Florin Despa

Personal Information
Title Associate Professor
Expertise Cardiovascular
Institution University of Kentucky
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Data Summary
Grants/SubContracts 1
Progress Reports 1
Publications 8
Protocols 0
Committees 2

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

Annual Reports
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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
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

Year: 2016; Items: 2

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

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
Hyperamylinemia as a risk factor for accelerated cognitive decline in diabetes.
Ly H, Despa F
Expert review of proteomics, 2015, 1 - 3

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)
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
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