The brain in diabetes: molecular changes in neurons and their implications for end-organ damage

doi:10.1016/S1474-4422(03)00503-9

The Lancet Neurology

Volume 2, Issue 9, September 2003, Pages 548-554

https://doi.org/10.1016/S1474-4422(03)00503-9 Get rights and content

Summary

Although secondary end-organ damage in diabetes has generally been thought to result from long-term passive shunting of excess glucose through alternative metabolic pathways, recent studies have elucidated a second mechanism of pathogenesis that involves active changes in gene expression in neurons of the CNS. These changes in gene expression result in molecular and functional changes that can become maladaptive over time. In this review, we examine two neuronal populations in the brain that have been studied in human beings and animal models of diabetes. First, we discuss overactivation of magnocellular neurosecretory cells within the hypothalamus and how it relates to the development of diabetic nephropathy. And second, we describe how changes in hippocampal synaptic plasticity can lead to cognitive and behavioural deficits in chronic diabetes. Changes in neuronal gene expression in diabetes represent a new pathway for diabetic pathogenesis. This pathway may hold clues for the development of therapies that, via the targeting of neurons, can slow or prevent the development of diabetic end-organ damage.

Section snippets

Hyperglycaemia stimulates vasopressin secretion

An increase in serum concentration of glucose raises serum osmolality at the rate of 1 mOsm/L per 18 mg/dL glucose. Hyperosmolality triggers both behavioural (polydipsia) and physiological (natriuresis, water retention) responses within the body to maintain solute balance and minimise fluid shifts between intracellular and extracellular environments. This adaptive response to hyperosmolality is mediated by MNCs within the hypothalamic supraoptic nucleus and paraventricular nuclei, which

Hypoglycaemia leads to cognitive deficits

There is growing evidence that encephalopathy,27, 28 characterised by acquired cognitive and behavioural deficits,29, 31 can occur as a late complication of diabetes. In human diabetes, chronic hyperglycaemia is associated with a high incidence of progressive dementia.³² As in the case of diabetic nephropathy, the mechanism of pathogenesis has classically been thought to involve non-specific vascular injury. Recent work, however, indicates that there are specific changes in neuronal gene

Diabetic neurons as drivers and therapeutic targets in diabetic pathophysiology

As shown above, chronic hyperglycaemia triggers changes in the rate of transcription of specific genes within neurons of the hypothalamus and hippocampus, and possibly in other brain regions. Over time, these modifications of gene transcription cause changes in neurons that contribute to the development of secondary complications of diabetes.

Although dietary and medical management of hyperglycaemia is commonly sufficient to delay or prevent the appearance of secondary complications, the changes

Search strategy and selection criteria

Data for this review were identified by searches of PubMed and references from relevant articles. The search terms were “diabetes”, “brain”, “central nervous system”, “neuron”, “pathology”, and “gene expression”. Only papers published in English were reviewed. The selection of papers was based on the authors' opinion of their relevance and quality.

References (60)

DL Voisin et al.
Integration of sodium and osmosensory signals in vasopressin neurons
Trends Neurosci
(2002)
Y Luo et al.
Neuronal and glial response in the rat hypothalamus-neurohypophysis complex with streptozotocin-induced diabetes
Brain Res
(2002)
AL Goldin et al.
Nomenclature of voltage-gated sodium channels
Neuron
(2000)
WA Catterall
From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels
Neuron
(2000)
A Taddese et al.
Subthreshold sodium current from rapidly inactivating sodium channels drives spontaneous firing of tuberomammillary neurons
Neuron
(2002)
H Zheng et al.
Neuronal expression of fos protein in the forebrain of diabetic rats
Brain Res
(2002)
N Bouby et al.
Contribution of vasopressin to progression of chronic renal failure: study in Brattleboro rats
Life Sci
(1999)
GJ Biessels et al.
Ageing and diabetes: implications for brain function
Eur J Pharmacol
(2002)
WH Gispen et al.
Cognition and synaptic plasticity in diabetes mellitus
Trends Neurosci
(2000)
M Popovic et al.
Learning and memory in streptozotocin-induced diabetic rats in a novel spatial/object discrimination task
Behav Brain Res
(2001)

A Kamal et al.

Hippocampal synaptic plasticity in streptozotocin-diabetic rats: impairment of long-term potentiation and facilitation of long-term depression

Neuroscience

(1999)

SM Candy et al.

Neuronal excitability and conduction velocity changes in hippocampal slices from streptozotocin-treated diabetic rats

Brain Res

(2000)

J Levy et al.

Diabetes mellitus: a disease of abnormal cellular calcium metabolism?

