Valentina Tjandra Dewi, M.D.1, Anak Agung Ayu Putri Laksmidewi, M.D.1, Anak Agung Ayu Suryapraba, M.D.1, Wira Gotera, M.D.2, I Putu Eka Widyadharma, M.D.1, I Made Oka Adnyana, M.D.1
1Department of Neurology, Faculty of Medicine Universitas Udayana, Indonesia, 2Department of Internal Medicine, Faculty of Medicine Universitas
Udayana, Indonesia.
≥26. Vitamin D levels were assessed using serum 25-hydroxyvitamin D levels. The cut-off for vitamin D deficiency was obtained through the receiver operating curve characteristic.
Type 2 diabetes mellitus (T2DM) carries a high risk of mortality and morbidity in the community.1 Various complications can be caused by T2DM, including cognitive impairment.2,3 Insulin dysregulation is a key element of neurodegeneration in T2DM. Insulin binds to its receptors on the blood-brain barrier and is transported into the central nervous system. Insulin appears to have a neurotropic role in the brain.2
Several previous studies indicate an association
between vitamin D deficiency and a higher prevalence of diabetes.4–6 Vitamin D is also reported to be associated with cognitive function.7 This association is supported by the anti-inflammatory, antioxidant, and neuroprotective functions of vitamin D. These substances increase neurotrophic factors such as nerve growth factor (NGF) which maintains better brain health. Vitamin D also helps to prevent amyloid accumulation and supports amyloid clearance.8
Corresponding author: Anak Agung Ayu Putri Laksmidewi E-mail: putri_laksmidewi@unud.ac.id
Received 23 September 2023 Revised 31 October 2023 Accepted 20 November 2023 ORCID ID:http://orcid.org/0000-0002-6372-2399 https://doi.org/10.33192/smj.v76i1.265476
All material is licensed under terms of the Creative Commons Attribution 4.0 International (CC-BY-NC-ND 4.0) license unless otherwise stated.
Evidence regarding an association between vitamin D status and dementia risk in patients with diabetes is scant, although several epidemiological studies have linked lower vitamin D concentrations to dementia risk in the general population. A recent cohort study showed that a higher serum vitamin D level in type 2 DM patients was associated with a lower risk of dementia.9
No studies have been published analysing the association between vitamin D levels and cognitive impairment in patients with T2DM in Indonesia . Therefore the aim of this study was to analyse the impact of vitamin D levels in T2DM patients with and without cognitive impairment
The research was conducted at the neurology outpatient clinic and diabetic center of Prof. Dr. I.G.N.G Ngoerah Hospital from September to December 2022 using a case-control design. The study was reviewed and approved by the Institution Review Board of Faculty of Medicine Universitas Udayana/ RSUP Prof. Dr. I.G.N.G Ngoerah Denpasar No.2553/UN14.2.2.VII.14/LT/2022 on September, 22nd 2022. Written informed consent was obtained from each patient prior to the study.
Inclusion criteria were T2DM and age between 45 and 65 years. Exclusion criteria were chronic hepatic impairment, gastrointestinal disease (ulcerative colitis or Crohn's disease), having vitamin D supplementation regularly in the last 1 month, immobilization, history of stroke, central nervous system (CNS) infection, HIV-AIDS, brain tumor, Parkinson's disease, epilepsy, depression, pre-diabetic cognitive impairment, recurrent severe hypoglycemia, head trauma, heart failure, alcohol drinkers, and severe visual and hearing impairment.
The Montreal Cognitive Assessment questionnaire, Indonesian version, (MoCA-Ind) was applied to determine cognitive impairment. It is a brief, validated, and easy-to- use tool to identify mild and early Alzheimer's dementia with good sensitivity and specificity.10,11 A scores of <26 indicate cognitive impairment7. The Hamilton Depression Rating Scale (HDRS) was applied to determine presences of depression (score of ≥8).12 The Ascertain Dementia 8 – Indonesian version (AD 8-Ina) questionnaire answered by family or caregivers was applied to determine pre- diabetic cognitive impairment.10
All participants then underwent venous blood sampling by experts for laboratory examination of serum 25(OH)D levels measured in ng/ml using the Enzyme- Linked Immunosorbent Assay (ELISA) method in the Clinical Pathology Laboratory of Prof. Dr. I.G.N.G Ngoerah Hospital.
