Neurodegenerative disorders and diabetes: common underlying impairments N.M. Lalic (Serbia)
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
Agenda Neurodegenerative diseases and diabetes Insulin, insulin resistance and brain Insulin resistance and related metabolic disorders: the role in neurodegenerative diseases
Agenda Neurodegenerative diseases and diabetes Insulin, insulin resistance and brain Insulin resistance and related metabolic disorders: the role in neurodegenerative diseases
Diabetes mellitus Population Neurodegenerative diseases 20%
Prevalence of neurodegenerative diseases Disease No/100.000 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
Huntington s chorea chorea and other dyskinesia dementia behavioral changes inheritance with complete penetrance
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)
Alzheimer s disease
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
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
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)
Agenda Neurodegenerative diseases and diabetes Insulin, insulin resistance and brain Insulin resistance and related metabolic disorders: the role in neurodegenerative diseases
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
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
Mechanisms of insulin action in the CNS Lin Li, Brain Research Review, 2007
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
Insulin resistance and CNS Craft S, Neurobiology of aging, 2005
The current paradigm NGT IGT/IFG T2D Normal range Insulin secretion Plasma glucose 12 10 8 6 4 2 0 2 4 6 Years from diagnosis
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
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
Patients with T2D and nondiabetics with and without ischemic stroke Insulin levels Patients with T2D and different subtypes of ischemic stroke Insulin levels 25 20 * * * 30 25 20 * * * 15 15 10 10 5 5 0 0 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
Agenda Neurodegenerative diseases and diabetes Insulin, insulin resistance and brain Insulin resistance and related metabolic disorders: the role in neurodegenerative diseases
Huntington s chorea chorea and other dyskinesia dementia behavioral changes inheritance with complete penetrance
Insulin sensitivity NM.Lalic et al. Arch Neurol 2008; 65(4): 476-480
Insulin secretion NM.Lalic et al. Arch Neurol 2008; 65(4): 476-480
Correlation r CAG p AIR 0.17 0.003 HOMA-IR -0.32 0.10 Si 0.29 0.54 ΔI30 / ΔG30-0.22 0.27 NM.Lalic et al. Arch Neurol 2008; 65(4): 476-480
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) 5 14 4 3 * 12 10 8 ** 2 6 4 1 2 0 0 SCA 1 Controls SCA 1 Controls * p< 0.001 vs controls ** p<0.05 vs control NM.Lalic et al. Mov Disord. 2010 Sep 15;25(12):1976-80
Insulin secretion in patients with SCA 1 I30/ G30 AIR (mu/l) 90 25 80 70 20 60 50 40 30 20 ** 15 10 5 * 10 0 0 SCA 1 Controls SCA 1 Controls * p< 0.001 vs controls ** p<0.05 vs control NM.Lalic et al. Mov Disord. 2010 Sep 15;25(12):1976-80
Alzheimer s disease
AD: cognitive impairments and insulin resistance The InCHIANTI Study Geroldi C. et al, Arch Neurol. 2005;62:1067-1072
AD: cognitive impairments and metabolic syndrome The InCHIANTI Study Geroldi C. et al, Arch Neurol. 2005;62:1067-1072
GJ Biessels, et al. Lancet Neurol 2006; 5:64-74
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.
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