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Relationship between glycemic control and cognitive function in patients with type 2 diabetes in a hospital aged care unit
European Geriatric Medicine 2 (2011) 204–207
Research paper
Relationship between glycemic control and cognitive function in patients with type 2 diabetes in a hospital aged care unit S. Mahakaeo a,b,*, H. Zeimer a, M. Woodward a a b
Aged care services department, Heidelberg Repatriation Hospital, Melbourne, Australia Department of medicine, Samutprakarn general hospital, Samutprakarn province, Thailand
A R T I C L E I N F O
A B S T R A C T
Article history: Received 26 November 2010 Accepted 3 March 2011 Available online 4 May 2011
Objectives. – To examine the association between glycemic control and the degree of cognitive impairment in older patients with type 2 diabetes. Our hypothesis is less cognitive impairment is associated with better glycemic control. Design. – Cross-sectional study. Setting. – Patients in subacute aged care unit at Heidelberg Repatriation hospital in Melbourne, Australia. Participants. – A total of 142 subjects aged 63 to 96 with prior diagnosed type 2 diabetes. Methods. – Cognitive function was assessed using the Mini Mental State Examination (MMSE) and glycemic control was measured by a validated method. Results. – An inverse correlation was observed between the MMSE score and HbA1c levels (r = 0.239, P = 0.004), which persisted after controlling for variables of interest including age, gender, BMI, diabetes duration, years of education and other co-morbidities. A 1-point-higher MMSE score was associated with a 0.239 lower HbA1c value (P = 0.001). Conclusion. – This study suggests that better glycemic control is associated with less cognitive impairment in elderly patients with type 2 diabetes. ß 2011 Elsevier Masson SAS and European Union Geriatric Medicine Society. All rights reserved.
Keywords: Diabetes mellitus Glycemic control Cognitive function MMSE
Type 2 diabetes is a common disease, its prevalence increases with age and it has become a major health problem due to the aging of populations in developed countries. The prevalence of diabetes in all age-groups worldwide was estimated to be 2.8% in 2000 and is estimated to increase to 4.4% in 2030. The total number of people with diabetes worldwide has been predicted to increase from 171 million in 2000 to 366 million in 2030. By 2030, it is estimated that the number of people with diabetes more than 64 years of age will be greater than 82 million in developing countries and greater than 48 million in developed countries [1]. People with type 2 diabetes have abnormally high blood levels of glucose. Over time, particular types of damage to organs may ensue, including renal impairment secondary to diabetic nephropathy, impairment of vision due to retinopathy, peripheral neuropathy and arterial disease of the coronary, cerebral and peripheral arterial systems [2]. Although the effects of diabetes on the peripheral nervous system are well established, the effects of diabetes on the central nervous system have been less clear [2]. Cognitive impairment represents another serious problem and is rising in prevalence throughout the world, especially among the elderly. Cognition is a collective term for a range of higher brain functions, including
* Corresponding author. E-mail address: [email protected] (S. Mahakaeo).
memory, perception, language, and reasoning. Some degree of impairment of one or more cognitive function is common in later life. For a number of older people impairment may become severe, progressive and disabling and is described as dementia. Dementia is a devastating disease, which is challenging and costly to health and social services. Recent evidence from several epidemiological studies suggests that type 2 diabetes is also a risk factor for cognitive impairment [3–10]. One study suggests individuals with diabetes are 1.5 times more likely to experience cognitive decline and 1.6 times greater risk of future dementia than individuals without diabetes [11]. Neuropsychological tests have shown deficits in various aspects of cognitive function in both young and elderly populations with diabetes. Several studies found deficits in semantic memory [7,12,13], episodic memory [13], visuospatial ability [13], working memory [15], verbal fluency [15] and perceptual speed [7,13]. Some studies have found that higher glycated hemoglobin values were associated with moderate decline in motor speed [15] and psychomotor efficiency [4,14,15]. Also found in diabetic individuals are abnormalities in cognitive functions mediated by frontal lobe (executive functions), including a number of complex abilities such as problem solving, planning, organization, insight, reasoning and attention [5,15,16]. There is strong evidence that suggests intensive control of glycemia delays the onset and progression of long-term complications affecting the kidneys, eyes and arterial systems [17,18].
