Evaluation of the Effect of Hypoglycemia With PET and a Norepinephrine Transporter Ligand
Condition: Hypoglycemia
MeSH terms: Hypoglycemia
Study type: Observational

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.
    

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.
    

Intervention name(s): Norepinephrine Transporter (NET) ligand
Intervention type(s): Other
Intervention description(s): Norepinephrine Transporter (NET) ligand for iv administration during Positron Emission Tomography scan to measure changes in brain NET concentration based on insulin levels.
Other intervention name(s): [11C]MRB
Intervention MeSH terms: Norepinephrine
Observational model: Case-Crossover
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Potentially eligible subjects (healthy controls) will be recruited through flyers and the
        Yale web site for this pilot project.
      
Biospecimen description: 
      whole blood
    
Keywords: hypoglycemia; Positron Emission Tomography; norepinephrine transporter