Am J Med

(1994)

ZG Li et al.

Hippocampal neuronal apoptosis in type 1 diabetes

Brain Res

(2002)

G Baydas et al.

Increase of glial fibrillary acidic protein and S-100B in hippocampus and cortex of diabetic rats: effects of vitamin E

Eur J Pharmacol

(2003)

FE Saravia et al.

Increased astrocyte reactivity in the hippocampus of murine models of type 1 diabetes: the nonobese diabetic (NOD) and streptozotocin-treated mice

Brain Res

(2002)

S Nagamatsu et al.

Glucose transporter expression in brain. cDNA sequence of mouse GLUT3, the brain facilitative glucose transporter isoform, and identification of sites of expression by in situ hybridization

J Biol Chem

(1992)

S Nagamatsu et al.

Neuron-specific glucose transporter (NSGT): CNS distribution of GLUT3 rat glucose transporter (RGT3) in rat central neurons

FEBS Lett

(1993)

AL McCall et al.

Immunohistochemical localization of the neuron-specific glucose transporter (GLUT3) to neuropil in adult rat brain

Brain Res

(1994)

C Holscher

Nitric oxide, the enigmatic neuronal messenger: its role in synaptic plasticity

Trends Neurosci

(1997)

GJ Biessels et al.

Neuronal Ca(2+) disregulation in diabetes mellitus

Eur J Pharmacol

(2002)

R Donnelly et al.

ABC of arterial and venous disease: vascular complications of diabetes

BMJ

(2000)

M Brownlee

Biochemistry and molecular cell biology of diabetic complications

Nature

(2001)

ST Dheen et al.

Arginine vasopressin and oxytocin-like immunoreactive neurons in the hypothalamic paraventricular and supraoptic nuclei of streptozotocin- induced diabetic rats

Arch Histol Cytol

(1994)

R Serino et al.

Upregulation of hypothalamic nitric oxide synthase gene expression in streptozotocin-induced diabetic rats

Diabetologia

(1998)

Y Chakfe et al.

Excitatory peptides and osmotic pressure modulate mechanosensitive cation channels in concert

Nat Neurosci

(2000)

RD Andrew et al.

Burst discharge in mammalian neuroendocrine cells involves an intrinsic regenerative mechanism

Science

(1983)

B Sperlagh et al.

Local regulation of vasopressin and oxytocin secretion by extracellular ATP in the isolated posterior lobe of the rat hypophysis

J Endocrinol

(1999)

M Tanaka et al.

Molecular and functional remodeling of electrogenic membrane of hypothalamic neurons in response to changes in their input

Proc Natl Acad Sci USA

(1999)

JP Klein et al.

Sodium channel expression in hypothalamic osmosensitive neurons in experimental diabetes

NeuroReport

(2002)

Cited by (102)

