Hyperamylinemia Contributes to Cardiac Dysfunction in Obesity and Diabetes: A Study in Humans and Rats

Rationale: Hyperamylinemia is common in patients with obesity and insulin resistance, coincides with hyperinsulinemia, and results in amyloid deposition. Amylin amyloids are generally considered a pancreatic disorder in type 2 diabetes. However, elevated circulating levels of amylin may also lead to amylin accumulation and proteotoxicity in peripheral organs, including the heart. Objective: To test whether amylin accumulates in the heart of obese and type 2 diabetic patients and to uncover the effects of amylin accumulation on cardiac morphology and function. Methods and Results: We compared amylin deposition in failing and nonfailing hearts from lean, obese, and type 2 diabetic humans using immunohistochemistry and Western blots. We found significant accumulation of large amylin oligomers, fibrils, and plaques in failing hearts from obese and diabetic patients but not in normal hearts and failing hearts from lean, nondiabetic humans. Small amylin oligomers were even elevated in nonfailing hearts from overweight/obese patients, suggesting an early state of accumulation. Using a rat model of hyperamylinemia transgenic for human amylin, we observed that amylin oligomers attach to the sarcolemma, leading to myocyte Ca2+ dysregulation, pathological myocyte remodeling, and diastolic dysfunction, starting from prediabetes. In contrast, prediabetic rats expressing the same level of wild-type rat amylin, a nonamyloidogenic isoform, exhibited normal heart structure and function. Conclusions: Hyperamylinemia promotes amylin deposition in the heart, causing alterations of cardiac myocyte structure and function. We propose that detection and disruption of cardiac amylin buildup may be both a predictor of heart dysfunction and a novel therapeutic strategy in diabetic cardiomyopathy.

[1]  F. Haj,et al.  Subcutaneous administration of leptin normalizes fasting plasma glucose in obese type 2 diabetic UCD-T2DM rats , 2011, Proceedings of the National Academy of Sciences.

[2]  F. Despa,et al.  Amyloid oligomer formation probed by water proton magnetic resonance spectroscopy. , 2011, Biophysical journal.

[3]  G. Reaven Relationships Among Insulin Resistance, Type 2 Diabetes, Essential Hypertension, and Cardiovascular Disease: Similarities and Differences , 2011, Journal of clinical hypertension.

[4]  Catherine Rabouille,et al.  Golgi bypass: skirting around the heart of classical secretion. , 2011, Cold Spring Harbor perspectives in biology.

[5]  C. Ionescu-Tirgoviste,et al.  Biophysical alteration of the secretory track in β-cells due to molecular overcrowding: the relevance for diabetes. , 2011, Integrative biology : quantitative biosciences from nano to macro.

[6]  D. Bers,et al.  Abstract 18345: Accumulation of Islet Amyloid Polypeptide Oligomers in the Heart in Type-2 Diabetes Alters Ca Cycling in Myocytes , 2010 .

[7]  S. Griffen,et al.  Chronic Administration of the Glucagon-Like Peptide-1 Analog, Liraglutide, Delays the Onset of Diabetes and Lowers Triglycerides in UCD-T2DM Rats , 2010, Diabetes.

[8]  A. Strader,et al.  Ileal interposition surgery improves glucose and lipid metabolism and delays diabetes onset in the UCD-T2DM rat. , 2010, Gastroenterology.

[9]  T. Gillette,et al.  Diabetic Cardiomyopathy: Mechanisms and Therapeutic Targets. , 2010, Drug discovery today. Disease mechanisms.

[10]  J. Seward,et al.  Infiltrative cardiovascular diseases: cardiomyopathies that look alike. , 2010, Journal of the American College of Cardiology.

[11]  F. Despa,et al.  Endoplasmic reticulum overcrowding as a mechanism of beta-cell dysfunction in diabetes. , 2010, Biophysical journal.

[12]  R. Tanzi,et al.  Protein Aggregates and Novel Presenilin Gene Variants in Idiopathic Dilated Cardiomyopathy , 2010, Circulation.

[13]  E. Abel,et al.  Diabetic cardiomyopathy, causes and effects , 2010, Reviews in Endocrine and Metabolic Disorders.

[14]  L. Young Diet-induced obesity obstructs insulin signaling in the heart. , 2010, American journal of physiology. Heart and circulatory physiology.

[15]  D. Bers,et al.  Abstract 1157: Cardiac Consequences of Increased Amylin Secretion in Diabetics , 2009 .

[16]  P. Butler,et al.  Calcium-activated Calpain-2 Is a Mediator of Beta Cell Dysfunction and Apoptosis in Type 2 Diabetes* , 2009, The Journal of Biological Chemistry.

[17]  Guha Ashrith,et al.  Insulin resistance: marker or mediator? , 2009, The American journal of medicine.

[18]  S. Griffen,et al.  Development and characterization of a novel rat model of type 2 diabetes mellitus: the UC Davis type 2 diabetes mellitus UCD-T2DM rat. , 2008, American journal of physiology. Regulatory, integrative and comparative physiology.

[19]  R. Hajjar,et al.  Interplay between impaired calcium regulation and insulin signaling abnormalities in diabetic cardiomyopathy , 2008, Nature Clinical Practice Cardiovascular Medicine.

[20]  F. Reimann,et al.  Calcium elevation in mouse pancreatic beta cells evoked by extracellular human islet amyloid polypeptide involves activation of the mechanosensitive ion channel TRPV4 , 2008, Diabetologia.

[21]  Kim N. Green,et al.  Linking Calcium to Aβ and Alzheimer's Disease , 2008, Neuron.

[22]  J. Robbins,et al.  Cardiomyocyte Expression of a Polyglutamine Preamyloid Oligomer Causes Heart Failure , 2008, Circulation.

