Neurodegenerative disorders and diabetes: common underlying impairments. N.M. Lalic (Serbia)

Transcription

1 Neurodegenerative disorders and diabetes: common underlying impairments N.M. Lalic (Serbia)

2 Neurodegenerative disorders and diabetes: common underlying impairments Professor Nebojsa M. Lalic Faculty of Medicine, University of Belgrade Clinic for Endocrinology, Diabetes and Metabolic Diseases, Clinical Center of Serbia

3 Agenda Neurodegenerative diseases and diabetes Insulin, insulin resistance and brain Insulin resistance and related metabolic disorders: the role in neurodegenerative diseases

4 Agenda Neurodegenerative diseases and diabetes Insulin, insulin resistance and brain Insulin resistance and related metabolic disorders: the role in neurodegenerative diseases

5 Diabetes mellitus Population Neurodegenerative diseases 20%

6 Prevalence of neurodegenerative diseases Disease No/ population Prion diseases <1 Alzheimer s disease 1450 Parkinson s disease 360 Frontotemporal dementia 14 Pick s disease 2 PSP 5 ALS 7 Huntington s chorea 11 Spinocerebellar ataxias 4

7 Huntington s chorea chorea and other dyskinesia dementia behavioral changes inheritance with complete penetrance

8 Huntington s disease HD patients developed diabetes 4-7 times more often than matched healthy control individuals Inappropriate insulin secretion OGTT & i.v.itt: 50% of pts had abnormal glucose tolerance (Podolsky and Leopold, 1977) 1/3 of HD pts had impaired glucose tolerance vs 3% in controls HD patients experience weight loss (wasting, cachexia)

9 Alzheimer s disease

10 Alzheimer s disease (AD) AD is neurodegenerative disorder and most common form of nonvascular demetia which presents clinically with key symptoms including a progressive decline in memory, impairments in speach, language, spatial orientation and dysfunction in the sensormotor system. Ristow M, J Mol Med, 2004

11 AD - molecular mechanisms (II) Senile plaques extracellular amyloid deposits Neurofibrillary tangles amyloid deposits within and around blood vessels (tau protein) Ricardo B. Maccioni, Archives of Medical Research, 2001

12 AD and type 2 diabetes (T2D) Diabetic patients have less success than healthy subjects on memory tests, solving simple math problems as well as lower psychomotor efficiency (Miles and Root, 1922) Poor metabolic control may affect the reversible damage of cognitive function, which can recover with the optimal metabolic control (Rochester study) (Leibson et al, 1997) The prevalence of T2D is approximately three times higher in patients with AD (Rotterdam study) (Ott et al, 1999) Risk for AD is increased for 65% in T2D vs nondiabetics (Arvanitakis et al, 2004) Insulin resistance can further potentiate the formation of subcortical brain microvascular lesions, which further contributes to deterioration of dementia in patients with AD (InCHIANTI study) (Geroldi et al, 2005)

13 Agenda Neurodegenerative diseases and diabetes Insulin, insulin resistance and brain Insulin resistance and related metabolic disorders: the role in neurodegenerative diseases

14 Insulin-related mechanisms shared by most neurodegenerative disorders Decrease cerebral glucose metabolism Increased inflammation Increased oxidative stress Increased advanced glycation end products Increased vascular dysfunction Decreased neurogenesis Decreased neuronal repair

15 Physiological functions of insulin receptor signal transduction: effects in the rodent brain food intake Inhibition of hepatic gluconeogenesis counter-regulation to hypoglycemia reproduction modulation of tau phosphorilation metabolism of APP and Aβ clearance neuronal survival memory Plum et al., Trends Endocr Metabol 2005; 16, 2: 59-65

16 Mechanisms of insulin action in the CNS Lin Li, Brain Research Review, 2007

17 Insulin insensitive organ?! presence of insulin in the CNS readily transported into the CNS via a saturable, insulinreceptor mediated transport process an acute increase in the peripheral insulin concentration acutely increases the concentration in the brain and cerebrospinal fluid a prolonged peripheral hyperinsulinemia down regulates blood brain barrier insulin receptors and reduces insulin transport into the brain. brain-derived insulin synthesis in animal models presence of insulin receptors in the CNS selective distribution, predilection for hypothalamus, hippocampus, cerebral cortex, olfactory bulb, amygdala and septum

