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Colloque Medecine et Recherche of La Fondation Ipsen: "Diabetes, Insulin and Alzheimer's Disease".

PARIS -- The 24th Colloque Medecine et Recherche of La Fondation Ipsen dedicated to the Alzheimer series which was hold in Paris on April 6, 2009 and entitled "Diabetes, Insulin and Alzheimer's Disease". Although the molecular pathology of Alzheimer's disease (AD) is now fairly well understood, the reasons that people develop this and other neurodegenerative diseases in older age are still very unclear. In recent years, a strong association has emerged between metabolic dysregulation and the development of dementia, with insulin as the linking factor.

The increasing prevalence of obesity and type 2 diabetes world-wide as populations become more affluent, more sedentary and over-fed already poses a huge public health problem of morbidity, cardio-vascular disease and stroke. When the increased likelihood of developing AD or other neurodegenerative conditions leading to dementia are added to this mix, the prospects are grim indeed. However, the insulin connection also brings with it new possibilities for therapeutic interventions that can both protect against these diseases, ameliorate cognitive decline and slow down progression.

The meeting has been organised by Suzanne Craft (University of Washington School of Medicine, Seattle, USA) and Yves Christen (Fondation Ipsen, Paris), and a panel of other 11 experts from Europe and the USA reviewed the evidence for this association, the possible mechanisms and the implications for the treatment of Alzheimer's disease. Therapeutic options have been discussed including simple dietary measures and other life-style changes (Cole, Torres-Aleman), nasal administration of insulin and insulin sensitizers (Craft), enzyme inhibitors or modulators (Kahn; Alkon; Lovestone), regulation of corticosterone (Stranahan) and of leptin and serotonin (Gerozissis). The insights that the insulin connection may bring look like providing an important advance in understanding, preventing and perhaps treating Alzheimer's and related conditions.

Insulin, produced by the pancreas, is the key hormone for regulating blood glucose levels and therefore plays a crucial role in the control of metabolism. A strong link has been established between obesity, high levels of circulating glucose and type 2 diabetes, in which the insulin receptors stop recognizing the insulin signal (Jose A. Luchsinger, Columbia University Medical Center, New York, USA). A prevalence of mild cognitive decline in patients with type 2 diabetes and evidence for brain atrophy (Geert Jan Biessels, University Medical Center Utrecht, Utrecht, The Netherlands) focussed attention on a possible link with the neurodegenerative diseases, especially those, like Alzheimer's, that lead to dementia. Epidemiological studies have recently established obesity and type 2 diabetes as risk factors for AD (Luchsinger; Lenore J. Launer, Laboratory of Epidemiology, Demography, and Biometry, NIH, Bethesda, USA).

The regulation of metabolism is complex and multi-facetted. Like many other hormones, insulin is also active in the central nervous system: insulin receptors are widespread, and evidence is accumulating that insulin is involved in both the central regulation of energy balance and the metabolism of glucose and lipids. Particularly in the hypothalamus and the hippocampus, insulin converges with metabolic, endocrine and neural signals that regulate food intake, energy and glucose homeostasis (Kyriaki Gerozissis, INSERM UMR 7059 CNRS, Universite de Paris 7, Paris, France).

But insulin and its close relative, insulin-related growth factor 1 (IGF-1), are also involved in the brain as growth factors that help to maintain neuronal health and synaptic plasticity, particularly in the hippocampus, the brain area involved in memory storage and the site of early damage in Alzheimer's Disease (Daniel Alkon, Blanchette Rockefeller Neurosciences Institute, Morgantown USA). Administering insulin improves cognitive performance (Lawrence Reagan, University of South Carolina School of Medicine, Columbia, USA) and both cognitive performance and synaptic structure and function are compromised in diabetes, partly through raised corticosteroid levels resulting from increased physiological stress (Alexis Stranahan, Johns Hopkins University, Baltimore, USA). Insulin also activates other growth factors, including nerve growth factor and brain-derived growth factor, which are neuroprotective, both maintaining neuronal structure and promoting anti-apoptotic pathways (Alkon; Gregory Cole, UCLA, North Hills, USA).

Another well-documented consequence of hyperglycaemia and diabetes is the attrition of blood vessels. In the brain, this seems to contribute to cognitive decline and may also be a precursor to neurodegeneration (Biessels; Ignacio Torres-Aleman, Cajal Institute, Madrid, Spain). Blood levels of IGF-1, which easily crosses the blood-brain barrier, correlate with cognitive performance and both can be improved by life-style factors such as diet and exercise (Torres-Aleman).

Connections between metabolic regulation and the pathological processes underlying Alzheimer's Disease are also being discovered at the molecular level. Enzymes involved in metabolic regulation are also implicated in the hyperphosphorylation of the tau protein, responsible for the formation of neurofibrillary tangles, and amyloid-beta aggregation (Ronald Kahn, Harvard University, Joslin Diabetes Center, Boston, USA; Simon Lovestone, Kingos College, London, UK; Cole; Craft). The genes coding for insulin-related compounds and metabolic enzymes may also turn out to be susceptibility factors for developing Alzheimer's Disease (Lovestone). Another hormone, leptin, which is involved in the control of food intake and metabolism also seems to play a role in the metabolism of tau and amyloid beta. Leptin acts together with serotonin (5-HT), a neurotransmitter implicated in depression, another condition commonly associated with diabetes (Gerozissis).

La Fondation Ipsen Established in 1983 under the aegis of the Fondation de France, the mission of La Fondation Ipsen is to contribute to the development and dissemination of scientific knowledge. The long-standing action of La Fondation Ipsen is aimed at furthering the interaction between researchers and clinical practitioners, which is indispensable due to the extreme specialisation of these professions. The ambition of La Fondation Ipsen is not to offer definitive knowledge, but to initiate a reflection about the major scientific issues of the forthcoming years. It has developed an important international network of scientific experts who meet regularly at meetings known as Colloques Medecine et Recherche, dedicated to six main themes: Alzheimer's disease, neurosciences, longevity, endocrinology, the vascular system and cancer science. In 2007, La Fondation Ipsen started three new series of meetings. The first is in partnership with the Salk Institute and Nature and is an annual meeting which focuses on aspects of Biological Complexity; the second is the "Emergence and Convergence" series with Nature with 4 workshops a year, and the third annual meeting is with Cell and the Massachusetts General Hospital entitled "Exciting Biologies". Since its beginning, La Fondation Ipsen has organised more than 100 international conferences, published 69 volumes with renowned publishers and more than 205 issues of a widely distributed newsletter Alzheimer Actualites. It has also awarded more than 100 prizes and grants.
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Date:Apr 8, 2009
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