Download Impact of type 2 diabetes and a - American Journal of Physiology

Am J Physiol Cell Physiol 292: C1243–C1244, 2007;
doi:10.1152/ajpcell.00521.2006.
Editorial Focus
Hexosamine biosynthetic pathway flux and cardiomyopathy in type 2 diabetes
mellitus. Focus on “Impact of type 2 diabetes and aging on cardiomyocyte
function and O-linked N-acetylglucosamine levels in the heart”
Patrick H. McNulty
Bassett Healthcare and Columbia University College of Physicians and Surgeons, Cooperstown, New York
Address for reprint requests and other correspondence: P. H. McNulty,
Division of Cardiology, Bassett Healthcare, One Atwell Rd., Cooperstown,
NY 13326 (e-mail: [email protected]).
http://www.ajpcell.org
zyme that catalyzes the reversible O-GlcNAcylation of specific
serine/threonine residues of numerous cytosolic and nuclear
proteins (4). Posttranslational O-GlcNAcylation likely interferes with serine/threonine phosphorylation of these same proteins, thereby altering their function. Because protein substrates for OGT include broad-specificity nuclear transcription
factors and insulin-responsive metabolic enzymes resident in
the cytosol, the HBP has been hypothesized to function as a
cellular “fuel gauge” in which increased HBP flux mediates the
development of insulin resistance as a brake on excessive
glucose consumption (4, 12).
The significance of the HBP for diabetic cardiomyopathy
resides in a broad series of recent observations in isolated
cardiomyocytes and insulin-deficient rat models that demonstrate that cardiomyocyte excitation-contraction (E-C) coupling and ionotrophic reserve are sensitive to cellular levels of
UDP-GlcNAc and, correspondingly, to the balance between
the activities of OGT and its counterpart, O-GlcNAcase (5, 10,
14). These observations support the general premise that increased protein O-GlcNAcylation may mediate cardiac mechanical dysfunction in diabetes. However, a number of important points have remained uncertain, including whether this mechanism mediates the development of cardiomyopathy in the more
clinically relevant condition of insulin-resistant (type 2) diabetes,
and the relative importance of cellular UDP-GlcNAc concentration vs. OGT activity in mediating O-GlcNAcylation in the
diabetic heart.
In their new work, Fülöp and colleagues (8) report serial
measurements of cardiac UDP-GlcNAc, O-GlcNAc-modified
protein, and OGT expression, along with single-cell calcium
transients and mechanical performance, during the transition
from the insulin-resistant normoglycemic stage to the hyperglycemic stage in the Zucker diabetic fatty (ZDF) rat. This
study represents an important extension of previous work, both
in its comprehensive scope and in the attempt to characterize a
rodent model of obesity and insulin resistance highly relevant
to the increasingly prevalent form of human type 2 diabetes
sometimes referred to as “diabesity.” The transition from
normoglycemia to hyperglycemia in ZDF rats was found to be
associated with cellular accumulation of UDP-GlcNAc and
O-GlcNAc-modified protein, delayed calcium sequestration,
and impaired mechanical relaxation. However, OGT expression was no different in hyperglycemic ZDF rats than in hearts
of age-matched lean control rats, suggesting that protein
O-GlcNAcylation in this model may be predominantly substrate driven and therefore presumably determined by the
magnitude of cardiomyocyte HBP flux.
These observations demonstrate that increased cardiomyocyte HBP flux, with concomitantly increased protein
O-GlcNAcylation, may contribute to the development of a
specific cardiomyopathy in type 2 diabetes. Because both
0363-6143/07 $8.00 Copyright © 2007 the American Physiological Society
C1243
Downloaded from http://ajpcell.physiology.org/ by 10.220.33.5 on June 12, 2017
THE DEVELOPED WORLD IS CURRENTLY experiencing an epidemic
of type 2 diabetes mellitus, with an estimated worldwide
prevalence of ⬎140 million cases (16). Among the end organs
affected by diabetes is the myocardium, which has been demonstrated to exhibit a constellation of structural and functional
abnormalities known collectively as diabetic cardiomyopathy.
