Forkhead Box i2 Transcription Factor Regulates Systemic Energy Metabolism Via Neuropeptide AgRP.
Diabetes
The neuropeptide AgRP is essential for maintaining systemic energy homeostasis. In the current study, we show that hypothalamic Foxi2, as a novel regulator of nutrient sensing, controls systemic energy metabolism by specifically stimulating AgRP expression. Foxi2 was highly expressed in the hypothalamus, and its expression was induced by fasting. Immunofluorescence assays demonstrated that Foxi2 was localized in AgRP neurons. We stereotactically injected adeno-associated virus to selectively overexpress Foxi2 in AgRP-IRES-Cre mice and found that Foxi2 overexpression in AgRP neurons specifically increased AgRP expression, thereby increasing food intake and reducing energy expenditure, subsequently leading to obesity and insulin resistance. Mechanistically, Foxi2 stimulated AgRP expression by directly binding to it and activating its transcription. Furthermore, Foxi2 overexpression activated AgRP neuron activity, as revealed by whole-cell patch-clamp experiments. Conversely, global Foxi2-mutant mice became leaner with age and were resistant to high-fat diet-induced obesity and metabolic disturbances. Collectively, our data suggest that Foxi2 plays an important role in controlling energy metabolism by regulating AgRP expression.
10.2337/db22-0002
Diabetes and cognitive dysfunction.
McCrimmon Rory J,Ryan Christopher M,Frier Brian M
Lancet (London, England)
Cognitive dysfunction in type 1 and type 2 diabetes share many similarities, but important differences do exist. A primary distinguishing feature of type 2 diabetes is that people with this disorder often (but not invariably) do poorly on measures of learning and memory, whereas deficits in these domains are rarely seen in people with type 1 diabetes. Chronic hyperglycaemia and microvascular disease contribute to cognitive dysfunction in both type 1 and type 2 diabetes, and both disorders are associated with mental and motor slowing and decrements of similar magnitude on measures of attention and executive functioning. Additionally, both types are characterised by neural slowing, increased cortical atrophy, microstructural abnormalities in white matter tracts, and similar, but not identical, changes in concentrations of brain neurometabolites. Disconcertingly, the rapid rise in obesity and type 2 diabetes in all age groups might result in a substantial increase in prevalence of diabetes-related cognitive dysfunction.
10.1016/S0140-6736(12)60360-2
Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums.
Arnold Steven E,Arvanitakis Zoe,Macauley-Rambach Shannon L,Koenig Aaron M,Wang Hoau-Yan,Ahima Rexford S,Craft Suzanne,Gandy Sam,Buettner Christoph,Stoeckel Luke E,Holtzman David M,Nathan David M
Nature reviews. Neurology
Considerable overlap has been identified in the risk factors, comorbidities and putative pathophysiological mechanisms of Alzheimer disease and related dementias (ADRDs) and type 2 diabetes mellitus (T2DM), two of the most pressing epidemics of our time. Much is known about the biology of each condition, but whether T2DM and ADRDs are parallel phenomena arising from coincidental roots in ageing or synergistic diseases linked by vicious pathophysiological cycles remains unclear. Insulin resistance is a core feature of T2DM and is emerging as a potentially important feature of ADRDs. Here, we review key observations and experimental data on insulin signalling in the brain, highlighting its actions in neurons and glia. In addition, we define the concept of 'brain insulin resistance' and review the growing, although still inconsistent, literature concerning cognitive impairment and neuropathological abnormalities in T2DM, obesity and insulin resistance. Lastly, we review evidence of intrinsic brain insulin resistance in ADRDs. By expanding our understanding of the overlapping mechanisms of these conditions, we hope to accelerate the rational development of preventive, disease-modifying and symptomatic treatments for cognitive dysfunction in T2DM and ADRDs alike.
10.1038/nrneurol.2017.185
Inflammation and gut-brain axis link obesity to cognitive dysfunction: plausible pharmacological interventions.
Solas Maite,Milagro Fermin I,Ramírez María J,Martínez J Alfredo
Current opinion in pharmacology
Obesity prevalence is increasing steadily throughout the world's population in most countries and in parallel the prevalence of metabolic disorders including cardiovascular diseases and type 2 diabetes is also rising, but less is reported about excessive adiposity relationship with poorer cognitive performance, cognitive decline and dementia. Some human clinical studies have evidenced that obesity is related to the risk of the development of mild cognitive impairment, in the form of short-term memory and executive function deficits, as well as dementia and Alzheimer's disease. The precise mechanisms that underlie the connections between obesity and the risk of cognitive impairment are still largely unknown but potential avenues of further research include insulin resistance, the gut-brain axis, and systemic mediators and central inflammation processes. A common feature of metabolic diseases is a chronic and low-grade activation of the inflammatory system. This inflammation may eventually spread from peripheral tissue to the brain, and recent reports suggest that neuroinflammation is an important causal mechanism in cognitive decline. This inflammatory status could be triggered by changes in the gut microbiota composition. Consumption of diets high in fat and sugar influences the microbiota composition, which may lead to an imbalanced microbial population in the gut. Thus, it has recently been hypothesized that the gut microbiota could be part of a mechanistic link between the consumption of high fat and other unbalanced diets and impaired cognition, termed 'gut-brain axis'. The present review will aim at providing an integrative analysis of the effects of obesity and unbalanced diets on cognitive performance and discusses some of the potential mechanisms involved, namely inflammation and changes in gut-brain axis. Moreover, the review aims to analyze anti-inflammatory drugs that have been tested for the treatment of cognition and obesity, recently approved anti-obesity drugs that could also have an impact on central nervous system, and bioactive food compounds that modulate gut microbiota and could have an impact through the gut-brain axis. In this era of precision nutrition medicine, it is imperative to identify the various metabolic-neurocognitive phenotypes in order to understand the processes that drive these diseases so that targeted therapeutic strategies to prevent and successfully manage these complex, multifactorial diseases could be designed and developed.
10.1016/j.coph.2017.10.005
Prediabetes and diabetes accelerate cognitive decline and predict microvascular lesions: A population-based cohort study.
Marseglia Anna,Fratiglioni Laura,Kalpouzos Grégoria,Wang Rui,Bäckman Lars,Xu Weili
Alzheimer's & dementia : the journal of the Alzheimer's Association
INTRODUCTION:The impact of prediabetes and diabetes on cognitive decline and the potential underlying mechanisms remain unclear. We investigated whether prediabetes and diabetes accelerate cognitive decline and brain aging, and the initial pathological changes linked to microvascular processes. METHODS:Nine-year longitudinal data from the Swedish National Study on Aging and Care-Kungsholmen (n = 2746, age ≥60 years) and the magnetic resonance imaging subsample (n = 455) were used. Cognitive function was assessed with Mini-Mental State Examination. Brain magnetic resonance imaging markers included total brain tissue, white matter, gray matter, white matter hyperintensities, and hippocampal volumes. RESULTS:Compared with diabetes-free status, prediabetes and diabetes were independently associated with accelerated cognitive decline. Prediabetes was cross-sectionally associated with smaller total brain tissue volume (P < .01), particularly smaller white matter volume. Diabetes was associated with larger white matter hyperintensities volume. Longitudinally, diabetes was associated with faster white matter hyperintensities accumulation. No associations between prediabetes or diabetes and hippocampal volume were found. DISCUSSION:Diabetes and prediabetes accelerate cognitive decline and might predict microvascular lesions among dementia-free older adults.
10.1016/j.jalz.2018.06.3060
Type 2 diabetes mellitus and biomarkers of neurodegeneration.
Moran Chris,Beare Richard,Phan Thanh G,Bruce David G,Callisaya Michele L,Srikanth Velandai,
Neurology
OBJECTIVE:Our objective was to investigate whether type 2 diabetes mellitus (T2DM) influences neurodegeneration in a manner similar to Alzheimer disease (AD), by promoting brain β-amyloid (Aβ) or tau. METHODS:We studied the cross-sectional associations of T2DM with cortical thickness, brain Aβ load, and CSF levels of Aβ and tau in a sample of people from the Alzheimer's Disease Neuroimaging Initiative with diagnoses of AD dementia, mild cognitive impairment, and normal cognition. All (n=816) received MRI, and a subsample underwent brain amyloid imaging (n=102) and CSF Aβ and tau measurements (n=415). Analyses were performed across and within cognitive diagnostic strata. RESULTS:There were 124 people with T2DM (mean age 75.5 years) and 692 without T2DM (mean age 74.1 years). After adjusting for age, sex, total intracranial volume, APO ε4 status, and cognitive diagnosis, T2DM was associated with lower bilateral frontal and parietal cortical thickness (mL) (β=-0.03, p=0.01). T2DM was not associated with 11C Pittsburgh compound B standardized uptake value ratio (AU) in any brain region or with CSF Aβ42 levels (pg/mL). T2DM was associated with greater CSF total tau (pg/mL) (β=16.06, p=0.04) and phosphorylated tau (β=5.84, p=0.02). The association between T2DM and cortical thickness was attenuated by 15% by the inclusion of phosphorylated tau. CONCLUSIONS:T2DM may promote neurodegeneration independent of AD dementia diagnosis, and its effect may be driven by tau phosphorylation. The mechanisms through which T2DM may promote tau phosphorylation deserve further study.
10.1212/WNL.0000000000001982
Diabetes and Cognitive Impairment.
