Cognitive impairment in diabetes and poor glucose utilization in the intracellular neural milieu
Introduction
Diabetes comprises two main clinical entities. Type-1 diabetes results from chronically low insulin secretion. Type-2 diabetes is a heterogeneous group of disorders that are characterized by varying degrees of insulin resistance, a decrease in insulin secretion, and an increase in glucose production. Diabetes is a complex syndrome that is associated with excess extracellular glucose and deficient intracellular glucose disposition. Three neurological and psychiatric entities are often observed in diabetes: anxiety, depression, and cognitive impairment [1], [2], [3]. A low level of anxiety may be a useful adaptive response [4] that helps the individual cope with ailments that are associated with diabetes. When the level of anxiety surpasses a certain threshold, it can be considered a disease that is frequently associated with the course of diabetes. Depression in diabetes negatively influences quality of life. Individuals who suffer from diabetes must cope with managing their disease, especially in the presence of complications and stress associated with their work life [5]. Although anxiety and depression might not be considered to be a direct consequence of diabetes per se, diabetes is associated with cognitive deficits and a higher risk of dementia [3] that is likely related to neural tissue damage.
Section snippets
The hypothesis
Type-1 and type-2 diabetes present substantial differences, ranging from pathophysiology to therapeutic management. Their similarities usually consist of clinical manifestations that commonly occur with different timing. In both cases, hyperglycemia causes endothelial and tissue damage. In type-1 diabetes, the restoration of plasma insulin levels can reduce some tissue damage. In type-2 diabetes, hypoglycemic medications do not restore the function of glucose in the intracellular compartment,
Course of diabetes and daily stress
Any chronic disease may constitute a strong stressor that disrupts homeostasis. Allostasis is an adaptive response and essential component of maintaining homeostasis. Allostasis allows the organism to effectively cope with challenges and survive. When allostatic systems are overstimulated or do not perform normally, allostatic load can occur [6]. In many cases, allostatic load can result in a disease state [7], with the participation of glucocorticoids (e.g., cortisol), and lead to mood
Prospective
One way to lessen neurological and psychiatric ailments in diabetes is to maintain good glycemic control by restoring insulin activity and/or insulin receptor sensitivity [25]. Pharmacological treatments for diabetes do not have direct beneficial effects on cognitive function. Metformin has been reported to have protective effects in the domains of verbal learning, working memory, and executive function [79], but these findings may be masked by other additional factors, such as other treatments
Conclusion
Conclusive relationships between diabetes and anxiety/depression are elusive and involve both adaptive and reactive processes. Endothelial vascular damage, deficits in neuronal glucose utilization and neuronal damage lead to blunting of the activation of specific cerebral areas that are involved in cognitive and psychomotor performance. Currently, there is no diabetes-specific treatment for cognitive decline. Aside from insulin, drugs that are currently used to treat diabetes target the
Author contributions
All authors equally contributed to this manuscript.
Conflict of interest
The authors declare that they have no competing interests and no financial support to report.
Acknowledgements
The authors thank Michael Arends for revising and editing the English of the manuscript.
References (103)
- et al.
Executive functioning and diabetes: the role of anxious arousal and inflammation
Psychoneuroendocrinology
(2016) - et al.
Cognitive disorders in diabetic patients
Handb Clin Neurol
(2014) Mood disorders and allostatic load
Biol Psychiatry
(2003)Glucocorticoids, depression, and mood disorders: structural remodeling in the brain
Metabolism
(2005)- et al.
Increased risk of diabetes in patients with anxiety disorders: a population-based study
J Psychosomatic Res
(2016) - et al.
Anxiety and depression in juvenile diabetes: a critical review
Clin Psychol Rev
(2003) - et al.
Psychological screening in adolescents with type 1 diabetes predicts outcomes one year later
Diabet Res Clin Practice
(2011) - et al.
Oxidative stress: a potential recipe for anxiety, hypertension and insulin resistance
Brain Res
(2010) - et al.
Abnormal benzodiazepine receptor function in the depressive-like behavior of diabetic mice
Pharmacol Biochem Behav
(2005) - et al.