1878-7649/$ – see front matter ß 2011 Elsevier Masson SAS and European Union Geriatric Medicine Society. All rights reserved. doi:10.1016/j.eurger.2011.03.002
S. Mahakaeo et al. / European Geriatric Medicine 2 (2011) 204–207
However, there is no conclusive evidence that treatment or level of control of type 2 diabetes influences cognitive function. Our study aims to evaluate the cognitive function of hospitalized patients with type 2 diabetes using the Mini Mental State Examination (MMSE) [19] and to look for any association with glycemic control by measuring HbA1c. 1. Methods A cross-sectional study was conducted in 229 consecutive patients with a history of type 2 diabetes admitted to a subacute aged care unit at Heidelberg Repatriation Hospital. Data collection started in June, 2009 and was completed in June, 2010. Patients had to have been diagnosed with type 2 diabetes at least three months prior to entering the study. Of the eligible patients, 87 were excluded for reasons such as ongoing infection, cirrhosis with hepatic encephalopathy, end stage renal failure without dialysis, history of severe head injury, uncontrolled epilepsy, Parkinson’s disease, aphasia, delirium as documented in medical record, refusal to participate and inability to communicate in English. All patients were asked to undergo the MMSE. Glycated Hemoglobin (HbA1c) was measured by Cobas Integra1800 (Roche Diagnostics) with a reference value of 4.3–6%. Demographic characteristics and medical history were collected including age, gender, years of education, duration of diabetes, body mass index (BMI), history of hypertension, dyslipidemia, previous stroke including transient ischemic attack, previous cardiovascular disease including myocardial infarction, angina and coronary artery bypass grafting, history or current depression, diagnosed dementia, current smoking, current alcohol consumption and treatment of diabetes. This study was approved by Austin Health’s Human Research Ethics Committee (No.H2010/04005). 2. Statistic analysis All continuous data were tested for normality with Kolmogorov-Smirnov (KS) test. Statistical analysis was performed for comparison between groups (variables) with Independent t-test (normally distributed) and Mann-Whitney U test (non-normally distributed) for continuous data. The Chi2 test was used for comparison of categorical variables. Series of Pearson correlation and Spearman rank correlation methods were used to determine the variables that correlated with MMSE. These analyses were performed using the Statistical Package for the Social Science (SPSS Graduate Student Version 16.0 for Windows). A P-value of less than 0.05 was considered to be significant.
205
Table 1 Demographics and clinical characteristics. Number of patients
MMSE mean (SD)
Age (yr) 65 > 65
7 (4.9%) 135 (95.1%)
26.4 (2.07) 24.2 (4.61)
0.066
0.438
Gender Male Female
64 (45.1%) 78 (54.9%)
24.43 (4.09) 24.19 (4.68)
0.028
0.743
Current smoker Yes 5 (3.5%) No 137 (96.5%)
23.6 (6.14) 24.32 (4.36)
0.031
0.719
Hypertension Yes No
114 (80.3%) 28 (19.7%)
24.73 (3.98) 22.53 (5.58)
0.199
0.018a
Dyslipidemia Yes No
89 (62.7%) 53 (37.3%)
24.50 (4.09) 23.96 (4.93)
0.06
0.480
Stroke Yes No
34 (23.9%) 108 (76.1%)
23.85 (3.77) 24.45 (4.62)
Previous CVD Yes No
82 (57.7%) 60 (42.3%)
24.74 (4.01) 23.70 (4.88)
Dementia Yes No
18 (12.7%) 124 (87.3%)
18.88 (5.15) 25.08 (3.71)
0.469
< 0.00a
Past or current depression Yes 23 (16.2%) No 119 (83.8%)
23.69 (4.57) 24.42 (4.39)
0.061
0.473
a
Correlation value
0.057
0.117
P-value
0.498
0.165
Statistically significant by Pearson correlation method.
between MMSE score and HbA1c levels (r = 0.239, P = 0.004) (Fig. 1), which persisted after controlling for variables of interest including age, gender, BMI, diabetes duration, years of education and other comorbidities (r = 0.239, P = 0.001). MMSE scores correlated with age (r = 0.258, P = 0.002), years of education (r = 0.195, P=0.034) and diagnosis of hypertension (r = 0.199, P = 0.018). The association between MMSE score and age, years of education and diagnosis of hypertension did remain after adjusted for other variables by Linear regression method (r = 0.258, P = 0.001), (r = 0.195, P = 0.002) and [()TD$FIG](r = 0.199, P = 0.014) respectively. There was no association between
3. Results The study group was composed of 142 type 2 diabetic hospitalized patients, aged 79 7.6 years, 45.1% were male and 54.9% were female. The duration of diabetes was 12.6 9.8 years, 80.3% had hypertension, 62.7% had dyslipidemia, 23.9% had previous stroke, 57.7% had previous cardiovascular disease and 12.7% had dementia. Demographics and clinical characteristics of the patients are shown in Table 1. The treatment of diabetes was 35 (24.6%) diet alone and 67 (47.1%) taking one or more oral hypoglycemic agents (OHA). Insulin therapy alone and insulin plus one or more OHA was seen in 28 (19.7%) and 12 (8.4%) respectively. A total of 46.5% of patients had between eight or less years of education and 53.5% had more than nine years of education. The mean MMSE score was 24.3 4.4 points, with men (24.43 4.09) having an equal mean MMSE score to women (24.19 4.68) (P = 0.743). We then evaluated the relationship between cognitive function and glycemic control as measured by HbA1c levels. An inverse correlation was observed
Fig. 1. Relationship between glycated hemoglobin (HbA1c) concentration and MMSE scores on type 2 diabetes patients (N = 142).