Zilliox Lindsay A,Chadrasekaran Krish,Kwan Justin Y,Russell James W
Current diabetes reports
Both type 1 (T1DM) and type 2 diabetes mellitus (T2DM) have been associated with reduced performance on multiple domains of cognitive function and with evidence of abnormal structural and functional brain magnetic resonance imaging (MRI). Cognitive deficits may occur at the very earliest stages of diabetes and are further exacerbated by the metabolic syndrome. The duration of diabetes and glycemic control may have an impact on the type and severity of cognitive impairment, but as yet we cannot predict who is at greatest risk of developing cognitive impairment. The pathophysiology of cognitive impairment is multifactorial, although dysfunction in each interconnecting pathway ultimately leads to discordance in metabolic signaling. The pathophysiology includes defects in insulin signaling, autonomic function, neuroinflammatory pathways, mitochondrial (Mt) metabolism, the sirtuin-peroxisome proliferator-activated receptor-gamma co-activator 1α (SIRT-PGC-1α) axis, and Tau signaling. Several promising therapies have been identified in pre-clinical studies, but remain to be validated in clinical trials.
10.1007/s11892-016-0775-x
Cerebrovascular complications of diabetes: focus on cognitive dysfunction.
Clinical science (London, England : 1979)
The incidence of diabetes has more than doubled in the United States in the last 30 years and the global disease rate is projected to double by 2030. Cognitive impairment has been associated with diabetes, worsening quality of life in patients. The structural and functional interaction of neurons with the surrounding vasculature is critical for proper function of the central nervous system including domains involved in learning and memory. Thus, in this review we explore cognitive impairment in patients and experimental models, focusing on links to vascular dysfunction and structural changes. Lastly, we propose a role for the innate immunity-mediated inflammation in neurovascular changes in diabetes.
10.1042/CS20160397
Tau underlies synaptic and cognitive deficits for type 1, but not type 2 diabetes mouse models.
Aging cell
Diabetes mellitus (DM) is one of the most devastating diseases that currently affects the aging population. Recent evidence indicates that DM is a risk factor for many brain disorders, due to its direct effects on cognition. New findings have shown that the microtubule-associated protein tau is pathologically processed in DM; however, it remains unknown whether pathological tau modifications play a central role in the cognitive deficits associated with DM. To address this question, we used a gain-of-function and loss-of-function approach to modulate tau levels in type 1 diabetes (T1DM) and type 2 diabetes (T2DM) mouse models. Our study demonstrates that tau differentially contributes to cognitive and synaptic deficits induced by DM. On one hand, overexpressing wild-type human tau further exacerbates cognitive and synaptic impairments induced by T1DM, as human tau mice treated under T1DM conditions show robust deficits in learning and memory processes. On the other hand, neither a reduction nor increase in tau levels affects cognition in T2DM mice. Together, these results shine new light onto the different molecular mechanisms that underlie the cognitive and synaptic impairments associated with T1DM and T2DM.
10.1111/acel.12919
The effect of type 1 diabetes on the developing brain.
Cameron Fergus J,Northam Elisabeth A,Ryan Christopher M
The Lancet. Child & adolescent health
The effect of type 1 diabetes on the developing brain is a topic of primary research interest. A variety of potential dysglycaemic insults to the brain can cause cellular and structural injury and lead to altered neuropsychological outcomes. These outcomes might be subtle in terms of cognition but appear to persist into adult life. Age and circumstance at diagnosis appear to play a substantial role in potential CNS injury. A history of diabetic ketoacidosis and chronic hyperglycaemia appear to be more injurious than previously suspected, whereas a history of severe hypoglycaemia is perhaps less injurious. Neurocognitive deficits manifest across multiple cognitive domains, including executive function and speed of information processing. Some evidence suggests that subtle brain injury might directly contribute to psychological and mental health outcomes. Impaired executive function and mental health, in turn, could affect patients' adherence and the ability to make adaptive lifestyle choices. Impaired executive functioning creates a potential feedback loop of diabetic dysglycaemia leading to brain injury, further impaired executive function and mental health, which results in suboptimal adherence, and further dysglycaemia. Clinicians dealing with patients with suboptimal glycaemic outcomes should be aware of these potential issues.
10.1016/S2352-4642(19)30055-0
The impact of diabetes on cognitive impairment and its progression to dementia.
Dove Abigail,Shang Ying,Xu Weili,Grande Giulia,Laukka Erika J,Fratiglioni Laura,Marseglia Anna
Alzheimer's & dementia : the journal of the Alzheimer's Association
INTRODUCTION:Diabetes is a well-established risk factor for dementia, but its impact on the prodromal phase of dementia is unclear. METHODS:Cohorts of older adults who were cognitively healthy (n = 1840) or had cognitive impairment-no dementia (CIND; n = 682) were followed over 12 years to detect incident CIND and dementia, respectively. RESULTS:Poorly controlled diabetes (glycated hemoglobin [HbA1c] ≥7.5%; reference = normoglycemia) was associated with double the risk of CIND (Cox regression multi-adjusted hazard ratio [HR] 2.01, 95% confidence interval [CI] 1.13-3.58) and triple the risk CIND progressing to dementia (HR 2.87, 95% CI 1.20-6.85). Co-morbid diabetes and heart disease doubled the risk of incident CIND and dementia, although neither disease conferred a significant risk of either outcome alone. Elevated systemic inflammation contributed to the diabetes-associated increased dementia risk. CONCLUSIONS:Diabetes characterized by poor glycemic control or cardiovascular complications is related to a greater risk of the development and progression of cognitive impairment. Inflammation may play a role in these relationships.
10.1002/alz.12482
The role of glucose in cognition, risk of dementia, and related biomarkers in individuals without type 2 diabetes mellitus or the metabolic syndrome: A systematic review of observational studies.
Kirvalidze Mariam,Hodkinson Alexander,Storman Dawid,Fairchild Timothy J,Bała Malgorzata M,Beridze Giorgi,Zuriaga Ana,Brudasca Nicoleta I,Brini Stefano
Neuroscience and biobehavioral reviews
BACKGROUND:Excessive blood glucose promotes neuropathological cognitive decline in individuals with type 2 diabetes mellitus and the metabolic syndrome, but no systematic synthesis of the evidence for the same association exists in individuals without these conditions. OBJECTIVES:To systematically review studies exploring the role of glucose on cognition, dementia risk, and related biomarkers in adults without diabetes or metabolic syndrome. DATA SOURCES:We searched databases from inception until July 2021 and manually searched the reference lists of included studies. Risk of bias was assessed using the Joanna Briggs Institute tool. RESULTS:We found 46 observational studies including approximately 98,216 participants. Substantial heterogeneity in study results precluded drawing definitive conclusion whether blood glucose levels are associated with cognition or dementia risk. Higher blood glucose, however, was associated with greater amyloid burden, brain atrophy, and reduced cortical thickness. CONCLUSIONS AND IMPLICATIONS:High glucose concentrations in blood may exacerbate dementia-related neuropathology but whether this translates into pathological cognitive decline or elevate dementia risk later in life remains unclear.
10.1016/j.neubiorev.2022.104551
The Association of Late-Life Diabetes Status and Hyperglycemia With Incident Mild Cognitive Impairment and Dementia: The ARIC Study.
Diabetes care
OBJECTIVE:We sought to examine associations in older adults among diabetes, glycemic control, diabetes duration, and biomarkers of hyperglycemia with incident mild cognitive impairment (MCI) and incident dementia. RESEARCH DESIGN AND METHODS:We conducted a prospective analysis of 5,099 participants from the Atherosclerosis Risk in Communities (ARIC) Study who attended the fifth (2011-2013) exam. Cognitive status was assessed during follow-up via telephone calls, death certificate codes, surveillance, and a follow-up examination (2016-2017). We defined incident cognitive impairment as incident MCI or incident dementia in persons dementia-free at the index examination; we also examined each outcome separately. Diabetes was defined using self-report, medications, or HbA ≥6.5%; poor glycemic control in persons with diabetes was defined as HbA ≥7%. We examined the following biomarkers of hyperglycemia: HbA, fructosamine, glycated albumin, and 1,5-anhydroglucitol. RESULTS:Mean age at baseline was 76 years, 59% were female, and 21% were black. Diabetes (hazard ratio [HR] 1.14 [95% CI 1.00, 1.31]), poor glycemic control in persons with diabetes (HR 1.31 [95% CI 1.05, 1.63]), and longer diabetes duration (≥5 vs. <5 years; HR 1.59 [95% CI 1.23, 2.07]) were significantly associated with incident cognitive impairment. We found a J-shaped association between HbA and incident dementia. Glycated albumin and fructosamine were also associated with incident dementia, independently of HbA. HbA and fructosamine were also associated with incident MCI. CONCLUSIONS:Diabetes status, poor glycemic control, and longer diabetes duration were associated with worse cognitive outcomes over a median follow-up of 5 years.
10.2337/dc19-0120
Metformin Use Is Associated With Slowed Cognitive Decline and Reduced Incident Dementia in Older Adults With Type 2 Diabetes: The Sydney Memory and Ageing Study.
