Diabetes Volume 65, December 2016 3521 Lea M.D. Delbridge,1 Vicky L. Benson,2 Rebecca H. Ritchie,3 and Kimberley M. Mellor1,2,4 Diabetic Cardiomyopathy: The Case for a Role of Fructose in Disease Etiology Diabetes 2016;65:3521–3528 | DOI: 10.2337/db16-0682 A link between excess dietary sugar and cardiac disease as a specific myocardial pathology, the occurrence of which is clearly evident and has been largely attributed to is independent of coronary and hypertensive disease. Di- systemic metabolic dysregulation. Now a new paradigm abetic cardiomyopathy is generally characterized by early is emerging, and a compelling case can be made that signs of diastolic dysfunction, which precede progression to fructose-associated heart injury may be attributed to the systolic failure (6,7). direct actions of fructose on cardiomyocytes. Plasma While the relationship between excess fructose exposure and cardiac fructose levels are elevated in patients with and cardiac disease development has been identified, the PERSPECTIVES IN DIABETES diabetes, and evidence suggests that some unique underlying mechanisms are as yet only partially under- fi properties of fructose (vs. glucose) have speci c car- stood. Aspects of diabetic cardiomyopathy that may be diomyocyte consequences. Investigations to date have attributed specifically to high fructose intake or to selective demonstrated that cardiomyocytes have the capacity to myocardial fructose metabolic dysregulation have not been transport and utilize fructose and express all of the determined. Whether cardiac vulnerability associated with necessary proteins for fructose metabolism. When di- etary fructose intake is elevated and myocardial glucose fructose exposure produces an injury response beyond uptake compromised by insulin resistance, increased effects that may be attributed to general overnutrition or fi cardiomyocyte fructose flux represents a hazard in- to overall excess consumption of re ned sugar (either volving unregulated glycolysis and oxidative stress. The glucose or fructose) in different diabetic settings is also high reactivity of fructose supports the contention that not yet known (8,9). fructose accelerates subcellular hexose sugar-related In this Perspective, these questions relating to fructose, protein modifications, such as O-GlcNAcylation and ad- diabetes, and the heart are examined, and the case for a role vanced glycation end product formation. Exciting recent of fructose in diabetic cardiomyopathy disease etiology is discoveries link heart failure to induction of the specific explored. Evidence to support the proposition that fructose high-affinity fructose-metabolizing enzyme, fructokinase, is a distinctive cardiopathogenic agent in diabetes and in an experimental setting. In this Perspective, we review states of metabolic disturbance is considered. Findings from key recent findings to synthesize a novel view of fructose a diverse range of investigative approaches are reviewed to as a cardiopathogenic agent in diabetes and to identify synthesize a novel view of fructose (of exogenous and en- important knowledge gaps for urgent research focus. dogenous origin) as a perpetrator of cardiac damage. New insights into fructose-induced myocardial functional and signaling dysregulation are discussed, and knowledge gaps Links between excess fructose consumption, diabetes in- for priority research focus are identified. cidence, and cardiovascular disease risk have been clearly demonstrated (1–4). The systemic effects of high fructose DIETARY FRUCTOSE AND CARDIOMYOPATHY intake have been well described experimentally and include Dietary Fructose Increases Cardiovascular Risk hyperglycemia, dyslipidemia, atherosclerosis, and in some The dramatic rise in the prevalence of diabetes has oc- cases hypertension (5). Diabetic cardiomyopathy is recognized curred in parallel with an escalation in dietary sugar 1Department of Physiology, University of Melbourne, Victoria, Australia Received 31 May 2016 and accepted 9 September 2016. 2 Department of Physiology, University of Auckland, Auckland, New Zealand © 2016 by the American Diabetes Association. Readers may use this article as 3 Heart Failure Pharmacology, Baker IDI Heart and Diabetes Institute, Victoria, long as the work is properly cited, the use is educational and not for profit, and the Australia work is not altered. More information is available at http://www.diabetesjournals 4 Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand .org/content/license. Corresponding author: Lea M.D. Delbridge, [email protected]. 