercise within 48 hours of CRC visits, and to comply with
 the dietary/stimulant restrictions for 48 hours before PET and fMRI studies.

 10. Able and willing to follow prescribed menus plans

 Exclusion Criteria:

 1. Known or suspected hypersensitivity to study drug (insulin detemir)

 2. Significant co-morbidities including cardiovascular disease, atherosclerotic disease,
 pulmonary disease, metabolic disease, liver or renal insufficiency

 3. Significant pathologic finding on MRI (research MRI scans are not clinical scans and
 are not standardly read by a neuroradiologist, but if an overt anomaly is noted by
 study personnel, an advisory read will be obtained and the patient will be provided
 with the information for follow-up with his/her physician).

 4. Clinically significant abnormalities on screening EKG

 5. History of Substance Abuse, including but not exclusive to alcohol, cocaine,
 marijuana, heroin, nicotine

 6. Any tobacco use in last 3 months

 7. History of psychiatric disorder deemed too severe to permit participation (PI
 discretion) including subjects with a lifetime history of lifetime Psychotic Disorder
 (Schizophrenia, Schizoaffective, Psychosis NOS) or Bipolar Disorder, suicide attempt
 or history of any suicidal behavior or history within the past 6 months of Post
 Traumatic Stress Disorder, Generalized Anxiety Disorder

 8. Long term use of steroids or medications that may cause weight gain within 3 months of
 study or in foreseeable need (e.g. uncontrolled asthma or rheumatologic disorder).

 9. Inability to abstain from alcohol, physical exercise or > 1 cup of coffee or
 equivalent daily for 2 days prior to imaging studies

 10. Any contraindication which would interfere with MRI or PET studies, e.g.
 claustrophobia, cochlear implant, metal fragments in eyes, cardiac pacemaker, neural
 stimulator, tattoos with iron pigment and metallic body inclusions or other metal
 implanted in the body

 11. Females of childbearing potential who are pregnant, breast-feeding or intend to become
 pregnant or are not using adequate contraceptive methods (abstinence or the following
 methods: diaphragm with spermicide, condom with spermicide by male partner,
 intrauterine device, sponge, spermicide, Norplant, Depo-Provera or oral
 contraceptives)

 12. History of uncontrolled thyroid disease evidenced by TSH outside normal range

 13. Obesity induced by other endocrinologic disorders (e.g. Cushing Syndrome, Polycystic
 ovarian syndrome)

 14. Previous surgery for weight loss

 15. High level aerobic activity such as running for longer than 60 minutes more than 2
 times a week regularly in last 3months

 16. Significant eating disorder or dietary restraints as determined by three factor eating
 questionnaire (TFEQ)

 17. Appetite reducing diet supplement or herbal supplement use in last 6 months

 18. . Food allergy or diet restrictions that would interfere with balanced intake and
 caloric goals.

 19. Dietary supplements of such as EPA, DHA or omega-3 fatty acids.

 20. Daily intakes of coffee, black tea and other caffeinated beverages will be assessed
 and subjects who consume the equivalent of >4 cups coffee or black tea/day at baseline
 will be excluded

 21. Any condition felt by PI or co-investigators to interfere with ability to complete the
 study