While historically it has been somewhat challenging to dissociate the effects of diabetes per se on the myocardium from
those mediated by co-morbid conditions, studies applying
Doppler echocardiographic techniques to both patients (9, 13)
and rodent models of diabetes (1) have demonstrated generally
consistent abnormalities of cardiac ventricular diastolic compliance attributable to cardiomyocyte hypertrophy, myocyte
dropout, increased production of extracellular matrix, and impaired energy-dependent diastolic sequestration of intracellular
calcium (7, 10). The effects of diabetes on the myocardium are
perhaps less familiar to cardiovascular scientists and clinicians
than its well-known effects on the coronary vasculature, yet
diabetic cardiomyopathy nevertheless appears to have important clinical implications; for example, patients with diabetes
have a substantially increased lifetime risk of congestive heart
failure and are more than twice as likely to develop congestive
heart failure in the setting of acute myocardial infarction as
nondiabetic peers (16). These observations raise questions:
does a predominant mechanism mediate the development of
diabetic cardiomyopathy, and, if so, can its operation be
suppressed pharmacologically?
In this issue of AJP-Cell Physiology, Fülöp et al. (8; see p.
1370) report the latest in a productive series of examinations by
their group and others of the hypothesis that increased flux of
glucose carbon through the cardiomyocyte hexosamine biosynthetic pathway (HBP) is responsible for many of the manifestations of diabetic cardiomyopathy. Hexosamine biosynthesis
normally represents only a minor alternative metabolic fate for
glucose carbon at the fructose-6-phosphate step of glycolysis.
However, HBP flux may increase under conditions of excess
availability of exogenous glucose (when glucose is imported
into cardiomyocytes in excess of their capacity to readily
metabolize it via glycolysis and pyruvate oxidation) or free fatty
acids (whose uptake and metabolism may inhibit pyruvate oxidation) (11, 12). Oxidative stress, another consistent feature of
diabetes, may also increase HBP flux by inhibiting the operation of glyceraldehyde-3-phosphate dehydrogenase, the ratelimiting enzyme of glycolysis (2, 3, 6). The major product of
the HBP, UDP-N-acetylglucosamine (UDP-GlcNAc), is the
obligatory substrate for O-GlcNAc transferase (OGT), an en-
Editorial Focus
C1244
AJP-Cell Physiol • VOL
REFERENCES
1. Abe T, Ohga Y, Tabayashi N, Kobayashi S, Sakata S, Misawa H, Tsuji
T, Kohzuki H, Suga H, Taniguchi S, Takaki M. Left ventricular
diastolic dysfunction in type 2 diabetes mellitus model rats. Am J Physiol
Heart Circ Physiol 282: H138 –H148, 2002.
2. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 414: 813– 820, 2001.
3. Brownlee M. The pathobiology of diabetic complications: a unifying
mechanism. Diabetes 54: 1615–1625, 2005.
4. Buse MG. Hexosamines, insulin resistance, and the complications of
diabetes: current status. Am J Physiol Endocrinol Metab 290: E1–E8,
2006.
5. Clark RJ, McDonough PM, Swanson E, Trost SU, Suzuki M, Fukada
M, Dillman WH. Diabetes and the accompanying hyperglycemia impairs
cardiomyocyte calcium cycling through increased nuclear O-GlcNAcylation. J Biol Chem 278: 44230 – 44237, 2003.
6. Du X, Edelstein D, Rossetti L, Fantus IG, Goldberg H, Ziyadeh F, Wu
J, Brownlee M. Hyperglycemia-produced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen
activator inhibitor-1 expression by increasing Sp1 glycosylation. Proc
Natl Acad Sci USA 97: 12222–12226, 2000.
7. Frustaci A, Kajstura J, Chimenti C, Jakoniuk I, Leri A, Maseri A,
Nadal-Ginard B, Anversa P. Myocardial cell death in human diabetes.
Circ Res 87: 1123–1132, 2000.
8. Fülöp N, Manson MM, Dutta K, Wang P, Davidoff AJ, Marchase RB,
Chatham JC. Impact of type 2 diabetes and aging on cardiomyocyte
function and O-linked N-acetylglucosamine levels in the heart. Am J
Physiol Cell Physiol 292: C1370 –C1378, 2007.
