Accardi G, Verga S, Emanuele F, Caruso C, Virruso C, Vasto S, Licastro F, Candore G

Recent findings suggest a strong correlation between Type 2 diabetes (T2D) and Alzheimer’s disease (AD). It is well known that an impairment of insulin signaling pathway can lead to insulin resistance and T2D, raising blood glucose levels. However, insulin and insulin growth factor-1 (IGF-1) contribute to neuronal survival, cognitive function and learning and memory processes as well. Indeed, many studies demonstrate that hyperinsulinemia, a pre-insulin resistance condition, is linked to higher risk of AD. Moreover, in vivo studies show an increased risk for cognitive decline in diabetic mice. The molecular explanation of this correlation is unclear but insulin resistance and impairment of insulin pathway seem to have a key role. In the brain, altered metabolism makes neurons more sensible to oxidation causing mitochondrial damages. Moreover, AD brains have a lower insulin utilization, a reduced expression of its receptors and of IGF-1, all necessary for neuronal survival and learning and memory processes. The attenuation of AKT, a kinase involved in downstream insulin cascade, causes the augmented activity of GSK-3 beta that, in mice and maybe in human, increases neuronal apoptosis and in human causes hyperphosphorilation of tau protein.

SHIP2, a 5-phosphatase, is an antagonist of PI3K and its expression, in brain of diabetic mice is increased. Moreover, its over-expression causes impairment of insulin/IGF-1 signaling, hence the decline of all related functions. This is linked to the reduction of PI(3,4,5)P3 level, also in the central nervous system. Since some single nucleotide polymorphisms (SNPs) of the INPPL1, gene encoding SHIP2, in particular rs2276047, rs9886 and rs144989913, are significantly associated with T2D in European and Japanese people, we performed a case-control study with type 2 diabetic and AD Italian people. Moreover we compared these populations with younger one.

Preliminary results suggest a putative correlation between this rs144989913 and ageing rather than age-related diseases. Since this SNP is an insertion/deletion of 28 base pairs, it may cause an alteration in SHIP2 expression, confirming the evidence previous shown in old mice in which SHIP2 levels were raised.

Keywords (Optional): 
Alzheimer's disease
Type 2 Diabetes
Insulin pathway