Potential confounding variables were poor glycemic
control (HbA1c ≥7%), T2DM duration >5 years, hypertension, dyslipidemia, obesity, chronic kidney disease (CKD), and low education level (<12 years).
The data analysis was carried out using IBM SPSS Statistics version 25. All of the analyzed variables are presented in nominal variables. Bivariate associations were analysed using Chi-Square test. The cut-off for vitamin D deficiency was obtained through the receiver operating curve (ROC) characteristics. All variables with a significance value of less than 0.25 from the bivariate analysis will be included in the multivariate or logistic regression analysis. Logistic regression analysis was applied to explore associations of confounding variables with cognitive impairment. A p-value ≤ 0.05 was regarded as statistically significant.
There were 71 patients eligible for the study but 9 patients refused to participate. Thirty-one patients from each of the case and control groups were included in the study (Table 1). The ROC method yielded an Area Under the Curve (AUC) value of 75.3% [95% Confidence Interval (CI) 63.3 to 87.2%] (Fig 1). A vitamin D cut-off value of 24.6 ng/ml resulted in a sensitivity of 61.3% and specificity of 64.5% (Fig 2).
T2DM patients with vitamin D deficiency had a significantly higher risk of experiencing cognitive impairment compared to the control group (OR 2.8; 95% CI [1.1 to 8.1]; p=0.042) (Table 1). Confounding variables significantly associated with cognitive impairment in T2DM were education level, diabetes duration, hypertension, and gender (Table 2). The obesity variable has a significance value of less than 0.25 so it also be analyzed in the multivariate analysis. In the multivariable logistic regression analysis vitamin D deficiency, low education level, and T2DM duration >5 years were associated with cognitive impairments (Table 3).
The mean serum vitamin D level in the case group was significantly higher than in the control group (Table 1). These results are in line with a study by Rui- Hua et al. which found that the average vitamin D level in patients with T2DM with mild cognitive impairment (MCI) was 15.75 ng/ml and significantly lower than the normal cognitive group (23.04 ng/ml) (p<0.001).7
Vitamin D deficiency is associated with cognitive impairment in T2DM patients in this study. A cohort study involving 13,486 patients in the United Kingdom used a 20 ng/ml limit for all outcomes in measuring the association between vitamin D levels and the risk
TABLE 1. Characteristics of cases and controls.
Characteristics | Cases Cognitive Impairment | Controls Without Cognitive Impairment | p |
(n= 31) | (n=31) | ||
Age, | |||
(mean ± SD) years | 55.1 ± 6.2 | 56.1 ± 5.2 | 0.507† |
Gender, | |||
Female, n (%) | 16 (52%) | 8 (26%) | 0.037*‡ |
Duration of education, | |||
median (25th; 75th percentile) years | 12 (6 ; 15) | 12 (12 ; 14) | 0.217§ |
BMI, | |||
median (min-max) kg/m2 | 25.80 | 25.5 | 0.068‡ |
(19.7-36.7) | (18.3-36.7) | ||
Occupation, | |||
Civil workers, n (%) | 3 (9.7%) | 2 (6.5%) | 0.364‡ |
Teacher | 1 (3.2%) | 1 (3.2%) | |
Unemployed | 9 (29%) | 4 (12.9%) | |
Farmer | 0 (0%) | 1 (3.2%) | |
Medical workers | 3 (9.7%) | 1 (3.2%) | |
Entrepreneur | 15 (48.4%) | 22 (71%) | |
MoCA-Ina score, | |||
median (min-max) | 22 (11-25) | 27 (26-30) | 0.000*§ |
HbA1c, | |||
median (min-max) % | 7.2 (5.2-14) | 6.6 (5.9-14) | 0.866§ |
Vitamin D serum, | |||
(mean±SD) ng/ml | 20.5 ± 7 | 28.6 ± 9 | 0.000*† |
Vitamin D category | |||
Deficiency, n (%) | 20 (64.5%) | 12 (38.7%) | 0.042; OR |
Without deficiency | 11 (35.5%) | 19 (61.3%) | (95% CI) |
2.9 (1.1 to 8.1) | |||
*p<0.05 †independent T-test, ‡chi-square test, §mann-whitney test. BMI, Body Mass Index; MoCA-Ina, Montreal Cognitive Assessment- Indonesian Version; HbA1c, glycated hemoglobin; SD, standard deviation
TABLE 2. Results of the bivariate analysis between potential confounding variables and cognitive impairment in T2DM patients.
