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Amylin amyloid, a link between pancreas and brain pathologies in diabetes

Type-2 diabetes (T2D) is a chronic metabolic disorder that increases the risk for dementia linked to cerebrovascular disease and/or Alzheimer’s disease. Increased risk for these diseases develops years before the onset of clinically apparent T2D and is higher in people with obesity or insulin resistance. Amylin is an amyloidogenic peptide synthesized and co-secreted with insulin by pancreatic ß-cells, is elevated in obesity and pre-diabetic insulin resistance, and has binding sites in the brain regulating satiety and gastric emptying. With increased secretion, amylin forms oligomers in the secretory vesicles of pancreatic ß-cells and large amyloids extracellularly, in pancreatic islets. Accumulation of oligomerized amylin in pancreatic islets is an important source of oxidative and inflammatory stress leading to ß-cell apoptosis and development of T2D. Our preliminary data show that, in addition to plaques laden with ß-amyloid, the brain of demented T2D patients also contains large deposits of amylin. Hence, we hypothesize that hyperamylinemia contributes to the development of dementia in T2D by a steady infiltration of oligomerized amylin in cerebral vasculature and brain parenchyma. To test the association of cerebral deposition of amylin with dementia in T2D, we will now compare amylin pathology in the brain of cognitively normal T2D patients with that in cognitively impaired T2D patients and non-diabetic controls (aged =65 years) to determine how amylin concentration and distribution of amylin deposits differ from our initial findings in demented T2D patients. In a broader sample, including appropriate controls, we will assess the level of co-localization of amylin and Aß in cerebral blood vessels and brain parenchyma of demented diabetics. This research proposal exploits our laboratory’s expertise in molecular mechanisms linking hyperamylinemia with diabetic degenerative disease and the skill of UK ADC in employing human brain tissue to characterize brain responses to aging and pathological stress. If the hypothesis of toxic amylin accumulation in the cerebrovascular system and brain is proven, then hyperamylinemia could be a feasible therapeutic target to slow the neurodegenerative process in diabetic patients.

Progress Reports


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Application	Complete Date	Report	Options
Amylin amyloid, a link between pancreas and brain pathologies in diabetes (Despa, Florin)	10/24/2014	View Progress Report Document

Annual Reports

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Publication	Submitted By	PubMed ID	Status
Year: 2017; Items: 2
Brain microvascular injury and white matter disease provoked by diabetes-associated hyperamylinemia. Ly H, Verma N, Wu F, Liu M, Saatman KE, Nelson PT, Slevin JT, Goldstein LB, Biessels GJ, Despa F Annals of neurology, 2017	Despa, Florin	28696548	Published
Amylin and diabetic cardiomyopathy - amylin-induced sarcolemmal Ca(2+) leak is independent of diabetic remodeling of myocardium. Liu M, Hoskins A, Verma N, Bers DM, Despa S, Despa F Biochimica et biophysica acta, 2017	Despa, Florin	29066284	Published
Year: 2016; Items: 2
Intraneuronal Amylin Deposition Peroxidative Membrane Injury and Increased IL-1ß Synthesis in Brains of Alzheimer's Disease Patients with Type-2 Diabetes and in Diabetic HIP Rats. Verma N, Ly H, Liu M, Chen J, Zhu H, Chow M, Hersh LB, Despa F Journal of Alzheimer's disease : JAD, 2016	Despa, Florin	27163815	Published
Hyperamylinemia Increases IL-1ß Synthesis in the Heart via Peroxidative Sarcolemmal Injury. Liu M, Verma N, Peng X, Srodulski S, Morris A, Chow M, Hersh LB, Chen J, Zhu H, Netea MG, Margulies KB, Despa S, Despa F Diabetes, 2016	Despa, Florin	27335231	Published
Year: 2015; Items: 2
The Mitochondrial Peptidase Pitrilysin Degrades Islet Amyloid Polypeptide in Beta-Cells. Guan H, Chow KM, Song E, Verma N, Despa F, Hersh LB PLoS ONE, 2015 (10), e0133263	Submitted Externally	26191799	Published
Hyperamylinemia as a risk factor for accelerated cognitive decline in diabetes. Ly H, Despa F Expert review of proteomics, 2015, 1 - 3	Despa, Florin	26503000	Published
Year: 2014; Items: 2
Cardioprotection by controlling hyperamylinemia in a "humanized" diabetic rat model. Despa S, Sharma S, Harris TR, Dong H, Li N, Chiamvimonvat N, Taegtmeyer H, Margulies KB, Hammock BD, Despa F Journal of the American Heart Association, 2014 (3)	Despa, Florin	25146704	Published
Neuroinflammation and neurologic deficits in diabetes linked to brain accumulation of amylin. Srodulski S, Sharma S, Bachstetter AB, Brelsfoard JM, Pascual C, Xie XS, Saatman KE, Van Eldik LJ, Despa F Molecular neurodegeneration, 2014 (9), 30	Despa, Florin	25149184	Published

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Steering Committee

The DiaComp Steering Committee is the governing body of the consortium. The principle function of this committee is to guide the scientific direction of the consortium. This is accomplished by creating various subcommittees necessary to advance the scientific goals and providing guidance to the broader complications research community. Policies for the consortium are developed through consultation with the External Evaluation Committee

Cardiovascular

The DiaComp Cardiovascular Committee has the principal function of furthering the mission of the consortium with regard to diabetic cardiomyopathy and macrovascular disease.

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