Glucose and insulin improve cardiac efficiency and postischemic functional recovery in perfused hearts from type 2 diabetic (db/db) mice

Abstract

Hafstad AD, Khalid AM, How OJ, Larsen TS, Aasum E. Glucose and insulin improve cardiac efficiency and postischemic functional recovery in perfused hearts from type 2 diabetic (db/db) mice. Am J Physiol Endocrinol Metab 292: E1288 -E1294, 2007. First published January 9, 2007; doi:10.1152/ajpendo.00504.2006.-Hearts from type 2 diabetic (db/db) mice demonstrate altered substrate utilization with high rates of fatty acid oxidation, decreased functional recovery following ischemia, and reduced cardiac efficiency. Although db/db mice show overall insulin resistance in vivo, we recently reported that insulin induces a marked shift toward glucose oxidation in isolated perfused db/db hearts. We hypothesize that such a shift in metabolism should improve cardiac efficiency and consequently increase functional recovery following low-flow ischemia. Hearts from db/db and nondiabetic (db/ϩ) mice were perfused with 0.7 mM palmitate plus either 5 mM glucose (G), 5 mM glucose and 300 U/ml insulin (GI), or 33 mM glucose and 900 U/ml insulin (HGHI). Substrate oxidation and postischemic recovery were only moderately affected by GI and HGHI in db/ϩ hearts. In contrast, GI and particularly HGHI markedly increased glucose oxidation and improved postischemic functional recovery in db/db hearts. Cardiac efficiency was significantly improved in db/db, but not in db/ϩ hearts, in the presence of HGHI. In conclusion, insulin and glucose normalize cardiac metabolism, restore efficiency, and improve postischemic recovery in type 2 diabetic mouse hearts. These findings may in part explain the beneficial effect of glucose-insulin-potassium therapy in diabetic patients with cardiac complications. glucose; insulin; myocardial oxygen consumption; pressure-volume area TYPE 2 DIABETES IS THE MOST prevalent form (90%) of diabetes, resulting from a combination of insulin resistance and, eventually, a ␤-cell secretory defect. Increased cardiovascular disease is the most common complication of diabetes (10). Both clinical (4) and experimental (2, 35) studies have shown that type 2 diabetes and/or insulin resistance is associated with reduced myocardial tolerance to ischemia, which may explain the increased morbidity of ischemic heart disease in diabetes (10). Type 2 diabetes and/or insulin resistance are associated with increased cardiac fatty acid oxidation (FA ox ) and a concomitant decrease in glucose utilization (2,5,9,33). This change in substrate utilization has been considered a metabolic maladaptation that may contribute to the development of cardiac dysfunction and/or reduced ischemic tolerance in type 2 diabetes. In line with this notion, transgenic mice with increased cardiac fatty acid (FA) uptake/utilization show a diabetic phenotype with reduced ventricular function and/or reduced postischemic recovery (3, 6).There has been a long-standing interest in metabolic modulation as a means to improve functional recovery following myocardial ischemia, and administration of glucose and insulin, as part of glucose-insulin-potassium (GIK) treatment, ...

Chronic and acute exposure of mouse hearts to fatty acids increases oxygen cost of excitation-contraction coupling

“…Taken together, these observations may suggest that long-term exposure to elevated circulating lipid levels under diabetic conditions leads to an adaptation to the increased FA load, which could improve resistance to the detrimental effect of an acute FA load. In addition, data from our laboratory have previously demonstrated that an acute inhibition of FA oxidation and increased glucose oxidation [induced by glucose and insulin (22) and DCA (unpublished data)] decreased MV O 2 and increased cardiac efficiency in db/db hearts. This shows that in contrast to that in nondiabetic hearts, there is a potential for improving cardiac efficiency by acute changes in substrate utilization in diabetic hearts.…”

Rodent models of diabetic cardiomyopathy

“…Using echocardiography, reduced fractional shortening and a reduction in the velocity of circumferential shortening have been demonstrated (Semeniuk et al, 2002;Carley et al, 2004;Pereira et al, 2006). Cardiac output, LV-developed pressure and cardiac power are all reduced in isolated, working db/db hearts, whereas LV end diastolic pressure is increased (Belke et al, 2000;Aasum et al, 2003;Carley et al, 2004;Hafstad et al, 2006;Hafstad et al, 2007). Similar contractile deficits are observed in Langendorff-perfused db/db hearts, in which ±dP/dt, peak systolic pressure, rate pressure product and developed pressure are all reduced Disease Models & Mechanisms DMM PERSPECTIVE .…”

Metabolic abnormalities of the heart in type II diabetes

“…15,17 For example, in ex vivo mice hearts, glucose-insulin infusions improved glucose oxidation and contractile efficiency, while incretinbased therapies (Liraglutide and Exendin-4) reversed steatosis, oxidative stress and SERCA downregulation. [81][82][83][84] Limited data exist in humans, and some of them are at odds with findings in animals. In a retrospective analysis, biguanide (metformin) use was associated with reduced natiuretic peptide levels and lower cardiovascular morbidity and mortality.…”