Diabetes Mellitus and the Brain: Special Emphasis to Cognitive Function
Sherifa A. Hamed
Consultant Neurologist, Professor, Department of Neurology and Psychiatry, Assiut University, Assiut, Egypt.
Sherifa A. Hamed
Department of Neurology and Psychiatry,
Assiut University, Assiut, Egypt.
Tel: +2 088 2371820
Fax: +2 088 2333327/+2 088 2332278
Article Type: Review Article
Received: November 14, 2013; Accepted: December 13, 2013; Published: December 18, 2013
Citation: Hamed SA (2013) Diabetes Mellitus and the Brain: Special Emphasis to Cognitive Function. Int J Diabetol Vasc Dis Res. 1(5), 37-42.doi: dx.doi.org/10.19070/2328-353X-130007
Copyright: Sherifa A. Hamed© 2013 This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.
Diabetes mellitus (DM) is a major public health problem. Cognitive deficits are common with DM which range from subclinical or subtle to severe deficits as dementia. Both hypoglycemia and hyperglycemia are causes of cognitive impairment with DM. In patients with DM, not only severe hypoglycemia but also recurrent mild or moderate hypoglycemia have deleterious effect on the brain. Recurrent mild/moderate hypoglycemia is associated with intellectual decline, reduced attention, impaired mental abilities and memory deficits. Hypoglycemia may result in abnormalities of neuronal plasticity, synaptic weakening and scattered neuronal death in the cerebral cortex and the hippocampus. Chronic hyperglycemia in type 1 and type 2 DM is associated with low IQ (verbal, performance and total) and abnormalities in testing for different domains of cognitive function as verbal relations, comprehension, visual reasoning, pattern analysis, quantitation, memory, learning, mental control, psychomotor efficiency, mental and motor processing speed and executive function. The suggested mechanisms incriminated in the pathogenesis of hyperglycemia related cognitive dysfunction include, macro- and micro-vascular disease or vasculopathy, hyperlipidemia, hypertension, insulin resistance and hyperinsulinemia, stress response, direct toxic effect of chronic hyperglycemia on the brain, advanced glycation end products, inflammatory cytokines and oxidative stress. Hyperglycemia causes oxidative stress, amyloidosis, angiopathy, abnormal lipid peroxidation, accumulation of β-amyloid and tau phosphorylation, neuroinflammation, mitochondrial pathology, apoptosis and neuronal degeneration in the cortex and hippocampus. Depression has been identified as a risk for accelerated cognitive decline with DM. The knowledge that diagnosis at early age, frequency of hypoglycemia, poor glycemic control and presence of risk factors negatively affect cognitive functions in DM, will have important implications for treatment and for research purposes.
3.Cognitive Dysfunction With Hypoglycemia
4 Cognitive Dysfunction With Hyperglycemia
5 Cognitive Dysfunction With Hyperinslinemia
6.Depression Accelerates Cognitive Decline With Dm
7.Clinical and Research Perspectives
Diabetes Mellitus; Hypoglycemia; Insulin Resistance; Cognition; Vascular Disease.
Diabetes mellitus (DM) is one of the most common and most important metabolic disease worldwide. The incidence and prevalence of DM are increasing rapidly due to industrialization, inappropriate diet, sedentary life style and increased obesity . Hypoglycemia, hyperlipidemia and vascular diseases (as angiopathy, nephropathy and cardiovascular, cerebrovascular and peripheral vascular diseases) are common complications of DM . Cognitive deficits are common with DM which range from subclinical or subtle to severe deficits as dementia. Cognition refers to the set of integrated and inter-related mental processes and systems involved in acquiring knowledge and comprehending, storing, retrieving and using this knowledge to perform day-to-day activities. Both hypoglycemia and hyperglycemia are causes of cognitive impairment with DM [3-39]. Intellectual decline, impaired mental abilities and memory deficits are common with recurrent hypoglycemic episodes [3-10]. Studies indicate that repetitive mild and moderate hypoglycemia cause impairment in synaptic plasticity with inability to induce long term potentiation (LTP) which has a crucial role in memory and this contributes to cognitive impairments [11,12]. Recurrent moderate hypoglycemia result in scattered neuronal death in the cerebral cortex [13,14] and hippocampus . While severe hypoglycemia result in oxidative stress and wide spread neuronal death in the cerebral cortex and hippocampus [16,17]. In hyperglycemia, low IQ and reduced performance on various domains of cognitive function including verbal relations, comprehension, visual reasoning, pattern analysis, quantitation, digit forward, digit backward, memory, mental control, associate learning, psychomotor efficiency, problem solving, mental and motor processing speed, eye-hand coordination and executive function, are common [18-26]. Metabolic derangement, macro- and micro-vascular complications [27,28], oxidative stress [29,30] and diabetes-related depression [31-35]. Chronic hyperglycemia causes oxidative stress, amyloidosis, angiopathy, abnormal lipid peroxidation, increase the formation of advanced glycation end products, accumulation of β-amyloid and tau phosphorylation, neuroinflammation, mitochondrial pathology, apoptosis, neurodegeneration in the cortex and hippocampus and brain atrophy [36-39].
