Occult RV systolic dysfunction detected by CMR derived RV circumferential strain in patients with pectus excavatum.

AIMS: To investigate the right ventricular (RV) strain in pectus excavatum (PE) patients using cardiac magnetic resonance tissue tracking (CMR TT). MATERIALS AND METHODS: Fifty consecutive pectus excavatum patients, 10 to 32 years of age (mean age 15 ± 4 years), underwent routine cardiac magnetic resonance imaging (CMR) including standard measures of chest geometry and cardiac size and function. The control group consisted of 20 healthy patients with a mean age of 17 ± 5 years. RV longitudinal and circumferential strain magnitude was assessed by a dedicated RV tissue tracking software. RESULTS: Fifty patients with images of sufficient quality were included in the analysis. The mean right and left ventricular ejection fractions were 55 ± 5% and 59 ± 4%. The RV global longitudinal strain was -21.88 ± 4.63%. The RV circumferential strain at base, mid-cavity and apex were -13.66 ± 3.09%, -11.31 ± 2.79%, -20.73 ± 3.45%, respectively. There was no statistically significant decrease in right ventricular or left ventricular ejection fraction between patients and controls (p > 0.05 for each). There was no significant difference in RV global longitudinal strain between two groups (-21.88 ± 4.63 versus -21.99 ± 3.58; p = 0.93). However, there was significant decrease in mid-cavity circumferential strain magnitude in pectus patients compared with controls (-11.31 ± 2.79 versus -16.19 ± 2.86; p < 0.001). PE patients had a significantly higher basal circumferential strain (-13.66 ± 3.09% versus -9.76 ± 1.79; p < 0.001) as well as apical circumferential strain (-20.73 ± 3.45% versus -12.07 ± 3.38) than control group. CONCLUSION: Mid-cavity circumferential strain but not longitudinal strain is reduced in pectus excavatum patients. Basal circumferential strain as well as apical circumferential strain were increased as compensatory mechanism for reduced mid-cavity circumferential strain. Further studies are needed to establish clinical significance of this finding.

Regulation of endogenous glucose production in glucose transporter 4 over-expressing mice.

Strategies to amplify whole-body glucose disposal are key therapies to treat type 2 diabetes. Mice that over-express glucose transporter 4 (Glut4) in skeletal muscle, heart, and adipose tissue (G4Tg) exhibit increased fasting glucose disposal and thus lowered blood glucose. Intriguingly, G4Tg mice also exhibit improved insulin-stimulated suppression of endogenous glucose production even though Glut4 is not present in the liver. It is unclear, however, if hepatic gluco-regulation is altered in G4Tg mice in the basal, non-insulin-stimulated state. The current studies were performed to examine fasting hepatic glucose metabolism in G4Tg mice and to determine whether gluco-regulatory adaptations exist in the non-insulin-stimulated condition. To test this question, phloridzin-glucose clamps were used to match blood glucose and pancreatic hormone levels while tracer dilution techniques were used to measure glucose flux. These techniques were performed in chronically-catheterized, conscious, and un-stressed 5h-fasted G4Tg and wild-type (WT) littermates. Results show reduced blood glucose, hepatic glycogen content, and hepatic glucokinase (GK) activity/expression as well as higher endogenous glucose production, glucose disposal, arterial glucagon, and hepatic glucose-6-phosphatase (G6Pase) activity/expression in G4Tg mice versus WT controls. Clamping blood glucose for 90 min at ~115 mg/dLin G4Tg and WT mice normalized nearly all variables. Notably, however, net hepatic glycogen synthetic rates were disproportionately elevated compared to changes in blood glucose. In conclusion, these studies demonstrate that basal improvements in glucose tolerance due to increased uptake in extra-hepatic sites provoke important gluco-regulatory adaptations in the liver. Although changes in blood glucose underlie the majority of these adaptations, net hepatic glycogen synthesis is sensitized. These data emphasize that anti-diabetic therapies that target skeletal muscle, heart, and/or adipose tissue likely positively impact the liver.

Fibroblast growth factor 21 controls glycemia via regulation of hepatic glucose flux and insulin sensitivity.

