type 2 diabetes mellitus and cns - static.livemedia.gr · players in alzheimer's disease and...

Type 2 Diabetes Mellitus and CNS

Grigorios Nasios, MD, Ph.DNeurologist, Associate Professor, TEI of Epirus,

Department of Speech and Language Therapy, Ioannina, [email protected]

03/02/2017 110th Panhellenic Conference on

Alzheimer's disease & 2nd Mediterranean Conference on Neurodegenerative Diseases



Whenever You Lose Concentration, Take Intranasal Insulin?

Antje Gottschalk and Bjorn Ellger

Diabetes 2015 Mar; 64(3): 687-688.

https://doi.org/10.2337/db14-1549



“Intranasal Insulin Boosts Cognitive Function”

Shemesh E, Rudich A, Harman-Boehm I, Cukierman-Yaffe T.

J Clin Endocrinol Metab. 2012 Feb;97(2):366-76

“Effect of intranasal insulin on cognitive function: a systematic review”.

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10th Panhellenic Conference on Alzheimer's disease & 2nd Mediterranean

Conference on Neurodegenerative Diseases

Intranasal Insulin Enhanced Resting-State Functional Connectivity of Hippocampal Regions in Type 2

DiabetesHui Zhang et al.

Diabetes 2015 Mar; 64(3): 1025-1034.

https://doi.org/10.2337/db14-1000



We are talking about the…

diabetic brain !

Type 1. 2 DM: A multi-organ epidemic disease

1. T2DM and the Brain

Mechanisms underlying altered cognition1.

1. T2DM and Alzheimer’s dementia

Concluding remarks1.

03/02/201710th Panhellenic Conference on


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TALK’S OUTLINE

1. The number of people with diabetes has risen from 108 million in 1980 to 422 million in 2014.

1. The global prevalence of diabetes among adults over 18 years of age has risen from 4.7% in 1980 to 8.5% in 2014.

1. Diabetes is a major cause of blindness, kidney failure, heart attacks, stroke and lower limb amputation.

1. Almost half of all deaths attributable to high blood glucose occur before the age of 70 years. WHO projects that diabetes will be the 7th leading cause of death in 2030.

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World Health Organization’s 2016 Global

report on Diabetes

• Occurs due to insulin resistance or insensitivity of tissues to insulin and relative insulin deficiency.

• Obesity is a major risk factor.

• Decreased entry of glucose into insulin-sensitive cells and increased release of glucose from the liver leads to hyperglycemia.



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Diabetes Mellitus Type 2 (T2DM) - I

Complications are related to both • duration of diabetes and uncontrolled plasma glucose levels.

Heritability • is high (estimated to be > 50%) and provides evidence to the genetic risk associated.

High calorie food intake• , lack of physical activity, sleep deprivation, and low socioeconomic status seem to play important role.



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Diabetes Mellitus Type 2 (T2DM) - II

T2DM affects most body’s systems and organs, among them more importantly :

• endocrine system (pancreas, liver, visceral fat)

• circulatory system (heart, large and small vessels, hypertension, elevated lipid levels)

• nervous system (brain, eyes, ears, nerves)

• urinary system (Kidneys, bladder)

• immune system (bone marrow, white blood cells)

• myoskeletal system (muscles, bones, the feet)

• digestive system (intenstine)

• reproductive system



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DM type 2 : A multi-organ epidemic disease

1. Type 2 DM: A multi-organ epidemic disease


1. Mechanisms underlying altered cognition


1. Concluding remarks



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TALK’S OUTLINE

1. Measures of verbal learning, abstract reasoning, and

complex psychomotor functioning were performed

more poorly by diabetic than nondiabetic subjects.

2. Within the diabetic group, individuals with poorer

metabolic control performed more poorly on tasks

involving learning, reasoning, and complex

psychomotor performance, although this relationship

was not evident for simple verbal or motor tasks.

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Relationship Between Hyperglycemia and Cognitive Function in Older NIDDM Patients.

Diabetes Care 1990 Jan; 13(1): 16-21. Gerald M Reaven, et. al.

1. Auditory P300 event-related potentials were recorded in 60 NIDDM patients who had no evidence of stroke, dementia, or any other neurological illnesses.

1. Diabetic patients had significantly longer P300 latencies than control subjects.

1. There was a trend toward longer P300 latencies in diabetic patients with retinopathy and in those with HbA1 of > or = 10%.

1. Microangiopathy and metabolic derangement may contribute to the pathophysiology of central nervous system involvement.



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Neurophysiological evidence for altered higher brain functions in NIDDM.

Diabetes Care. 1996 Apr;19(4):360-4. Kurita A, Katayama K, Mochio S.

Hippocampus and 1. parahippocampal gyrus may be particularly vulnerable to the deleterious effects of T2DM. (J Clin Exp Neuropsychol. 2014;36(1):74-87).

1. T2DM has been related to diminished cerebral blood flow and cerebrovascular reactivity, particularly in more advanced disease. (Eur Neuropsychopharmacol. 2014 Dec;24(12):1967-81).

Impaired cerebral perfusion 1. during mental tasks is accompanied by poor cognitive performance and stiffness in the cerebral vessels. (J Diabetes Complications. 2016 Jun 30. pii: S1056-8727(16)30254-9).

