Epidemiology/Health Services/Psychosocial Research ORIGINAL ARTICLE Relationships Between Hyperglycemia and Cognitive Performance Among Adults With Type 1 and Type 2 Diabetes DANIEL J. COX, PHD ANTHONY MCCALL, MD, PHD test cognitive functioning at 14.5 and 16 BORIS P. KOVATCHEV, PHD KEVIN J. GRIMM, MA mmol/l in adults with type 2 diabetes. LINDA A. GONDER-FREDERICK, PHD WILLIAM L. CLARKE, MD During hyperglycemia, significant dis- KENT H. SUMMERS, PHD ruptions occurred in the performance of complex tests of cognitive functioning, such as four-choice reaction time. How- ever, other investigators (5,6) were un- OBJECTIVE — Hyperglycemia is a common event among patients with type 1 and type 2 able to detect decay in cognitive-motor diabetes. While the cognitive-motor slowing associated with hypoglycemia is well documented, the acute effects of hyperglycemia have not been studied extensively, despite patients’ reports of performance on selected neuropsycho- negative effects. This study prospectively and objectively assessed the effects of hyperglycemia on logical tests during hyperglycemia. cognitive-motor functioning in subjects’ natural environment. Contrary to hypoglycemia and its associated neuroglycopenia, a major RESEARCH DESIGN AND METHODS — Study 1 investigated 105 adults with type 1 barrier to the investigation of the effects of diabetes (mean age 37 years and mean duration of diabetes 20 years), study 2 investigated 36 hyperglycemia on cognitive-motor per- adults with type 2 diabetes (mean age 50 years and mean duration of diabetes 10 years), and formance is the absence of a clear physi- study 3 investigated 91 adults with type 1 diabetes (mean age 39 years and mean duration of ological mechanism that explains how diabetes 20 years). Subjects used a hand-held computer for 70 trials over 4 weeks, which hyperglycemia negatively influences required them to complete various cognitive-motor tasks and then measure and enter their current blood glucose reading. brain functioning. However, research suggests several possible mechanisms (6). RESULTS — Hyperglycemia (blood glucose Ͼ15 mmol/l) was associated with slowing of all Blood-brain barrier microvascular dys- cognitive performance tests (P Ͻ 0.02) and an increased number of mental subtraction errors for function may occur as a result of transient both type 1 and type 2 diabetic subjects. The effects of hyperglycemia were highly individualized, hyperglycemia (7). Altered synthesis or impacting ϳ50% of the subjects. reuptake of monoamine neurotransmit- ters as a result of altered precursor avail- CONCLUSIONS — Acute hyperglycemia is not a benign event for many individuals with ability to the brain or changes in insulin diabetes, but it is associated with mild cognitive dysfunction. availability to the brain are other possible Diabetes Care 28:71–77, 2005 explanations (8,9). Complex effects on peptide neurotransmitters may be pro- duced by uncontrolled diabetes (10,11). Any one of these mechanisms alone may atients with diabetes often report a blood glucose level of 16.7 mmol/l but be insufficient, and several of these mech- acute and transient cognitive dis- were unable to replicate this subsequently anisms could be additive. At this point, no ruptions associated with hypergly- using an auditory reaction-time task (2). P conclusion can be drawn about any spe- cemia. The impact of such effects could Davis et al. (3) reported that blood glu- influence quality of life and daily func- cose in the 20- to 30-mmol/l range was cific mechanism(s) responsible for possi- tioning, as well as indicate cues to aid pa- associated with a 9.5% reduction in type 1 ble short-term cognitive dysfunction. tients in better recognizing the presence diabetic children’s performance IQ. Per- However, hyperglycemia’s disruptive ef- of hyperglycemia. Holmes et al. (1) re- formance IQ was worsened in 67% of the fects on cognitive-motor functioning ported significant slowing of visual reac- children studied. Summerfield et al. (4) must first be verified, and then exploring tion time during a hospital clamp study at used a hyperinsulinic glucose clamp to possible physiological mechanisms will be justified. ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● The specific hypotheses tested in this From the University of Virginia Health System, Charlottesville, Virginia. study are 1) hyperglycemia is associated Address correspondence and reprint requests to Daniel J. Cox, Center for Behavioral Medicine Research, with cognitive-motor dysfunctions, 2) hy- Box 800-223, University of Virginia Health System, Charlottesville, VA, 22908. E-mail: [email protected]. perglycemia disrupts cognitive-motor Received for publication 8 March 2004 and accepted in revised form 21 September 2004. functioning in adults with either type 1 or K.H.S. is currently affiliated with Purdue University School of Pharmacy, West Lafayette, Indiana. Abbreviations: HHC, hand-held computer; PSAT, Paced Serial Addition Test; SMBG, self-monitoring of type 2 diabetes, and 3) cognitive-motor blood glucose. disruptions associated with hyperglyce- A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion mia are individualized. The last hypothe- factors for many substances. sis is based on our previous findings that © 2005 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby symptoms, as well as cognitive motor dis- marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. ruptions, associated with hypoglycemia DIABETES CARE, VOLUME 28, NUMBER 1, JANUARY 2005 71 Hyperglycemia cognitive-motor dysregulation Table 1—Demographic variables for the three study groups Study 1 Study 2 Study 3 Age (years) 37.5 Ϯ 0.9 (23–59) 50 Ϯ 11 (28–75) 39.4 Ϯ 10.4 (25–61) Disease duration (years) 19.7 Ϯ 9.9 (2–46) 10 Ϯ 9 (1–35) 20.2 Ϯ 10.7 (1–52) Mean blood glucose (mmol/l) 9.6 Ϯ 1.8 (4.7–16.9) 9.7 Ϯ 3.7 (5.9–23.9) 9.3 Ϯ 5.1 (1.1–33.3) Ϯ Ϯ Ϯ HbA1c (%) 8.6 2.3 (6.3–16.9)* 6.9 1 (7–14) 7.6 1.2 (4.0–12.6) BMI (kg/m2) NA 34 Ϯ 10 (19–65) 25.4 Ϯ 4.4 (17.7–41.2) % female 62 42 57 % using insulin 100 58 100 Ϯ Data are means SD (range) unless otherwise noted. *HbA1c estimate based on HbA1 assay. are individualized (12–14) in terms of came to mind. Then, the subject was pre- Study 2 subjects glycemic threshold for occurrence and in- sented with 10 mental subtraction prob- Thirty-four adults with type 2 diabetes dividual vulnerability. lems that involved subtracting a were recruited through newspaper and randomly generated single-digit number television announcements in Central Vir- RESEARCH DESIGN AND from a three-digit number with answers ginia. The subject group consisted of 15 METHODS entered on the HHC number pad. Finally, women and 19 men, with a mean (Ϯ SD) 15 four-choice reaction-time trials oc- age of 50 Ϯ 11 years and a mean diabetes Study 1 subjects curred in which the number 1, 3, 7, or 9 duration of 10 Ϯ 9 years (Table 1). A total of 105 adults with type 1 diabetes was randomly presented on the screen Procedures were identical to those of were recruited through three different and the subject pressed the correspond- study 1, except for the following differ- ϭ sites: the University of Virginia (n 33), ing number on the keypad as quickly as ences. The Handspring Visor Platinum ϭ Vanderbilt University (n 39), and the possible. The dependent variables were served as the HHC. Because the reaction- ϭ Joslin Diabetes Center (n 33). Because the number of “A” words recalled, time time test did not have a significant hyper- subjects were recruited to participate in to complete 10 mental subtractions, as glycemic group effect in study 1, in study the Blood Glucose Awareness Training well as the number of errors, and time to 2 it was replaced with two levels of the study (15), and not for the expressed pur- complete the 15 reaction-time trials. Paced Serial Addition Test (PSAT). The pose of investigating the acute effects of Next, the HHC prompted the subject PSAT presented a sequence of single-digit hyperglycemia, subjects and research as- to measure and enter his/her blood glu- numbers, and the subject entered the sum sistants collecting the data were blind to cose reading from the One Touch meter of each pair of sequential numbers. Levels the hypotheses. The subject group con- after completing the cognitive-motor 1 and 2 presented the numbers at 4- and sisted of 65 women and 40 men with a tests. To assess reliability, the 1-month 2-s intervals, respectively. The dependent mean (Ϯ SD) age of 37.5 Ϯ 9.0 years, a variables were the number of correct ad- HHC data collection was repeated 5 diabetes duration of 19.7 Ϯ 9.9 years, and ditions on the faster and slower PSAT. months later, generating an average of an HbA1 of 10.4 Ϯ 2.3% (equivalent to an 82.5 valid HHC trials per subject. HbA of 8.6%) (Table 1). Study 3 subjects 1c Three precautions were taken to en- In groups of four to eight subjects, the Ninety-one adults with type 1 diabetes study was described, informed consent courage and monitor valid data entry, i.e., were recruited through newspaper and was secured, and subjects were taught to cognitive-motor testing before SMBG and television announcements in Central use and demonstrated competency in the thus blind to actual blood glucose level. Virginia to participate in a study investi- use of One Touch memory meters (Lifes- First, the HHC prompted subjects with gating bio-behavioral precursors to hypo- can, Milpitas, CA) and the Psion 250 the message “No blood sample yet” as glycemia.