This review was performed through a comprehensive search in the PubMed, ISI web of science, Science Direct and Scopus databases from 1990 to 2013 using the following search terms: cognitive function in diabetes, hypoglycemia and cognition, type 1 DM (T1DM) and cognition and type 2 DM (T2DM) and cognition. Data of epidemiological, longitudinal, prospective, doubleblinded and clinical trial studies and case reports were considered. We also checked the reference lists of the retrieved studies for additional reports. In this review, we summarized the experimental and clinical evidence of cognitive dysfunction with DM, the possible mechanisms underlying cognitive dysfunction in DM, the relationship between DM and neurodegeneration and the clinical and research approaches with the aim to prevent and treat cognitive dysfunction with DM.
Cognitive Dysfunction With Hypoglycemia
The brain is an energy-intensive organ. Glucose is the primary fuel of brain cells. Approximately 25% of total body glucose is required for proper brain function . The normal range for human blood glucose concentration is 3.9 to 7.1 mM (1 mM = approximately 18 mg/dl). Hypoglycemia is defined as blood glucose level below which brain function deteriorates in most patients (i.e. less than 3 mmol/l or 54 mg/l00 ml) . In patients with DM, not only severe hypoglycemia (blood glucose level below 2 mM) but also recurrent mild (blood glucose level is 3.2 to 3.6 mM) or moderate (blood glucose level is 2.3 to less than 3.2 mM) hypoglycemia have deleterious effect on the brain [3-11, 13-17]. Hypoglycemia is common with intensive insulin therapy. It has been indicated that the oscillations in glycaemia, owing to the nature of subcutaneous insulin administration, are more common and result in increase in the frequency of hypoglycemia in those treated for DM . Recurrent mild and moderate hypoglycemia are more common than severe hypoglycemia [7, 10, 43]. It has been reported that most hypoglycemic events were found to be asymptomatic in 90% of children treated with insulin, 98% of those occurring at night and the majority of untreated hypoglycemic events were associated with a relapse into hypoglycemia within 3 hours . Attention, associative learning and mental flexibility are affected with acute hypoglycemia . Recurrent mild and moderate hypoglycemia is associated with intellectual decline particularly performance IQ, impaired mental abilities and memory deficits [3,45]. It was reported that recurrent mild and moderate hypoglycemia in children younger than 5 years old with T1DM may commonly develop reduced attention, spatial memory and intelligence in adolescence [6,8,46].
Experimental and clinical studies indicate that severe hypoglycemia for a least 10 minutes result in microglial activation and oxidative stress with the release of several neurotoxic substances, including superoxide, nitric oxide, and metalloproteinase and wide spread neuronal death in the cerebral cortex and hippocampus. While recurrent moderate hypoglycemia result in scattered neuronal death in the second and third cerebral cortex layers and hippocampal CA1 dendritic region and hippocampal thinning [14-16,47,48]. It has been suggested that cognitive impairment in children and adults with repetitive mild and moderate hypoglycemia is due to deterioration in synaptic injury with an inability to induce or persistent inhibition of long term potentiation (LTP) and facilitation of LTD at hippocampal CA1 (which plays a crucial role in memory) in the absence of apparent neuronal somatic injuries. This in turn result in activity-dependent synapse weakening and contribute to cognitive impairments [11,12].
Cognitive Dysfunction With Hyperglycemia
DM is defined by the presence of symptoms of hyperglycemia and presence of fasting plasma glucose (FBG) level ≥ 7.0 mmol/l or126 mg/dl or post-prandial blood glucose (PBG) ≥ 11.1 mmol/l or 200 mg/dL or a random plasma glucose ≥ 11.1 mmol/l or 200 mg/dl or glycated hemoglobin (HbA1C) ≥ 6.5% .
At the experimental level, detrimental effects on learning and memory were observed in streptozotocin (STZ) (rodent model of T1DM) and GK rat , db/db mouse and Zucker rat  (genetic models of T2DM) as observed with impaired performance in Morris water maze spatial test [51,52] and inhibitory  or active avoidance tasks  and an objectdiscrimination task tests , all are indicative of impairment in hippocampus and its related structures. At the clinical level, children and adults with DM demonstrate low IQ and reduced performance on various domains of cognitive function including verbal relations, comprehension, visual reasoning, pattern analysis,quantitation, digit forward, digit backward, shortterm memory, memory for sentences, verbal memory,logical memory, mental control, associate learning,psychomotor efficiency, problem solving, mental and motor processing speed, eye-hand coordination and executive function [18-26,55-57]. Many authors reported that cognitive deficits were correlated with the degree of chronic hyperglycemia and improvement in performance of cognitive testing with improvement in glucose tolerance [58,59]. Wu et al.  observed that compared to treated patients, the untreated patients with DM had 2 points decline over 2 years on Mini Mental State Examination test (MMSE) with duration of illness < 5 years and 6 points decline on MMSE with duration of illness ≥5 years. Cox et al.  observed that the increase of blood glucose >15mmol/l was associated with marked decline in cognition and poor performance in arithmetic tasks. The research showed that those with the DM have a 1.2 to 1.5-fold greater rate of decline in cognitive function compared to those without diabetes . At the neurophysiological level, studies also reported abnormalities in P300 component of event related potentials (ERPs), a physiological analogue of cognitive testing [25,61,62] and prolongation of I-III and I-V interpeak latencies of the auditory brainstem response (ABR), an indicative of central auditory pathway function [52,63], in patients with T1DM and T2DM and regardless of the recent metabolic derangement and disease duration. At the neuroimaging level, structural brain atrophy particularly in the limbic structures such the hippocampus and amygdala, smaller total brain volume, smaller gray matter volume, larger ventricular volume, larger white matter lesion volume and accelerated increase in ventricular volume over time and increased risk for incident brain infarcts, were seen in magnetic resonance imaging (MRI) of the brain of patients with T2DM and also in patients with early manifestation of impaired glucose tolerance (i.e. PBG ≥140 mg/dl or 7.8 mmol/L but not over 200 mg/dl or 11.1 mmol/L) [28,38,39,64-66]. Studies also reported that well-controlled middle-aged individuals with T2DM , nondiabetic individuals with insulin resistance (IR) (a prediabetic state)  had declarative memory deficits and specific hippocampal volume reduction and deficits in hippocampal synaptic plasticity  which were correlated with the present deficits in declarative memory.
