Exenatide Regulates Cerebral Glucose Metabolism in Brain Areas Associated With Glucose Homeostasis and Reward System.

Glucagon-like peptide 1 receptors (GLP-1Rs) have been found in the brain, but whether GLP-1R agonists (GLP-1RAs) influence brain glucose metabolism is currently unknown. The study aim was to evaluate the effects of a single injection of the GLP-1RA exenatide on cerebral and peripheral glucose metabolism in response to a glucose load. In 15 male subjects with HbA1c of 5.7 ± 0.1%, fasting glucose of 114 ± 3 mg/dL, and 2-h glucose of 177 ± 11 mg/dL, exenatide (5 µg) or placebo was injected in double-blind, randomized fashion subcutaneously 30 min before an oral glucose tolerance test (OGTT). The cerebral glucose metabolic rate (CMRglu) was measured by positron emission tomography after an injection of [(18)F]2-fluoro-2-deoxy-d-glucose before the OGTT, and the rate of glucose absorption (RaO) and disposal was assessed using stable isotope tracers. Exenatide reduced RaO0-60 min (4.6 ± 1.4 vs. 13.1 ± 1.7 µmol/min ⋅ kg) and decreased the rise in mean glucose0-60 min (107 ± 6 vs. 138 ± 8 mg/dL) and insulin0-60 min (17.3 ± 3.1 vs. 24.7 ± 3.8 mU/L). Exenatide increased CMRglu in areas of the brain related to glucose homeostasis, appetite, and food reward, despite lower plasma insulin concentrations, but reduced glucose uptake in the hypothalamus. Decreased RaO0-60 min after exenatide was inversely correlated to CMRglu. In conclusion, these results demonstrate, for the first time in man, a major effect of a GLP-1RA on regulation of brain glucose metabolism in the absorptive state.

Effect of acute exercise on glycogen synthase in muscle from obese and diabetic subjects.

Insulin stimulates glycogen synthase (GS) through dephosphorylation of serine residues, and this effect is impaired in skeletal muscle from insulin-resistant [obese and type 2 diabetic (T2DM)] subjects. Exercise also increases GS activity, yet it is not known whether the ability of exercise to affect GS is impaired in insulin-resistant subjects. The objective of this study was to examine the effect of acute exercise on GS phosphorylation and enzyme kinetic properties in muscle from insulin-resistant individuals. Lean normal glucose-tolerant (NGT), obese NGT, and obese T2DM subjects performed 40 min of moderate-intensity cycle exercise (70% of Vo(2max)). GS kinetic properties and phosphorylation were measured in vastus lateralis muscle before exercise, immediately after exercise, and 3.5 h postexercise. In lean subjects, GS fractional activity increased twofold after 40 min of exercise, and it remained elevated after the 3.5-h rest period. Importantly, exercise also decreased GS K(m) for UDP-glucose from ≈0.5 to ≈0.2 mM. In lean subjects, exercise caused significant dephosphorylation of GS by 50-70% (Ser(641), Ser(645), and Ser(645,649,653,657)), and phosphorylation of these sites remained decreased after 3.5 h; Ser7 phosphorylation was not regulated by exercise. In obese NGT and T2DM subjects, exercise increased GS fractional activity, decreased K(m) for UDP-glucose, and decreased GS phosphorylation as effectively as in lean NGT subjects. We conclude that the molecular regulatory process by which exercise promotes glycogen synthesis in muscle is preserved in insulin-resistant subjects.

Reduction in reactive oxygen species production by mitochondria from elderly subjects with normal and impaired glucose tolerance.