3522 Fructose-Induced Cardiac Pathology Diabetes Volume 65, December 2016 consumption. In “westernized” cultures, the use of added results in metabolic dysregulation and cell death vulnera- sweeteners containing fructose(sucroseandhigh-fructose bility. Rodents fed a high-fructose diet for several months corn syrup) has increased by approximately 25% over the display significant decreases in the levels of phosphory- past three decades (10). Meta-analyses of cohort studies lated Akt (Ser473) and the downstream signaling inter- have determined that high intake of fructose-sweetened mediate S6 (Ser235/236) with decreased PI3K activity beverages is associated with a 26% greater risk of cardio- and phosphorylation of Akt (19,20). Interestingly, insulin metabolic pathology (2). Experimental studies of hepatic growth factor 1 (IGF1) and IGF1 receptor expression are fructose metabolism have shown that genetically modified both decreased in this setting, suggesting involvement rodents unable to metabolize fructose (fructokinase knock- from the IGF1 signaling pathway in addition to insulin- out) are protected from high-carbohydrate–induced meta- receptor–mediated effects (20). Fructose feeding also di- bolic syndrome, supporting the contention that fructose is minishes cardiac glucose uptake (21). Thus despite elevated the toxic component of the sugar complex (11,12). Although extracellular glucose levels, intracellular glucose availability increased cardiovascular disease risk may be partially attrib- is reduced, which is associated with upregulation of cardiac uted to fructose-induced dyslipidemia, atherosclerosis, hy- lipid derivatives and transporters (22), indicative of a sub- pertension, obesity, or insulin resistance/diabetes/metabolic strate shift from glucose to fatty acids for energy supply. syndrome (13,14), it is increasingly apparent that fructose- Energetic disturbances may manifest as triggers for oxi- specific cardiac factors are important. Recent studies have dative stress in response to excess dietary fructose (23). demonstrated that dietary fructose is not necessarily asso- Mitochondrial uncoupling is evident in hearts of fructose- ciated with changes in blood pressure (15), and the relation- fed rodents (24) and is associated with elevated myocar- ship between high sugar intake and increased risk for both dial production of reactive oxygen species (25). Impaired type 2 diabetes and cardiovascular disease is independent of glucose uptake and utilization has also been linked to an BMI (2,16), which indicates that calorie intake and adipose inability to respond to an ischemic challenge. In contrast deposition are not the underlying etiology. to controls, fructose-fed animals do not increase cardiomyo- Emerging evidence suggests that cardiac complications cyte GLUT4 translocation and glycolytic flux in response to in patients with diabetes (and their attenuation) are not ischemia (26), a response deficit that may underlie chronic alwayslinkedtothedegreeofbloodglucosecontrol.Meta- ischemic vulnerability in diabetic settings. Interestingly, two analyses of large randomized controlled clinical trials report studies have reported smaller infarct size in isolated hearts that drugs used to lower blood glucose levels in patients with from fructose-fed rats (27,28), suggesting that metabolic diabetes may exacerbate heart failure symptoms and in- adaptation involving modified routes of cardiomyocyte crease the risk of heart failure (17,18). While some glucose- hexose sugar uptake may actually have a role in acute lowering agents (metformin, emphafliglozin) have been cardioprotection. shown to be cardioprotective in patients with diabetes, others do not improve cardiac dysfunction and can lead Dietary Fructose–Induced Cardiac Cell Loss to increased heart failure risk (e.g., peroxisome proliferator– and Dysfunction activated receptor agonists, dipeptidyl peptidase 4 inhibitors, Downregulation of the cardiomyocyte PI3K/Akt “cell sur- thiazolidinediones). Thus negative cardiac impacts in di- vival’’ pathway can promote cell death signaling as inhibi- abetes involve mechanisms not necessarily responsive to tion of programmed cell death pathways via the PI3K/Akt normalization of circulating glucose levels. As cardiac tis- axis is relieved. Fructose feeding in rodents is associated sue is both insulin sensitive and glycolysis dependent, with low-level constitutive loss of cardiomyocytes coupled increased cardiac vulnerability to fructose in the context with increased collagen deposition, producing a progressive of metabolic dysregulation is plausible (5) and supported fibrotic replacement of viable myocardium (19). In feeding by an accumulating experimental evidence base. As empha- interventions where the metabolic disturbance is moderate, sized in important recent commentaries (4,12), although of apoptotic signaling pathways are not found to be activated caloric equivalence, fructose and glucose are very different but