The etiology of cognitive impairment in people with hyperglycemia is multifactorial. Vascular [27,28] as well as neurodegenation [65,66] contribute to cognitive dysfunction with chronic hyperglycemia. The followings have been suggested as causes of hyperglycemiainduced cognitive impairment: chronic complication as macro- and micro-vascular complications (diabetic vasculopathy) [20,27,28], hyperlipidemia [68,69], hypertension [70,71], insulin resistance (IR) and hyperinsulinemia , dysregulation of limbic-hypothalamic- adrenal pituitary axis (LHPA) with chronic hypercortisolemia and impairments in hippocampal neurogenesis, synaptic plasticity and learning [72-74], direct toxic effect of chronic hyperglycemia on the brain [25,55], advanced glycation end products, inflammatory cytokines, oxidative stress [29,30] and diabetesrelated depression [32-35].
DM is a risk for arterial stiffness and atherosclerotic and cerebrovascular diseases [27,28]. Experimental and human studies also indicate that chronic hyperglycemia result in brain injury with specific vulnerability to memory and learning processing, regardless of vascular pathology. In experimental models, it was observed that chronic hyperglycemia and spontaneous onset of T2DM cause blood brain barrier (BBB) disruption, alteration of insulin transporter and decrease in insulin receptors which are expressed in discrete neuronal populations in the CNS, including the hippocampus. Impairment of insulin function result in reduction in the uptake of glucose into the neurons, impairment of energy metabolism and impairment of brain’s capacity to generate the connections vital to memory and learning . Reduction of insulin like growth factor 1 (ILGF-1) [75,76] and brain derived neurotrophic factor (BDNF) were observed in rat models of T2DM . IGFs regulate adult brain mass by maintaining brain protein content and supports synapses and is required for learning and memory. It was observed that replacement doses of insulin and IGFs in diabetic rats can cross the blood-brain barrier, improve brain atrophy and prevent hippocampus-dependent memory impairment [75-77]. Researchers found that insulin and GF-I were significantly reduced in the frontal cortex, hippocampus and hypothalamus but not the cerebellum in postmortem brain tissue from people with DM . It has been indicated that hyperglycemia causes oxidative stress, amyloidosis, angiopathy, abnormal lipid peroxidation, increase the formation of advanced glycation end products, accumulation of β-amyloid and tau phosphorylation, neuroinflammation, mitochondrial pathology, increase in Bax expression (proapoptotic protein) and caspase-3 (apoptotic element) levels, reduction in Bcl-2 protein levels (antiapoptotic rotein), increase in the ratio of Bax to Bcl-2, DNAfragmentation in the cortex and hippocampus, neuronal degeneration and brain atrophy [36,37]. Recently, it was reported that adults and middle aged patients with T2DM had higher concentrations of serum NSE (which is a marker of neuronal cell damage which was significantly correlated with cognitive deficits’ regardless the level of glycemic control and after adjustment of confounders , indicating direct brain injury due to chronic hyperglycemia. Several studies have shown higher serum and cerebrospinal fluid (CSF) levels of NSE and also their over-expression increases the vulnerability to neurodegeneration, cerebral hypoxic-ischemic injury and traumatic brain injury [78,79].
Cognitive Dysfunction With Hyperinslinemia
Insulin is a key protein in the control of intermediary metabolism. It organizes the use of fuels for either storage or oxidation. It influences carbohydrate, lipid, protein and mineral metabolism . Binding of insulin to its receptors phosphorylates many intracellular protein and generating a biological response. Insulin acts on cells though out the body to stimulate uptake, utilization and storage of glucose. In the brain, as with peripheral insulin, insulin is in part responsible for the uptake of glucose into the neurons which is important for energy metabolism. The most of brain insulin originates from systemic blood circulation but to less extent, it is produced in the brain . Insulin crosses the blood-brain barrier (BBB) using a saturable transporter . Insulin-sensitive glucose transporters, insulin receptors and insulin downstream signaling molecules, are distributed throughout the human brain on both neurons and astrocytes . Insulin receptors are densely expressed in the medial temporal lobe, hippocampus and prefrontal cortex, which mediate long-term memory and working memory . Insulin affect a wide range of normal brain functions, such as reward, motivation, cognition, attention and memory formation. Insulin’s anabolic effect in the brain includes stimulation of the growth, neuronal differentiation, survival (neurotropism) and remodeling (neuromodulation) . The synapses (which transmit information between neurons) contain insulin receptors. Insulin serves as a vital element for normal synaptic structure and function and subsequently for the strength of connections between neurons. Insulin binds to receptors at the synapse and together with proper inulin signaling, both contribute to brain plasticity and formation of new brain circuitries essential for learning and memory . Insulin in the brain is degraded by insulin degrading enzyme (IDE). IDE regulates the generation and clearance of amyloid β (Aβ) from the brain [85,86].
