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Table 3 Studies of hyperglycemia or hyperinsulinemia and cognitive function in type 2 diabetes

From: The impact of diabetes on cognitive decline: potential vascular, metabolic, and psychosocial risk factors

Study Sample Design Number Baseline mean age Hyperglycemia/ hyperinsulinemia Cognitive measures Adjustment variables Association with cognitive function
Abbatecola et al. [30] (2006) Patients with diabetes free of vascular disease, receiving repaglinide or glibenclamide; Italy 12-month trial on glycemic control 156 Mean 74 ± 2 years Variation in post-prandial blood glucose, fasting plasma glucose, and HbA1c. (No difference between groups in reduction of HbA1c and plasma glucose during trial. Decline in variation in post-prandial glucose only in group treated with repaglinide.) Composite score of attention/executive function (Trail-Making Test, Digit Span, and verbal fluency), MMSE, cortical atrophy, and white matter lesions Age, education, physical activity, depression, blood pressure, cIMT, insulin resistance, and body mass index Association of higher variation in fasting plasma glucose and post-prandial blood glucose with lower cognitive function across groups at baseline (fully adjusted analyses). Composite score and MMSE declined in glibenclamide but not in repaglinide group during trial (analyses controlling only for HbA1c and variation in fasting plasma glucose).
Bruce et al. [14] (2008) Patients with type 2 diabetes participating in the Fremantle Diabetes Study; Australia 8-year retrospective, observational 302 Mean 76 ± 5 years HbA1c at baseline and 8 years earlier Dementia and MCI identified from screening instruments/clinical interview None No association
Bruce et al. [21] (2008) Patients with type 2 diabetes participating in the Fremantle Diabetes Study; Australia 8-year retrospective, 2-year prospective, observational. 205 Mean 75 ± 4 years HbA1c 8 years prior to baseline cognitive assessment Dementia and MCI identified from screening instruments/clinical interview at baseline and at 2-year follow-up. ‘Cognitive decline’ defined as downward conversion between ‘normal’, MCI, and dementia. None No association
Chen et al. [9] (2011) Patients with type 2 diabetes; China Cross-sectional, observational 101 Mean 63 ± 8 years HbA1c MCI identified on the basis of cognitive screening instrument None Higher HbA1c in group with MCI compared with group free of MCI
Chen et al. [11] (2012) Patients with type 2 diabetes; China Cross-sectional, observational 157 Mean 55 ± 7 years HbA1c MCI identified on the basis of cognitive screening instrument None No association
Cukierman-Yaffe et al. [13] (2009) Patients with type 2 diabetes participating in ACCORD-MIND; North America Cross-sectional analysis of trial on blood pressure, lipids, and glycemic control 2,977 Mean 63 ± 6 years HbA1c and fasting plasma glucose Digit Symbol Coding (primary outcome), MMSE, Rey Auditory Verbal Learning, and Stroop (secondary outcomes) Total of 18 demographic and clinical risk factors Higher HbA1c associated with lower Digit Symbol Coding. Findings for other cognitive tests did not survive full adjustment. No findings for fasting plasma glucose.
Launer et al. [28] (2011) Patients with type 2 diabetes participating in ACCORD-MIND trial, with HbA1c targets of <6.0 % versus 7.0 % to 7.9 %; North America 40-month trial on blood pressure, lipids and glycemic control 2,977 Mean 62 ± 6 years Successful manipulation of glycemic control. (Treatment groups differed in glycemic control following intervention.) Total brain volume and abnormal white matter at baseline and 40 months. Digit Symbol Coding (primary outcome), MMSE, Rey Auditory Verbal Learning, and Stroop (secondary outcomes) at baseline and 20 and 40 months. Second trial assignment (lipid or blood pressure trials), group allocation within second trial assignment, clinical center, and history of cardiovascular disease No difference in 20- or 40-month cognitive decline between intervention groups (fully adjusted analyses). Total brain volume declined at slower rate in intensively treated compared with standard treatment groups (independent of adjustment variables and of age, sex, duration of diabetes, Digit Symbol Coding). Greater abnormal white matter in intensively treated compared with standard treatment group at 40 months.
Manschot et al. [20] (2006) Patients with type 2 diabetes participating in the Utrecht Diabetic Encephalopathy Study; The Netherlands Cross-sectional, observational 122 Mean 66 ± 6 years HbA1c Composite scores on five cognitive domains from 11 cognitive tests, estimate of pre-morbid ability, cortical atrophy, and white matter lesions Age, sex, and estimated pre-morbid ability Association of higher HbA1c with steeper estimated lifetime decline in processing speed. No association of HbA1c with brain imaging data.