Samaras Katherine,Makkar Steve,Crawford John D,Kochan Nicole A,Wen Wei,Draper Brian,Trollor Julian N,Brodaty Henry,Sachdev Perminder S
Diabetes care
OBJECTIVE:Type 2 diabetes (diabetes) is characterized by accelerated cognitive decline and higher dementia risk. Controversy exists regarding the impact of metformin, which is associated with both increased and decreased dementia rates. The objective of this study was to determine the association of metformin use with incident dementia and cognitive decline over 6 years in participants with diabetes compared with those not receiving metformin and those without diabetes. RESEARCH DESIGN AND METHODS:A prospective observational study was conducted of = 1,037 community-dwelling older participants without dementia aged 70-90 years at baseline (the Sydney Memory and Ageing Study). Exclusion criteria were dementia, major neurological or psychiatric disease, or progressive malignancy. Neuropsychological testing measured cognitive function every 2 years; a battery of tests measured executive function, memory, attention/speed, language, and visuospatial function individually. These were used to determine the measure of global cognition. Incident dementia was ascertained by a multidisciplinary panel. Total brain, hippocampal, and parahippocampal volumes were measured by MRI at baseline and 2 years ( = 526). Data were analyzed by linear mixed modeling, including the covariates of age, sex, education, BMI, heart disease, hypertension, stroke, smoking, and apolipoprotein Eε4 carriage. RESULTS:Of = 1,037, 123 had diabetes; 67 received metformin (DM+MF) and were demographically similar to those who did not (DM-noMF) and participants without diabetes (no-DM). DM+MF had significantly slower global cognition and executive function decline compared with DM-noMF. Incident dementia was significantly higher in DM-noMF compared with DM+MF (odds ratio 5.29 [95% CI 1.17-23.88]; = 0.05). CONCLUSIONS:Older people with diabetes receiving metformin have slower cognitive decline and lower dementia risk. Large randomized studies in people with and without diabetes will determine whether these associations can be attributed to metformin.
10.2337/dc20-0892
Altered Intranetwork and Internetwork Functional Connectivity in Type 2 Diabetes Mellitus With and Without Cognitive Impairment.
Yang Shi-Qi,Xu Zhi-Peng,Xiong Ying,Zhan Ya-Feng,Guo Lin-Ying,Zhang Shun,Jiang Ri-Feng,Yao Yi-Hao,Qin Yuan-Yuan,Wang Jian-Zhi,Liu Yong,Zhu Wen-Zhen
Scientific reports
Type 2 diabetes mellitus (T2DM) is associated with cognitive impairment. We investigated whether alterations of intranetwork and internetwork functional connectivity with T2DM progression exist, by using resting-state functional MRI. MRI data were analysed from 19 T2DM patients with normal cognition (DMCN) and 19 T2DM patients with cognitive impairment (DMCI), 19 healthy controls (HC). Functional connectivity among 36 previously well-defined brain regions which consisted of 5 resting-state network (RSN) systems [default mode network (DMN), dorsal attention network (DAN), control network (CON), salience network (SAL) and sensorimotor network (SMN)] was investigated at 3 levels (integrity, network and connectivity). Impaired intranetwork and internetwork connectivity were found in T2DM, especially in DMCI, on the basis of the three levels of analysis. The bilateral posterior cerebellum, the right insula, the DMN and the CON were mainly involved in these changes. The functional connectivity strength of specific brain architectures in T2DM was found to be associated with haemoglobin A1c (HbA1c), cognitive score and illness duration. These network alterations in intergroup differences, which were associated with brain functional impairment due to T2DM, indicate that network organizations might be potential biomarkers for predicting the clinical progression, evaluating the cognitive impairment, and further understanding the pathophysiology of T2DM.
10.1038/srep32980
Type 2 diabetes mellitus, brain atrophy, and cognitive decline.
Moran Chris,Beare Richard,Wang Wei,Callisaya Michele,Srikanth Velandai,
Neurology
OBJECTIVE:To study longitudinal relationships between type 2 diabetes mellitus (T2DM), cortical thickness, and cognitive function in older people with normal cognition, mild cognitive impairment, and Alzheimer disease (AD). METHODS:The sample was derived from the Alzheimer's Disease Neuroimaging Initiative cohort who underwent brain MRI and cognitive tests annually for 5 years. Presence of T2DM was based on fasting blood glucose ≥7.0mml/L or the use of glucose-lowering agents. We used latent growth curve modeling to explore longitudinal relationships between T2DM, cortical thickness, and cognitive function, adjusting for relevant covariates and testing for interactions. RESULTS:There were 124 people with T2DM (mean age 75.5 years, SD 6.2) and 693 without T2DM (mean age 75.1 years, SD 6.9) with at least 1 MRI available. AD and lower cortical thickness at study entry was associated with a lower chance of having a MRI available at each follow-up phase (all < 0.001). T2DM was associated with lower baseline cortical thickness ( = 0.01). We found no direct effect of T2DM on decline in cortical thickness or cognitive function, but there was an indirect pathway linking T2DM and cognitive decline via baseline cortical thickness (β = -0.17, = 0.022). There was an interaction between T2DM and education whereby the negative effect of T2DM on baseline cortical thickness was reduced in those with greater education (β = 0.34, = 0.037). These associations changed minimally when adjusted for baseline cognitive diagnosis. CONCLUSIONS:In an older cohort with low cerebrovascular disease burden, T2DM contributes to cognitive decline via neurodegeneration. Prior brain and cognitive reserve may protect against this effect.
10.1212/WNL.0000000000006955
Metabolic encephalopathy secondary to diabetic ketoacidosis: a case report.
Tomkins Maria,McCormack Richard,O'Connell Karen,Agha Amar,Merwick Áine
BMC endocrine disorders
INTRODUCTION:Metabolic encephalopathy is a rare but potentially devastating complication of diabetic ketoacidosis (DKA). This case highlights the dramatic cognitive decline of a young man due to metabolic encephalopathy complicating DKA. The aims of this case report are to highlight metabolic encephalopathy as a complication of DKA and to explore the current research in diabetic related brain injury. The importance of investigation and treatment of reversible causes of encephalopathy is also demonstrated. CASE PRESENTATION:A 35-year-old man with a background of type 1 diabetes mellitus (T1DM) and relapsing remitting multiple sclerosis (RRMS) presented to the emergency department (ED) in a confused and agitated state. Prior to admission he worked as a caretaker in a school, smoked ten cigarettes per day, took excess alcohol and smoked cannabis twice per week. Following initial investigations, he was found to be in DKA. Despite timely and appropriate management his neurological symptoms and behavioural disturbance persisted. Neuroimaging revealed temporal lobe abnormalities consistent with an encephalopathic process. The patient underwent extensive investigation looking for evidence of autoimmune, infective, metabolic, toxic and paraneoplastic encephalopathy, with no obvious cause demonstrated. Due to persistent radiological abnormalities a temporal lobe biopsy was performed which showed marked astrocytic gliosis without evidence of vasculitis, inflammation, infarction or neoplasia. A diagnosis of metabolic encephalopathy secondary to DKA was reached. The patient's cognitive function remained impaired up to 18 months post presentation and he ultimately required residential care. CONCLUSIONS:Metabolic encephalopathy has been associated with acute insults such as DKA, but importantly, the risk of cerebral injury is also related to chronic hyperglycaemia. Mechanisms of cerebral injury in diabetes mellitus continue to be investigated. DKA poses a serious and significant neurological risk to patients with diabetes mellitus. To our knowledge this is the second case report describing this acute complication.
10.1186/s12902-019-0398-8
Quercetin protects against diabetic encephalopathy via SIRT1/NLRP3 pathway in db/db mice.
Hu Tian,Lu Xin-Yi,Shi Jing-Jing,Liu Xiao-Qi,Chen Qu-Bo,Wang Qi,Chen Yun-Bo,Zhang Shi-Jie
Journal of cellular and molecular medicine
Epidemiological studies have found that diabetes and cognitive dysfunction are closely related. Quercetin has been certified with the effect on improving diabetes mellitus (DM) and cognitive impairment. However, the effect and related mechanism of quercetin on diabetic encephalopathy (DE) are still ambiguous. In this study, we used the db/db mice (diabetic model) to discover whether quercetin could improve DE through the Sirtuin1/NLRP3 (NOD-, LRR- and pyrin domain-containing 3) pathway. Behavioural results (Morris water maze and new object recognition tests) showed that quercetin (70 mg/kg) improved the learning and memory. Furthermore, quercetin alleviated insulin resistance and the level of fasting blood glucose. Besides, Western blot analysis also showed that quercetin increased the protein expressions of nerve- and synapse-related protein, including postsynapticdensity 93 (PSD93), postsynapticdensity 95 (PSD95), brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the brain of db/db mice. Quercetin also increased the protein expression of SIRT1 and decreased the expression of NLRP3 inflammation-related proteins, including NLRP3, the adaptor protein ASC and cleaved Caspase-1, the pro-inflammatory cytokines IL-1β and IL-18. In conclusion, the present results indicate that the SIRT1/NLRP3 pathway may be a crucial mechanism for the neuroprotective effect of quercetin against DE.
10.1111/jcmm.15026
Intracerebral Hemorrhage and Diabetes Mellitus: Blood-Brain Barrier Disruption, Pathophysiology and Cognitive Impairments.