Hyperinsulinemia is a most common consequence of IR which is the main defect in T2DM. It has been indicated that prolonged exposure of the brain to higher than physiological levels of insulin may alter signaling and metabolic pathways in a manner that is deleterious to cognitive circuitry which mainly depends on proper metabolic processes . Chronic elevation of insulin concentrations in the periphery may paradoxically causes a relative hypoinsulinized state in the brain and thus resultant hyperinsulinemia could actually impair cognition by disturbing insulin-mediated utilization of glucose by cells in the brain particularly the hippocampus,which is enriched with insulin receptors. Central hypoinsulinemia may promote central inflammation, β-amyloid generation and reduced neuroplasticity . Decrease in levels of insulin degrading enzyme (IDE) was observed in rat models of T2DM. IDE, an enzyme responsible for insulin degradation in the brain, also degrades amyloid plaque. As insulin has a very similar molecular structure to amyloid plaque, thus the latter might compete for the benefits of IDE in presence of hyperinsulinemia . Elevated insulin levels are implicated in the brain cells’ failure to clear β-amyloid, formation of senile plaques and tau protein phosphorylation [87-89].
Depression Accelerates Cognitive Decline With Dm
Epidemiological studies suggested that diabetic patients are 2-3 fold more likely to develop depressive illness when compared to non-diabetic individuals. On the other hand, individuals with depression have an approximately 60 percent higher risk of developing T2DM [32-34] In general, the prevalence of depression with DM was estimated to be 31.1% . Comorbid depression has been identified as a risk factor for accelerated cognitive decline among patients T2DM. Depression has been identified as a risk factor for dementia among patients with T2DM in all domains .
Clinical and Research Perspectives
The knowledge that diagnosis at early age, frequency of hypoglycemia, poor glycemic control and presence of risk factors negatively affect cognitive functions in DM, will have important implications for treatment of DM and for research purposes. Preventive strategies include modification of lifestyle, patient education, diet orientations (i.e. eliminating high-glycemic foods, including processed carbohydrates and sweets, would sensitize insulin receptors and correct hyperinsulinemia [91-95]), stopping smoking, maintaining a healthy body weight, mental and physical exercise, control of hypertension and dyslipidemia and treatment of brain infarcts, cardiovascular diseases and depression [70,96,97]. In hyperglycemia, it is important to regularly monitor the blood glucose level and to keep glycemic control with the aim is an HbA1C level of 6.5%, but should not be lower than that, and may be set higher . Hypoglycemia should be treated with a defined dose of carbohydrates rather than a mixed meal. Insulin-sensitizing drug are able to slow down, prevent, or perhaps even improve DM-related cognitive decline. Neuroprotective strategies have to be included aside to the treatment of DM from the beginning to prevent the long-term diabetic complications, those include: free radical scavengers/antioxidants (as alpha lipoic acid (ALPA), evening primrose oil (EPO), vitamin C, vitamin E and vitamin B complex) [68,99], modifiers of mitochondrial dysfunction, anti-apoptotics, and neurotrophic factors . Future studies has to be directed for better understanding of the pathophysiological mechanisms underlying the cognitive dysfunction in diabetes. There is also a need for construction of longitudinal studies that prospectively assess the relation of the disease process to cognition over time and randomized clinical trials that compare cognitive function in DM patients receiving memory enhancers, antidepressants, versus a control group of DM patients.
- 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 – 1053.
- Dyck PJ, Kratz KM, Karnes JL, Litchy WJ, Klein R, Pach JM, Wilson DM, O’Brien PC, Melton LJ 3rd, Service FJ. The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester Diabetic Neuropathy Study. Neurology 1993; 43 :817 – 824.
- Langan SJ, Deary IJ, Hepburn DA, Frier BM. Cumulative cognitive impairment following recurrent severe hypoglycaemia in adult patients with insulin-treated diabetes mellitus. Diabetologia 1991; 34: 337 – 344.
- Deary IJ, Crawford JR, Hepburn DA, Langan SJ, Blackmore LM, Frier BM. Severe hypoglycemia and intelligence in adult patients with insulin- treated diabetes. Diabetes 1993; 42: 341 – 344.
- Draelos MT, Jacobson AM, Weinger K, Widom B, Ryan CM, Finkelstein DM, Simonson DC. Cognitive function in patients with insulin-dependent diabetes mellitus during hyperglycemia and hypoglycemia. Am J Med 1995; 98: 135 – 144.
- Rovet J, Alvarez M. Attentional functioning in children and adolescents with IDDM. Diabetes Care 1997; 20: 803 – 810.
- Sommerfield AJ, Deary IJ, McAulay V, Frier BM. Short-term, delayed, and working memory are impaired during hypoglycemia in individuals with type 1 diabetes. Diabetes Care 2003; 26: 390–339.
- Hershey T, Perantie DC, Warren SL, Zimmerman EC, Sadler M, White NH. Frequency and timing of severe hypoglycemia affects spatial memory in children with type 1 diabetes. Diabetes Care 2005;28: 2372–2377.
- Wright RJ, Frier BM, Deary IJ. Effects of acute insulin-induced hypoglycemia on spatial abilities in adults with type 1 diabetes. Diabetes Care 2009; 32: 1503–1506.
