Evaluation of the Effect of Hypoglycemia With PET and a Norepinephrine Transporter Ligand
Information source: Yale University
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Hypoglycemia
Intervention: Norepinephrine Transporter (NET) ligand (Other)
Phase: N/A
Status: Completed
Sponsored by: Yale University Official(s) and/or principal investigator(s): Renata Belfort De Aguiar, MD, Principal Investigator, Affiliation: Yale University
Summary
The aim of this study is to use Positron Emission Tomography (PET) imaging to measure
changes in norepinephrine transporter (NET) concentrations in the brain and periphery of
healthy individuals during hypoglycemia.
We hypothesize that during hypoglycemia, NE levels will increase within the brain,
especially the hypothalamus, and this likely contributes to activation of glucose
counterregulatory responses. We further hypothesize that during hypoglycemia, NET
concentrations in key glucoregulatory regions will change in order to sustain or prolong
sympathetic nervous system activation of counterregulatory responses.
Clinical Details
Official title: Evaluation of the Effect of Hypoglycemia on the Noradrenergic System With PET and a Highly Selective Norepinephrine Transporter Ligand
Study design: Observational Model: Case-Crossover, Time Perspective: Prospective
Primary outcome: norepinephrine transporter (NET) ligand concentrations at Baselinenorepinephrine transporter (NET) ligand concentrations in hyperinsulinemic-hypoglycemic Condition
Detailed description:
Hypoglycemia elicits a multifaceted hormonal response that aims to restore glycemic levels
to normal. As blood glucose levels start to fall, there is a cessation of insulin secretion.
At the top of this hierarchy of counterregulatory responses are glucagon and epinephrine,
which are the two principal circulating hormones that increase glucose production and
inhibit glucose utilization to raise plasma glucose levels back to normal. In conjunction
with these circulating hormones there is activation of the sympathetic nervous system, which
acts to stimulate hepatic glucose production and lipolysis and suppress peripheral glucose
uptake. In cases of prolonged and/or more severe hypoglycemia, growth hormone and cortisol
are mobilized to stimulate the synthesis of gluconeogenic enzymes and inhibit glucose
utilization. In non-diabetic individuals, glucagon and epinephrine are usually very effective
and the latter responses are rarely required in the acute situation. In contrast, impaired
glucose counterregulation presents itself in longstanding diabetes and with antecedent
hypoglycemia. Within the first five years after the onset of type 1 diabetes, the primary
defense against hypoglycemia, the release of glucagon, either becomes significantly
attenuated or is completely absent and this impairment appears to be specific for the
stimulus of hypoglycemia. Hence, patients with diabetes primarily depend on the release of
catecholamines as their main defense against hypoglycemia. Unfortunately, with longer
duration of diabetes and especially with poor glycemic control, epinephrine secretion and
sympathetic activation are also compromised, making these patients even more vulnerable to
the threat of hypoglycemia. In patients with diabetes, hypoglycemia arises from the
interplay of a relative excess of exogenous insulin and defective glucose counterregulation
and it remains a limiting factor in attaining proper glycemic management. Both the Diabetes
Control and Complications Trial (DCCT) conducted in type 1 patients and the United Kingdom
Prospective Diabetes Study (UKPDS) conducted in type 2 patients have established the
importance of maintaining good glucose control over a lifetime of diabetes to avoid
ophthalmologic, renal and neurological complications. However, lowering glycemic goals for
patients with diabetes increases their risk for hypoglycemia exposure. According to the
DCCT, type 1 patients put on intensive insulin therapy, though having improved outcomes for
diabetic complications, are at a 3-fold higher risk of experiencing severe hypoglycemia
compared to those on conventional insulin therapy9. Moreover, recent antecedent hypoglycemia
reduces autonomic response (catecholamines) and development of symptoms (which normally
prompts behavioral defenses such as eating) to subsequent hypoglycemia10-13. Thus begins the
vicious cycle of recurrent hypoglycemia where hypoglycemia leads to further impairment of
counterregulatory responses which in turn, begets more hypoglycemia and so forth. Because of
the imperfections of current insulin therapies, those patients attempting to achieve tight
glycemic control suffer an untold number of asymptomatic hypoglycemic episodes. Current
estimates of symptomatic hypoglycemic episodes range from 2-3 incidences per week on average
and severe, debilitating episodes occur once or twice each year. Therefore, understanding
how the body senses falling blood glucose levels and initiates counterregulatory mechanisms
will be crucial if we are to prevent or eliminate hypoglycemia. Sensors that detect changes
in blood glucose levels and initiate glucose counterregulatory responses have been
identified in the hepatic portal vein, the carotid body and most importantly in the brain.