Bahadar Ghaith A,Shah Zahoor A
CNS & neurological disorders drug targets
There is a surge in diabetes incidence, with an estimated 463 million individuals been diagnosed worldwide. Diabetes Mellitus (DM) is a major stroke-related comorbid condition that increases the susceptibility of disabling post-stroke outcomes. Although less common, intracerebral hemorrhage (ICH) is the most dramatic subtype of stroke associated with higher mortality, particularly in the DM population. Previous studies have focused mainly on the impact of DM on ischemic stroke. Few studies have focused on the impact of DM on ICH and discussed the blood- -brain barrier disruption, brain edema, and hematoma formation. However, more recently, investigating the role of oxidative damage and Reactive Oxygen Species (ROS) production in preclinical studies involving DM-ICH animal models has gained attention. But, little is known about the correlation between neuroinflammatory processes, glial cells activation, and peripheral immune cell invasion with DM-ICH injury. DM and ICH patients experience impaired abilities in multiple cognitive domains by relatively comparable mechanisms, which could get exacerbated in the setting of comorbidities. In this review, we discuss both the pathology of DM as a comorbid condition for ICH and the potential molecular therapeutic targets for the clinical management of the ICH and its recovery.
10.2174/1871527320666210223145112
Cerebral perfusion alterations in type 2 diabetes mellitus - a systematic review.
Wang Yaqiong,Sun Lin,He Guangyu,Gang Xiaokun,Zhao Xue,Wang Guixia,Ning Guang
Frontiers in neuroendocrinology
Type 2 diabetes mellitus (T2DM) is related to abnormal brain structure and function, increasing the risk of cognitive impairment and dementia. We systematically reviewed the published literature focusing on cerebral perfusion in patients with T2DM. Although no significant difference was found in global cerebral blood flow (CBF) between the T2DM group and the healthy control group, the regional cerebral perfusion in T2DM was significantly reduced in multiple locations, including the occipital lobe, domains involved in the default mode network and the cerebellum. The decline in regional CBF was associated with a wide range of cognitive disorders in T2DM, including learning, memory, attention, and executive processing, as well as visual function. In addition, diabetes-related biochemical indicators, such as glycated hemoglobin and insulin resistance, were negatively correlated with regional CBF. In general, these functional perfusion imaging studies indicate that decreased CBF in T2DM may be a potential cause of cognitive impairment.
10.1016/j.yfrne.2021.100916
F1F0 ATP Synthase-Cyclophilin D Interaction Contributes to Diabetes-Induced Synaptic Dysfunction and Cognitive Decline.
Diabetes
Mitochondrial abnormalities are well known to cause cognitive decline. However, the underlying molecular basis of mitochondria-associated neuronal and synaptic dysfunction in the diabetic brain remains unclear. Here, using a mitochondrial single-channel patch clamp and cyclophilin D (CypD)-deficient mice (Ppif ) with streptozotocin-induced diabetes, we observed an increase in the probability of Ca-induced mitochondrial permeability transition pore (mPTP) opening in brain mitochondria of diabetic mice, which was further confirmed by mitochondrial swelling and cytochrome c release induced by Ca overload. Diabetes-induced elevation of CypD triggers enhancement of FF ATP synthase-CypD interaction, which in turn leads to mPTP opening. Indeed, in patients with diabetes, brain cypD protein levels were increased. Notably, blockade of the FF ATP synthase-CypD interaction by CypD ablation protected against diabetes-induced mPTP opening, ATP synthesis deficits, oxidative stress, and mitochondria dysfunction. Furthermore, the absence of CypD alleviated deficits in synaptic plasticity, learning, and memory in diabetic mice. Thus, blockade of ATP synthase interaction with CypD provides a promising new target for therapeutic intervention in diabetic encephalopathy.
10.2337/db16-0556
Diabetes mellitus and risks of cognitive impairment and dementia: A systematic review and meta-analysis of 144 prospective studies.
Ageing research reviews
BACKGROUND:Uncertainties persist about the associations of diabetes with risk of cognitive impairment and dementia. We aimed to illuminate these associations from various aspects. METHODS:We identified relevant prospective studies by searching PubMed up to Jun 2019. Summary relative risks (RR) were estimated using random-effects models. Credibility of each meta-analysis was assessed. Meta-regression and subgroup analyses were conducted. RESULTS:Of 28,082 identified literatures, 144 were eligible for inclusion in the systematic review, among which 122 were included in the meta-analysis. Diabetes conferred a 1.25- to 1.91-fold excess risk for cognitive disorders (cognitive impairment and dementia). Subjects with prediabetes also had higher risk for dementia. As for diabetes-related biochemical indicators, fasting plasma glucose (FPG) was non-linearly related to cognitive disorders; the elevated levels of 2 -h postload glucose (2h-PG), glycosylated hemoglobin (HbA1c), low and high levels of fasting plasma insulin (FPI) were associated with an increased risk of dementia. Encouragingly, the use of pioglitazone exhibited a 47% reduced risk of dementia in diabetic population. CONCLUSIONS:Diabetes, even prediabetes and changes of diabetes-related biochemical indicators, predicted increased incidence of cognitive impairment and dementia. The protective effects of pioglitazone warrant further investigation in randomized trials.
10.1016/j.arr.2019.100944
Diabetic Cognitive Dysfunction: From Bench to Clinic.
Zhou Jiyin,Zhang Zuo,Zhou Hongli,Qian Guisheng
Current medicinal chemistry
Type 2 diabetes increases the risk of developing cognitive dysfunction in the elderly in the form of short-term memory and executive function impairment. Genetic and diet-induced models of type 2 diabetes further support this link, displaying deficits in working memory, learning, and memory performance. The risk factors for diabetic cognitive dysfunction include vascular disease, hypoglycaemia, hyperlipidaemia, adiposity, insulin resistance, lifestyle factors, and genetic factors. Using neuronal imaging technologies, diabetic patients with cognitive dysfunction show atrophy of the whole brain, particularly the grey matter, hippocampus and amygdala; increased volume of the ventricular and white matter; brain infarcts; impaired network integrity; abnormal microstructure; and reduced cerebral blood flow and amplitude of low-frequency fluctuations. The pathogenesis of type 2 diabetes with cognitive dysfunction involves hyperglycaemia, macrovascular and microvascular diseases, insulin resistance, inflammation, apoptosis, and disorders of neurotransmitters. Large clinical trials may offer further proof of biomarkers and risk factors for diabetic cognitive dysfunction. Advanced neuronal imaging technologies and novel disease animal models will assist in elucidating the precise pathogenesis and to provide better therapeutic interventions and treatment.
10.2174/1871530319666190206225635
Vascular cognitive impairment and dementia in type 2 diabetes mellitus: An overview.
Lyu Fan,Wu Dan,Wei Changwei,Wu Anshi
Life sciences
Type 2 diabetes mellitus (T2DM) as well as vascular cognitive impairment and dementia (VCID), are both chronic diseases, severely affecting patients, families, and society. A growing number of studies have found that T2DM may double the incidence of cognitive impairment. To help patients with T2DM prevent cognitive dysfunction more scientifically, as well as providing researchers with clearer research ideas, we summarized the risk factors, mechanisms and prevention methods of VCID which is induced by T2DM. This is a great significance for patients with T2DM to prevent the occurrence of VCID, meanwhile, it provides a reference for future researches on the relationship between T2DM and VCID.
10.1016/j.lfs.2020.117771
Association of Type 2 Diabetes, According to the Number of Risk Factors Within Target Range, With Structural Brain Abnormalities, Cognitive Performance, and Risk of Dementia.
Diabetes care
OBJECTIVE:Type 2 diabetes is associated with increased risks of cognitive dysfunction and brain abnormalities. The extent to which risk factor modification can mitigate these risks is unclear. We investigated the associations between incident dementia, cognitive performance, and brain abnormalities among individuals with type 2 diabetes, according to the number of risk factors on target, compared with control subjects without diabetes. RESEARCH DESIGN AND METHODS:Prospective data were from UK Biobank of 87,856 individuals ( = 10,663 diabetes, = 77,193 control subjects; baseline 2006-2010), with dementia follow-up until February 2018. Individuals with diabetes were categorized according to the number of seven selected risk factors within the guideline-recommended target range (nonsmoking; guideline-recommended levels of glycated hemoglobin, blood pressure, BMI, albuminuria, physical activity, and diet). Outcomes were incident dementia, domain-specific cognitive performance, white matter hyperintensities, and total brain volume. RESULTS:After a mean follow-up of 9.0 years, 147 individuals (1.4%) with diabetes and 412 control subjects (0.5%) had incident dementia. Among individuals with diabetes, excess dementia risk decreased stepwise for a higher number of risk factors on target. Compared with control subjects (incidence rate per 1,000 person-years 0.62 [95% CI 0.56; 0.68]), individuals with diabetes who had five to seven risk factors on target had no significant excess dementia risk (absolute rate difference per 1,000 person-years 0.20 [-0.11; 0.52]; hazard ratio 1.32 [0.89; 1.95]). Similarly, differences in processing speed, executive function, and brain volumes were progressively smaller for a higher number of risk factors on target. These results were replicated in the Maastricht Study. CONCLUSIONS:Among individuals with diabetes, excess dementia risk, lower cognitive performance, and brain abnormalities decreased stepwise for a higher number of risk factors on target.
10.2337/dc21-0149
Diabetes-Specific Dementia: A Structured Literature Review of Cognitive Assessment Methods.