OBJECTIVE: Aging increases the risk of developing impaired glucose tolerance (IGT) and type 2 diabetes. It has been proposed that increased reactive oxygen species (ROS) generation by dysfunctional mitochondria could play a role in the pathogenesis of these metabolic abnormalities. We examined whether aging per se (in subjects with normal glucose tolerance [NGT]) impairs mitochondrial function and how this relates to ROS generation, whether older subjects with IGT have a further worsening of mitochondrial function (lower ATP production and elevated ROS generation), and whether exercise reverses age-related changes in mitochondrial function. RESEARCH DESIGN AND METHODS: Mitochondrial ATP and ROS production were measured in muscle from younger individuals with NGT, older individuals with NGT, and older individuals with IGT. Measurements were performed before and after 16 weeks of aerobic exercise. RESULTS: ATP synthesis was lower in older subjects with NGT and older subjects with IGT versus younger subjects. Notably, mitochondria from older subjects (with NGT and IGT) displayed reduced ROS production versus the younger group. ATP and ROS production were similar between older groups. Exercise increased ATP synthesis in the three groups. Mitochondrial ROS production also increased after training. Proteomic analysis revealed downregulation of several electron transport chain proteins with aging, and this was reversed by exercise. CONCLUSIONS: Old mitochondria from subjects with NGT and IGT display mitochondrial dysfunction as manifested by reduced ATP production but not with respect to increased ROS production. When adjusted to age, the development of IGT in elderly individuals does not involve changes in mitochondrial ATP and ROS production. Lastly, exercise reverses the mitochondrial phenotype (proteome and function) of old mitochondria.

Circulating fibroblast growth factor-21 is elevated in impaired glucose tolerance and type 2 diabetes and correlates with muscle and hepatic insulin resistance.

OBJECTIVE Fibroblast growth factor (FGF)-21 is highly expressed in the liver and regulates hepatic glucose production and lipid metabolism in rodents. However, its role in the pathogenesis of type 2 diabetes in humans remains to be defined. The aim of this study was to quantitate circulating plasma FGF-21 levels and examine their relationship with insulin sensitivity in subjects with varying degrees of obesity and glucose tolerance. RESEARCH DESIGN AND METHODS Forty-one subjects (8 lean with normal glucose tolerance [NGT], 9 obese with NGT, 12 with impaired fasting glucose [IFG]/impaired glucose tolerance [IGT], and 12 type 2 diabetic subjects) received an oral glucose tolerance test (OGTT) and a hyperinsulinemic-euglycemic clamp (80 mU/m(2) per min) combined with 3-[(3)H] glucose infusion. RESULTS Subjects with type 2 diabetes, subjects with IGT, and obese subjects with NGT were insulin resistant compared with lean subjects with NGT. Plasma FGF-21 levels progressively increased from 3.9 +/- 0.3 ng/ml in lean subjects with NGT to 4.9 +/- 0.2 in obese subjects with NGT to 5.2 +/- 0.2 in subjects with IGT and to 5.3 +/- 0.2 in type 2 diabetic subjects. FGF-21 levels correlated inversely with whole-body (primarily reflects muscle) insulin sensitivity (r = -0.421, P = 0.007) and directly with the hepatic insulin resistance index (r = 0.344, P = 0.034). FGF-21 levels also correlated with measures of glycemia (fasting plasma glucose [r = 0.312, P = 0.05], 2-h plasma glucose [r = 0.414, P = 0.01], and A1C [r = 0.325, P = 0.04]). CONCLUSIONS Plasma FGF-21 levels are increased in insulin-resistant states and correlate with hepatic and whole-body (muscle) insulin resistance. FGF-21 may play a role in pathogenesis of hepatic and whole-body insulin resistance in type 2 diabetes.

Dissecting intramyocardial hematoma: clinical presentation, pathophysiology, outcomes and delineation by echocardiography.

BACKGROUND: In large necropsy studies dissecting intramyocardial hematoma (DIH) with serpiginous tracts across the myocardial fibers has been reported in both the septum and the left ventricle free wall. METHODS: We studied 15 patients admitted to the hospital with acute myocardial infarction (AMI) in which DIH was demonstrated by either transthoracic and/or transesophageal and confirmed intraoperatively or by necropsy. RESULTS: In nine patients the hemorrhagic dissection was predominantly in the septum and in the remaining it was in the free wall of the left ventricle (LV). Myocardial infarction involved the left ventricular inferior wall in two, and the anterior wall in 13 patients. The overall mortality was 47%, and in the group with septal hematoma it reached to 78%. Echocardiography disclosed the various acoustic densities of the evolving intramyocardial hematoma, its extension through the hemorrhagic dissection, its spontaneous reabsorption, as well as its communication with the ventricular cavities. CONCLUSIONS: Echocardiography is the method of choice for the noninvasive diagnosis of patients with suspected myocardial rupture and intramyocardial dissection postmyocardial infarction.

Deleterious action of FA metabolites on ATP synthesis: possible link between lipotoxicity, mitochondrial dysfunction, and insulin resistance.