18 Insulin resistance and CNS Craft S, Neurobiology of aging, 2005

19 The current paradigm NGT IGT/IFG T2D Normal range Insulin secretion Plasma glucose Years from diagnosis

20 Ischemic stroke in Type 2 diabetic patients and nondiabetics Insulin sensitivity Si (min -1 /mu/lx10 4 ) 8,0 7,0 6,0 5,0 4,0 3,0 2,0 1,0 0,0 P<0.05 P<0.001 DM+ Stroke + DM + Stroke - DM - Stroke + Controls Lalić NM, et al: Diabetes 2004; 53 (Suppl 1): A 97

21 Subtypes of ischemic stroke in Type 2 diabetic patients Insulin sensitivity 3,0 Si (min -1 /mu/lx10 4 ) 2,5 2,0 1,5 1,0 0,5 * * * 0,0 DM+ ATI DM+ LAA DM+ LAC DM+ Stroke - * p<0.05 vs DM+ Stroke - A. Jotic et al, Int J Endocrinol, 2013

22 Patients with T2D and nondiabetics with and without ischemic stroke Insulin levels Patients with T2D and different subtypes of ischemic stroke Insulin levels * * * * * * DM+ stroke+ DM+ stroke- DMstroke- controls DM+ ATI DM+ LAA DM+ LAC DM+ Stroke- *p<0,05 * *p<0,001 * p<0,001 A. Jotic et al, Int J Endocrinol, 2013

23 Agenda Neurodegenerative diseases and diabetes Insulin, insulin resistance and brain Insulin resistance and related metabolic disorders: the role in neurodegenerative diseases

24 Huntington s chorea chorea and other dyskinesia dementia behavioral changes inheritance with complete penetrance

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26 Insulin sensitivity NM.Lalic et al. Arch Neurol 2008; 65(4):

27 Insulin secretion NM.Lalic et al. Arch Neurol 2008; 65(4):

28 Correlation r CAG p AIR HOMA-IR Si ΔI30 / ΔG NM.Lalic et al. Arch Neurol 2008; 65(4):

29 Insulin sensitivity in patients with SCA 1 12 normoglycemic patients with SCA1 (BMI: 22.8 kg/m 2, mean age: 37.7 yrs) 25 matched controls (BMI: 22.9 kg/m 2, mean age: 36.9 yrs) HOMA M value (mg/kg/min) * ** SCA 1 Controls SCA 1 Controls * p< vs controls ** p<0.05 vs control NM.Lalic et al. Mov Disord Sep 15;25(12):

30 Insulin secretion in patients with SCA 1 I30/ G30 AIR (mu/l) ** * SCA 1 Controls SCA 1 Controls * p< vs controls ** p<0.05 vs control NM.Lalic et al. Mov Disord Sep 15;25(12):

31 Alzheimer s disease

32 AD: cognitive impairments and insulin resistance The InCHIANTI Study Geroldi C. et al, Arch Neurol. 2005;62:

33 AD: cognitive impairments and metabolic syndrome The InCHIANTI Study Geroldi C. et al, Arch Neurol. 2005;62:

34 GJ Biessels, et al. Lancet Neurol 2006; 5:64-74

35 Conclusions Neurodegenerative diseases are found to be more frequent in diabetes than in general population. Both in diabetes and in neurodegenerative diseases, insulin resistance has been found to play a significant role in the appearance of the disease. The effect of insulin resistance was found to be present in neurodegenerative diseases with different underlying mechanisms. Thus, the role of insulin resistance might be to facilitate the activation of the pre-existing mechanism leading to the disease development.

36 Collaborators Clinic for Endocrinology, CCS Prof Aleksandra Jotic Asst Ljiljana Lukic Asst Tanja Milicic Mr Sc Marija Macesic Prof Katarina Lalic Asst Natasa Rajkovic Clinic for Neurology, CCS Prof Vladimir S. Kostic Prof Marina Svetel Prof Elka Stefanova Mr Sc Jelena Maric Prof Nadezda Sternic Mr Sc Milija Mijailovic Prof Aleksandra Pavlovic