In the brain, the predominant sensors are located in the VMH and they are crucial for
detecting falling blood glucose levels and for initiating counterregulatory responses.
Although the VMH has been implicated as the primary glucose sensor in rodents, no human data
are available. Moreover, the exact mechanism leading to VMH activation is not well
understood. It was proposed that during hypoglycemia, a rise in VMH norepinephrine (NE)
levels improves the counterregulatory response to hypoglycemia27. While these studies
highlight the importance of the local NE elevation in the VMH, no one has examined the
mechanisms that regulate local NE levels during hypoglycemia. NETs limit the action of NE
through reuptake into the cytoplasm, regulating the extent of time that NE remains in the
synapse28. Studies in rats showed that chronic elevations of intracerebral insulin can
significantly decrease NET mRNA expression in the locus coeruleus, while hypoinsulinemia
resulting from streptozotocin-induced diabetes significantly elevates NET mRNA levels. These
data suggest that endogenous insulin may be one factor that regulates the synthesis and
re-uptake of NE in the CNS. This hypothesis has been confirmed and showed that treating
hippocampal tissue and cervical ganglion neurons cells with insulin led to a decrease in NET
surface expression. However, the direct effect of insulin on NET levels in humans has never
been studied.
We have developed a novel approach to measure noradrenergic function using PET scanning and
a highly selective norepinephrine transporter (NET) ligand, (S,S)-[11C]O-methylreboxetine
([11C]MRB). Measuring changes in brain NET concentration is now possible with the use of
[11C]MRB and a high resolution HRRT PET system.
Eligibility
Minimum age: 18 Years.
Maximum age: 55 Years.
Gender(s): Both.
Criteria:
Inclusion Criteria:
1. Males or females between 18 and 55 years of age
2. Who are able to give voluntary written informed consent
3. Able to tolerate PET and MR imaging
4. Have clinical laboratory test results within normal reference range for the
population or investigator site, or results with acceptable deviations that are
judged to be not clinically significant by the investigator.
5. Have no current uncontrolled medical condition such as neurological, cardiovascular,
endocrine, renal, liver, or thyroid pathology
6. Have no history of a neurological or psychiatric disorder
7. No history of previous allergic reactions to drugs
8. Do not suffer from claustrophobia or any MRI contradictions
Exclusion Criteria:
1. History of liver disease
2. Pregnancy/breast feeding (as documented by pregnancy testing at screening and on days
of the imaging studies).
3. Anemia (Hct <37 in women and < 40 in men)
4. Presence of acute or unstable medical or neurological illness. Subjects will be
excluded from the study if they present with any history of serious medical or
neurological illness or if they show signs of a major medical or neurological illness
on examination or lab testing including history of seizures, head injury, brain
tumor, heart, liver or kidney disease, eating disorder, diabetes.
5. Drug abuse (except nicotine)(Nicotine dependence will be permitted in all groups but
controlled for in the analysis).
6. Use of antidepressants.
7. Clotting disorders or recent anticoagulant therapy.
8. MRI-incompatible implants and other contraindications for MRI, such as pace-maker,
artificial joints, non-removable body piercings, tattoos larger than 1 cm in
diameter, claustrophobia, etc
9. Clinically significant pulmonary, renal, cardiac or hepatic impairment or cancer,
have clinically significant infectious disease, including AIDS or HIV infection, or
previous positive test for hepatitis B, hepatitis C, HIV-1, or HIV-2; subjects will
be asked about this. No testing will be performed.
10. Have received a diagnostic or therapeutic radiopharmaceutical within 7 days prior to
participation in this study.
11. Blood donation during the 8-week period preceding the PET scan.
12. Participation in other research studies involving ionizing radiation within one year
of the PET scans that would cause the subject to exceed the yearly dose limits for
normal volunteers.
13. Unable to fast overnight prior to the PET scan.
Locations and Contacts
PET Center, YCCI Hospital Research Unit (HRU), New Haven, Connecticut 06519, United States
Additional Information
Starting date: June 2011
Last updated: October 1, 2014
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