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Amylin oligomers may predict heart failure in obese and diabetic patients
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Large amylin oligomers accumulated in failing hearts of obese and diabetic patients, but not in lean patients with failing hearts, according to study results.
Florin Despa, PhD, of the department of pharmacology at the University of California, Davis, and colleagues aimed to determine whether amylin accumulates in the heart of obese and type 2 diabetic patients. They also aimed to further illuminate the effects of amylin accumulation on cardiac morphology and function.
Both failing and nonfailing hearts from lean and obese participants and also those with type 2 diabetes were evaluated for amylin deposition. The researchers used immunohistochemistry and Western blots to make these evaluations.
Significant accumulation of large amylin oligomers, fibrils and plaques were observed in failing hearts from obese and diabetic patients. This accumulation was not observed in normal hearts or failing hearts from lean or nondiabetic participants.
Overweight or obese patients with nonfailing hearts demonstrated elevations in small amylin oligomers, which the researchers said suggests an early state of accumulation.
“We found accumulation of large (32 kDa) amylin oligomers in failing hearts from obese and diabetic patients, but not in nonfailing and failing hearts from lean humans,” Despa told Endocrine Today. “Intriguingly, small amylin oligomers were also present in nonfailing hearts from overweight/obese individuals, suggesting an early stage of amylin accumulation.”
The development of a rat model of hyperamylinemia transgenic for human amylin allowed the researchers to observe that amylin oligomers attach to the sarcolemma. This, in turn, leads to myocyte Ca2+ dysregulation, pathological myocyte remodeling and diastolic dysfunction, starting from prediabetes, according to the results.
Prediabetic rats that expressed the same level of wild-type rat amylin, a nonamyloidogenic isoform, also exhibited normal heart structure and function.
“Our study shows that toxic molecular species derived from amylin are causally implicated not only in pancreatic disorders and development of [type 2 diabetes], but also in cardiac dysfunction,” Despa said. “Thus, secretory dysfunction of pancreatic beta-cells leading to amylin oligomer formation results in a feed forward process, whereby the secretion of these toxic amyloidogenic species in the blood causes additional damage in the heart.”
The other key conclusion is that “the detection and disruption of amylin oligomers circulating from pancreas to heart may be both a novel predictor of heart failure in prediabetes and a novel therapeutic strategy to interfere with heart failure development,” he said.
Regarding the clinical implications of the study, Despa said, “We expect that one consequence of this work will be a realization that treatments/diets that increase insulin amylin secretion in patients with prediabetes and diabetes should be avoided in favor of treatments that reduce insulin resistance, or insulin itself.”
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