- Blasetti A, Chiuri RM, Tocco AM, Di Giulio C, Mattei PA, Ballone E, Chiarelli F, Verrotti A. The effect of recurrent severe hypoglycemia on cognitive performance in children with type 1 diabetes: a meta-analysis. J Child Neurol 2011; 26: 1383 – 1391.
- Yamada KA, Rensing N, Izumi Y, De Erausquin GA, Gazit V, Dorsey DA, Herrera DG. Repetitive hypoglycemia in young rats impairs hippocampal long-term potentiation. Pediatr Res 2004; 55: 372 – 379.
- Hara Y, Park CS, Janssen WG, Punsoni M, Rapp PR, Morrison JH. Synaptic characteristics of dentate gyrus axonal boutons and their relationships with aging, menopause, and memory in female rhesus monkeys. J Neurosci 2011; 31: 7737 – 7744.
- Tkacs NC, Pan Y, Raghupathi R, Dunn-Meynell AA, Levin BE. Cortical Fluoro- Jade staining and blunted adrenomedullary response to hypoglycemia after noncoma hypoglycemia in rats. J Cereb Blood Flow Metab 2005; 25: 1645 – 1655.
- Haces ML, Montiel T, Massieu L. Selective vulnerability of brain regions to oxidative stress in a non-coma model of insulin-induced hypoglycemia. Neuroscience 2010; 165: 28 – 38.
- Won SJ, Yoo BH, Kauppinen TM, Choi BY, Kim JH, Jang BG, Lee MW, Sohn M, Liu J, Swanson RA, Suh SW. Recurrent/moderate hypoglycemia induces hippocampal dendritic injury, microglial activation, and cognitive impairment in diabetic rats. J Neuroinflammation 2012; 9: 182.
- Auer RN, Wieloch T, Olsson Y, Siesjo BK. The distribution of hypoglycemic brain damage. Acta Neuropathol 1984; 64: 177 – 191.
- Chao CC, Hu S, Molitor TW, Shaskan EG, Peterson PK. Activated microglia mediate neuronal cell injury via a nitric oxide mechanism. J Immunol 1992; 149: 2736 – 2741.
- Liebson CL, Rocca WA, Hanson VA, Cha R, Kokmen E, O’Brien PC, Palumbo PJ. Risk of dementia among persons with diabetes mellitus: a population-based cohort study. Am J Epidemiol 1997;145: 301 - 308.
- Naor M, Steingrüber HJ, Westhoff K, Schottenfeld-Naor Y, Gries AF. Cognitive function in elderly non-insulin-dependent diabetic patients before and after inpatient treatment for metabolic control. J Diabetes Complications 1997; 11: 40 - 46.
- Ryan CM, Geckle MO. Circumscribed cognitive dysfunction in middle-aged adults with type 2 diabetes. Diabetes Care 2000; 23: 1486 - 1493.
- Cosway R, Strachan MW, Dougall A, Frier BM, Deary IJ. Cognitive function and information processing in type 2 diabetes. Diabet Med 2001; 18: 803 - 810.
- Popoviç M, Biessels GJ, Isaacson RL, Gispen WH. Learning and memory in streptozotocin-induced diabetic rats in a novel spatial/object discrimination task. Behav Brain Res 2001; 122: 201 - 207.
- Wu JH, Haan MN, Liang J, Ghosh D, Gonzalez HM, Herman WH. Impact of diabetes on cognitive function among older Latinos: a population-based cohort study. J Clin Epidemiol 2003; 56: 686 - 693.
- Cox DJ, Kovatchev BP, Gonder-Frederick LA, Summers KH, Mc-Call A, Grimm KJ, Clarke WL. Relationships between hyperglycemia and cognitive performance among adults with type 1 and type 2 diabetes. Diabetes Care 2005; 28: 71 - 77.
- Hamed SA, Abd Elaal RF, Mohamad KA, Youssef AH, Abdou MA. Neuropsychological, Neurophysiological and Laboratory Markers of Direct Brain Injury in Type 2 Diabetes Mellitus. Journal of Neurology and Neuroscience 2012; 3: 2.
- Rouch I, Roche F, Dauphinot V, Laurent B, Antérion CT, Celle S, Krolak-Salmon P, Barthélémy JC. Diabetes, impaired fasting glucose, and cognitive decline in a population of elderly community residents. Aging Clin Exp Res 2012; 24: 377 - 383.
- Mehrabian S, Raycheva M, Gateva A, Todorova G, Angelova P,Traykova M, Stankova T, Kamenov Z, Traykov L. Cognitive dysfunction profile and arterial stiffness in type 2 diabetes. J Neurol Sci 2012; 322: 152 -156.
- Kooistra M, Geerlings MI, Mali WP, Vincken KL, van der Graaf Y, Biessels GJ; SMART-MR Study Group. Diabetes mellitus and progression of vascular brain lesions and brain atrophy in patients with symptomatic atherosclerotic disease. The SMART-MR study. J Neurol Sci 2013; 332: 69 - 74.
- Rösen P, Nawroth PP, King G, Möller W, Tritschler HJ, Packer L. The role of oxidative stress in the onset and progression of diabetes and its complications: a summary of a Congress Series sponsored by UNESCO-MCBN, the American Diabetes Association and the German Diabetes Society. Diabetes/Metab Res Rev 2001; 17: 189– 212.
- Bekyarova GY, Ivanova DG, Madjova VH. Molecular mechanisms associating oxidative stress with endothelial dysfunction in the development of various vascular complications in diabetes mellitus. Folia Med (Plovdiv) 2007; 49: 13 - 9.