Manschot et al. [25] (2007) Patients with type 2 diabetes participating in the Utrecht Diabetic Encephalopathy Study; The Netherlands Cross-sectional, observational 122 Mean 66 ± 6 years HbA1c and plasma insulin Composite score from 11 cognitive tests, estimate of pre-morbid ability, cortical atrophy, and white matter lesions Age, sex, and estimated pre-morbid ability Association of higher HbA1c with steeper estimated lifetime decline in overall cognitive function. Association of higher insulin with greater severity of white matter lesions.
Ravona-Springer et al. [27] (2014) Patients with type 2 diabetes participating in the Israel Diabetes and Cognitive Decline Study; Israel 12-year retrospective observational 835 Mean 73 ± 5 years Data on HbA1c from diabetes register (mean 18 ± 10 measurements per patient). Six HbA1c trajectories identified (for example, high/increasing and high/stable). Measured at 12 years only: CDR, MMSE, and battery of seven cognitive tests. Sum of z-scores calculated for four cognitive domains. Age, sex, education, cardiovascular disease, years in diabetes register, anti-diabetes treatment, and depression Associations of HbA1c trajectories with level of overall cognitive function, semantic categorization, and executive function. Relatively poorest cognitive function in high/decreasing group and high/increasing groups. Relatively highest performance in low/stable group.
Ryan et al. [29] (2006) Patients with type 2 diabetes, receiving rosiglitazone or glibenclamide; USA 24-week trial 145 Mean 60 ± 1 years Successful manipulation of glycemic control and insulin sensitivity. (Treatment groups differed in fasting plasma glucose and fasting serum insulin following intervention.) CANTAB, Digit Symbol Coding, Rey Auditory Verbal Learning, and estimate of pre-morbid ability Age, center, pre-morbid ability, and baseline measurement of fasting plasma glucose/insulin Cognitive function improved equally in both treatment groups (fully adjusted analysis). Correlation of reduction in fasting plasma glucose with improvements in working memory across groups (unadjusted analysis). No finding for insulin.
Seaquist et al. [41] (2013) Patients with type 2 diabetes participating in ACCORD-MIND, with HbA1c targets of less than 6.0 % versus 7.0 % to 7.9 %; North America 40-month trial on blood pressure, lipids, and glycemic control 2,977 Mean 62 ± 6 years Treatment with insulin at enrolment and during trial Digit Symbol Coding at baseline and 20 and 40 months Total of 21 demographic, lifestyle, and clinical covariates Association of insulin use at enrolment with lower baseline cognitive function. Loss of statistical significance upon full adjustment. No association of insulin use during trial with 40-month cognitive decline in standard treatment group. Association of insulin use with steeper 40-month cognitive decline in intensive treatment group; loss of statistical significance upon full adjustment.
Umegaki et al. [16] (2014) Patients with type 2 diabetes; Japan 6-year prospective, observational 79 Mean 74 ± 5 years Mean of HbA1c and plasma immunoreactive insulin at baseline and annual follow-ups. Composite score from MMSE, Digit Symbol Coding, Stroop, and word recall. Analyses of ‘decliners’ versus ‘non-decliners’ on bases of composite score and individual cognitive tests. None No associations for HbA1c or insulin, except for higher mean 6-year insulin in ‘decliners’ compared with ‘non-decliners’ on Stroop.
Yanagawa et al. [15] (2011) Patients with diabetes receiving exercise program four times/week versus none; Japan 12-week trial on physical exercise intervention 16 Mean 71 ± 4 years HbA1c, fasting blood glucose, GIR, MCR in euglycemic clamp, and immunoreactive insulin. (No intervention effect on any of these measurements.) MMSE, word recall, Digit Symbol Coding, Stroop, and Trail-Making Test Age, education, and body mass index No difference in cognitive function between groups following intervention. Across groups, changes in HbA1c and changes in GIR correlated with changes in word recall. Changes in fasting blood glucose correlated with changes in Trail-Making.
  1. ACCORD-MIND, Action to Control Cardiovascular Risk in Diabetes-Memory in Diabetes; CANTAB, Cambridge Neuropsychological Test Automated Battery; CDR, Clinical Dementia Rating Scale; cIMT, carotid intima-media thickness; GIR, glucose infusion rate; MCI, mild cognitive impairment; MCR, metabolic clearance rate; MMSE, Mini-Mental State Examination