Aurothioglucose encapsulated nanoparticles fostered neuroprotection in streptozotocin-induced Alzheimer's disease
2024, Brain Research
Alzherimer’s disease (AD) is an age-dependent ubiquitous ailment worldwide with limited therapies that only alleviate the symptoms of AD but do not cure them entirely because of the restricted blood–brain barrier passage of the drug. Hence with new advanced technology, nanoparticles can offer an opportunity as the active candidate to overcome the above limitations. Aurothioglucose, a synthetic glucose derivative of the gold compound, has been clinically proven to be an effective anti-inflammatory drug for rheumatic arthritis. Recently, several scientific groups have developed gold nanoparticle preparations and tested them for the treatment of dementia. This study was planned to prepare the PLGA nanoparticles of aurothioglucose (ATG) and check the neuroprotective potential against STZ-induced AD in rats. The nanoparticles were prepared using the double emulsion solvent evaporation method and characterized for various parameters such as drug-excipient interaction, particle size, zeta potential, and morphology. Then, rats were injected STZ (3 mg/kg/i.c.v., days 1 and 3) and ATG (5 and 10 mg/kg/s.c.), ATG NPs (2.5 and 5 mg/kg/s.c.) and donepezil (2 mg/kg/p.o) from 15th to 29th day. Behavior parameters were performed using an actophotometer, MWM, and ORT. On the 30th day, all the animals were sacrificed, and the brains were isolated for estimating biochemical, neurochemical, and proinflammatory markers. It was observed that ATG NPs significantly restored all behavior and neurotransmitter alterations caused by STZ. Also, it increased antioxidant levels and decreased inflammatory cytokines significantly, then ATG alone. Thus, the study suggests that ATG loaded PLGA NPs could be used as a novel therapeutic strategy to slow the process of AD.
Type 2 diabetes mellitus-associated cognitive dysfunction: Advances in potential mechanisms and therapies
2022, 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.
Alpha lipoic acid decreases neuronal damage on brain tissue of STZ-induced diabetic rats
2022, Physiology and Behavior
Neuropathy that develops due to diabetic complications causes cognitive im-pairment due to functional and structural damage. The aim of this study was to evaluate the biochemical, histological and physiological effects of Alpha Lipoic Acid (ALA) against brain tissue damage caused by diabetes. Fourty male Wistar albino rats were separated into four groups as control, diabetes mellitus (DM), ALA and DM+ALA. Single dose of 50 mg/kg intraperitonal streptozotocin (STZ) was used to induce DM. For six weeks, ALA (100 mg/kg/day) was administered to the ALA and DM+ALA groups. At the end of the six week rats were sacrificed by collecting blood samples and collected brain tissues (hippocampus, cortex, hippotalamus and stri-atum) were histologically evaluated in addition to the oxidant-antioxidant parameters. ALA administration showed significant improvement in cognitive functions evaluated by MWM in rats with diabetes mellitus (p<0.05). SOD, CAT, GSH-Px activities, which were decreased in the DM group compared to the control group, increased statistically significantly in rats in DM+ALA group (p<0.05). While MDA and PC levels increased in the DM group, they decreased statistically significantly in the DM+ALA group (p<0.05). According to the histological examinations made by light and electron microscopies, it was determined that the ultrastructural damage and degeneration findings observed in the sections of the DM group were significantly ameliorated in the sections of rats in the DM+ALA group. ALA may be effective in restoring cell damage and cognitive functions in brain tissue with its antioxidant and neuroprotective effects without showing antidiabetic effects.
HMGB1/TLR4 promotes apoptosis and reduces autophagy of hippocampal neurons in diabetes combined with OSA
2019, Life Sciences
Citation Excerpt :
Our previous experimental results indicated that IH exposure aggravates apoptosis of hippocampal neurons and cognitive deficits in T2DM mice [17]. Chronic hyperglycemia may eventually lead to hippocampal neuronal apoptosis; therefore, the prevention of hippocampal neuronal apoptosis may delay the onset of diabetes-related cognitive deficits [7]. Our experiments showed that the hippocampus of IH-exposed T2DM mice exhibited more obvious apoptosis and autophagy defects, and the expression of HMGB1 and TLR4 was further increased.
Obstructive sleep apnea (OSA) combined with type 2 diabetes (T2DM) may lead to cognitive dysfunction. We previously reported that cognitive impairment is exacerbated in KKAy mice exposed to intermittent hypoxia (IH), during which the DNA binding protein HMGB1 mediates hippocampal neuronal apoptosis by maintaining microglia-associated neuroinflammation, but the underlying mechanism remains largely unknown.
We performed immunofluorescence, Western blotting, and immunohistochemistry experiments in mouse hippocampal tissues and HT22 cells. KKAy type 2 diabetes model mice and normal C57BL/6J mice were exposed to IH or intermittent normoxia. HT22 cells were cultured in high glucose medium and exposed to IH or intermittent normoxia. We transfected HMGB1 siRNA into HT22 cells and then treated them with high glucose combined with intermittent hypoxia.
In conclusion, IH aggravated apoptosis and autophagy defects in T2DM mice, and increased the protein expression of HMGB1 and TLR4. This was also confirmed in HG + IH-treated hippocampal HT22 cells. HMGB1 siRNA can significantly reduce the protein expression of HMGB1 and TLR4, reverse neuronal apoptosis and enhance autophagy.
We believe that HMGB1 is a key factor in the regulation of hippocampal neuronal apoptosis and autophagy defects in T2DM combined with OSA. Targeting HMGB1/TLR4 signaling as a novel approach may delay or prevent the increased apoptosis and decreased autophagy induced by T2DM combined with OSA, and may ultimately improve cognitive dysfunction.
Effects of hypertension on cerebral cortical thickness alterations in patients with type 2 diabetes
2019, Diabetes Research and Clinical Practice
Although hypertension (HTN) is the high comorbidity of Type 2 diabetes mellitus (T2DM) and known to be a vascular risk factor for brain damage, the effects of HTN on brain function in T2DM patients are not well understood. Present study was performed to investigate whether HTN might accelerate the Cerebral cortical thickness (CT) alterations in patients with T2DM.
We enrolled 35 participants with only T2DM, 25 T2DM patients with HTN (HT2DM) and 28 healthy controls (HCs). The cognitive function was assessed and brain image data was collected then the CT was calculated for each participant. Partial correlations between the CT of each brain region and standard laboratory testing data and neuropsychological scale scores were also analyzed. Multivariable regression analysis was performed to evaluated the vascular risk factors and brain regions with different CT in HT2DM patients.
Cognitive impairment is associated with thinning of the cerebral cortical thickness reduction in T2DM patients. CT thinning in the left inferior parietal lobe, left posterior cingulate and right precuneus were observed in HT2DM group relative to only T2DM group. Furthermore, the CT decreasing in the right precuneus was negatively correlated with duration of HTN.
The current study revealed that coexistent HTN may accelerate the CT reduction in T2DM patients.
Diabetes and anxiety adversely affect cognition in multiple sclerosis
2019, Multiple Sclerosis and Related Disorders
To determine whether comorbid diabetes and hypertension are associated with cognition in multiple sclerosis (MS) after accounting for psychiatric comorbidities.
Participants completed a structured psychiatric interview, the Hospital Anxiety and Depression Scale (HADS), a comorbidity questionnaire, and cognitive testing including the Symbol Digit Modalities Test (SDMT), California Verbal Learning Test (CVLT-II), Brief Visuospatial Memory Test-Revised (BVMT-R), and verbal fluency. Test scores were converted to age-, sex- and education-adjusted z-scores. We evaluated associations between diabetes and hypertension and the four cognitive z-scores using a multivariate linear model, adjusting for comorbid depression and anxiety disorders, psychotropic medications, disease-modifying therapies, smoking status and body mass index.
Of 111 participants, most were women (82.9%) with relapsing remitting MS (83.5%), of mean (SD) age 49.6 (12.7) years. Comorbidity was common; 22.7% participants had hypertension, 10.8% had diabetes, 9.9% had current major depression, and 9.9% had current anxiety disorders. Mean (SD) z-scores were: SDMT −0.66 (1.15), CVLT-II −0.43 (1.32), BVMT-R −0.49 (1.07) and fluency −0.59 (0.86). Diabetes (p = 0.02) and anxiety disorder (p = 0.02) were associated with cognitive function overall. Diabetes was associated with lower BVMT-R (β = −1.18, p = 0.0015) and fluency (β = −0.63, p = 0.037) z-scores. Anxiety was associated with lower SDMT (β = -1.07, p = 0.0074) z-scores. Elevated anxiety symptoms (HADS-A ≥ 11) were associated with lower z-scores on the SDMT and CVLT-II.
Comorbidities, including diabetes and anxiety, are associated with cognitive dysfunction in MS. Their presence may contribute to the heterogeneous pattern of impairments seen across individuals and they may represent targets for improved management of cognitive symptoms.