Faaitiiti Kelli L,Jupiter Daniel C
The Journal of foot and ankle surgery : official publication of the American College of Foot and Ankle Surgeons
Diabetes mellitus is a known risk factor for the development of multiple subtypes of dementia and mild cognitive impairment. Recent research identifies a cause-specific diabetes-related dementia with a unique set of characteristics. Currently, there is no standard cognitive assessment battery recommended to specifically assess dementia that is a direct consequence of chronic diabetes, and some evaluations have been used for decades with minimal revisions, regardless of appropriateness. We performed a systematic review of the dementia/cognition evaluation methods most commonly used in the literature for assessing diabetic patients and identified which cognitive domains are typically assessed in this setting, and whether cognitive changes were more reflective of a vascular pathology, Alzheimer's pathology, or something else entirely. Search results yielded 1089 articles. After screening for appropriateness, a total of 11 full-text articles were assessed. In general, subjects in the reviewed studies were assessed using a variety of testing methods, examining different combinations of cognitive domains. A standard, clear definition of which cognitive domains are the most important to assess in diabetic patients is needed in order to determine what combination of assessment tools are most pertinent. Given the growing subset of the US population, careful reconsideration of cognitive assessment methods is needed to create self-care plans that take into account a specific collection of cognitive challenges for those with diabetes.
10.1053/j.jfas.2021.11.003
A Tale of Two Diseases: Exploring Mechanisms Linking Diabetes Mellitus with Alzheimer's Disease.
Lynn Jessica,Park Mingi,Ogunwale Christiana,Acquaah-Mensah George K
Journal of Alzheimer's disease : JAD
Dementias, including the type associated with Alzheimer's disease (AD), are on the rise worldwide. Similarly, type 2 diabetes mellitus (T2DM) is one of the most prevalent chronic diseases globally. Although mechanisms and treatments are well-established for T2DM, there remains much to be discovered. Recent research efforts have further investigated factors involved in the etiology of AD. Previously perceived to be unrelated diseases, commonalities between T2DM and AD have more recently been observed. As a result, AD has been labeled as "type 3 diabetes". In this review, we detail the shared processes that contribute to these two diseases. Insulin resistance, the main component of the pathogenesis of T2DM, is also present in AD, causing impaired brain glucose metabolism, neurodegeneration, and cognitive impairment. Dysregulation of insulin receptors and components of the insulin signaling pathway, including protein kinase B, glycogen synthase kinase 3β, and mammalian target of rapamycin are reported in both diseases. T2DM and AD also show evidence of inflammation, oxidative stress, mitochondrial dysfunction, advanced glycation end products, and amyloid deposition. The impact that changes in neurovascular structure and genetics have on the development of these conditions is also being examined. With the discovery of factors contributing to AD, innovative treatment approaches are being explored. Investigators are evaluating the efficacy of various T2DM medications for possible use in AD, including but not limited to glucagon-like peptide-1 receptor agonists and peroxisome proliferator-activated receptor-gamma agonists. Furthermore, there are 136 active trials involving 121 therapeutic agents targeting novel AD biomarkers. With these efforts, we are one step closer to alleviating the ravaging impact of AD on our communities.
10.3233/JAD-210612
Cognitive functioning and structural brain abnormalities in people with Type 2 diabetes mellitus.
Mankovsky B,Zherdova N,van den Berg E,Biessels G-J,de Bresser J
Diabetic medicine : a journal of the British Diabetic Association
AIMS:Type 2 diabetes mellitus is associated with cognitive dysfunction, but the underlying structural brain correlates are uncertain. This study examined the association between cognitive functioning and structural brain abnormalities in people with long-standing Type 2 diabetes. METHODS:Ninety-three people with Type 2 diabetes (age 62.3 ± 5.4 years, diabetes duration 9.7 ± 6.7 years; HbA 65 ± 10 mmol/mol, 8.1 ± 1.3%) were included. Cognitive functioning was assessed by a test battery covering the domains memory, processing speed and executive functioning. Brain tissue volumes and white matter hyperintensity volumes were automatically determined on MRI. Linear regression analyses were performed adjusted for age, sex and education. RESULTS:In people with Type 2 diabetes, increased white matter hyperintensity volume was associated with decreased processing speed [regression B coefficient = -0.22 (-0.38 to -0.06), P = 0.009], but not with memory or executive function (P > 0.05). Brain tissue volumes were not significantly related to cognitive functioning (P > 0.05). CONCLUSIONS:In people with long-standing, less strictly controlled Type 2 diabetes, white matter hyperintensities volumes were associated with decreased processing speed. This suggests that cerebral small vessel disease is an underlying disease mechanism of cognitive dysfunction in these individuals.
10.1111/dme.13800
Cognitive decline and dementia in diabetes mellitus: mechanisms and clinical implications.
Nature reviews. Endocrinology
Cognitive dysfunction is increasingly recognized as an important comorbidity of diabetes mellitus. Different stages of diabetes-associated cognitive dysfunction exist, each with different cognitive features, affected age groups and prognoses and probably with different underlying mechanisms. Relatively subtle, slowly progressive cognitive decrements occur in all age groups. More severe stages, particularly mild cognitive impairment and dementia, with progressive deficits, occur primarily in older individuals (>65 years of age). Patients in the latter group are the most relevant for patient management and are the focus of this Review. Here, we review the evolving insights from studies on risk factors, brain imaging and neuropathology, which provide important clues on mechanisms of both the subtle cognitive decrements and the more severe stages of cognitive dysfunction. In the majority of patients, the cognitive phenotype is probably defined by multiple aetiologies. Although both the risk of clinically diagnosed Alzheimer disease and that of vascular dementia is increased in association with diabetes, the cerebral burden of the prototypical pathologies of Alzheimer disease (such as neurofibrillary tangles and neuritic plaques) is not. A major challenge for researchers is to pinpoint from the spectrum of diabetes-related disease processes those that affect the brain and contribute to development of dementia beyond the pathologies of Alzheimer disease. Observations from experimental models can help to meet that challenge, but this requires further improving the synergy between experimental and clinical scientists. The development of targeted treatment and preventive strategies will therefore depend on these translational efforts.
10.1038/s41574-018-0048-7
Alzheimer's disease and type 2 diabetes mellitus are distinct diseases with potential overlapping metabolic dysfunction upstream of observed cognitive decline.
Brain pathology (Zurich, Switzerland)
Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are highly prevalent aging-related diseases associated with significant morbidity and mortality. Some findings in human and animal models have linked T2DM to AD-type dementia. Despite epidemiological associations between the T2DM and cognitive impairment, the interrelational mechanisms are unclear. The preponderance of evidence in longitudinal studies with autopsy confirmation have indicated that vascular mechanisms, rather than classic AD-type pathologies, underlie the cognitive decline often seen in self-reported T2DM. T2DM is associated with cardiovascular and cerebrovascular disease (CVD), and is associated with increased risk of infarcts and small vessel disease in the brain and other organs. Neuropathological examinations of post-mortem brains demonstrated evidence of cerebrovascular disease and little to no correlation between T2DM and β-amyloid deposits or neurofibrillary tangles. Nevertheless, the mechanisms upstream of early AD-specific pathology remain obscure. In this regard, there may indeed be overlap between the pathologic mechanisms of T2DM/"metabolic syndrome," and AD. More specifically, cerebral insulin processing, glucose metabolism, mitochondrial function, and/or lipid metabolism could be altered in patients in early AD and directly influence symptomatology and/or neuropathology.
10.1111/bpa.12655
Differential Levels of Hippo Signaling in Selected Brain and Peripheral Tissues in Streptozotocin-Induced Cognitive Dysfunction in Mice.
Yu Fan,Han Wei,Zhan Gaofeng,Li Shan,Jiang Xiaohong,Xiang Shoukui,Zhu Bin,Yang Ling,Hua Dongyu,Luo Ailin,Hua Fei,Yang Chun
Neuroscience
Increasing studies have revealed that metabolic disorders, especially diabetes, are high risk factors for the development of Alzheimer's disease (AD) and other neurodegenerative diseases. It has been reported that patients with diabetes are prone to suffer from cognitive dysfunction (CD). Although abnormal glucose metabolism and deposition of amyloid β (Aβ) are proven to have a closely relationship with diabetes-induced CD, its exact mechanism is still undetermined. In this study, a total of 14 mice were intraperitoneally injected with streptozotocin for 5 consecutive days to mimic diabetic models, and then hierarchical cluster analysis was adopted to classify the diabetic mice into CD and Non-CD phenotypes by the results of Morris water maze test (MWMT). Furthermore, we detected Hippo signaling including mammalian sterile 20-like protein kinases1 (MST1), large tumor suppressors 1 (LATS1), Yes-associated protein (YAP) and phosphorylation of YAP (p-YAP) in brain and peripheral tissues. As compared with control mice, the levels of MST1, LATS1 and p-YAP/YAP ratio were increased in medial prefrontal cortex (mPFC), striatum and hippocampus of CD mice, while these proteins were decreased in gut tissue of CD mice. Additionally, there were significant positive correlations between escape latency and p-YAP/YAP ratio in mPFC, anterior cingulate cortex (ACC) and hippocampus, as well as the level of LATS1 in liver, kidney and gut tissues. In conclusion, alterations in Hippo signaling may contribute to CD induced by diabetes. Therefore, therapeutic interventions improving Hippo signaling might be beneficial to the treatment of diabetes-induced CD and other neurodegenerative diseases.