[23]  H. Taegtmeyer,et al.  Nonischemic heart failure in diabetes mellitus , 2008, Current opinion in cardiology.

[24]  Maarten F. M. Engel,et al.  Membrane damage by human islet amyloid polypeptide through fibril growth at the membrane , 2008, Proceedings of the National Academy of Sciences.

[25]  D. Bers Calcium cycling and signaling in cardiac myocytes. , 2008, Annual review of physiology.

[26]  S. Simon,et al.  HSP60 in heart failure: abnormal distribution and role in cardiac myocyte apoptosis. , 2007, American Journal of Physiology. Heart and Circulatory Physiology.

[27]  C. Zeng,et al.  Amylin deposition in the kidney of patients with diabetic nephropathy. , 2007, Kidney international.

[28]  D. Bers,et al.  Functional analysis of Na+/K+-ATPase isoform distribution in rat ventricular myocytes. , 2007, American journal of physiology. Cell physiology.

[29]  D. Selkoe,et al.  Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide , 2007, Nature Reviews Molecular Cell Biology.

[30]  P. Butler,et al.  β-Cell Deficit Due to Increased Apoptosis in the Human Islet Amyloid Polypeptide Transgenic (HIP) Rat Recapitulates the Metabolic Defects Present in Type 2 Diabetes , 2006, Diabetes.

[31]  G. Merlini,et al.  Circulating amyloidogenic free light chains and serum N-terminal natriuretic peptide type B decrease simultaneously in association with improvement of survival in AL. , 2006, Blood.

[32]  S. Herzig,et al.  Mechanisms of [Ca2+]i transient decrease in cardiomyopathy of db/db type 2 diabetic mice. , 2006, Diabetes.

[33]  C. Kahn,et al.  From mice to men: insights into the insulin resistance syndromes. , 2006, Annual review of physiology.

[34]  P. Lansbury,et al.  Protofibrillar islet amyloid polypeptide permeabilizes synthetic vesicles by a pore-like mechanism that may be relevant to type II diabetes. , 2002, Biochemistry.

[35]  J. Knowles,et al.  Ventricular expression of natriuretic peptides in Npr1(-/-) mice with cardiac hypertrophy and fibrosis. , 2002, American journal of physiology. Heart and circulatory physiology.

[36]  O. Frazier,et al.  Downregulation of Myocardial Myocyte Enhancer Factor 2C and Myocyte Enhancer Factor 2C-Regulated Gene Expression in Diabetic Patients With Nonischemic Heart Failure , 2002, Circulation.

[37]  R. Falk,et al.  Infusion of Light Chains From Patients With Cardiac Amyloidosis Causes Diastolic Dysfunction in Isolated Mouse Hearts , 2001, Circulation.

[38]  N. Dhalla,et al.  Depressed levels of Ca2+-cycling proteins may underlie sarcoplasmic reticulum dysfunction in the diabetic heart. , 2001, Diabetes.

[39]  J. Concato,et al.  Effect of Non–Insulin-Dependent Diabetes Mellitus on Myocardial Insulin Responsiveness in Patients With Ischemic Heart Disease , 2001, Circulation.

[40]  Masahiro Kawahara,et al.  Alzheimer's β-Amyloid, Human Islet Amylin, and Prion Protein Fragment Evoke Intracellular Free Calcium Elevations by a Common Mechanism in a Hypothalamic GnRH Neuronal Cell Line* , 2000, The Journal of Biological Chemistry.

[41]  D. Harrison,et al.  The mechanism of islet amyloid polypeptide toxicity is membrane disruption by intermediate-sized toxic amyloid particles. , 1999, Diabetes.

[42]  M. Redfield,et al.  Differential atrial and ventricular expression of myocardial BNP during evolution of heart failure. , 1998, American journal of physiology. Heart and circulatory physiology.

[43]  U. Ruotsalainen,et al.  Insulin resistance characterizes glucose uptake in skeletal muscle but not in the heart in NIDDM , 1998, Diabetologia.

[44]  S. Anker,et al.  Insulin resistance in chronic heart failure: relation to severity and etiology of heart failure. , 1997, Journal of the American College of Cardiology.

[45]  K. Schlüter,et al.  Hypertrophic effects of calcitonin gene-related peptide (CGRP) and amylin on adult mammalian ventricular cardiomyocytes. , 1995, Journal of molecular and cellular cardiology.

[46]  M. Mattson,et al.  Different amyloidogenic peptides share a similar mechanism of neurotoxicity involving reactive oxygen species and calcium , 1995, Brain Research.

[47]  C. Betsholtz,et al.  Islet amyloid polypeptide: pinpointing amino acid residues linked to amyloid fibril formation. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[48]  C. Betsholtz,et al.  Islet amyloid, islet-amyloid polypeptide, and diabetes mellitus. , 1989, The New England journal of medicine.

[49]  J. Ballinger AMYLOID HEART DISEASE , 1949, The American journal of the medical sciences.

[50]  C. Folmes,et al.  Myocardial fatty acid metabolism in health and disease. , 2010, Physiological reviews.

[51]  E. Olson,et al.  Cardiac plasticity. , 2008, The New England journal of medicine.

[52]  P. Butler,et al.  Islet amyloid polypeptide (IAPP) transgenic rodents as models for type 2 diabetes. , 2006, ILAR journal.

[53]  M. Nakazato,et al.  Plasma islet amyloid polypeptide levels in obesity, impaired glucose tolerance and non-insulin-dependent diabetes mellitus. , 1992, Diabetes research and clinical practice.

[54]  P. Westermark,et al.  Impaired glucose tolerance is associated with increased islet amyloid polypeptide (IAPP) immunoreactivity in pancreatic beta cells. , 1989, The American journal of pathology.