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S. Mahakaeo et al. / European Geriatric Medicine 2 (2011) 204–207
smoking or BMI and MMSE score. Although our study had a small number of patients with dementia (n = 18), a correlation between MMSE and diagnosis of dementia was found (r = 0.469, P < 0.001) and strongly confirmed after controlling for variables using a Linear regression method (r = 0.469, P < 0.001). Nevertheless, the small number of patients with dementia did not allow further analysis. Cognitive function did not show an association with diabetes duration (r = 0.063, P = 0.472) and diagnosis of depression (r = 0.061, P = 0.473). 4. Discussion Many studies have reported cognitive deficits in elderly type 2 diabetics when compared to a non-diabetic population [3–7,10]. Elevated blood glucose levels have been assumed to have a detrimental effect on cognition. A small number of studies suggest that improving metabolic control may lead to better cognitive function [20–24]. This analysis of 142 individuals with established type 2 diabetes demonstrates a significant inverse relationship between cognitive function and the degree of glycemic control as measured by the HbA1c level. This study shows that a 1-pointhigher MMSE score was associated with a 0.239– lower HbA1c value. The relationship between the HbA1c level and cognition remained significant after adjustment for other factors. This evidence supports the hypothesis that lowering HbA1c levels has an impact on cognitive performance. Even if the effect is small, the effect may be clinically significant. Moreover, three studies demonstrated better functional and social outcomes with better glycemic control. For example, one study identified that elderly people with type 2 diabetes had a higher incidence of cognitive dysfunction compared to matched non-diabetic controls, and diabetics with a MMSE score of less than 23 had poorer ability in diabetes self-care and greater dependency [25]. Another study has shown that cognitive impairment was associated with worse glycemic control and identified those individuals with type 2 diabetes who may need higher levels of social support [26]. In addition, McGuire et al. found that individuals with diabetes who have low normal levels of cognition were approximately 20% more likely to die and 13% more likely to become disabled than those with higher levels of cognitive function [27]. The mechanism responsible for cognitive decline associated with diabetes is still unclear. A number of possible mechanisms have been raised. Firstly, hyperglycemia appears to be related to abnormalities in cognitive function in patients with type 2 diabetes. In other organs, hyperglycemia alters function through a variety of mechanisms including polyol pathway activation, increased formation of advanced glycation end products (AGEs), diacylglycerol activation of protein kinase C and increased glucose shunting in the hexosamine pathway [28–30]. These mechanisms may be occuring in the brain and induce the changes in cognitive function in patients with type 2 diabetes. Secondly, patients with diabetes have a two to six fold increased risk of thrombotic (but not hemorrhagic) stroke and even modest hyperglycemia increases the risk of stroke significantly [31]. Vascular disease has been long hypothesized to contribute to cognitive impairment in such patients. Thickening of capillary basement membranes, the hallmark of diabetic microangiopathy, has been demonstrated in the brain of diabetic animals [32]. Decreased cerebral blood flow has also been related to both acutely and chronically hyperglycemic animals [33]. In addition, cerebrovascular reactivity through the mechanism of sympathetic dysfunction and increased stimulation of the thromboxane A2 receptor is impaired in long-term diabetic patients and animals [34,35]. It could contribute to inability of cerebral vessels to adequately vasodilate, which may increase risk of ischemia [36]. Thirdly, many studies have shown that insulin affects the central nervous system [37,38] and could potentially impair
cognitive function. Insulin receptors are widely distributed in the brain [39], particularly in the hippocampus, and insulin crosses the blood brain barrier via a receptor-mediated active transport process [40]. Despite the presence of insulin receptors and insulinsensitive glucose transporters, the effect of insulin on cerebral glucose metabolism remains unclear. Animal studies have demonstrated that central insulin administration leads to improvements on spatial memory task [41] and can ameliorate memory deficits associated with streptozotocin-induced diabetes [42]. However, despite increasing evidence of possible linkages between insulin and cognition [37,38], many epidemiological studies found no evidence that treatment-induced differences in circulating insulin or insulin sensitivity were associated with a corresponding improvement in cognition [43]. A recent study suggests that rosiglitazone may prevent cognitive decline through insulin resistance mechanism in elderly with type 2 diabetes [44]. A suggested mechanism has been a possible linkage between peripheral hyperinsulinemia and reduced brain b-amyloid clearance by altered cerebral insulin degrading enzyme activity [45]. Fourthly, recurrent episodes of hypoglycemia causing neuroglycopenia have been implicated as a possible etiological factor for cognitive impairment in diabetes. This is significant because to recommend intensive glycemic control to minimize the risk of developing microvascular complications of diabetes will increase risk of hypoglycemic episodes [18]. History of severe hypoglycemic episodes in elderly with type 2 diabetes was found in a recent study to be associated with a greater risk of dementia [46]. With diabetes and cognition, some coexisting conditions, such as hypertension, depression and cardiovascular disease may be important confounders. In our study, type 2 diabetes patients with hypertension had higher MMSE scores compared to diabetic