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Brain Glucose Concentrations in Patients with Type 1 Diabetes and Hypoglycemia Unawareness

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Brain Glucose Concentrations in Patients with Type 1 Diabetes and Hypoglycemia Unawareness View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Infoscience - École polytechnique fédérale de Lausanne Journal of Neuroscience Research 79:42–47 (2005) Brain Glucose Concentrations in Patients with Type 1 Diabetes and Hypoglycemia Unawareness Amy B. Criego,1* Ivan Tkac,3 Anjali Kumar,2 William Thomas,5 Rolf Gruetter,3,4 and Elizabeth R. Seaquist2 1Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota 2Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota 3Department of Radiology, University of Minnesota Medical School, Minneapolis, Minnesota 4Department of Neuroscience, University of Minnesota Medical School, Minneapolis, Minnesota 5Division of Biostatistics, University of Minnesota School of Public Health, Minneapolis, Minnesota Although it is well established that recurrent hypoglyce- Recurrent hypoglycemia frequently leads to the mia leads to hypoglycemia unawareness, the mecha- condition of hypoglycemia unawareness in which a patient nisms responsible for this are unknown. One hypothesis is no longer able to perceive symptoms of hypoglycemia is that recurrent hypoglycemia alters brain glucose trans- and consequently is unable to take action to prevent the port or metabolism. We measured steady-state brain development of severe hypoglycemia. In these cases, the glucose concentrations during a glucose clamp to deter- autonomic symptoms of hypoglycemia (tachycardia, ner- mine whether subjects with type 1 diabetes and hypo- vousness, and tremor) are not recognized or do not occur glycemia unawareness may have altered cerebral glu- before development of neuroglycopenia. Intensively cose transport or metabolism after exposure to recurrent treated patients with type 1 diabetes require a lower glu- hypoglycemia. We compared 14 subjects with diabetes cose level to elicit a counterregulatory response than do and hypoglycemia unawareness to 27 healthy control more poorly controlled patients (Amiel et al., 1988; subjects. Brain glucose concentrations were measured 1 Dagogo-Jack et al., 1993; Cryer, 1994). The mechanism under similar metabolic conditions using in vivo H nu- underlying this condition, which has been termed clear magnetic resonance (NMR) spectroscopy at 4 Tesla hypoglycemia-associated autonomic failure (HAAF), is ϭ during a hyperglycemic clamp (plasma glucose unclear but may involve a compensatory increase in cere- 16.7 mmol/l) with somatostatin and insulin. Subjects with bral glucose transport rate so that sufficient glucose is type 1 diabetes and hypoglycemia unawareness had provided to the brain for its energy needs even in the face significantly higher brain glucose concentrations com- of systemic hypoglycemia (Boyle et al., 1994). pared to that in controls under the same conditions Ϯ Ϯ ␮ ϭ Traditional thinking is that a continuous supply of (5.5 0.3 vs. 4.7 0.1 mol/g wet weight, P 0.016). glucose is necessary for normal brain function with the These data suggest that changes in brain glucose trans- brain being unable to store more than a few minutes worth port or metabolism may occur as a result of recurrent of glucose for use during hypoglycemia (Pardridge, 1983). hypoglycemia. © 2004 Wiley-Liss, Inc. Glucose reaches the central nervous system (CNS) by crossing the blood–brain barrier via the specific transport Key words: hypoglycemia unawareness; type 1 diabe- protein, GLUT1 (Pardridge et al., 1990). When exposed tes; magnetic resonance spectroscopy; brain glucose to hypoglycemia, transcription and translation (Boado and Pardridge 1993) of endothelial GLUT1 at the blood–brain barrier are increased. Chronic and prolonged hypoglyce- Hypoglycemia remains the limiting factor for achieving mia in rodents increased the number of glucose transport- normal glycemic control in patients with type 1 diabetes ers in the brain (Koranyi et al., 1991), resulting in in- (Cryer, 1994). The findings of the Diabetes Control and creased movement of glucose (McCall et al., 1982). In Complications Trial (DCCT) established that improved glu- cose control significantly reduces the rate at which diabetes- related complications occur in subjects with type 1 diabetes Contract grant sponsor: National Institutes of Health; Contract grant num- (DCCT Research Group, 1993). It also determined, how- ber: RO1-NS35192, MO1 RR00400, P41 RR08079; Contract grant sponsor: Juvenile Diabetes Research Foundation; Contract grant number: ever, that patients with type 1 diabetes and hemoglobin A1c 13-2002-445. values less than 7.5% experience hypoglycemia three times more often than do those with poor control (DCCT Re- *Correspondence to: Amy B. Criego, MD, MMC 404, 420 