Austin J Pharmacol Ther. 2014; 2 (6). 1032
Department of Pharmacology, University of Saskatchewan, Canada
*Corresponding author: : Changiz Taghibiglou, Department of Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, Canada
Received: Aug 02, 2014; Accepted: Aug 05, 2014; Published: Aug 08, 2014
More than 347 million people worldwide have diabetes and the number grows considering many more are living with pre-diabetes/ insulin resistance . In Canada, more than 9 million Canadians live with diabetes or pre-diabetes with an estimated cost to the Canadian healthcare system of $16.9 billion a year by the year 2020 (http:// www.diabetes.ca/diabetes-and- you/what/prevalence/). The overall risk of death among people with diabetes is at least double the risk of those without diabetes . Diabetes contributes to the deaths of 41,500 Canadians each year and most of these (80%) will succumb to heart disease or stroke. Stroke, particularly ischemic stroke, is the leading cause of disability and the second most frequent cause of death in Canada and worldwide. The risk of stroke is increased 1.5 to 3-times in diabetic patients. Moreover, pre-diabetes is now also recognized as a stroke risk factor [3,4]. The widespread obesity and insulin resistance will most likely increase the incidence of stroke. The situation is further exacerbated given that diabetes and hyperglycemia also drastically hinder and worsen post-stroke clinical recovery outcomes [5-7]. A strong body of evidence suggests that diabetes and insulin resistance is no longer affecting peripheral tissues, and also has far reaching pathological consequences on the central nervous system (CNS).
Insulin and its signaling pathway play a pivotal role in brain physiology and pathophysiology (recently Reviewed in [8,9]). However, the direct effect of diabetes, as it pertains to stroke, on the CNS has not been well understood.
Pre-diabetes and diabetes, particularly diet-induced type 2 diabetes, has reached epidemic levels in all age groups. These conditions have been found to impair peripheral insulin functions and also compromises brain insulin signaling pathway [10,11]. The age-related decrease in neuronal insulin receptor (IR) expression , may contribute to the accelerated cognitive decline and pathogenesis of Alzheimer’s disease (AD) [13,14], as well as more susceptibility to ischemic stroke due to brain insulin resistance. We have recently found that in a rat model of diet-induced brain insulin resistance, the expression of cellular prion protein (PrPc) was significantly suppressed compared with normal control rats . The PrPc, in contrast to its misfolded scrapie isoform (PrPsc), has several important physiological functions including neuro protective activity (reviewed in ). It is thus plausible to suggest that the drastic suppression in the insulin resistant brain may partly be involved in higher susceptibility and vulnerability of pre-diabetic/diabetic individuals to ischemic stroke or even neurodegenerative disease. Insulin and other growth factors may have a regulatory role on PrPc gene expression. Both insulin and nerve growth factor can enhance PrPc expression levels in a PI-3kinase-independent manner . Human growth hormone and dexamethasone also increase PrPc gene expression . Furthermore, insulin receptor functional impairment and glucose-intolerance have been reported in PrPc knockout mice , as well as scrapie- infected animals and cells [19,20]. It is also noteworthy that in the prion knockout fibroblasts, IGF1 levels increase (most likely to compensate IR signaling impairment) , but it was functionally impaired [19,20].
Although studies in animal models of diabetes suggest co-existence of peripheral and central diabetes/insulin resistance [10,11,22], there is still a need for finding specific biomarkers for identifying pre-diabetic brains in individuals with no apparent symptoms but in a higher risk of having ischemic stroke. Moreover, it appears that those therapeutic agents with positive impacts on PrPc expression may also be beneficial against ischemic diabetic stroke or reduce its risk. However, more studies are needed to prove the neuro protective role of PrPc in diabetic stroke.
- Danaei G, Finucane MM, Lu Y, Singh GM, Cowan MJ, Paciorek CJ, et al. National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2•7 million participants. See comment in PubMed Commons below Lancet. 2011; 378: 31-40.
- Roglic G, Unwin N, Bennett PH, Mathers C, Tuomilehto J, Nag S, et al. The burden of mortality attributable to diabetes: realistic estimates for the year 2000. See comment in PubMed Commons below Diabetes Care. 2005; 28: 2130-2135.
- Carson AP, Muntner P, Kissela BM, Kleindorfer DO, Howard VJ, Meschia JF, et al. Association of prediabetes and diabetes with stroke symptoms: the REasons for Geographic and Racial Differences in Stroke (REGARDS) study. See comment in PubMed Commons below Diabetes Care. 2012; 35: 1845-1852.
- Lee M, Saver JL, Hong KS, Song S, Chang KH, Ovbiagele B. Effect of pre-diabetes on future risk of stroke: meta-analysis. See comment in PubMed Commons below BMJ. 2012; 344: e3564.
