CNS Neurol Disord Drug Targets. 2013 Jun;12(4):520-4.

Ageing as a Trait de Union between diabetes and dementia for frailty.

Semprini R, Ragonese M, Poggi M, Franze A, Martorana A.

ACISMOM Centro Diabetologico- Via LE Morselli, 13 00148 Roma, Italy.

Correspondence to: roberta.semprini@gmail.com

 

Abstract

A frail patient is one who carries a sum of poly-pathologies, whose co-existence may shorten his life expectation. Diabetes mellitus type 2 and metabolic syndrome play a substantial role in it, but dementia has increasingly risen in importance. Interestingly, the insulin pathway was suggested to be responsible for the metabolic cascade that leads to amyloid-beta deposit and pathology. Nevertheless, a clear relationship between them was just experimentally, rather than clinically demonstrated. In this work the authors suggest a possible link between insulin, diabetes and Alzheimer’s disease, whose co-existence could be responsible for physical and cognitive decline but not for frailty. We suggest that these factors could be responsible for frailty only if senescence-associated.

PMID: 23574169

 

Supplement

Alzheiemr’s disease (AD) is a neurodegenerative disorder responsible for the most diffused form of dementia worldwide. AD is characterized by the progressive disarrangement of cortical and hippocampal neuronal network, that hampers synaptic plasticity mechanisms, induces neuronal cell degeneration and death. The leading hypothesis on the pathophysiology of AD is the amyloid cascade hypothesis. Due to an error in the metabolic pathway of the Amyloid Precursor Protein, a protein likely involved in cell-to-cell signaling, pathologic forms of amyloid peptides produced intracellularly, spill over exerting a highly toxic effect on neurotransmission. The disease progression lead to the formation of extracellular senile plaque, deposits mainly formed of amyloid peptides, and then to the intracellular formation of neurofibrillary tangles, pathologic forms of hyperphsporylated cytoskeleton protein tau. The formation of amyloid peptides species activates an imbalance between anti-apoptotic and apoptotic metabolic pathways inducing progressive cells shrinkage until cell death. The diffusion of these pathologic hallmarks correlate with cognitive deficits and dementia symptoms.

Diabetes mellitus (DM) is the most common metabolic disturbances and cause of chronic disease particularly among elderly. Underdiagnosed DM is frequently associated to ageing, and is cause of life shortening, frailty and death. DM derives from the degeneration of pancreatic Beta cells that produce and release insulin. In old aged patients often rather than a defect in insulin release, various degree of insulin resistance can cause DM. Amyloid cascade could induce insulin or IGF resistance as well, with reduced metabolic rate and activation of apoptotic pathways responsible for cell degeneration. This particular condition is called diabetes type 3.

The novelty of our work is to consider ageing as the real predisposing condition to develop cognitive decline. Thus, DM or better the impairment of the glucose utilization is not sufficient to induce cognitive decline in absence of senescence. Sarcopenia, mitochondrial dysfunction, quiescence of metabolic pathways associated to changes intracellular cell signaling, increased production of oxidative metabolism, normally associated to ageing to our opinion represent the real predisposing condition for development of cognitive decline in patients with DM. In this sense ageing is a trait de union between the two conditions.  

 

Roberta Semprini-fig1

Fig 1: Ageing, Diabetes and Neural Degeneration

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