10.1016/j.neuroscience.2019.09.018
A New Neurovascular Panel Discriminates Between Patients with Type 2 Diabetes Mellitus with Cognitive Impairment and Cognitive Impairment Alone.
Zhang Weiwei,Liu Yiming,Bao Hong,Zhang Mengguo,Gao Feng,Kang Dongmei,Shen Yong
Journal of Alzheimer's disease : JAD
BACKGROUND:Recent studies showed that type 2 diabetes mellitus (T2DM) may increase the risk of cognitive impairment, but there are few biomarkers to diagnostically discriminate T2DM-associated cognitive impairment and cognitive impairment alone. In this study, we assessed certain cytokines involved in inflammation and vascular diseases and identified special panel of cytokines that could differentiate between T2DM and cognitive impairment. OBJECTIVE:To investigate associations and differences between T2DM and cognitive impairment by cytokines analysis. METHODS:A total of 264 participants were recruited, their blood samples were collected, and plasma and serum were separated and stored at - 80°C until the assessment of amyloid-β (Aβ)42, Aβ40 and 8 kinds of cytokines by Luminex multiplex assays. RESULTS:Plasma Aβ40 is higher whereas Aβ42/40 ratio is lower in cognitive impairment and T2DM-associated cognitive impairment compared to other groups. As compared to health control, YKL-40 level was upregulated in cognitive impairment, PRGN was downregulated in T2DM associated cognitive impairment, OPN was substantially decreased in T2DM, and IL-6 was elevated in cognitive impairment and T2DM-associated cognitive impairment. Interestingly, VEGF and S100B were induced in T2DM when compared with cognitive impairment, and NSE level in T2DM-associated cognitive impairment is significantly lower than in T2DM or cognitive impairment. CONCLUSION:Aβ42, Aβ40, and Aβ42/40 ratio cannot distinguish T2DM-associated cognitive impairment from cognitive impairment. Certain cytokines (YKL-40, NSE, and VEGF) have good performance in distinguishing T2DM-associated cognitive impairment from simple cognitive impairment. Taken together, this may improve the accuracy of the diagnosis and establishment of individualized therapy.
10.3233/JAD-200095
Impaired cerebral blood flow in type 2 diabetes mellitus - A comparative study with subjective cognitive decline, vascular dementia and Alzheimer's disease subjects.
Chau Anson C M,Cheung Eva Y W,Chan K H,Chow W S,Shea Y F,Chiu Patrick K C,Mak Henry K F
NeuroImage. Clinical
The link between non-demented type 2 diabetes mellitus (T2DM) and different types of cognitive impairment is controversial. By controlling for co-morbidities such as cerebral macrovascular and microvascular changes, cerebral atrophy, amyloid burden, hypertension or hyperlipidemia, the current study investigated the cerebral blood flow of T2DM individuals as compared to cognitively impaired subjects recruited from a memory clinic. 15 healthy control (71.8 ± 6.1 years), 18 T2DM (62.5 ± 3.7 years), as well as 8 Subjective Cognitive Decline (69.5 ± 7.5 years), 12 Vascular Dementia (79.3 ± 4.2 years) and 17 Alzheimer's Disease (75.1 ± 8.2 years) underwent multi-parametric MRI brain scanning. Subjects with T2DM and from the memory clinic also had 18-F Flutametamol PET-CT scanning to look for any amyloid burden. Pseudocontinuous Arterial Spin Labeling (PCASL), MR Angiography Head, 3D FLAIR and 3D T1-weighted sequences were used to quantify cerebral blood flow, cerebrovascular changes, white matter hyperintensities and brain atrophy respectively. Vascular risk factors were retrieved from the medical records. The 37 subjects from memory clinic were classified into subjective cognitive decline (SCD), vascular dementia (VD) and Alzheimer's disease (AD) subgroups by a multi-disciplinary panel consisting of a neuroradiologist, and 2 geriatricians. Absolute cortical CBF in our cohort of T2DM, SCD, VD and AD was significantly decreased (p < 0.01) as compared to healthy controls (HC) in both whole brain and eight paired brain regions, after age, normalized grey matter volume and gender adjustment and Bonferroni correction. Subgroup analysis between T2DM, SCD, VD, and AD revealed that CBF of T2DM was not significantly different from AD, VD or SCD. By controlling for co-morbidities, impaired cortical CBF in T2DM was not related to microangiopathy or amyloid deposition, but to the interaction of triple risk factors (such as diabetes mellitus, hypertension, and hyperlipidemia). There was statistically significant negative correlation (p ≤ 0.05) between adjusted CBF and HbA1c in all brain regions of T2DM and HC (with partial correlation ranging from -0.30 to -0.46). Taken together, altered cerebral blood flow in T2DM might be related to disruption of cerebrovascular autoregulation related to vascular risk factors, and such oligemia occurred before clinical manifestation due to altered glycemic control.
10.1016/j.nicl.2020.102302
Diabetes Mellitus and Cognition: Pathway Analysis in the MEMENTO Cohort.
Neurology
OBJECTIVE:To assess the role of biomarkers of Alzheimer disease (AD), neurodegeneration, and small vessel disease (SVD) as mediators in the association between diabetes mellitus and cognition. METHODS:The study sample was derived from MEMENTO, a cohort of French adults recruited in memory clinics and screened for either isolated subjective cognitive complaints or mild cognitive impairment. Diabetes was defined based on blood glucose assessment, use of antidiabetic agent, or self-report. We used structural equation modeling to assess whether latent variables of AD pathology (PET mean amyloid uptake, Aβ/Aβ ratio, and CSF phosphorylated tau), SVD (white matter hyperintensities volume and visual grading), and neurodegeneration (mean cortical thickness, brain parenchymal fraction, hippocampal volume, and mean fluorodeoxyglucose uptake) mediate the association between diabetes and a latent variable of cognition (5 neuropsychological tests), adjusting for potential confounders. RESULTS:There were 254 (11.1%) participants with diabetes among 2,288 participants (median age 71.6 years; 61.8% women). The association between diabetes and lower cognition was significantly mediated by higher neurodegeneration (standardized indirect effect: -0.061, 95% confidence interval: -0.089, -0.032), but not mediated by SVD and AD markers. Results were similar when considering latent variables of memory or executive functioning. CONCLUSION:In a large clinical cohort in the elderly, diabetes is associated with lower cognition through neurodegeneration, independently of SVD and AD biomarkers.
10.1212/WNL.0000000000012440
HMGB1 plays an important role in pyroptosis induced blood brain barrier breakdown in diabetes-associated cognitive decline.
Liu Lumei,Wang Neng,Kalionis Bill,Xia Shijin,He Qinghu
Journal of neuroimmunology
Diabetes mellitus increases the risk of dementia, and evidence suggests hyperglycemia is a key contributor to neurodegeneration. However, our understanding of diabetes-associated cognitive decline, an important complication of diabetes mellitus, is lacking and the underlying mechanism is unclear. Blood brain barrier (BBB) breakdown is a possible cause of dementia in diabetes mellitus and Alzheimer's disease. Accumulating evidence shows BBB dysfunction caused by hyperglycemia contributes to cognitive decline. A specific type of inflammatory programmed cell death, called pyroptosis, has potential as a therapeutic target for BBB-associated diseases. Potential inducers of pyroptosis include inflammasomes such as NLRP3, whose activation relies on damage-associated molecular patterns. High mobility group box 1 (HMGB1) is a highly conserved, ubiquitous protein found in most cell types, and acts as a damage-associated molecular pattern when released from the nucleus. We propose that HMGB1 influences vascular inflammation by activating the NLRP3 inflammasome and thereby initiating pyroptosis in vascular cells. Moreover, HMGB1 plays a pivotal role in the pathogenesis of diabetes mellitus and diabetic complications. Here, we review the role of HMGB1 in BBB dysfunction induced by hyperglycemia and propose that HMGB1 is a promising therapeutic target for countering diabetes-associated cognitive decline.
10.1016/j.jneuroim.2021.577763
What magnetic resonance imaging reveals - A systematic review of the relationship between type II diabetes and associated brain distortions of structure and cognitive functioning.
Rosenberg Jessica,Lechea Nazim,Pentang Gael N,Shah Nadim J
Frontiers in neuroendocrinology
Due to its increasing prevalence, Type 2 diabetes mellitus (T2DM) represents a major health challenge for modern society. Despite it being of fundamental interest, only a few MRI studies have conducted statistical analyses to draw scientifically valid conclusions about the complex interplay of T2DM and its associated clinical, structural, functional, metabolite, as well as cognitive distortions. Therefore, a systematic review of 68 manuscripts, following the PRISMA guidelines, was conducted. Notably, although the associations between imaging, clinical, and cognitive variables are not fully homogeneous, findings show a clear trend towards a link between altered brain structure and a decline in cognitive processing ability. The results of the review highlight the heterogeneity of the methods used across manuscripts in terms of assessed clinical variables, imaging, and data analysis methods. This is particularly significant as, if the subjects' criteria are not carefully considered, results are easily prone to confounding factors.
10.1016/j.yfrne.2018.10.001
Cognitive Dysfunction in Type 1 Diabetes Mellitus.