patients without hypertension. This finding is in contrast to other studies that report increased cognitive decline related to comorbid hypertension and diabetes [47,48]. Our study has a number of limitations. Firstly, as there was no non-diabetic control group of patients, we cannot comment on whether or not diabetes itself is associated with lower MMSE scores or whether there is a link between MMSE and HbA1c in nondiabetics. Next, our finding of an inverse relationship may be a consequence of having evaluated individuals with modest cognitive deficits who had few co-morbid conditions and were in relatively good metabolic control at study entry. Furthermore, the data collection of some factors including smoking, years of education and co-morbidity (CVD and hypertension) was based on self-report and the medical record which may have lead to recall bias. In addition, the MMSE is considered a screening test to detect delirium or dementia and provides only a ‘‘snapshot’’ of a patient’s cognitive status at a particular point in time. It may be influenced by acute disease and/or the patient’s concentration, and when used in isolation, as in this study, is not a reliable indicator of a patient’s cognitive function. We did not use other more comprehensive and confirmatory methods to better investigate cognitive impairment in our patients. Also, we excluded individuals from non-English speaking background, and so the study sample was not a true representation of all diabetic patients, which could lead to bias. However, this sample size was considered to be sufficiently powered to examine the relationship between HbA1c levels and cognition in diabetic patients. Moreover, our study was conducted in hospitalized elderly in an aged care unit in contrast to most studies in the literature which were conducted in outpatient clinics. Hospitalized patients are usually recovering from an acute illness or event, may have residual effects of a delirium, and tend to have more co-morbidities than outpatients. In summary, we found that better glycemic control was associated with less cognitive impairment in patients with type 2 diabetes. Further confirmation of the association is required in
S. Mahakaeo et al. / European Geriatric Medicine 2 (2011) 204–207
the form of a randomized, controlled trial of intensive versus less intensive glycemic control with cognitive endpoints. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Acknowledgements We would like to thank Dr. Sahaphol Anannumchareon and Plaiwan Suttanon for statistical analysis and data interpretation. Author contributions: Dr. Mahakaeo: concept and design, data collection, data analysis and interpretation, and preparation of manuscript. Dr. Zeimer: concept and design and preparation of manuscript. Dr. Woodward: preparation of manuscript. Sponsor’s Role: None. References [1] Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 2004;27:1047–53. [2] Evans JG, Sastre AA. Effect of the treatment of Type II diabetes mellitus on the development of cognitive impairment and dementia. Cochrane Database Syst Rev )2003;(1). doi: 10.1002/14651858.CD003804 [Art. No.: CD003804]. [3] Croxson SC, Jagger C. Diabetes and cognitive impairment: a community-based study of elderly subjects. Age Aging 1995;24(5):421–4. [4] Gregg EW, Yaffe K, Cauley JA, Rolka DB, Blackwell TL, Narayan V, et al. Is diabetes associated with cognitive impairment and cognitive decline among older women? Arch Intern Med 2000;160:174–80. [5] Fontbonne A, Ducimetiere P, Berr C, Alperovitch A. Changes in cognitive abilities over a 4-year period are unfavorably affected in elderly diabetic subjects. Diabetes Care 2001;24(2):366–70. [6] Logroscino G, Kang JH, Grodstein F. Prospective study of type 2 diabetes and cognitive decline in women aged 70–81 years. BMJ 2004;328(7439):548. [7] Arvanitakis Z, Wilson RS, Li Y, Aggarwal NT, Bennett DA. Diabetes and function in different cognitive systems in older individuals without dementia. Diabetes Care 2006;29(3):560–5. [8] Munshi M, Grande L, Hayes M, Ayres D, Suhl E, Capelson R, et al. Cognitive dysfunction is associated with poor diabetes control in older adults. Diabetes Care 2006;29(8):1794–9. [9] Arvanitakis Z, Wilson RS, Bennett DA. Diabetes mellitus, dementia, and cognitive function in older persons. J Nutr Health Aging 2006;10(4):287–91. [10] Okereke OI, Kang JH, Cook NR, Gaziano JM, Manson JE, Buring JE, et al. Type 2 diabetes mellitus and cognitive decline in two large cohorts of communitydwelling older adults. J Am Geriatr Soc 2008;56:1028–36. [11] Cukierman T, Gerstein HC, Williamson JD. Cognitive decline and dementia in diabetes – a systemic overview of prospective observational studies. Diabetologia 2005;42:2460–5. [12] Arvanitakis Z, Bennett DA, Wilson RS, Barnes LL. Diabetes and cognitive system in older black and white persons. Alzheimer Dis Assoc Disord 2010;24(1):37–42. [13] Arvanitakis Z, Wilson RS, Bienias JL, Evans DA, Bennett DA. Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function. Arch Neurol 2004;61:661–7. [14] The Diabetes Control. Complications trial/epidemiology of diabetes interventions and complications (DCCT/EDIC) Study Research Group. Long-Term Effect of Diabetes and Its Treatment on Cognitive Function. N Engl J Med 2007;356:1842–52. [15] Reaven GM, Thompson LW, Nahum D, Haskin E. Relationship between hyperglycemia and cognitive function in older NIDDM patients. Diabetes Care 1990;13(1):16–21. [16] Nguyen HT, Grzywacz JG, Arcury TA, Chapman C, Kirk JK, Ip EH, et al. Linking glycemic control and executive function in rural older adults with diabetes mellitus. J Am Geriatr Soc 2010;58:1123–7. [17] Stratton IM, Adler AI, Neil AW, Matthews DR, Manley SE, Cull CA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS35): prospective observational study. BMJ 2000;321:405–12. [18] Group UKPDS. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837–53. [19] Folstein MF, Folstein SE, McHugh PR. ‘‘Mini-mental state’’ a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189–98.