Streptozotocin diabetic mice display depressive-like behavior and alterations in the structure, neurotransmission and plasticity of medial prefrontal cortex interneurons
Brain Res Bull
(2015)
Symptoms of depression and anxiety in youth with type 1 diabetes: a systematic review and meta-analysis
Psychoneuroendocrinology
Effects of diabetes on hippocampal neurogenesis: links to cognition and depression
Neurosci Biobehav Rev
Diabetes as a chronic metabolic stressor: causes, consequences and clinical complications
Exp Neurol
Diabetes attenuates psychological stress-elicited 5-HT secretion in the prefrontal cortex but not in the amygdala of mice
Brain Res
The change of insulin levels after six weeks antidepressant use in drug-naive major depressive patients
J Affect Disord
Regulation of insulin receptor phosphorylation in the brains of prenatally stressed rats: new insight into the benefits of antidepressant drug treatment
Eur Neuropsychopharmacol
Depression and diabetes: treatment and health-care delivery
Lancet Diabetes Endocrinol
Anxiety and depression in juvenile diabetes: a critical review
Clin Psychol Rev
Epidemiology of depression in diabetes: international and cross-cultural issues
J Affect Disord
Selectively disrupted functional connectivity networks in type 2 diabetes mellitus
Front Aging Neurosci
Impaired cerebrovascular responsiveness and cognitive performance in adults with type 2 diabetes
J Diabetes Complications
Links between cognitive impairment in insulin resistance: an explanatory model
Neurobiol Aging
The role of insulin in the vascular contributions to age-related dementia
Biochim Biophys Acta
Widespread blunting of hypothalamic and amygdala-septal activity and behavior in rats with long-term hyperglycemia
Behav Brain Res
The neurobiology of positive emotions
Neurosci Biobehav Rev
A revised limbic system model for memory, emotion and behaviour
Neurosci Biobehav Rev
Neural circuit underlying the pathophysiology of mood disorders
Trends Cogn Sci
The autonomic nervous system: a balancing act
Handb Clin Neurol
Redrawing Papez’ circuit: a theory about how acute stress becomes chronic and causes disease
Med Hypotheses
Glucocorticoid feedback increases the sensitivity of the limbic system to stress
Physiol Behav
Cerebral glucose metabolism in diabetes mellitus
Eur J Pharmacol
Potential effects of current drug therapies on cognitive impairment in patients with type 2 diabetes
Front Neuroendocrinol
Novel peroxisome proliferator-activated receptor (PPAR) and PPAR ligands produce distinct biological effects
J Biol Chem
Peroxisome proliferator-activated receptor gamma in diabetes and metabolism
Trends Pharmacol Sci
The many faces of PPAR
Cell
Efficacy and risk profile of anti-diabetic therapies: conventional vs traditional drugs – a mechanistic revisit to understand their mode of action
Pharmacol Res
Neuroprotective effects of pioglitazone against transient cerebral ischemic reperfusion injury in diabetic rats: Modulation of antioxidant, anti-inflammatory, and anti-apoptotic biomarkers
Pharmacol Rep
Rosiglitazone attenuates inflammation and CA3 neuronal loss following traumatic brain injury in rats
Biochem Biophys Res Commun
Depression mediates impaired glucose tolerance and cognitive dysfunction: a neuromodulatory role of rosiglitazone
Horm Behav
In type 1 diabetics, high-dose biotin may compensate for low hepatic insulin exposure, promoting a more normal expression of glycolytic and gluconeogenic enyzymes and thereby aiding glycemic control
Med Hypotheses
Mortality reduction among persons with type 2 diabetes: (-)-Epicatechin as add-on therapy to metformin?
Med Hypotheses
Intracerebroventricular insulin enhances memory in a passive-avoidance task
Physiol Behav
Insulin and ghrelin: peripheral hormones modulating memory and hippocampal function
Curr Opin Pharmacol
Brain insulin signaling: a key component of cognitive processes and a potential basis for cognitive impairment in type 2 diabetes
Neurobiol Learn Mem
Prevalence and prognostic value of depression and anxiety in patients with diabetic foot ulcers and possibilities of their treatment
Curr Diabetes Rev
Anxiety: an adaptive emotion
Depression and diabetes distress
Diabet Med
Stress, adaptation, and disease. Allostasis and allostatic load
Ann N Y Acad Sci
Cortisol dysregulation in obesity-related metabolic disorders
Curr Opin Endocrinol Diabetes Obes
Endocrine stress responses and risk of type 2 diabetes mellitus
Stress
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