View all citing articles on Scopus

View full text

ReviewThe brain in diabetes: molecular changes in neurons and their implications for end-organ damage

Summary

Section snippets

Hyperglycaemia stimulates vasopressin secretion

Hypoglycaemia leads to cognitive deficits

Diabetic neurons as drivers and therapeutic targets in diabetic pathophysiology

Search strategy and selection criteria

Trends Neurosci

Brain Res

Neuron

Neuron

Neuron

Brain Res

Life Sci

Eur J Pharmacol

Trends Neurosci

Behav Brain Res

Neuroscience

Brain Res

Am J Med

Brain Res

Eur J Pharmacol

Brain Res

J Biol Chem

FEBS Lett

Brain Res

Trends Neurosci

Eur J Pharmacol

ABC of arterial and venous disease: vascular complications of diabetes

BMJ

Biochemistry and molecular cell biology of diabetic complications

Nature

Arginine vasopressin and oxytocin-like immunoreactive neurons in the hypothalamic paraventricular and supraoptic nuclei of streptozotocin- induced diabetic rats

Arch Histol Cytol

Upregulation of hypothalamic nitric oxide synthase gene expression in streptozotocin-induced diabetic rats

Diabetologia

Excitatory peptides and osmotic pressure modulate mechanosensitive cation channels in concert

Nat Neurosci

Burst discharge in mammalian neuroendocrine cells involves an intrinsic regenerative mechanism

Science

Local regulation of vasopressin and oxytocin secretion by extracellular ATP in the isolated posterior lobe of the rat hypophysis

J Endocrinol

Molecular and functional remodeling of electrogenic membrane of hypothalamic neurons in response to changes in their input

Proc Natl Acad Sci USA

Sodium channel expression in hypothalamic osmosensitive neurons in experimental diabetes

NeuroReport

Review
The brain in diabetes: molecular changes in neurons and their implications for end-organ damage