Shalimova Anna,Graff Beata,Gąsecki Dariusz,Wolf Jacek,Sabisz Agnieszka,Szurowska Edyta,Jodzio Krzysztof,Narkiewicz Krzysztof
The Journal of clinical endocrinology and metabolism
CONTEXT:We have summarized key studies assessing the epidemiology, mechanisms, and consequences of cognitive dysfunction (CD) in type 1 diabetes. EVIDENCE SYNTHESIS:In a number of studies, the severity of CD in type 1 diabetes was affected by the age of onset and duration, and the presence of proliferative retinopathy and autonomic neuropathy. Diabetes-related CD has been observed, not only in adults, but also in children and adolescents. Most neuroimaging studies of patients with type 1 diabetes did not show any differences in whole brain volumes; however, they did reveal selective deficits in gray matter volume or density within the frontal, posterior, and temporal cortex and subcortical gray matter. Studies of middle-age adults with long-standing type 1 diabetes using diffusion tensor imaging have demonstrated partial lesions in the white matter and decreased fractional anisotropy in posterior brain regions. The mechanisms underlying diabetes-related CD are very complex and include factors related to diabetes per se and to diabetes-related cardiovascular disease and microvascular dysfunction, including chronic hyperglycemia, hypoglycemia, macro- and microvascular disease, and increased inflammatory cytokine expression. These mechanisms might contribute to the development and progression of both vascular dementia and Alzheimer disease. CONCLUSIONS:Higher rates of CD and faster progression in type 1 diabetes can be explained by both the direct effects of altered glucose metabolism on the brain and diabetes-related cardiovascular disease. Because the presence and progression of CD significantly worsens the quality of life of patients with diabetes, further multidisciplinary studies incorporating the recent progress in both neuroimaging and type 1 diabetes management are warranted to investigate this problem.
10.1210/jc.2018-01315
D-ribose is elevated in T1DM patients and can be involved in the onset of encephalopathy.
Aging
Although many mechanisms have been proposed for diabetic encephalopathy in type 2 diabetes mellitus (T2DM), the risk factors for cognitive impairment in type 1 diabetes mellitus (T1DM) are less clear. Here, we show that streptozotocin (STZ)-induced T1DM rats showed cognitive impairment in both Y maze and Morris water maze assays, accompanied with D-ribose was significantly increased in blood and urine, in addition to D-glucose. Furthermore, advanced glycation end products (AGE), Tau hyperphosphorylation and neuronal death in the hippocampal CA4/DG region were detected in T1DM rats. The expression and activity of transketolase (TKT), an important enzyme in the pentose shunt, were decreased in the brain, indicating that TKT may be involved in D-ribose metabolism in T1DM. Support for these change was demonstrated by the activation of TKT with benfotiamine (BTMP) treatment. Decreased D-ribose levels but not D-glucose levels; markedly reduced AGE accumulation, Tau hyperphosphorylation, and neuronal death; and improved cognitive ability in T1DM rats were shown after BTMP administration. In clinical investigation, T1DM patients had high D-ribose levels in both urine and serum. Our work suggests that D-ribose is involved in the cognitive impairment in T1DM and may provide a potentially novel target for treating diabetic encephalopathy.
10.18632/aging.102089
Type 1 diabetes induces cognitive dysfunction in rats associated with alterations of the gut microbiome and metabolomes in serum and hippocampus.
Gao Hongchang,Jiang Qiaoying,Ji Hui,Ning Jie,Li Chen,Zheng Hong
Biochimica et biophysica acta. Molecular basis of disease
Cognitive decline is a common symptom at advanced stage of type 1 diabetes (T1D), but its potential pathogenesis remains unclear. In this study, therefore, we investigated changes in the gut microbiome and metabolome in serum and hippocampus between advanced-stage T1D (AST1D) rats with cognitive decline and age-matched controls (AMC), and explored the possible mechanism of the gut-microbiota-metabolite axis in T1D-induced cognitive dysfunction. The results demonstrated that AST1D rats possessed peculiar metabolic phenotypes in serum and hippocampus relative to AMC rats, as characterized by decreases in tricarboxylic acid (TCA) cycle and amino acid and choline metabolism as well as disturbances in glutamate/GABA-glutamine cycle and astrocyte-neuron metabolism. We also found that AST1D rats had higher relative abundances of Prevotella_9, Bacteroides and Lachnospiraceae_NK4A136_group as well as lower relative abundances of Clostridium_sensu_stricto_1, Romboutsia and Turicibacter than AMC rats. Microbiota-host metabolic correlation analysis suggests that metabolic alterations in serum and hippocampus may be modulated by the gut microbiota, especially Clostridium_sensu_stricto_1, Romboutsia and Turicibacter. Therefore, our study implies that the modification of host metabolism by targeting the gut microbiota may be a novel avenue for prevention and treatment of diabetic encephalopathy in the future.
10.1016/j.bbadis.2019.165541
The neuroprotective effect and action mechanism of polyphenols in diabetes mellitus-related cognitive dysfunction.
Zhang Shenshen,Xue Ran,Hu Ruizhe
European journal of nutrition
BACKGROUND:Diabetes mellitus (DM) is a complex and prevalent metabolic disorder worldwide. Strong evidence has emerged that DM is a risk factor for the accelerated rate of cognitive decline and the development of dementia. Though traditional pharmaceutical agents are efficient for the management of DM and DM-related cognitive decrement, long-term use of these drugs are along with undesired side effects. Therefore, tremendous studies have focused on the therapeutic benefits of natural compounds at present. Ample evidence exists to prove that polyphenols are capable to modulate diabetic neuropathy with minimal toxicity and adverse effects. PURPOSE:To describe the benefits and mechanisms of polyphenols on DM-induced cognitive dysfunction. In this review, we introduce an updated overview of associations between DM and cognitive dysfunction. The risk factors as well as pathological and molecular mechanisms of DM-induced cognitive dysfunction are summarized. More importantly, many active polyphenols that possess preventive and therapeutic effects on DM-induced cognitive dysfunction and the potential signaling pathways involved in the action are highlighted. CONCLUSIONS:The therapeutic effects of polyphenols on DM-related cognitive dysfunction pave a novel way for the management of diabetic encephalopathy.
10.1007/s00394-019-02078-2
Cerebral microvascular complications of type 2 diabetes: stroke, cognitive dysfunction, and depression.
van Sloten Thomas T,Sedaghat Sanaz,Carnethon Mercedes R,Launer Lenore J,Stehouwer Coen D A
The lancet. Diabetes & endocrinology
Adults with type 2 diabetes are at an increased risk of developing certain brain or mental disorders, including stroke, dementia, and depression. Although these disorders are not usually considered classic microvascular complications of diabetes, evidence is growing that microvascular dysfunction is one of the key underlying mechanisms. Microvascular dysfunction is a widespread phenomenon in people with diabetes, including effects on the brain. Cerebral microvascular dysfunction is also apparent in adults with prediabetes, suggesting that cerebral microvascular disease processes start before the onset of diabetes. The microvasculature is involved in the regulation of many cerebral processes that when impaired predispose to lacunar and haemorrhagic stroke, cognitive dysfunction, and depression. Main drivers of diabetes-related cerebral microvascular dysfunction are hyperglycaemia, obesity and insulin resistance, and hypertension. Increasing amounts of data from observational studies suggest that diabetes-related microvascular dysfunction is associated with a higher risk of stroke, cognitive dysfunction, and depression. Cerebral outcomes in diabetes might be improved following treatments targeting the pathways through which diabetes damages the microcirculation. These treatments might include drugs that reduce dicarbonyl compounds, augment cerebral insulin signalling, or improve blood-brain barrier permeability and cerebral vasoreactivity.
10.1016/S2213-8587(19)30405-X
Cognitive Dysfunction in Older Adults with Type 2 Diabetes: Links, Risks, and Clinical Implications.
Sinclair Alan,Abdelhafiz Ahmed
Clinics in geriatric medicine
The prevalence of comorbid diabetes and cognitive dysfunction increases as the population ages. Diabetes increases the risk of progression of cognitive dysfunction through a spectrum of cognitive decline to mild cognitive impairment then to dementia. Cognitive dysfunction, especially impairment in the executive domain, has a negative impact on patients' self-care tasks. With further progression of dementia and the development of behavioral problems, the challenge to carers and health care professionals looking after these patients is significant. Therefore, clinical trials are needed to explore the impact of novel hypoglycemic therapy on cognitive function as an important outcome in this population.
10.1016/j.cger.2020.04.002
A novel hippocampus metabolite signature in diabetes mellitus rat model of diabetic encephalopathy.
Chen Guanghui,Wang Yizhong,Li Yang,Zhang Lujun,Dong Meixue
Metabolic brain disease
Diabetic encephalopathy (DE) is one of the chronic complications of diabetes. Even then, the molecular mechanism underlying DE remains unexplored. In this study, we have made an attempt to investigate the metabolic changes associated with the streptozocin (STZ)-induced cognitive dysfunction in the hippocampus of the rat model, a classical rodent model for DE, with the help of Gas Chromatography-Mass Spectrometry-based method. The STZ injections led to the rise of mean blood glucose levels in the diabetes mellitus (DM) group of rats as compared to the control (CON) group of rats throughout the experiment. However, we did not find any significant difference between the blood glucose levels of the DM & the CON groups of rats before the STZ injection. The results indicated a behavioral and morphological cognitive dysfunction in the DM groups of rats. The metabolomic investigation of these DE rats demonstrated a lower level of N-acetylaspartate and dihydroxyacetone phosphate accompanied by a higher level of homocysteine and glutamate as against the CON group of rats. The outcome of this study may unravel the underlying pathophysiological mechanism of DE. Also, the metabolomic data from this study may provide a platform for the development of DE biomarkers.