Variables | Cases | Controls | OR | p |
n (%) | n (%) | (95% CI) | ||
Duration of education | ||||
Low (<12 years) | 13 (21%) | 5 (16.1%) | 3.8 | 0.025* |
High (≥12 years) | 18 (58.1%) | 26 (83.9%) | (1.1 to 12.4) | |
Duration of T2DM | ||||
> 5 years | 15 (48.4%) | 7 (22.6%) | 3.2 | 0.034* |
≤ 5 years | 16 (51.6%) | 24 (77.4%) | (1.1 to 9.6) | |
Glycemic control | ||||
Poor | 17 (54.8%) | 13 (41.9%) | 1.7 | 0.309 |
Good | 14 (45.2%) | 18 (58.1%) | (0.6 to 4.6) | |
Hypertension | ||||
Present | 19 (61.3%) | 11 (35.5%) | 2.9 | 0.042* |
Not present | 12 (38.7%) | 20 (64.5%) | (1.1 to 8.1) | |
Dyslipidemia | ||||
Present | 11 (35.5%) | 9 (29%) | 1.3 | 0.587 |
Not present | 20 (64.5%) | 22 (71%) | (0.5 to 3.9) | |
Obesity | ||||
Present | 10 (32.3%) | 4 (12.9%) | 3.2 | 0.068 |
Not present | 21 (67,.7%) | 27 (87.1%) | (0.9 to 11.7) | |
CKD | ||||
Present | 7 (22.6%) | 7 (22.6%) | 1 | 1.000 |
Not present | 24 (77.4%) | 24 (77.4%) | (0.3 to 3.3) | |
Gender | ||||
Female | 16 (51.6%) | 8 (25.8%) | 3.1 | 0.037* |
Male | 15 (48.4%) | 23 (74.2%) | (1.1 to 8.9) | |
*p<0.05. OR, Odd Ratio; CI, Confidence Interval; T2DM, type 2 Diabetes Mellitus; CKD, Chronic Kidney Disease.
TABLE 3. Results of the multivariable logistic regression analysis to statistically predict cognitive impairment in patients with T2DM
Variables | B | S.E | Adjusted OR Final step | 95% CI | p |
Vitamin D deficiency | 1.3 | 0.6 | 3.8 | 1.1 to 13.4 | 0.036 |
Duration of T2DM >5 years | 1.4 | 0.6 | 4.1 | 1.2 to 14.4 | 0.030 |
Duration of education <12 years | 1.7 | 0.7 | 5.4 | 1.3 to 22.2 | 0.019 |
Hypertension | 1.3 | 0.6 | 3.5 | 1 to 12.3 | 0.050 |
Obesity | 1.5 | 0.8 | 4.3 | 0.9 to 19.8 | 0.061 |
B, Beta; S.E, Standard Error; OR, Odd Ratio; CI, Confidence Interval; T2DM, type 2 Diabetes Mellitus
of dementia in T2DM. The results obtained from this 8-year cohort study showed that higher serum 25(OH)D levels were significantly associated with a lower risk of Alzheimer's dementia (AD), vascular dementia (VD), and all-cause dementia.9
The exact mechanism underlying the relationship between vitamin D and dementia in diabetics still needs further research, the most frequently suggested pathways from are the neurodegenerative and vascular pathways.9 Experimental studies show that vitamin D can enhance the clearance of amyloid plaques by stimulating macrophages13, in addition, vitamin D can suppress macrophage migration among patients with diabetes.9 In vivo studies demonstrated increased vitamin
D receptors in diabetic mice neurons indicating that the vitamin D signaling system could be a potential therapeutic target for diabetic neuropathy.14 In addition, there is mounting evidence that vitamin D can improve glycemic control, blood pressure, and lipid metabolism in diabetic patients.9
Vitamin D can play an important role in normal neural function supported by the presence of vitamin D3 25-hydroxylase and 25-hydroxyvitamin D3-1α-hydroxylase in brain tissue.15 Observations showed that the cultured microglia of mice could produce 1,25(OH)2D3, and there were findings of 1,25(OH)2D3 in human cerebrospinal fluid.16 1,25(OH)2D3 is thought to bind and act on vitamin
D receptors found in the brain and spinal cord, while
vitamin D receptor (VDR) gene expression was observed in neuronal and glial cells. It was found that 1,25(OH)2D3 therapy increases choline acetyltransferase activity in the brain nuclei of mice.17 Another relatively direct effect of vitamin D on normal neural function is through
increased neurotrophin synthesis as demonstrated by the finding that 1,25(OH)2D3 stimulates the synthesis of NGF, glial cell line-derived neurotrophic factor (GDNF), and neurotrophin 3 (NT3) in various non-clinical studies.18 Vitamin D appears to protect the brain from free radical-induced damage by inhibition of 1,25(OH)2D3 inducible Nitric Oxide Synthase (iNOS) synthesis.17 Moreover, protection against oxygen-derived free radicals can come from increasing glutathione levels through upregulation of gamma-glutamyl transpeptidase as seen
