Mitochondria respiration and susceptibility to ischemia–reperfusion injury in diabetic hearts q Ossama Lashin and Andrea Romani * Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH, USA Received 17 June 2003, and in revised form 4 September 2003 Communicated by Luke Szweda Abstract Cardiovascular complications are the primary cause of death for diabetic patients. Clinical and experimental observation has showed the development of dysfunctional cardiomyopathy as one of the main complications of diabetes. Whether the cardiomy- opathy results from an increased susceptibility of cardiac tissue to ischemic insult or from a specific functional defect of cardiac mitochondria is a controversial issue. The investigation of possible functional defect in cardiac mitochondria from diabetic rats indicates a decline in state 3 respiration only in animals presenting a marked decrease in body weight. Mitochondria from rats presenting a level of hyperglycemia similar to diabetic animals but not the marked weight loss typical of the latter group show no decline in state 3 respiration, the values being indistinguishable from those of control mitochondria. Mitochondria from hyper- glycemic rats, however, show a 15–20% increase in state 4 oxygen consumption but only when glutamate is used as energetic substrate, as compared to a 40–50% increase in state 4 respiration in mitochondria from diabetic rats under similar experimental conditions. This phenomenon is unrelated to diabetes duration, as it is observed at 2 as well as 8 weeks after diabetes onset. Taken together, these data argue against hyperglycemia per se being a direct cause of the decline in state 3 oxygen consumption observed in cardiac mitochondria of type-I diabetic rats and indicate that differences exist in cardiac mitochondrial function in rats generically labeled as diabetic. These differences can contribute to explain discrepancies in experimental results reported by various groups in the field and provide an additional parameter to be taken into consideration in evaluating the varying sensitivity of diabetic hearts to ischemia–reperfusion injury. Ó 2003 Elsevier Inc. All rights reserved. Keywords: Hyperglycemia; Type-I diabetes; Mitochondria respiration; Streptozotocin; Ischemia–reperfusion Cardiovascular complications, especially atheroscle- rosis and cardiomyopathy, are the primary cause of death for diabetic patients [1–3]. The incidence and se- verity of cardiac complication are increased in male di- abetic patients as well as in the diabetic female population, which actually exhibits a greater incidence than the diabetic male counterpart [1]. Whether these complications result from metabolic or functional changes within cardiac myocytes or an increased sus- ceptibility to episodes of myocardial ischemia/reperfu- sion is still an open question. While a general consensus exists from the clinical point of view about an increased sensitivity of diabetic hearts to ischemic insult [1,2], ex- periments in animal models have provided contradictory results. Both an increased [4–11] and a decreased sensi- tivity [12–20] of diabetic hearts to ischemia/reperfusion have been reported. To complicate the issue further, other laboratories and even laboratories that have re- ported changes in sensitivity under certain conditions have observed no variation in cardiac functions in dia- betic hearts undergoing episodes of ischemia/reperfusion in other studies under apparently similar experimental conditions [21–27]. Furthermore, different functional and metabolic parameters considered within the same study have shown an increase, a decrease, or no vari- ation in diabetic animals as compared to controls q Supported by NIAAA R9-AA-11594 and NIH HL 18708. * Corresponding author. Fax: 1-216-368-3952. E-mail address: amr5@po.cwru.edu (A. Romani). 0003-9861/$ - see front matter Ó 2003 Elsevier Inc. All rights reserved. doi:10.1016/j.abb.2003.09.024 Archives of Biochemistry and Biophysics 420 (2003) 298–304 ABB www.elsevier.com/locate/yabbi