Microangiopathy1. and metabolic derangement may contribute to the pathophysiology of central nervous system involvement.



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T2DM alters brain’s structure and functions - I

5. Declines of gray matter volume, cortical thickness, and surface area were found in T2DM patients. (Neurosci Lett. 2015 Oct 8;606:100-5).

6. Markers of cortical atrophy and white matter lesion volume are associated with cognitive function in African Americans with type 2 diabetes. (AJNR Am J Neuroradiol. 2015 Sep;36(9):1648-53).

7. Patients with T2DM had lower total gray, white, and hippocampal volumes. Regions with loss of gray matter include the medial temporal, anterior cingulate, and medial frontal lobes. White matter loss was found in the frontal and temporal regions. (Diabetes Care 2013 Dec; 36(12): 4036-4042).

8. Using diffusion MRI microstructural abnormalities and disruptions in the white matter network were found in individuals with T2DM compared with controls. (Diab. Care 2013;36: 137–144).

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T2DM alters brain’s structure and functions - II

1. Type 2 DM: A multi-organ epidemic disease


1. Mechanisms underlying altered cognition


1. Concluding remarks



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TALK’S OUTLINE

T2DM is usually diagnosed at an older age and is commonly associated with obesity, insulin resistance, hypertension, and dyslipidemia, all of which can have a negative impact on the brain. Important role play :

imperfect 1. glycaemic control

microvascular1. complications

age1.

comorbidity1.



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Mechanisms underlying altered cognition in T2DM

1. Insulin signaling plays an important role in synaptic plasticity by modulating neurotransmitter channel activity, including excitatory, and inhibitory receptors. (Diabetes. 2014 Jul;63(7):2232-43).

1. Defects in brain insulin signaling may give rise to neuronal dysfunction and impaired cognitive performance. (Diabetes Care. 2013 Sep;36(9):2787-93).

1. Proton MR spectroscopy (1H-MRS) provides the unique opportunity to assess noninvasively the concentrations of neurometabolites in vivo.

1. Participants with type 2 diabetes have alterations in the GABAergicneurotransmitter system, which are related to lower cognitive functioning, and hint at the involvement of an underlying metabolic mechanism.



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Increased GABA concentrations in type 2 diabetes mellitus are related to lower cognitive functioning

Medicine (Baltimore). 2016 Sep;95(36):e4803. Van Bussel FC, et. al.

1. Both diseases share several common abnormalities.

2. Both diseases disrupt common cellular and molecular pathways and

3. Each disease potentiates the progression of the other.

Correia SC et al. : Insulin signaling, glucose metabolism and mitochondria: major players in Alzheimer's disease and diabetes interrelation. Brain Res. 2012 Mar 2;1441:64-78.



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T2DM and Alzheimer’s dementia - I

Both diseases are characterized by :

1. impaired glucose metabolism,

1. increased oxidative stress,

1. insulin resistance and

1. deposition of amyloidogenic proteins.

Correia SC et al. : Insulin signaling, glucose metabolism and mitochondria: major players in Alzheimer's disease and diabetes interrelation. Brain Res. 2012 Mar 2;1441:64-78.

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T2DM and Alzheimer’s dementia - II



Diabetes Mellitus Induces Alzheimer’s Disease Pathology: Histopathological

Evidence from Animal ModelsNobuyuki Kimura

Int. J. Mol. Sci. 2016, 17(4), 503; doi:10.3390/ijms17040503



“…because the fundamental abnormalities in AD represent effects of brain insulin resistance

and deficiency, and the molecular and biochemical consequences overlap with

type 1 and Type 2 diabetes, we suggest the term ‘Type 3 diabetes’ to account for the

underlying abnormalities associated with AD-type neurodegeneration”.

Type 3 Diabetes is Sporadic Alzheimer’s disease: Mini-Review

Eur Neuropsychopharmacol. 2014 Dec; 24(12): 1954–1960.

Suzanne M. de la Monte

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“…Programs that promote dietary change and physical activity are effective in reducing the likelihood that people at risk of developing

type 2 diabetes will do so”.

Diet and exercise are effective in preventing type 2 diabetes, task force

findsBMJ 2015;351:h3785Michael McCarthry



“…A better lifetime management of blood glucose levels may contribute to improved

cerebral and cognitive health in later life and possibly protect against dementia.”Mortby ME, Janke AL, Anstey KJ, Sachdev PS, Cherbuin N.

PLoS One. 2013 Sep 4;8(9):e73697.

“High "normal" blood glucose is associated with decreased brain volume and cognitive performance

in the 60s: the PATH through life study”.

Type 1. 2 DM: A multi-organ epidemic disease


Mechanisms underlying altered cognition1.


Concluding remarks1.



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TALK’S OUTLINE

• Type 2 diabetes is the new global epidemic and has been associated with high risk for dementia.

• It is linked with structural and functional changes in the brain which challenge cognition.

• Dietary change and physical activity are important both to prevent and offer better control of T2DM.

• Increased awareness about the risk of cognitive impairment in diabetes among medical providers is warranted.



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CONCLUDING REMARKS

Thank you very much for your

attention!



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