10.1007/s11011-020-00541-2
The Role of Molecular and Inflammatory Indicators in the Assessment of Cognitive Dysfunction in a Mouse Model of Diabetes.
International journal of molecular sciences
The brain is the most vulnerable organ to glucose fluctuations, as well as inflammation. Considering that cognitive impairment might occur at the early stage of diabetes, it is very important to identify key markers of early neuronal dysfunction. Our overall goal was to identify neuroinflammatory and molecular indicators of early cognitive impairment in diabetic mice. To confirm cognitive impairment in diabetic mice, series of behavioral tests were conducted. The markers related to cognitive decline were classified into the following two groups: Neuroinflammatory markers: IL-1, IL-6, tumor necrosis factor- (TNF-) and genetic markers (, , ) which were estimated in brain regions. Our studies showed a strong association between hyperglycemia, hyperinsulinemia, neuroinflammation, and cognitive dysfunction in T2DM mice model. Cognitive impairment recorded in diabetes mice were associated not only with increased levels of cytokines but also decreased and mRNA expression level in brain regions associated with learning process and memory formation. The results of our research show that these indicators may be useful to test new forms of treatment of early cognitive dysfunction associated not only with diabetes but other diseases manifesting this type of disorders. The significant changes in and gene expression in early stage diabetes create opportunities it possible to use them to track the progression of CNS dysfunction and also to differential disease diagnosis running with cognitive impairment.
10.3390/ijms22083878
The relationship between diabetes-related cognitive dysfunction and leukoaraiosis.
Yuan Chun-Lan,Yi Ran,Dong Qi,Yao Li-Fen,Liu Bin
Acta neurologica Belgica
Cognitive dysfunction is a degenerative disease of the central nervous system, which often associates with ageing brain as well as neurodegenerative diseases. A growing body of evidence suggests that patients with diabetes mellitus (DM) have a significantly higher risk of cognitive impairment. In recent years, studies have found that patients with diabetes-related cognitive dysfunction have an increased burden of leukoaraiosis (LA), and larger white matter hyperintensity (WMH) volume. With the recent advancement of technologies, multimodal imaging is widely exploited for the precise evaluation of central nervous system diseases. Emerging studies suggest that LA pathology can be used as a predictive signal of white matter lesions in patients with diabetes-related cognitive dysfunction, providing support for early identification and diagnosis of disease. This article reviews the findings, epidemiological characteristics, pathogenesis, imaging features, prevention and treatment of LA pathophysiology in patients with diabetes-related cognitive dysfunction.
10.1007/s13760-021-01676-4
Activation of Glucagon-Like Peptide-1 Receptor Ameliorates Cognitive Decline in Type 2 Diabetes Mellitus Through a Metabolism-Independent Pathway.
Li Qiang,Jia Mengxiao,Yan Zhencheng,Li Qiang,Sun Fang,He Chengkang,Li Yingsha,Zhou Xunmei,Zhang Hexuan,Liu Xiaoli,Bu Xiaona,Gao Peng,He Hongbo,Zhao Zhigang,Zhu Zhiming
Journal of the American Heart Association
Background Patients with hypertension and diabetes mellitus are susceptible to dementia, but regular therapy fails to reduce the risk of dementia. Glucagon-like peptide-1 receptor agonists have neuroprotective effects in experimental studies. We aimed to assess the effect of liraglutide, a glucagon-like peptide-1 receptor agonist, on cognitive function and whether its effect was associated with metabolic changes in patients with type 2 diabetes mellitus. Methods and Results Fifty patients with type 2 diabetes mellitus were recruited in this prospective study. All patients underwent cognitive assessment and brain activation monitoring by functional near-infrared spectroscopy. At 12 weeks, patients in the glucagon-like peptide-1 group acquired better scores in all cognitive tests and showed remarkable improvement in memory and attention (=0.040) test compared with the control group after multivariable adjustment. Compared with the control group, liraglutide significantly increased activation of the dorsolateral prefrontal cortex and orbitofrontal cortex brain regions (=0.0038). After liraglutide treatment, cognitive scores were significantly correlated with changes in these activating brain regions (<0.05), but no correlation was observed between the changes in cognitive function and changes of body mass index, blood pressure, and glycemic levels. Conclusions We concluded that liraglutide improves cognitive decline in patients with type 2 diabetes mellitus. This beneficial effect is independent of its hypoglycemic effect and weight loss. The optimal intervention should be targeted to cognitive decline in the early stages of dementia. Registration URL: https://www.ClinicalTrials.gov; Unique identifier: NCT03707171.
10.1161/JAHA.120.020734
Prevention of Diabetes-Associated Cognitive Dysfunction Through Oral Administration of Lipopolysaccharide Derived From .
Mizobuchi Haruka,Yamamoto Kazushi,Yamashita Masashi,Nakata Yoko,Inagawa Hiroyuki,Kohchi Chie,Soma Gen-Ichiro
Frontiers in immunology
Diabetes-related cognitive dysfunction (DRCD) is a serious complication induced by diabetes. However, there are currently no specific remedies for DRCD. Here, we show that streptozotocin-induced DRCD can be prevented without causing side effects through oral administration of lipopolysaccharide (LPS) derived from . Oral administration of LPS (OAL) prevented the cerebral cortex atrophy and tau phosphorylation induced by DRCD. Moreover, we observed that neuroprotective transformation of microglia (brain tissue-resident macrophages) is important for preventing DRCD through OAL. These findings are contrary to the general recognition of LPS as an inflammatory agent when injected systemically. Furthermore, our results strongly suggest that OAL promotes membrane-bound colony stimulating factor 1 (CSF1) expression on peripheral leukocytes, which activates the CSF1 receptor on microglia, leading to their transformation to the neuroprotective phenotype. Taken together, the present study indicates that controlling innate immune modulation through the simple and safe strategy of OAL can be an innovative prophylaxis for intractable neurological diseases such as DRCD. In a sense, for modern people living in an LPS-depleted environment, OAL is like a time machine that returns microglia to the good old LPS-abundant era.
10.3389/fimmu.2021.650176
Cognitive impairment and type 2 diabetes mellitus: Focus of SGLT2 inhibitors treatment.
Rizzo Maria Rosaria,Di Meo Irene,Polito Rita,Auriemma Maria Chiara,Gambardella Antonio,di Mauro Gabriella,Capuano Annalisa,Paolisso Giuseppe
Pharmacological research
Gliflozins are a novel class of oral anti-diabetic drugs, acting as inhibitors of sodium-glucose co-transporters (SGLTs) through the proximal convoluted tubules (PCT) and intestinal epithelium. The sodium-glucose co-transporters 2 (SGLT2) are mainly expressed in S1 and S2 segments of the proximal convoluted tubule in the kidneys. Clinical guidelines recommend their use especially in Type 2 Diabetes mellitus (T2DM) patients with vascular complications and/or heart failure highlighting the importance of sodium-glucose co-transporter 2 inhibitors (SGLT2i) pleiotropic effects. Interestingly, cognitive decline is a widely recognized complication of T2DM and, in addition, to clarify its pathophysiology, there is an urgent need to understand how and if diabetes therapies can control diabetes-related cognitive dysfunction. At the time, although SGLT2 proteins are present in the Central Nervous System (CNS), the SGLT2i effects on cognitive impairments remain partly unknown. In pre-clinical studies, SGLT2i ameliorates cognitive dysfunction in obese and T2DM mice, reducing oxidative stress, neuroinflammation and improving neuronal plasticity and mitochondrial brain pathway. In addition, SGLT2i could bring back mTOR to a physiological state of activation, stopping neurodegenerative diseases' onset or progression. Instead, clinical studies on T2DM-related cognitive dysfunction treated by SGLT2i are much more limited. For these reasons, further studies are needed to better elucidate if SGLT2i therapy can affect T2DM-related cognitive decline. In this scenario, this review aims to summarize the state of knowledge on the role of SGLT2i in T2DM-related cognitive dysfunction and stimulate new clinical trials.
10.1016/j.phrs.2022.106062
Type 2 diabetes mellitus-associated cognitive dysfunction: Advances in potential mechanisms and therapies.
Neuroscience and biobehavioral reviews
Type 2 diabetes (T2D) and its target organ injuries cause distressing impacts on personal health and put an enormous burden on the healthcare system, and increasing attention has been paid to T2D-associated cognitive dysfunction (TDACD). TDACD is characterized by cognitive dysfunction, delayed executive ability, and impeded information-processing speed. Brain imaging data suggest that extensive brain regions are affected in patients with T2D. Based on current findings, a wide spectrum of non-specific neurodegenerative mechanisms that partially overlap with the mechanisms of neurodegenerative diseases is hypothesized to be associated with TDACD. However, it remains unclear whether TDACD is a consequence of T2D or a complication that co-occurs with T2D. Theoretically, anti-diabetes methods are promising neuromodulatory approaches to reduce brain injury in patients with T2D. In this review, we summarize potential mechanisms underlying TDACD and promising neurotropic effects of anti-diabetes methods and some neuroprotective natural compounds. Constructing screening or diagnostic tools and developing targeted treatment and preventive strategies would be expected to reduce the burden of TDACD.
10.1016/j.neubiorev.2022.104642