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).

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