Insulin resistance is a characteristic feature of type 2 diabetes and obesity. Insulin-resistant individuals manifest multiple disturbances in free fatty acid (FFA) metabolism and have excessive lipid accumulation in insulin target tissues. Although much evidence supports a causal role for altered FFA metabolism in the development of insulin resistance, i.e., "lipotoxicity", the intracellular mechanisms by which elevated plasma FFA levels cause insulin resistance have yet to be completely elucidated. Recent studies have implicated a possible role for mitochondrial dysfunction in the pathogenesis of insulin resistance in skeletal muscle. We examined the effect of FFA metabolites [palmitoyl carnitine (PC), palmitoyl-coenzyme A (CoA), and oleoyl-CoA] on ATP synthesis in mitochondria isolated from mouse and human skeletal muscle. At concentrations ranging from 0.5 to 2 microM, these FFA metabolites stimulated ATP synthesis; however, above 5 microM, there was a dose-response inhibition of ATP synthesis. Furthermore, 10 microM PC inhibits ATP synthesis from pyruvate. Elevated PC concentrations (> or =10 microM) inhibit electron transport chain activity and decrease the mitochondrial inner membrane potential. These acquired mitochondrial defects, caused by a physiological increase in the concentration of FFA metabolites, provide a mechanistic link between lipotoxicity, mitochondrial dysfunction, and muscle insulin resistance.

Adipocytes in subjects with impaired fasting glucose and impaired glucose tolerance are resistant to the anti-lipolytic effect of insulin.

Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are two intermediate states in the transition from normal glucose metabolism to type 2 diabetes. Insulin clamp studies have shown that subjects with IGT have increased insulin resistance in skeletal muscle, while subjects with IFG have near normal muscle insulin sensitivity. Because of the central role of altered free fatty acid (FFA) metabolism in the pathogenesis of insulin resistance, we have examined plasma free fatty acid concentration under fasting conditions, and during OGTT in subjects with IGT and IFG. Seventy-one NGT, 70 IGT and 46 IFG subjects were studied. Fasting plasma FFA in IGT subjects was significantly greater than NGT, while subjects with IFG had similar fasting plasma FFA concentration to NGT. However, fasting plasma insulin concentration was significantly increased in IFG subjects compared to NGT while subjects with IGT had near normal fasting plasma insulin levels. The adipocyte insulin resistance index (product of fasting plasma FFA and FPI) was significantly increased in both IFG and IGT subjects compared to NGT. During the OGTT both IFG and IGT subjects suppressed their plasma FFA concentration similarly to NGT subjects, but the post-glucose loads were significantly increased in both IFG and IGT subjects. These data suggest that both subjects with IFG and IGT have increased resistance to the antilipolytic action of insulin. However, under basal conditions, fasting hyperinsulinemia in IFG subjects is sufficient to offset the adipocyte insulin resistance and maintain normal fasting plasma FFA concentration while the lack of increase in FPI in IGT subjects results in an elevated fasting plasma FFA.

Long-term follow-up of intramyocardial dissecting hematomas complicating acute myocardial infarction.

Intramyocardial dissecting hematoma is a form of subacute cardiac rupture complicating acute myocardial infarction. Initially contained within the myocardial wall, the hematoma may expand, rupture into adjacent structures, or spontaneously resolve. However, long-term follow-up is unknown because clinical and serial imaging data are lacking. The purpose of this study was to characterize the early and late myocardial wall changes after transmural myocardial infarction using serial ultrasound examinations of the infarct-related segments. Clinical, electrocardiographic, and echocardiographic features of 8 patients (7 men, mean age 59 years) who presented with acute myocardial infarction and echocardiographically documented intramyocardial dissecting hematoma were analyzed. All patients had precordial echocardiography and 6 underwent transesophageal echocardiography. Differentiating hematoma from trabeculations, thrombus, or pseudoaneurysm was done with contrast and color flow Doppler. Seven patients presented with S-T elevation in V1 to V4, and in 3 the elevation extended to V5, V6, I, and aVL. One patient presented with S-T elevation in II, III, aVF, V3R, and V4R. The most striking feature was persistent S-T elevation of more than 72 hours in all patients. Hematoma consisted of a cysticlike, echolucent cavity variable in size, adjacent to severely hypokinetic or dyskinetic infarct-related segments. Hematoma acoustic characteristics depended on time of evolution. Two patients underwent elective revascularization and the rest were medically treated. Two patients died and 6 were alive at the mean follow-up of 12 months. In conclusion, persistent S-T elevation is an important clue in suggesting intramyocardial dissecting hematoma, which is confirmed by its unique ultrasound appearance. Serial echocardiography is useful in determining its evolving nature, and may guide outcome.