- Verma SK, Luo N, Subramaniam M, Sum CF, Stahl D, Liow PH, Chong SA. Impact of depression on health related quality of life in patients with diabetes. Ann Acad Med Singapore 2010; 39: 913- 917.
- Everson SA, Maty SC, Lynch JW, Kaplan GA. Epidemiologic evidence for the relation between socioeconomic status and depression, obesity, and diabetes. J Psychosom Res 2002; 53: 891 – 895.
- Musselman DL, Betan E, Larsen H, Phillips LS. Relationship of depression to diabetes types 1 and 2: epidemiology, biology, and treatment. Biol Psychiatry 2003; 54: 317 – 329.
- Katon W, von Korff M, Ciechanowski P, Russo J, Lin E, Simon G, Ludman E, Walker E., Bush T, Young B. Behavioral and clinical factors associated with depression among individuals with diabetes. Diabetes Care 2004; 27: 914 – 920.
- Sullivan MD, Katon WJ, Lovato LC, Miller ME, Murray AM, Horowitz KR, Bryan RN, Gerstein HC, Marcovina S, Akpunonu BE, Johnson J, Yale JF, Williamson J, Launer LJ. Association of Depression With Accelerated Cognitive Decline Among Patients With Type 2 Diabetes in the ACCORD-MIND Trial. JAMA Psychiatry 2013; 70: 1041 - 1047.
- Li ZG, Zhang W, Grunberger G, Sima AAF. Hippocampal neuronal apoptosis in type 1 diabetes. Brain Research 2002; 946: 221 – 231.
- Jafari Anarkooli,M. Sankian, S. Ahmadpour, A. R. Varasteh, H.Haghir. Evaluation of Bcl-2 family gene expression and Caspase-3 activity in hippocampus STZ-induced diabetic rats. Exp Diabetes Res 2008; 2008: 638467.
- Manschot SM, Brands AM, van der GJ, Kessels RP, Algra A, Kappelle LJ, Biessels GJ. Brain magnetic resonance imaging correlates of impaired cognition in patients with type 2 diabetes. Diabetes 2006; 55: 1106 – 1113.
- Espeland MA, Bryan RN, Goveas JS, Robinson JG, Siddiqui MS, Liu S, Hogan PE, Casanova R, Coker LH, Yaffe K, Masaki K, Rossom R, Resnick SM; WHIMS-MRI Study Group. Influence of type 2 diabetes on brain volumes and changes in brain volumes: results from the Women’s Health Initiative Magnetic Resonance Imaging studies. Diabetes Care 2013; 36: 90 - 97.
- Brüning JC, Gautam, D, Burks DJ, Gillette J, Schubert M, Orban PC, Klein R, Krone W, Müller-Wieland D, Kahn CR. Role of brain insulin receptor in control of body weight and reproduction. Science 2000; 289: 2122 - 2125.
- Sucov A, Woolard RH. Ethanol-associated hypoglycemia is uncommon Acad Emerg Med 1995; 2: 185–189.
- Davis EA, Jones TW. Hypoglycemia in children with diabetes: incidence, counterregulation and cognitive dysfunction. J Pediatr Endocrinol Metab 1998; 11: 177 – 182.
- Zammitt NN, Streftaris G, Gibson GJ, Deary IJ, Frier BM. Modeling the consistency of hypoglycemic symptoms: high variability in diabetes. Additional file 1: Figure S1. Experimental protocol for R/M Diabetes. Technol Ther 2011; 13: 571 – 578.
- Deiss D, Kordonouri O, Hartmann R, Hopfenmüller W, Lüpke K, Danne T. Treatment with insulin glargine reduces asymptomatic hypoglycemia detected by continuous subcutaneous glucose monitoring in children and adolescents with type 1 diabetes. Pediatr Diabetes 2007; 8: 157 - 162.
- Perantie DC, Lim A, Wu J, Weaver P, Warren SL, Sadler M, White NH Hershey T. Effects of prior hypoglycemia and hyperglycemia on cognition in children with type 1 diabetes mellitus. Pediatr Diabetes 2008; 9: 87 – 95.
- Bjorgaas M, Gimse R, Vik T, Sand T. Cognitive function in type 1 diabetic children with and without episodes of severe hypoglycaemia. Acta Paediatr 1997; 86: 148 – 153.
- Kalimo H, Olsson Y. Effects of severe hypoglycemia on the human brain. Neuropathological case reports. Acta Neurol Scand 1980; 62:345 – 356.
- Auer RN, Hugh J, Cosgrove E, Curry B. Neuropathologic findings in three cases of profound hypoglycemia. Clin Neuropathol 1989; 8: 63 – 68.
- Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation.Diabet Med 1998; 15: 539 - 553.
- Marfaing-Jallat P, Portha B, Penicaud L. Altered conditioned taste aversion and glucose utilization in related brain nuclei of diabetic GK rats. Brain Res Bull 1995; 37: 639 – 643.
- Li XL, Aou S, Oomura Y, Hori N, Fukunaga K, Hori T. Impairment of long-term potentiation and spatial memory in leptin receptor deficient rodents. Neuroscience 2002; 113: 607 – 615.
- Biessels GJ, Kamal A, Urban IJ, Spruijt BM, Erkelens DW, Gispen WH. Water maze learning and hippocampal synaptic plasticity in streptozotocin-diabetic rats: effects of insulin treatment. Brain Res 1998; 800: 125 – 135.