in the mice brain treated with 1,25(OH)2D3.19
Low education level and diabetes duration of more
than 5 years were also significantly associated with risk of cognitive impairment. Educational level is widely used as an indicator of cognitive reserve capacity. Individuals with greater cognitive reserves can tolerate a higher neuropathological burden than those with smaller cognitive reserves.20 A low education level is also associated with a lack of ability to control vascular risk factors, maintain healthy diets and a lack of affordability to access health services.21
A study by Sun et al. also found that T2DM patients experienced an average of MCI after having diabetes for 6.34±2.53 years, whereas patients who had severe cognitive dysfunction had an average of T2DM for 10.14±8.24 years. Along with diabetes duration, there is an increase of neuronal damage which comes from macrovascular and microvascular disease, oxidative stress, and insulin resistance.22
In this study glycemic control, hypertension, dyslipidemia, obesity, chronic kidney disease, and female gender were not associated with cognitive impairment in T2DM patients. Poor glycemic control is thought
to be one of the risk factors for cognitive impairment in patients with T2DM, however, previous studies still show contrasting results to date.23,24 Analysis of mean HbA1c and fasting blood glucose over a certain period is suggested to be more important than static measurements.25 Glycemic variability is not represented completely by HbA1c values especially in patients with good metabolic control.26 Hypertension is a risk factor for cardio-cerebrovascular disease, cerebral small vessel disease (CSVD), and cerebral atrophy but the direct association between hypertension and cognitive decline is uncertain.27
The association between obesity and cognitive impairment was not significant. Both case and control groups in this study had a greater percentage of patients without obesity. A meta-analysis showed that being underweight, overweight, and obese in middle age increases the risk of dementia.28 Obesity is stated by Xiu et al. not an independent factor of cognitive impairment in T2DM.29
Chronic kidney disease was not associated significantly with cognitive impairment in this study. This could be due to the incidentally balanced proportion of CKD sufferers in the case and control groups. The accumulation of advanced glycated end products (AGEs) triggers vascular endothelial dysfunction which can lead to increased fragility and permeability of cerebral vessels.30 The direct neuronal toxicity effect of uremic toxins on the cerebral vasculature will accelerate vascular calcification and endothelial dysfunction.31
Female gender in multivariable analysis was not significantly related to cognitive impairment in T2DM. Results of previous research regarding the role of gender in cognitive impairment risk in T2DM are varying. That could be the result of different eligibility criterias and the presence of confounding factors.32,33 A meta- analysis showed that women have a higher relative risk of developing vascular dementia associated with T2DM than men, however, in non-vascular dementia there was no difference. The exact underlying mechanism is unknown, increased exposure to endogenous estradiol especially in women with post-menopausal diabetes is thought to carry a higher risk of dementia.34 The study by Espeland et al concluded that only the carrier status of the apoE-epsilon 4 gene influenced the degree of sex- related differences.33 More in-depth research including assessment of the menopausal phase, lifestyle, and genetic factors still needed to evaluate the role of gender in the diabetics' cognitive function.