Delaware St. search Group, 1993). The fear associated with an increased SE, Minneapolis, MN 55455. E-mail: [email protected] frequency of hypoglycemia is a major barrier in intensifying Received 9 July 2004; Revised 4 August 2004; Accepted 6 August 2004 insulin management for the purpose of preventing the long- Published online 2 December 2004 in Wiley InterScience (www. term complications of diabetes. interscience.wiley.com). DOI: 10.1002/jnr.20296 © 2004 Wiley-Liss, Inc. Brain Glucose in Hypoglycemia Unawareness 43 patients with frequent hypoglycemia and near normal questionnaire consists of eight questions about the frequency values of hemoglobin A1c (7.2 Ϯ 0.5%), brain glucose and severity of asymptomatic hypoglycemia (defined as home uptake in the face of systemic hypoglycemia is unchanged glucose readings Ͻ70 mg/dl) and severe hypoglycemia (defined from euglycemia, whereas patients with poorly controlled as episodes in which the subjects was unconscious or had a diabetes and healthy controls have reduced brain glucose seizure and needed glucagon or intravenous glucose for recov- uptake during systemic hypoglycemia (Boyle et al., 1995). ery), and has been validated as a reliable method to identify These observations suggest that brain glucose uptake may subjects with type 1 diabetes and hypoglycemia unawareness be increased in response to recurrent hypoglycemia in (Clarke et al., 1995). In addition to these criteria, subjects also patients with well-controlled diabetes, therefore causing met the requirements for the MR study, which excludes subjects an increase in brain glucose concentration to ensure an weighing more than 300 pounds. Control subjects were re- adequate delivery of substrate during subsequent episodes cruited from the Fairview-University Medical Center and Uni- of hypoglycemia. This compensatory increase in brain versity of Minnesota communities and were similar to the sub- glucose concentration may be partly responsible for the jects with type 1 diabetes and hypoglycemia unawareness with inability to detect symptoms of hypoglycemia in patients respect to body mass index and gender. The study protocol was with hypoglycemia unawareness. Studies with positron conducted according to procedures approved by the Institu- emission tomography (PET) have been unable to support tional Review Board at the University of Minnesota. this hypothesis, although none were sufficiently powered to identify metabolic differences that were smaller than Protocol 20% (Segel et al., 2001). Subjects with type 1 diabetes were asked to monitor and Although other methods have been used to examine record their blood glucose values before bedtime and at each brain glucose metabolism, proton magnetic resonance meal during the week before the study. The subjects with type (MR) spectroscopy is currently the only method that 1 diabetes were admitted to the General Clinical Research allows quantification of in vivo native glucose concentra- Center at the University of Minnesota the night before the tions. With current methodology, sufficient signal-to- experiment. Their evening dose of long-acting insulin was with- noise to permit good resolution of the glucose signal and held and they were maintained on an intravenous infusion of accurate quantification of brain glucose concentrations is insulin overnight (approximately 8–10 hr) to maintain their obtained only under hyperglycemic conditions (Gruetter, blood glucose between 5.6–10.0 mmol/l (100–180 mg/dl). At 1996). We have demonstrated previously that a linear 7:30 AM the following morning, the insulin infusion was dis- relationship exists between plasma and brain glucose con- continued and subjects were transported to the Center for centrations with plasma glucose values ranging from 4.4– Magnetic Resonance Research for the experiment. 24.5 mmol/l in humans (Seaquist et al., 2001). Similar All subjects were studied in the morning at the Center for observations have been made by Choi et al. (2001) in Magnetic Resonance Research after an overnight fast. In prepara- animals with plasma glucose values ranging from 0.2– tion for the experiment, an intravenous catheter was placed in each 30 mmol/l. We can therefore anticipate that differences in in each antecubital region for the delivery of glucose, insulin, brain glucose concentrations detected during hyperglyce- potassium, and somatostatin. A third intravenous catheter was mia would also exist during hypoglycemia. placed retrograde in the foot for blood sampling. This leg was To determine whether recurrent hypoglycemia in wrapped in heated towels and hot packs to arterialize the venous patients with type 1 diabetes results in small but presum- blood (Seaquist, 1997). At baseline, samples were obtained for ably clinically relevant changes in brain glucose metabo- glucose, insulin, and ketones. The somatostatin
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