9. Galderisi M, Anderson KM, Wilson PW, Levy D. Echocardiographic
evidence for the existence of a distinct diabetic cardiomyopathy (The
Framingham heart study). Am J Cardiol 68: 85– 89. 1991.
10. Ganguly PK, Pierce GN, Dhalla KS, Dhalla NS. Defective sarcoplasmic
reticular calcium transport in diabetic cardiomyopathy. Am J Physiol
Endocrinol Metab 244: E528 –E535, 1983.
11. Hawkins M, Barzilai N, Liu R, Hu M, Chen W, Rossetti L. Role of the
glucosamine pathway in fat-induced insulin resistance. J Clin Invest 99:
2173–2182, 1997.
12. McClain DA. Hexosamines as mediators of nutrient sensing and regulation in diabetes. J Diabetes Complications 16: 72– 80, 2002.
13. Poirier P, Bogaty P, Garneau C, Marois L, Dumesnil JG. Diastolic
dysfunction in normotensive men with well-controlled type 2 diabetes:
importance of maneuvers in echocardiographic screening for preclinical
diabetic cardiomyopathy. Diabetes Care 24: 5–10, 2001.
14. Ren J, Gintant GA, Miller RE, Davidoff AJ. High extracellular glucose
impairs cardiac E-C coupling in a glycosylation-dependent manner. Am J
Physiol Heart Circ Physiol 273: H2876 –H2883, 1997.
15. Rossetti L, Giaccari A, DeFronzo RA. Glucose toxicity. Diabetes Care
13: 610 – 630, 1990.
16. Taegtmeyer H, McNulty P, Young ME. Adaptation and maladaptation
of the heart in diabetes. Part I: general concepts. Circulation 105: 1727–
1733, 2002.
292 • APRIL 2007 •
www.ajpcell.org
Downloaded from http://ajpcell.physiology.org/ by 10.220.33.5 on June 12, 2017
excess glucose availability and excess fatty acid availability
can theoretically increase cardiomyocyte HBP flux, this mechanism would be a potential candidate to mediate the effects of
both “glucose toxicity” and “lipotoxicity” on the diabetic heart
(15, 16). Correspondingly, the observations of Fulop et al. (8)
suggest that strategies to inhibit entry of glucose carbon into
the HBP, either directly (e.g., by inhibiting the rate-limiting
enzyme glutamine:fructose-6-phosphate amidotransferase;
GFAT) or indirectly (e.g., by lowering circulating fatty acid or
glucose levels, or stimulating glycolysis and/or pyruvate oxidation), might prevent or reverse the development of diabetic
cardiomyopathy by reducing the level of cardiomyocyte
O-GlcNAcylation and therefore its functional consequences.
An interesting subsidiary observation of the current study of
Fülöp et al. (8) is that O-GlcNAcylation in the hearts of
hyperglycemic ZDF rats appeared to be largely limited to a
high-molecular-weight band of cardiomyocyte protein. Characterization of the specific high-molecular-weight protein(s)
involved, for example, determining whether these include contractile proteins or calcium channels, seems likely to shed
additional light on the precise mechanism by which elevated
circulating levels of glucose and free fatty acids impair cardiac
E-C coupling. Given the recognized difficulty of trying to
maintain circulating glucose and fatty acid levels normal over
long periods of time in obese patients with type 2 diabetes, a
pharmacological therapy targeted to the actual O-GlcNAcylation
event responsible for conferring diabetic cardiac mechanical
dysfunction would have obvious attraction.
A number of important questions regarding the relationship
between cardiomyocyte HBP flux and cardiac E-C coupling in
diabetes remain to be answered. Among these are how insulin
resistance and its attendant changes in substrate availability
influence the expression or activities of the other enzymes
involved, including perhaps most importantly GFAT and OGlcNAcase; whether the relationships among cellular UDPGlcNAc concentration, OGT expression, and O-GlcNAcylation are sensitive to ambient insulin level; and whether levels
of heart O-GlcNAcylation continue to increase with increasing
age in animals continuously exposed to a diabetic milieu. The
ZDF rat, and other genetic models of obesity and insulin
resistance, would seem a logical and potentially productive
venue for the study of these questions.