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Research paper
Relationship between glycemic control and cognitive function in patients with type 2 diabetes in a hospital aged care unit S. Mahakaeo a,b,*, H. Zeimer a, M. Woodward a a b
Aged care services department, Heidelberg Repatriation Hospital, Melbourne, Australia Department of medicine, Samutprakarn general hospital, Samutprakarn province, Thailand
A R T I C L E I N F O
A B S T R A C T
Article history: Received 26 November 2010 Accepted 3 March 2011 Available online 4 May 2011
Objectives. – To examine the association between glycemic control and the degree of cognitive impairment in older patients with type 2 diabetes. Our hypothesis is less cognitive impairment is associated with better glycemic control. Design. – Cross-sectional study. Setting. – Patients in subacute aged care unit at Heidelberg Repatriation hospital in Melbourne, Australia. Participants. – A total of 142 subjects aged 63 to 96 with prior diagnosed type 2 diabetes. Methods. – Cognitive function was assessed using the Mini Mental State Examination (MMSE) and glycemic control was measured by a validated method. Results. – An inverse correlation was observed between the MMSE score and HbA1c levels (r = 0.239, P = 0.004), which persisted after controlling for variables of interest including age, gender, BMI, diabetes duration, years of education and other co-morbidities. A 1-point-higher MMSE score was associated with a 0.239 lower HbA1c value (P = 0.001). Conclusion. – This study suggests that better glycemic control is associated with less cognitive impairment in elderly patients with type 2 diabetes. ß 2011 Elsevier Masson SAS and European Union Geriatric Medicine Society. All rights reserved.
Keywords: Diabetes mellitus Glycemic control Cognitive function MMSE
Type 2 diabetes is a common disease, its prevalence increases with age and it has become a major health problem due to the aging of populations in developed countries. The prevalence of diabetes in all age-groups worldwide was estimated to be 2.8% in 2000 and is estimated to increase to 4.4% in 2030. The total number of people with diabetes worldwide has been predicted to increase from 171 million in 2000 to 366 million in 2030. By 2030, it is estimated that the number of people with diabetes more than 64 years of age will be greater than 82 million in developing countries and greater than 48 million in developed countries [1]. People with type 2 diabetes have abnormally high blood levels of glucose. Over time, particular types of damage to organs may ensue, including renal impairment secondary to diabetic nephropathy, impairment of vision due to retinopathy, peripheral neuropathy and arterial disease of the coronary, cerebral and peripheral arterial systems [2]. Although the effects of diabetes on the peripheral nervous system are well established, the effects of diabetes on the central nervous system have been less clear [2]. Cognitive impairment represents another serious problem and is rising in prevalence throughout the world, especially among the elderly. Cognition is a collective term for a range of higher brain functions, including
* Corresponding author. E-mail address: [email protected] (S. Mahakaeo).
memory, perception, language, and reasoning. Some degree of impairment of one or more cognitive function is common in later life. For a number of older people impairment may become severe, progressive and disabling and is described as dementia. Dementia is a devastating disease, which is challenging and costly to health and social services. Recent evidence from several epidemiological studies suggests that type 2 diabetes is also a risk factor for cognitive impairment [3–10]. One study suggests individuals with diabetes are 1.5 times more likely to experience cognitive decline and 1.6 times greater risk of future dementia than individuals without diabetes [11]. Neuropsychological tests have shown deficits in various aspects of cognitive function in both young and elderly populations with diabetes. Several studies found deficits in semantic memory [7,12,13], episodic memory [13], visuospatial ability [13], working memory [15], verbal fluency [15] and perceptual speed [7,13]. Some studies have found that higher glycated hemoglobin values were associated with moderate decline in motor speed [15] and psychomotor efficiency [4,14,15]. Also found in diabetic individuals are abnormalities in cognitive functions mediated by frontal lobe (executive functions), including a number of complex abilities such as problem solving, planning, organization, insight, reasoning and attention [5,15,16]. There is strong evidence that suggests intensive control of glycemia delays the onset and progression of long-term complications affecting the kidneys, eyes and arterial systems [17,18].