- Baydas G, Nedzvetskii VS, Nerush PA, Kirichenko SV, Yoldas T. Altered expression of NCAM in hippocampus and cortex may underlie memory and learning deficits in rats with streptozotocin-induced diabetes mellitus. Life Sci 2003; 73: 1907 – 1916.
- Flood JF, Mooradian AD, Morley JE. Characteristics of learning and memory in streptozocin-induced diabetic mice. Diabetes 1990; 39: 1391 – 1398.
- Awad N, Gagnon M, Messier C. The relationship between impaired glucose tolerance, type 2 diabetes, and cognitive function. J Clin Exp Neuropsychol 2004; 26: 1044 - 1080.
- Mooradian AD, Perryman K, Fitten J, Kavonian GD, Morley JE. Cortical function in elderly non-insulin dependent diabetic patients: behavioral and electrophysiological studies. Arch Intern Med 1988; 148: 2369-2372.
- Gradman TJ, Laws A, Thompson LW, Reaven GM. Verbal learning and/or memory improves with glycemic control in older subjects with non-insulin-dependent diabetes mellitus. J Am Geriatr Soc 1993; 41: 1305 - 1312.
- Ryan CM, Williams TM. Effects of insulin-dependent diabetes on learning and memory efficiency in adults. J Clin Exp Neuropsychol 1993; 15: 685 - 700.
- Biessels GJ, Kappelle AC, Bravenboer B, Erkelens DW, Gispen WH. Cerebral function in diabetes mellitus. Diabetologia 1994; 37:643 - 650.
- Cukierman T, Gerstein HC, Williamson, JD. Cognitive decline and dementia in diabetes—systematic overview of prospective observational studies. Diabetologia, 2005; 48: 2460 - 2469.
- Pozzessere G, Valle E, de Crignis S, Cordischi VM, Fattapposta F, Rizzo PA, Pietravalle P, Cristina G, Morano S, di Mario U. Abnormalities of cognitive functions in IDDM revealed by P300 eventrelated potential analysis. Comparison with short-latency evoked potentials and psychometric tests. Diabetes 1991; 40: 952 - 958.
- Kurita A, Mochio S, Isogai Y. Changes in auditory P300 event-related potentials and brainstem evoked potentials in diabetes mellitus. Acta Neurol Scand 1995; 92: 319 - 323.
- Dejgaard A, Gade A, Larsson H, Balle V, Parving A, Parving HH. Evidence for diabetic encephalopathy. Diabet Med 1991; 8: 162 -167.
- Alosco ML, Brickman AM, Spitznagel MB, Griffith EY, Narkhede A, Raz N, Cohen R, Sweet LH, Colbert LH, Josephson R, Hughes J, Rosneck J, Gunstad J. The adverse impact of type 2 diabetes on brain volume in heart failure. J Clin Exp Neuropsychol 2013; 35: 309 - 318.
- Gold AE, Deary IJ, Jones RW, O’Hare JP, Reckless JPD, Frier BM. Severe deterioration in cognitive function and personality in five patients with long-standing diabetes: a complication of diabetes or a consequence of treatment?. Diabet Med 1994; 11: 499 – 505.
- den Heijer T, Vermeer SE, van Dijk EJ, Prins ND, Koudstaal PJ, Hofman A, Breteler MM. Type 2 diabetes and atrophy of the medial temporal lobe structures. Diabetologia 2005; 46: 1604 - 1610.
- Taylor VH, MacQueen GM. Cognitive dysfunction associated with metabolic syndrome. Obes Rev 2007; 8: 409 - 418.
- van Exel E, de Craen AJ, Gussekloo J, Houx P, Bootsma-van der Wiel A, Macfarlane PW, Blauw GJ, Westendorp RG. Association between high-density lipoprotein and cognitive impairment in the oldest old. Ann Neurol 2002; 51: 716 - 721.
- Henderson VW, Guthrie JR, Dennerstein L. Serum lipids and memory in a population based cohort of middle age women. J Neurol Neurosurg Psychiatry 2003; 74: 1530 - 1535.
- Elias PK, Wilson PW, Elias MF, Silbershatz H, D’Agostino RB,Wolf PA, Cupples LA. NIDDM and blood pressure as risk factors for poor cognitive performance. Diabetes Care 1997; 20: 1388 - 1395.
- Hassing LB, Hofer SM, Nilsson SE, Berg S, Pedersen NL, McClearn G, Johansson B. Comorbid type 2 diabetes mellitus and hypertension exacerbates cognitive decline: evidence from a longitudinal study. Age Ageing 2004; 33: 355 – 361.
- Hamed SA, Youssef AH, Elserogy YE, Herdan O, Abd-Elaal RF, Metwaly NA, Hassan MM, Mohamad HO. Cognitive function in patients with Type 2 Diabetes Mellitus: Relationship to stress hormone (Cortisol). J Neurol Neurosci 2013: 4: 3.
- Rosmond R. Stress induced disturbances of the HPA axis: a pathway to Type 2 diabetes?. Med Sci Monit 2003; 9: RA35 – RA9.
- Bruehl H, Rueger M, Dziobek I, Sweat V, Tirsi A, Javier E, Arentoft A, Wolf OT, Convit A. Hypothalamic-pituitary-adrenal axis dysregulation and memory impairments in type 2 diabetes. J Clin Endocrinol Metab 2007; 92: 2439 – 2445.