- Baird TA, Parsons MW, Phan T, Butcher KS, Desmond PM, Tress BM, et al. Persistent poststroke hyperglycemia is independently associated with infarct expansion and worse clinical outcome. See comment in PubMed Commons below Stroke. 2003; 34: 2208-2214.
- Capes SE, Hunt D, Malmberg K, Pathak P, Gerstein HC. Stress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients: a systematic overview. See comment in PubMed Commons below Stroke. 2001; 32: 2426-2432.
- Matz K, Keresztes K, Tatschl C, Nowotny M, Dachenhausen A, Brainin M, et al. Disorders of glucose metabolism in acute stroke patients: an underrecognized problem. See comment in PubMed Commons below Diabetes Care. 2006; 29: 792-797.
- Derakhshan F, Toth C. Insulin and the brain. See comment in PubMed Commons below Curr Diabetes Rev. 2013; 9: 102-116.
- Mielke JG, Wang YT. Insulin, synaptic function, and opportunities for neuroprotection. See comment in PubMed Commons below Prog Mol Biol Transl Sci. 2011; 98: 133-186.
- JG Mielke, Changiz Taghibiglou, Lidong Liu, Yu Zhang, Zhengping Jia, Khosrow Adeli, et al. A biochemical and functional characterization of diet-inducedbrain insulin resistance. J Neurochem. 2005; 93: 1568-1578.
- Pham N, Dhar A, Khalaj S, Desai K, Taghibiglou C. Down regulation of brain cellular prion protein in an animal model of insulin resistance: possible implication in increased prevalence of stroke in pre-diabetics/diabetics. See comment in PubMed Commons below Biochem Biophys Res Commun. 2014; 448: 151-156.
- Frölich L, Blum-Degen D, Bernstein HG, Engelsberger S, Humrich J, Laufer S, et al. Brain insulin and insulin receptors in aging and sporadic Alzheimer's disease. See comment in PubMed Commons below J Neural Transm. 1998; 105: 423-438.
- Craft S. Insulin resistance and Alzheimer's disease pathogenesis: potential mechanisms and implications for treatment. See comment in PubMed Commons below Curr Alzheimer Res. 2007; 4: 147-152.
- Talbot K, Wang HY, Kazi H, Han LY, Bakshi KP, Stucky A, et al. Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. See comment in PubMed Commons below J Clin Invest. 2012; 122: 1316-1338.
- Yusa S, Oliveira-Martins JB, Sugita-Konishi Y, Kikuchi Y. Cellular prion protein: from physiology to pathology. See comment in PubMed Commons below Viruses. 2012; 4: 3109-3131.
- Kuwahara C, Kubosaki A, Nishimura T, Nasu Y, Nakamura Y, Saeki K, et al. Enhanced expression of cellular prion protein gene by insulin or nerve growth factor in immortalized mouse neuronal precursor cell lines. See comment in PubMed Commons below Biochem Biophys Res Commun. 2000; 268: 763-766.
- Atouf F, Scharfmann R, Lasmezas C, Czernichow P. Tight hormonal control of PrP gene expression in endocrine pancreatic cells. See comment in PubMed Commons below Biochem Biophys Res Commun. 1994; 201: 1220-1226.
- Strom A, Wang GS, Scott FW. Impaired glucose tolerance in mice lacking cellular prion protein. See comment in PubMed Commons below Pancreas. 2011; 40: 229-232.
- Nielsen D, Gyllberg H, Ostlund P, Bergman T, Bedecs K. Increased levels of insulin and insulin-like growth factor-1 hybrid receptors and decreased glycosylation of the insulin receptor alpha- and beta-subunits in scrapie-infected neuroblastoma N2a cells. See comment in PubMed Commons below Biochem J. 2004; 380: 571-579.
- Ostlund P, Lindegren H, Pettersson C, Bedecs K. Up-regulation of functionally impaired insulin-like growth factor-1 receptor in scrapie-infected neuroblastoma cells. See comment in PubMed Commons below J Biol Chem. 2001; 276: 36110-36115.
- Satoh J, Kuroda Y, Katamine S. Gene expression profile in prion protein-deficient fibroblasts in culture. See comment in PubMed Commons below Am J Pathol. 2000; 157: 59-68.
- Taghibiglou C, Carpentier A, Van Iderstine SC, Chen B, Rudy D, Aiton A, et al. Mechanisms of hepatic very low density lipoprotein overproduction in insulin resistance. Evidence for enhanced lipoprotein assembly, reduced intracellular ApoB degradation, and increased microsomal triglyceride transfer protein in a fructose-fed hamster model. See comment in PubMed Commons below J Biol Chem. 2000; 275: 8416-8425.