Elsevier

Medical Hypotheses

Volume 104, July 2017, Pages 160-165
Medical Hypotheses

Cognitive impairment in diabetes and poor glucose utilization in the intracellular neural milieu

https://doi.org/10.1016/j.mehy.2017.06.007Get rights and content

Abstract

The main characteristic of diabetes is hyperglycemia. Depending on whether diabetes is type-1 or type-2, it is characterized by deficiencies in insulin secretion, insulin receptor sensitivity, hexokinase activity, and glucose transport. Current drug treatments are able to lower circulating glucose but do not address the problem of glucose utilization in the intracellular milieu, the consequence of which is tissue damage. In the long-term, such changes can produce structural damage in many cortical and subcortical brain areas that are related to cognitive function. Many epidemiological reports consider anxiety and depression as clinical entities that accompany diabetes. However, anxiety and depression in diabetes appear to occur in parallel and do not follow a causal relationship. From a behavioral perspective, anxiety may be considered adaptive, whereas depression can be considered reactive in response to changes in lifestyle and ailments that are caused by the disease. Therefore, the main alteration in diabetes seems to be cognitive function. We hypothesized that in type-2 diabetes, hypoglycemic medications do not restore the function of glucose in the intracellular compartment, which may have deleterious effects on neural tissue with behavioral consequences. In such a case, it is important to develop pharmacological interventions that directly restore plasma insulin levels, insulin receptor function, and hexokinase activity, thereby avoiding damage to neural tissue that is associated with cognitive deficits in diabetic patients, particularly patients with type-2 diabetes. The better management of such alterations in diabetes should be directed toward improving glucose utilization by neural tissue.

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)

  • B. Buchberger et al.

    Symptoms of depression and anxiety in youth with type 1 diabetes: a systematic review and meta-analysis

    Psychoneuroendocrinology

    (2016)
  • N. Ho et al.

    Effects of diabetes on hippocampal neurogenesis: links to cognition and depression

    Neurosci Biobehav Rev

    (2013)
  • L.P. Reagan

    Diabetes as a chronic metabolic stressor: causes, consequences and clinical complications

    Exp Neurol

    (2012)
  • S. Miyata et al.

    Diabetes attenuates psychological stress-elicited 5-HT secretion in the prefrontal cortex but not in the amygdala of mice

    Brain Res

    (2007)
  • H.H. Chang et al.

    The change of insulin levels after six weeks antidepressant use in drug-naive major depressive patients

    J Affect Disord

    (2013)
  • K. Glombik et al.

    Regulation of insulin receptor phosphorylation in the brains of prenatally stressed rats: new insight into the benefits of antidepressant drug treatment

    Eur Neuropsychopharmacol

    (2017)
  • F. Petrak et al.

    Depression and diabetes: treatment and health-care delivery

    Lancet Diabetes Endocrinol

    (2015)
  • C. Dantzer et al.

    Anxiety and depression in juvenile diabetes: a critical review

    Clin Psychol Rev

    (2003)
  • C.E. Lloyd et al.

    Epidemiology of depression in diabetes: international and cross-cultural issues

    J Affect Disord

    (2012)
  • Y. Chen et al.

    Selectively disrupted functional connectivity networks in type 2 diabetes mellitus

    Front Aging Neurosci

    (2015)
  • R.S. Nealon et al.

    Impaired cerebrovascular responsiveness and cognitive performance in adults with type 2 diabetes

    J Diabetes Complications

    (2017)
  • A. Convit

    Links between cognitive impairment in insulin resistance: an explanatory model

    Neurobiol Aging

    (2005)
  • T.M. Hughes et al.

    The role of insulin in the vascular contributions to age-related dementia

    Biochim Biophys Acta

    (2016)
  • M.L. Moreno-Cortes et al.

    Widespread blunting of hypothalamic and amygdala-septal activity and behavior in rats with long-term hyperglycemia

    Behav Brain Res

    (2016)
  • J. Burgdorf et al.

