Diabetes has been identified as a major independent risk factor for atrial fibrillation (AF), the most common sustained cardiac arrhythmia. However, it is unknown whether glucose and insulin disturbances observed during diabetes directly affect the function of the atria, leading to AF. Thus, we hypothesized that insulin deficiency and impaired glucose transport provide a metabolic substrate for the development and maintenance of AF during diabetes. Transesophageal atrial pacing was used to induce AF in healthy, streptozotocin-induced type 1 diabetic and insulin-treated (via a subcutaneous pump) diabetic mice (n=4-11/group). Translocation of insulin-sensitive glucose transporters (GLUTs) was measured using a photolabeled biotinylation assay in the perfused heart. Atrial fibrosis and glycogen accumulation were measured using histological analyses. As expected, insulin-deficient diabetic mice displayed hyperglycemia (434 ± 50.9 mg/dl) while insulin-treated diabetic mice remained euglycemic (118.8 ± 3.3 mg/dl, p<0.05). At 8 weeks, diabetic mice displayed increased duration and frequency of AF episodes vs. age-matched controls (e.g., AF duration: 18.7 ± 6.2 s vs. 1.8 ± 1.1 s, respectively, p=0.032), whereas insulin-treated diabetic animals did not. In addition, the frequency of AF episodes was significantly correlated to blood glucose level (p=0.01). GLUT-4 and -8 translocation to the atrial cell surface was significantly downregulated in diabetic mice (by 67% and 79%, respectively; p≤0.001), and rescued by insulin treatment. We did not observe any fibrosis or glycogen accumulation in the atria of (treated and untreated) diabetic mice. We conclude that, in the absence of structural remodeling and atrial fibrosis, insulin and glucose disturbances were sufficient to induce AF during diabetes. Therefore, these data suggest that insulin deficiency during diabetes leads to alterations in glucose transport and energy production in the atria, which enhances its vulnerability to atrial fibrillation.
Z. Maria: None. A. Campolo: None. B.J. Scherlag: None. J.W. Ritchey: None. V. Lacombe: None.