1878-7649/$ – see front matter ß 2011 Elsevier Masson SAS and European Union Geriatric Medicine Society. All rights reserved. doi:10.1016/j.eurger.2011.03.002
S. Mahakaeo et al. / European Geriatric Medicine 2 (2011) 204–207
However, there is no conclusive evidence that treatment or level of control of type 2 diabetes influences cognitive function. Our study aims to evaluate the cognitive function of hospitalized patients with type 2 diabetes using the Mini Mental State Examination (MMSE) [19] and to look for any association with glycemic control by measuring HbA1c. 1. Methods A cross-sectional study was conducted in 229 consecutive patients with a history of type 2 diabetes admitted to a subacute aged care unit at Heidelberg Repatriation Hospital. Data collection started in June, 2009 and was completed in June, 2010. Patients had to have been diagnosed with type 2 diabetes at least three months prior to entering the study. Of the eligible patients, 87 were excluded for reasons such as ongoing infection, cirrhosis with hepatic encephalopathy, end stage renal failure without dialysis, history of severe head injury, uncontrolled epilepsy, Parkinson’s disease, aphasia, delirium as documented in medical record, refusal to participate and inability to communicate in English. All patients were asked to undergo the MMSE. Glycated Hemoglobin (HbA1c) was measured by Cobas Integra1800 (Roche Diagnostics) with a reference value of 4.3–6%. Demographic characteristics and medical history were collected including age, gender, years of education, duration of diabetes, body mass index (BMI), history of hypertension, dyslipidemia, previous stroke including transient ischemic attack, previous cardiovascular disease including myocardial infarction, angina and coronary artery bypass grafting, history or current depression, diagnosed dementia, current smoking, current alcohol consumption and treatment of diabetes. This study was approved by Austin Health’s Human Research Ethics Committee (No.H2010/04005). 2. Statistic analysis All continuous data were tested for normality with Kolmogorov-Smirnov (KS) test. Statistical analysis was performed for comparison between groups (variables) with Independent t-test (normally distributed) and Mann-Whitney U test (non-normally distributed) for continuous data. The Chi2 test was used for comparison of categorical variables. Series of Pearson correlation and Spearman rank correlation methods were used to determine the variables that correlated with MMSE. These analyses were performed using the Statistical Package for the Social Science (SPSS Graduate Student Version 16.0 for Windows). A P-value of less than 0.05 was considered to be significant.
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Table 1 Demographics and clinical characteristics. Number of patients
MMSE mean (SD)
Age (yr) 65 > 65
7 (4.9%) 135 (95.1%)
26.4 (2.07) 24.2 (4.61)
0.066
0.438
Gender Male Female
64 (45.1%) 78 (54.9%)
24.43 (4.09) 24.19 (4.68)
0.028
0.743
Current smoker Yes 5 (3.5%) No 137 (96.5%)
23.6 (6.14) 24.32 (4.36)
0.031
0.719
Hypertension Yes No
114 (80.3%) 28 (19.7%)
24.73 (3.98) 22.53 (5.58)
0.199
0.018a
Dyslipidemia Yes No
89 (62.7%) 53 (37.3%)
24.50 (4.09) 23.96 (4.93)
0.06
0.480
Stroke Yes No
34 (23.9%) 108 (76.1%)
23.85 (3.77) 24.45 (4.62)
Previous CVD Yes No
82 (57.7%) 60 (42.3%)
24.74 (4.01) 23.70 (4.88)
Dementia Yes No
18 (12.7%) 124 (87.3%)
18.88 (5.15) 25.08 (3.71)
0.469
< 0.00a
Past or current depression Yes 23 (16.2%) No 119 (83.8%)
23.69 (4.57) 24.42 (4.39)
0.061
0.473
a
Correlation value
0.057
0.117
P-value
0.498
0.165
Statistically significant by Pearson correlation method.
between MMSE score and HbA1c levels (r = 0.239, P = 0.004) (Fig. 1), which persisted after controlling for variables of interest including age, gender, BMI, diabetes duration, years of education and other comorbidities (r = 0.239, P = 0.001). MMSE scores correlated with age (r = 0.258, P = 0.002), years of education (r = 0.195, P=0.034) and diagnosis of hypertension (r = 0.199, P = 0.018). The association between MMSE score and age, years of education and diagnosis of hypertension did remain after adjusted for other variables by Linear regression method (r = 0.258, P = 0.001), (r = 0.195, P = 0.002) and [()TD$FIG](r = 0.199, P = 0.014) respectively. There was no association between
3. Results The study group was composed of 142 type 2 diabetic hospitalized patients, aged 79 7.6 years, 45.1% were male and 54.9% were female. The duration of diabetes was 12.6 9.8 years, 80.3% had hypertension, 62.7% had dyslipidemia, 23.9% had previous stroke, 57.7% had previous cardiovascular disease and 12.7% had dementia. Demographics and clinical characteristics of the patients are shown in Table 1. The treatment of diabetes was 35 (24.6%) diet alone and 67 (47.1%) taking one or more oral hypoglycemic agents (OHA). Insulin therapy alone and insulin plus one or more OHA was seen in 28 (19.7%) and 12 (8.4%) respectively. A total of 46.5% of patients had between eight or less years of education and 53.5% had more than nine years of education. The mean MMSE score was 24.3 4.4 points, with men (24.43 4.09) having an equal mean MMSE score to women (24.19 4.68) (P = 0.743). We then evaluated the relationship between cognitive function and glycemic control as measured by HbA1c levels. An inverse correlation was observed
Fig. 1. Relationship between glycated hemoglobin (HbA1c) concentration and MMSE scores on type 2 diabetes patients (N = 142).