- Chiarelli F, Santilli F, Mohn A. Role of growth factors in the development of diabetic complications. Horm Res 2000; 53: 53 – 67.
- Serbedžija P, Ishii DN. Insulin and insulin-like growth factor prevent brain atrophy and cognitive impairment in diabetic rats. Indian J Endocrinol Metab 2012; 16: S601 - 610.
- Rao AA. Views and opinion on BDNF as a target for diabetic cognitive dysfunction. Bioinformation 2013 29; 9: 551 - 554.
- Skogseid IM, Nordby HK, Urdal P, Paus E, Lileaas F. Increased serum creatine kinase BB and neuron-specific enolase following head injury indicates brain damage. Acta Neurochir (Wien) 1992; 115:106 - 111.
- Herrmann M, Ehrenreich H. Brain derived proteins as markers of acute stroke: their relation to pathophysiology, outcome prediction and neuroprotective drug monitoring. Restor Neurol Neurosci 2003; 21: 177 – 190.
- Clarke DW, Mudd L, Boyd FT, Fields M, Raizada MK. Insulin is released from rat brain neuronal cells in culture. J Neurochem 1986;47: 831 – 836.
- Brant AM, Jess TJ, Milligan G, Brown CM, Gould GW. Immunlogical analysis of glucose transporters expressed in different regions of the rat brain and central nervous system. Biochem Biophys Res Commun 1993; 192: 1297 – 1302.
- Wozniak M, Rydzewski B, Baker P, Raizada MK. The cellular and physiological actions of insulin in the central nervous system. Neurochem Int 1993; 22: 1 – 40.
- Hopkins DF, Williams G. Insulin receptors are widely distributed in human brain and bind human and porcine insulin with equal affinity. Diabet Med 1997; 14: 1044 – 1050.
- Chiu S, Chen C, Cline H. Insulin Receptor Signaling Regulates Synapse Number, Dendritic Plasticity, and Circuit Function In Vivo. Neuron 2008; 58: 708 – 719.
- Fishel MA, Watson GS, Montine TJ, Wang Q, Green PS, Kulstad JJ, Cook DG, Peskind ER, Baker LD, Goldgaber D, Nie W, Asthana S, Plymate SR, Schwartz MW, Craft S. Hyperinsulinemia Provokes Synchronous Increases in Central Inflammation and -Amyloid in Normal Adults. Arch Neurol 2005; 62: 1539 - 1544.
- Farris W, Mansourian S, Chang Y, Lindsley L, Eckman EA, Frosch MP, Eckman CB, Tanzi RE, Selkoe DJ, Guenette S. Insulin-degrading enzyme regulates the levels of insulin, amyloid β-protein, and the β-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci USA 2003; 100: 4162 - 4167.
- Young SE, Mainous AG 3rd, Carnemolla M. Hyperinsulinemia and cognitive decline in a middle-aged cohort. Diabetes Care 2006; 29: 2688 - 2693.
- Exalto LG, Whitmer RA, Kappele LJ, Biessels GJ. An update on type 2 diabetes, vascular dementia and Alzheimer’s disease. Exp Gerontol 2012; 47: 858 - 864.
- Alafuzoff I, Aho L, Helisalmi S, Mannermaa A, Soininen H. beta- Amyloid deposition in brains of subjects with diabetes. Neuropathol Appl Neurobiol 2008; 35: 60 - 68.
- Lustman PJ, Clouse RE. Depression in diabetic patients: the relationship between mood and glycemic control. J Diabetes Complications 2005; 19: 113 – 122.
- Solfrizzi V, Panza F, Capurso A. The role of diet in cognitive decline.J Neural Transm 2003; 110: 95 - 110.
- Witte AV, Fobker M, Gellner R, Knecht S, Flöel A. Caloric restriction improves memory in elderly humans. Proc Natl Acad Sci USA 2009; 106: 1255 - 1260.
- Malik, VS; Popkin, BM, Bray, GA, Després, JP, Willett, WC, Hu,FB. Sugar-Sweetened Beverages and Risk of Metabolic Syndrome and Type 2 Diabetes: A meta-analysis. Diabetes Care 2010; 33: 2477 – 2483.
- Hu EA, Pan A, Malik V, Sun Q. White rice consumption and risk of type 2 diabetes: meta-analysis and systematic review. BMJ (Clinical research ed.) 2012; 344: e1454.
- Lee IM, Shiroma EJ, Lobelo F, Puska P, Blair SN, Katzmarzyk PT, Lancet Physical Activity Series Working Group. Effect of physical inactivity on major non-communicable diseases worldwide: an analysis of burden of disease and life expectancy. The Lancet 2012; 380: 219 – 229.
- Adler AI, Stratton IM, Neil HA, Yudkin JS, Matthews DR, Cull CA,Wright AD, Turner RC, Holman RR. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ2000; 321: 412–419.
- Risérus U, Willet W. Dietary fats and prevention of type 2 diabetes. Progress in Lipid Research 2009; 48: 44 – 51.
- National Institute for Health and Clinical Excellence. Clinical guideline 66: Type 2 diabetes. London, 2008.
- Kahler W, Kuklinski B, Ruhlmann C. Diabetes mellitus - a free radical- associated disease. Results of adjuvant antioxidant supplementation. Z Gesamte Inn Med 1993; 48: 223 – 232.