    The neurobiology of positive emotions

    Neurosci Biobehav Rev

    (2006)
  • M. Catani et al.

    A revised limbic system model for memory, emotion and behaviour

    Neurosci Biobehav Rev

    (2013)
  • J.L. Price et al.

    Neural circuit underlying the pathophysiology of mood disorders

    Trends Cogn Sci

    (2012)
  • R.M. Buijs

    The autonomic nervous system: a balancing act

    Handb Clin Neurol

    (2013)
  • A.E. Eggers

    Redrawing Papez’ circuit: a theory about how acute stress becomes chronic and causes disease

    Med Hypotheses

    (2007)
  • C.J. Cook

    Glucocorticoid feedback increases the sensitivity of the limbic system to stress

    Physiol Behav

    (2002)
  • A.L. McCall

    Cerebral glucose metabolism in diabetes mellitus

    Eur J Pharmacol

    (2004)
  • C. Palleria et al.

    Potential effects of current drug therapies on cognitive impairment in patients with type 2 diabetes

    Front Neuroendocrinol

    (2016)
  • J. Berger et al.

    Novel peroxisome proliferator-activated receptor (PPAR) and PPAR ligands produce distinct biological effects

    J Biol Chem

    (1999)
  • S.M. Rangwala et al.

    Peroxisome proliferator-activated receptor gamma in diabetes and metabolism

    Trends Pharmacol Sci

    (2004)
  • M. Lehrke et al.

    The many faces of PPAR

    Cell

    (2005)
  • P Gupta et al.

    Efficacy and risk profile of anti-diabetic therapies: conventional vs traditional drugs – a mechanistic revisit to understand their mode of action

    Pharmacol Res

    (2016)
  • A.E. El-Sahar et al.

    Neuroprotective effects of pioglitazone against transient cerebral ischemic reperfusion injury in diabetic rats: Modulation of antioxidant, anti-inflammatory, and anti-apoptotic biomarkers

    Pharmacol Rep

    (2015)
  • H. Liu et al.

    Rosiglitazone attenuates inflammation and CA3 neuronal loss following traumatic brain injury in rats

    Biochem Biophys Res Commun

    (2016)
  • S.S. Patel et al.

    Depression mediates impaired glucose tolerance and cognitive dysfunction: a neuromodulatory role of rosiglitazone

    Horm Behav

    (2016)
  • M.F. McCarty

    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

    (2016)
  • A. Moreno-Ulloa et al.

    Mortality reduction among persons with type 2 diabetes: (-)-Epicatechin as add-on therapy to metformin?

    Med Hypotheses

    (2016)
  • C.R. Park et al.

    Intracerebroventricular insulin enhances memory in a passive-avoidance task

    Physiol Behav

    (2000)
  • E.C. McNay

    Insulin and ghrelin: peripheral hormones modulating memory and hippocampal function

    Curr Opin Pharmacol

    (2007)
  • E.C. McNay et al.

    Brain insulin signaling: a key component of cognitive processes and a potential basis for cognitive impairment in type 2 diabetes

    Neurobiol Learn Mem

    (2011)
  • O. Udovichenko et al.

    Prevalence and prognostic value of depression and anxiety in patients with diabetic foot ulcers and possibilities of their treatment

    Curr Diabetes Rev

    (2016)
  • A.G. Gutiérrez-García et al.

    Anxiety: an adaptive emotion

  • A. Nouwen

    Depression and diabetes distress

    Diabet Med

    (2015)
  • B.S. McEwen

    Stress, adaptation, and disease. Allostasis and allostatic load

    Ann N Y Acad Sci

    (1998)
  • R. Baudrand et al.

    Cortisol dysregulation in obesity-related metabolic disorders

    Curr Opin Endocrinol Diabetes Obes

    (2015)
  • A. Siddiqui et al.

    Endocrine stress responses and risk of type 2 diabetes mellitus

    Stress

    (2015)
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