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smoking or BMI and MMSE score. Although our study had a small number of patients with dementia (n = 18), a correlation between MMSE and diagnosis of dementia was found (r = 0.469, P < 0.001) and strongly confirmed after controlling for variables using a Linear regression method (r = 0.469, P < 0.001). Nevertheless, the small number of patients with dementia did not allow further analysis. Cognitive function did not show an association with diabetes duration (r = 0.063, P = 0.472) and diagnosis of depression (r = 0.061, P = 0.473). 4. Discussion Many studies have reported cognitive deficits in elderly type 2 diabetics when compared to a non-diabetic population [3–7,10]. Elevated blood glucose levels have been assumed to have a detrimental effect on cognition. A small number of studies suggest that improving metabolic control may lead to better cognitive function [20–24]. This analysis of 142 individuals with established type 2 diabetes demonstrates a significant inverse relationship between cognitive function and the degree of glycemic control as measured by the HbA1c level. This study shows that a 1-pointhigher MMSE score was associated with a 0.239– lower HbA1c value. The relationship between the HbA1c level and cognition remained significant after adjustment for other factors. This evidence supports the hypothesis that lowering HbA1c levels has an impact on cognitive performance. Even if the effect is small, the effect may be clinically significant. Moreover, three studies demonstrated better functional and social outcomes with better glycemic control. For example, one study identified that elderly people with type 2 diabetes had a higher incidence of cognitive dysfunction compared to matched non-diabetic controls, and diabetics with a MMSE score of less than 23 had poorer ability in diabetes self-care and greater dependency [25]. Another study has shown that cognitive impairment was associated with worse glycemic control and identified those individuals with type 2 diabetes who may need higher levels of social support [26]. In addition, McGuire et al. found that individuals with diabetes who have low normal levels of cognition were approximately 20% more likely to die and 13% more likely to become disabled than those with higher levels of cognitive function [27]. The mechanism responsible for cognitive decline associated with diabetes is still unclear. A number of possible mechanisms have been raised. Firstly, hyperglycemia appears to be related to abnormalities in cognitive function in patients with type 2 diabetes. In other organs, hyperglycemia alters function through a variety of mechanisms including polyol pathway activation, increased formation of advanced glycation end products (AGEs), diacylglycerol activation of protein kinase C and increased glucose shunting in the hexosamine pathway [28–30]. These mechanisms may be occuring in the brain and induce the changes in cognitive function in patients with type 2 diabetes. Secondly, patients with diabetes have a two to six fold increased risk of thrombotic (but not hemorrhagic) stroke and even modest hyperglycemia increases the risk of stroke significantly [31]. Vascular disease has been long hypothesized to contribute to cognitive impairment in such patients. Thickening of capillary basement membranes, the hallmark of diabetic microangiopathy, has been demonstrated in the brain of diabetic animals [32]. Decreased cerebral blood flow has also been related to both acutely and chronically hyperglycemic animals [33]. In addition, cerebrovascular reactivity through the mechanism of sympathetic dysfunction and increased stimulation of the thromboxane A2 receptor is impaired in long-term diabetic patients and animals [34,35]. It could contribute to inability of cerebral vessels to adequately vasodilate, which may increase risk of ischemia [36]. Thirdly, many studies have shown that insulin affects the central nervous system [37,38] and could potentially impair
cognitive function. Insulin receptors are widely distributed in the brain [39], particularly in the hippocampus, and insulin crosses the blood brain barrier via a receptor-mediated active transport process [40]. Despite the presence of insulin receptors and insulinsensitive glucose transporters, the effect of insulin on cerebral glucose metabolism remains unclear. Animal studies have demonstrated that central insulin administration leads to improvements on spatial memory task [41] and can ameliorate memory deficits associated with streptozotocin-induced diabetes [42]. However, despite increasing evidence of possible linkages between insulin and cognition [37,38], many epidemiological studies found no evidence that treatment-induced differences in circulating insulin or insulin sensitivity were associated with a corresponding improvement in cognition [43]. A recent study suggests that rosiglitazone may prevent cognitive decline through insulin resistance mechanism in elderly with type 2 diabetes [44]. A suggested mechanism has been a possible linkage between peripheral hyperinsulinemia and reduced brain b-amyloid clearance by altered cerebral insulin degrading enzyme activity [45]. Fourthly, recurrent episodes of hypoglycemia causing neuroglycopenia have been implicated as a possible etiological factor for cognitive impairment in diabetes. This is significant because to recommend intensive glycemic control to minimize the risk of developing microvascular complications of diabetes will increase risk of hypoglycemic episodes [18]. History of severe hypoglycemic episodes in elderly with type 2 diabetes was found in a recent study to be associated with a greater risk of dementia [46]. With diabetes and cognition, some coexisting conditions, such as hypertension, depression and cardiovascular disease may be important confounders. In our study, type 2 diabetes patients with hypertension had higher MMSE scores compared to diabetic patients without hypertension. This finding is in