Authors:
Paresh Dandona, MD, Islam Mohamed, MS, Husam Ghanim, PhD, Chang L Sia, Sandeep Dhindsa, MD, Antoine Makdissi, MD, and Ajay Chaudhuri, MD
Summary:
Since Alzheimer's disease (AD) is characterized by chronic inflammation in the brain and since the major pathognomonic lesions of this disease are the amyloid plaque and the neurofibrillary tangle and since a low dose infusion of insulin exerts an anti-inflammatory effect, we hypothesized that insulin may suppress the expression of the proteins involved in the formation of these lesions. The plaque is formed by the β-amyloid which is formed from amyloid Precursor Protein (APP) by the enzymes, β-secretase and -secretase which has presenilin-1 (PS-1) and presenilin-2 (PS-2) subunits. The neuro-fibrillary tangle is formed from tau protein following its hyperphosphorylation by the enzyme GSK-3β. Ten fasting patients with type 2 diabetes were infused with insulin (2U/h) with glucose (5g/h) for 4h. Blood samples were collected at 0, 2, 4 and 6h. Peripheral blood mononuclear cells (MNC) and plasma were prepared for analysis. There was a significant reduction in the expression of APP, PS-1, PS-2 and GSK-3β by 19±5, 24±9, 28±6 and 40±7% respectively (p<0.05, for all) in MNC. This occurred in parallel with reductions in ROS generation, intranuclear NFkB binding and the expression of pro-inflammatory cytokines in MNC (p<0.05 for all). There was a significant reduction in plasma concentration of serum amyloid A and intercellular adhesion molecule-1 (p<0.05 for both). We conclude that insulin induces a rapid suppression of APP, PS-1, PS-2 and GSK-3β, all of which are cardinal in the pathogenesis of AD. This suppression occurs in parallel with other comprehensive anti-inflammatory effects. Insulin may have a potential in the treatment of AD provided it can be delivered into the brain directly avoiding its hypoglycemic effects. Indeed, it is currently being tried in the treatment of AD through intranasal delivery.
Source:
Endocrine Reviews; Vol. 32, P2-519 (2011)