Fibroblast growth factor 21 (FGF21) is a novel metabolic regulator shown to improve glycemic control. However, the molecular and functional mechanisms underlying FGF21-mediated improvements in glycemic control are not completely understood. We examined FGF21 effects on insulin sensitivity and glucose fluxes upon chronic (daily injection for 8 d) and acute (6 h infusion) administration in ob/+ and ob/ob mice. Results show that chronic FGF21 ameliorated fasting hyperglycemia in ob/ob mice via increased glucose disposal and improved hepatic insulin sensitivity. Acute FGF21 suppressed hepatic glucose production, increased liver glycogen, lowered glucagon, and improved glucose clearance in ob/+ mice. These effects were blunted in ob/ob mice. Neither chronic nor acute FGF21 altered skeletal muscle or adipose tissue glucose uptake in either genotype. In conclusion, FGF21 has potent glycemic effects caused by hepatic changes in glucose flux and improved insulin sensitivity. Thus, these studies define mechanisms underlying anti-hyperglycemic actions of FGF21 and support its therapeutic potential.

Glucose metabolism in vivo in four commonly used inbred mouse strains.

OBJECTIVE: To characterize differences in whole-body glucose metabolism between commonly used inbred mouse strains. RESEARCH DESIGN AND METHODS: Hyperinsulinemic-euglycemic (approximately 8.5 mmol/l) and -hypoglycemic (approximately 3.0 mmol/l) clamps were done in catheterized, 5-h-fasted mice to assess insulin action and hypoglycemic counter-regulatory responsiveness. Hyperglycemic clamps (approximately 15 mmol/l) were done to assess insulin secretion and compared with results in perifused islets. RESULTS: Insulin action and hypoglycemic counter-regulatory and insulin secretory phenotypes varied considerably in four inbred mouse strains. In vivo insulin secretion was greatest in 129X1/Sv mice, but the counter-regulatory response to hypoglycemia was blunted. FVB/N mice in vivo showed no increase in glucose-stimulated insulin secretion, relative hepatic insulin resistance, and the highest counter-regulatory response to hypoglycemia. In DBA/2 mice, insulin action was lowest among the strains, and islets isolated had the greatest glucose-stimulated insulin secretion in vitro. In C57BL/6 mice, in vivo physiological responses to hyperinsulinemia at euglycemia and hypoglycemia were intermediate relative to other strains. Insulin secretion by C57BL/6 mice was similar to that in other strains in contrast to the blunted glucose-stimulated insulin secretion from isolated islets. CONCLUSIONS: Strain-dependent differences exist in four inbred mouse strains frequently used for genetic manipulation and study of glucose metabolism. These results are important for selecting inbred mice to study glucose metabolism and for interpreting and designing experiments.

Glucose kinetics and exercise tolerance in mice lacking the GLUT4 glucose transporter.

The absence of GLUT4 severely impairs basal glucose uptake in vivo, but does not alter glucose homeostasis or circulating insulin. Glucose uptake in isolated contracting skeletal muscle (MGU) is also impaired by the absence of GLUT4, and onset of muscle fatigue is hastened. Whether the body can compensate and preserve glucose homeostasis during exercise, as it does in the basal state, is unknown. One aim was to test the effectiveness of glucoregulatory compensation for the absence of GLUT4 in vivo. The absence of GLUT4 was also used to further define the role of hexokinase (HK) II, which catalyses glucose phosphorylation after it is transported in the cell. HK II increases MGU during exercise, as well as exercise endurance. In the absence of GLUT4, HK II expression will not affect MGU. A second aim was to test whether, in the absence of GLUT4, HK II retains its ability to increase exercise endurance. Wild-type (WT), GLUT4 null (GLUT4(-/-)), and GLUT4 null overexpressing HK II (GLUT4(-/-)HK(Tg)) mice were studied using a catheterized mouse model that allows blood sampling and isotope infusions during treadmill exercise. The impaired capacity of working muscle to take up glucose in GLUT4(-/-) is partially offset by an exaggerated increase in the glucagon: insulin ratio, increased liver glucose production, hyperglycaemia, and a greater capillary density in order to increase the delivery of glucose to the exercising muscle of GLUT4(-/-). Hearts of GLUT4(-/-) also exhibited a compensatory increase in HK II expression and a paradoxical increase in glucose uptake. Exercise tolerance was reduced in GLUT4(-/-) compared to WT. As expected, MGU in GLUT4(-/-)HK(Tg) was the same as in GLUT4(-/-). However, HK II overexpression retained its ability to increase exercise endurance. In conclusion, unlike the basal state where glucose homeostasis is preserved, hyperglycaemia results during exercise in GLUT4(-/-) due to a robust stimulation of liver glucose release in the face of severe impairments in MGU. Finally, studies in GLUT4(-/-)HK(Tg) show that HK II improves exercise tolerance, independent of its effects on MGU.