This study has some strengths and limitations. Vitamin D examination is highly available and applicable nowadays
in many healthcare facilities at relatively affordable prices. The new limit value for vitamin D deficiency obtained from this study is expected to enrich the literature and provide a basis for further research on the prevention of cognitive impairment in T2DM patients. The limitation of this study is there were some confounding factors that could not be adjusted by design in this study since the research was carried out in a center referral hospital with a high complexity of cases. In addition, the sample size is limited, so it cannot be used to characterize the population as a whole.
In conclusion, vitamin D deficiency in T2DM patients is one of factors associated with cognitive impairment based on our study. Future research with a cohort design is needed to assess the causality relationship between vitamin D deficiency and cognitive impairment in diabetic patients.
Conflicts of interest
The authors have no potential conflicts of interest to disclose.
Mehrabian S, Raycheva M, Gateva A, Todorova G, Angelova P, Traykova M, et al. Cognitive dysfunction profile and arterial stiffness in type 2 diabetes. J Neurol Sci 2012;322:152-6.
Saedi E, Gheini MR, Faiz F, Arami MA. Diabetes mellitus and cognitive impairments. World J Diabetes 2016;7:412-22.
Mudanayasa IK. Diabetes Melitus Tipe 2 sebagai Faktor Risiko Gangguan Fungsi Kognitif pada Usia Dewasa Muda. 2012.
Mathieu C. Vitamin D and diabetes: where do we stand? Diabetes Res Clin Pract 2015;108:201-9.
Vondra K, Hampl R. Vitamin D and new insights into pathophysiology of type 2 diabetes. Horm Mol Biol Clin Investig 2021;42:203-8.
Berridge MJ. Vitamin D deficiency and diabetes. Biochem J 2017;474:1321-32.
Rui-Hua C, Yong-de P, Xiao-Zhen J, Chen J, Bin Z. Decreased levels of serum IGF-1 and vitamin D are associated with cognitive impairment in patients with type 2 diabetes. Am J Alzheimers Dis Dementias 2019;34:450-6.
Sultan S, Taimuri U, Basnan SA, Ai-Orabi WK, Awadallah A, Almowald F, et al. Low vitamin D and its association with cognitive impairment and dementia. J Aging Res 2020;2020.
Geng T, Lu Q, Wan Z, Guo J, Liu L, Pan A, et al. Association of serum 25-hydroxyvitamin D concentrations with risk of dementia among individuals with type 2 diabetes: A cohort study in the UK Biobank. PLoS Med 2022;19:e1003906.
Ong PA, Muis A, Rambe AS, Widjojo FS, Laksmidewi AA, Pramono A, et al. Panduan Praktik klinik diagnosis dan penatalaksanaan demensia. Jkt Perhimpun Dr Spes Saraf Indones 2015.
Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau S, Whitehead V, Collin I, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 2005;53:695-699.
American Psychiatric Association. Diagnostic and statistical manual of mental disorders (DSM-5®). Philadelphia: American Psychiatric Pub; 2013. 2013.
Grimm MO, Thiel A, Lauer AA, Winkler J, Lehmann J, Regner L, et al. Vitamin D and its analogues decrease amyloid-β (Aβ) formation and increase Aβ-degradation. Int J Mol Sci 2017;18:2764.
Filipović N, Ferhatović L, Marelja I, Puljak L, Grković I. Increased vitamin D receptor expression in dorsal root ganglia neurons of diabetic rats. Neurosci Lett 2013;549:140-5.
Hosseinpour F, Wikvall K. Porcine microsomal vitamin D3 25-hydroxylase (CYP2D25): catalytic properties, tissue distribution, and comparison with human CYP2D6. J Biol Chem 2000;275: 34650-5.