contrast to other studies that report increased cognitive decline related to comorbid hypertension and diabetes [47,48]. Our study has a number of limitations. Firstly, as there was no non-diabetic control group of patients, we cannot comment on whether or not diabetes itself is associated with lower MMSE scores or whether there is a link between MMSE and HbA1c in nondiabetics. Next, our finding of an inverse relationship may be a consequence of having evaluated individuals with modest cognitive deficits who had few co-morbid conditions and were in relatively good metabolic control at study entry. Furthermore, the data collection of some factors including smoking, years of education and co-morbidity (CVD and hypertension) was based on self-report and the medical record which may have lead to recall bias. In addition, the MMSE is considered a screening test to detect delirium or dementia and provides only a ‘‘snapshot’’ of a patient’s cognitive status at a particular point in time. It may be influenced by acute disease and/or the patient’s concentration, and when used in isolation, as in this study, is not a reliable indicator of a patient’s cognitive function. We did not use other more comprehensive and confirmatory methods to better investigate cognitive impairment in our patients. Also, we excluded individuals from non-English speaking background, and so the study sample was not a true representation of all diabetic patients, which could lead to bias. However, this sample size was considered to be sufficiently powered to examine the relationship between HbA1c levels and cognition in diabetic patients. Moreover, our study was conducted in hospitalized elderly in an aged care unit in contrast to most studies in the literature which were conducted in outpatient clinics. Hospitalized patients are usually recovering from an acute illness or event, may have residual effects of a delirium, and tend to have more co-morbidities than outpatients. In summary, we found that better glycemic control was associated with less cognitive impairment in patients with type 2 diabetes. Further confirmation of the association is required in
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the form of a randomized, controlled trial of intensive versus less intensive glycemic control with cognitive endpoints. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Acknowledgements We would like to thank Dr. Sahaphol Anannumchareon and Plaiwan Suttanon for statistical analysis and data interpretation. Author contributions: Dr. Mahakaeo: concept and design, data collection, data analysis and interpretation, and preparation of manuscript. Dr. Zeimer: concept and design and preparation of manuscript. Dr. Woodward: preparation of manuscript. Sponsor’s Role: None. References [1] Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 2004;27:1047–53. [2] Evans JG, Sastre AA. Effect of the treatment of Type II diabetes mellitus on the development of cognitive impairment and dementia. Cochrane Database Syst Rev )2003;(1). doi: 10.1002/14651858.CD003804 [Art. No.: CD003804]. [3] Croxson SC, Jagger C. Diabetes and cognitive impairment: a community-based study of elderly subjects. Age Aging 1995;24(5):421–4. [4] Gregg EW, Yaffe K, Cauley JA, Rolka DB, Blackwell TL, Narayan V, et al. Is diabetes associated with cognitive impairment and cognitive decline among older women? Arch Intern Med 2000;160:174–80. [5] Fontbonne A, Ducimetiere P, Berr C, Alperovitch A. Changes in cognitive abilities over a 4-year period are unfavorably affected in elderly diabetic subjects. Diabetes Care 2001;24(2):366–70. [6] Logroscino G, Kang JH, Grodstein F. Prospective study of type 2 diabetes and cognitive decline in women aged 70–81 years. BMJ 2004;328(7439):548. [7] Arvanitakis Z, Wilson RS, Li Y, Aggarwal NT, Bennett DA. Diabetes and function in different cognitive systems in older individuals without dementia. Diabetes Care 2006;29(3):560–5. [8] Munshi M, Grande L, Hayes M, Ayres D, Suhl E, Capelson R, et al. Cognitive dysfunction is associated with poor diabetes control in older adults. Diabetes Care 2006;29(8):1794–9. [9] Arvanitakis Z, Wilson RS, Bennett DA. Diabetes mellitus, dementia, and cognitive function in older persons. J Nutr Health Aging 2006;10(4):287–91. [10] Okereke OI, Kang JH, Cook NR, Gaziano JM, Manson JE, Buring JE, et al. Type 2 diabetes mellitus and cognitive decline in two large cohorts of communitydwelling older adults. J Am Geriatr Soc 2008;56:1028–36. [11] Cukierman T, Gerstein HC, Williamson JD. Cognitive decline and dementia in diabetes – a systemic overview of prospective observational studies. Diabetologia 2005;42:2460–5. [12] Arvanitakis Z, Bennett DA, Wilson RS, Barnes LL. Diabetes and cognitive system in older black and white persons. Alzheimer Dis Assoc Disord 2010;24(1):37–42. [13] Arvanitakis Z, Wilson RS, Bienias JL, Evans DA, Bennett DA. Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function. Arch Neurol 2004;61:661–7. [14] The Diabetes Control. Complications trial/epidemiology of diabetes interventions and complications (DCCT/EDIC) Study Research Group. Long-Term Effect of Diabetes and Its Treatment on Cognitive Function. N Engl J Med 2007;356:1842–52. [15] Reaven GM, Thompson LW, Nahum D, Haskin E. Relationship between hyperglycemia and cognitive function in older NIDDM patients. Diabetes Care 1990;13(1):16–21. [16] Nguyen HT, Grzywacz JG, Arcury TA, Chapman C, Kirk JK, Ip EH, et al. Linking glycemic control and executive function in rural older adults with diabetes mellitus. J Am Geriatr Soc 2010;58:1123–7. [17] Stratton IM, Adler AI, Neil AW, Matthews DR, Manley SE, Cull CA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS35): prospective observational study. BMJ 2000;321:405–12. [18] Group UKPDS. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837–53. [19] Folstein MF, Folstein SE, McHugh PR. ‘‘Mini-mental state’’ a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189–98.
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