C. Depre, M. E. Young, J. Ying, H. Singh Ahuja, Q. Han, N. Garza, P. J. A. Davies and H. Taegtmeyer. Streptozotocin-induced Changes in Cardiac Gene Expression in the Absence of Severe Contractile Dysfunction. Journal of Molecular and Cellular Cardiology (2000) 32, 985–996. Diabetes mellitus alters energy substrate metabolism and gene expression in the heart. It is not known whether the changes in gene expression are an adaptive or maladaptive process. To answer this question, we determined both the time-course and the extent of the alteration of gene expession induced by insulin-deficient diabetes. Transcript analysis with real-time quantitative polymerase chain reaction (PCR) was performed in rat hearts 1 week (acute group) or 6 months (chronic group) after administration of streptozotocin (55 mg/kg). In the acute group, insulin-dependent diabetes induced a 55–70% decrease of both glucose transporter 1 (GLUT1) and GLUT4 transcripts, a slight decrease of liver-specific carnitine palmitoyltransferase I (CPT I), and no change in muscle-specific CPT I. The uncoupling protein UCP-3 increased three-fold, with no change in UCP-2. These metabolic alterations were accompanied by an isoform switching from the normally expressed α myosin heavy chain (MHC) to the fetal isoform β MHC mRNA, by a 50% decrease of cardiac α -actin mRNA, a 30% decrease of the sarcoplasmic Ca⁺⁺-ATPase mRNA, and a 50% decrease of muscle creatine kinase (P<0.01 v controls). All genomic changes were also present in the chronic group. Genomic markers of ventricular dysfunction [tumor necrosis factor α (TNF- α), inducible nitric oxide synthase, cyclo-oxygenase-2] were not affected by chronic diabetes. In both groups, there were no changes in resting left ventricular function by echocardiography. Conclusion: the heart adapts to insulin-deficient diabetes by a rapid and simultaneous response of multiple genes involved in cardiac metabolism and function. This genomic adaptation resembles the adaptation of cardiac hypertrophy, remains stable over time, and does not lead to major contractile dysfunction.