Balabanova S, Richter H-P, Antoniadis G, Homoki J, Kremmer N, Hanle J, et al. 25-Hydroxyvitamin D, 24, 25-dihydroxyvitamin D and 1, 25-dihydroxyvitamin D in human cerebrospinal fluid. Klin Wochenschr 1984;62:1086-90.
Przybelski RJ, Binkley NC. Is vitamin D important for preserving cognition? A positive correlation of serum 25-hydroxyvitamin D concentration with cognitive function. Arch Biochem Biophys 2007;460:202-5.
Naveilhan P, Neveu I, Wion D, Brachet P. 1, 25-Dihydroxyvitamin D3, an inducer of glial cell line-derived neurotrophic factor. Neuroreport 1996;7:2171-5.
Ibi M, Sawada H, Nakanishi M, Kume T, Katsuki H, Kaneko S, et al. Protective effects of 1α, 25-(OH) 2D3 against the neurotoxicity of glutamate and reactive oxygen species in mesencephalic culture. Neuropharmacology 2001;40:761-71.
Wilson RS, Yu L, Lamar M, Schneider JA, Boyle PA, Bennett DA. Education and cognitive reserve in old age. Neurology 2019;92: e1041-e50.
Brucki SMD, Nitrini R. Cognitive impairment in individuals with low educational level and homogeneous sociocultural background. Dement Neuropsychol 2014;8:345-50.
Sun L, Diao X, Gang X, Lv Y, Zhao X, Yang S, et al. Risk factors for cognitive impairment in patients with type 2 diabetes. J Diabetes Res 2020;2020.
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;29:1794-9.
Launer LJ, Miller ME, Williamson JD, Lazar RM, Gerstein HC, Murray AM, et al. Effects of intensive glucose lowering on brain structure and function in people with type 2 diabetes (ACCORD MIND): a randomised open-label substudy. Lancet Neurol 2011;10:969-77.
Rizzo MR, Marfella R, Barbieri M, Boccardi V, Vestini F, Lettieri B, et al. Relationships between daily acute glucose fluctuations and cognitive performance among aged type 2 diabetic patients. Diabetes Care 2010;33:2169-74.
Suh S, Kim JH. Glycemic variability: how do we measure it and why is it important? Diabetes Metab J 2015;39:273-82.
Feinkohl I, Price JF, Strachan MW, Frier BM. The impact of diabetes on cognitive decline: potential vascular, metabolic, and psychosocial risk factors. Alzheimers Res Ther 2015;7:1-22.
Anstey KJ, Cherbuin N, Budge M, Young J. Body mass index in midlife and late-life as a risk factor for dementia: a meta- analysis of prospective studies. Obes Rev 2011;12:e426-e37.
Xiu S, Liao Q, Sun L, Chan P. Risk factors for cognitive impairment in older people with diabetes: a community-based study. Ther Adv Endocrinol Metab 2019;10:2042018819836640.
Chen G, Cai L, Chen B, Liang J, Lin F, Li L, et al. Serum level of endogenous secretory receptor for advanced glycation end products and other factors in type 2 diabetic patients with mild cognitive impairment. Diabetes Care 2011;34:2586-2590.
Ghoshal S, Allred ND, Freedman BI. The contribution of kidney disease to cognitive impairment in patients with type 2 diabetes. Curr Diab Rep 2020;20:1-10.
Tantanokit T, Bosittipichet T, Leesri T. The study of prevalence and associated factors of dementia in the elderly. Siriraj Med J 2021;73:224-35.
Espeland MA, Carmichael O, Yasar S, Hugenschmidt C, Hazzard W, Hayden KM, et al. Sex-related differences in the prevalence of cognitive impairment among overweight and obese adults with type 2 diabetes. Alzheimers Dement 2018;14:1184-92.
Chatterjee S, Peters SA, Woodward M, Mejia Arango S, Batty GD, Beckett N, et al. Type 2 diabetes as a risk factor for dementia in women compared with men: a pooled analysis of 2.3 million people comprising more than 100,000 cases of dementia. Diabetes Care 2016;39:300-7.