[Contrast echocardiography in myocardial perfusion today]. / Estado actual de la ecocardiografía de contraste en la perfusión miocárdica.

Advances in ultrasonic engineering have made possible the development of "intelligent" microparticles with the capacity of passing through the pulmonary circulation in sufficient amount to acquire images of the left heart, making possible the evaluation of myocardial perfusion. Although the Food and Drug Administration of the United States has approved several contrast agents for use in ventricular opacification and visualization of endocardial borders in subjects that have suboptimal studies, at this time, it has not approved any agent of contrast for use in myocardial perfusion. Currently, there are two multicenter studies on a great scale that were exclusively designed for myocardial perfusion in comparison with nuclear medicine and angiography. Our laboratory has had the opportunity to actively participate in both trials. This revision includes the design, interpretation criteria, and preliminary results of CARDIOsphere. As well, we are presenting the interpretation criteria of the AI-700 bubble, which is currently in phase III of clinical investigation. Myocardial perfusion assessment with contrast echocardiography faces several challenges that need to be addressed before it becomes established as an efficient alternative. A common limitation is the viability of this method in subjects with bad acoustic window, the creation of intrinsic artifacts to the system, as distal and lateral attenuation; the unavoidable learning curve, and the settlement of defect quantification criteria.

Risk factors, echocardiographic patterns, and outcomes in patients with acute ventricular septal rupture during myocardial infarction.

Ventricular septal rupture (VSR), which can complicate an acute myocardial infarction (MI), carries a high mortality rate. Because precordial and transesophageal echocardiography can identify the type of rupture and assess right ventricular (RV) function at the patient's bedside, we examined the prognostic significance of echocardiographic patterns in postinfarct VSR by postulating that complex rupture and RV involvement carry a worse prognosis. Seventeen patients (10 men; mean age 66 years) who had confirmed postinfarct VSR underwent precordial and transesophageal echocardiography followed by coronary angiography. Serial 12-lead and right precordial leads were also available. Type of septal rupture was classified as simple or complex based on autopsy-proved echocardiographic criteria. Three patients had inferior wall MI and 14 had anterior wall MI. ST-segment elevation persisted >72 hours in all 3 patients who had inferior wall MI and in 12 who had anterior wall MI. Segmental wall motion abnormalities helped in detecting the left ventricular entry site, and use of unconventional views superimposed with color flow Doppler provided the RV exit site. RV function was better appreciated with transesophageal echocardiography. Two patients who had inferior wall MI and 7 who had anterior wall MI had complex ruptures. All 3 patients who had inferior wall MI and 7 who had anterior wall MI had electrocardiographic and echocardiographic evidence of RV involvement. Mortality rate was higher in patients who had complex rupture (78% vs 38%, p <0.001) and in those who had RV extension (71% vs 29%, p <0.001). In conclusion, persistent ST elevation is a common finding in patients who have postinfarct VSR. Complex VSR and RV involvement are significant determinants of clinical outcome.

Estado actual de la ecocardiografía de contraste en la perfusión miocárdica / Contrast echocardiography in myocardial perfusion today

Avances en la ingeniería ultrasónica han llevado a la creación de micropartículas "inteligentes" con capacidad de atravesar en cantidad suficiente la barrera pulmonar transcapilar para permitir la obtención de imágenes de corazón izquierdo, lo que ha hecho posible la evaluación de la perfusión miocárdica. Si bien la Food and Drug Administration de los Estados Unidos ha aprobado varios agentes de contraste para empleo en opacificación ventricular y visualización de bordes endocárdicos en sujetos que tienen estudios subóptimos, no ha aprobado hasta el momento ningún agente de contraste para uso en perfusión miocárdica. En la actualidad existen dos estudios multicéntricos a gran escala que fueron diseñados exclusivamente para perfusión miocárdica en comparación con medicina nuclear y coronariografía. Nuestro laboratorio ha tenido la oportunidad de participar activamente en ambos estudios. Esta revisión incluye el diseño, criterios de interpretación y resultados preliminares de CARDIOsphere. Además, presentamos criterios de interpretación del estudio con la burbuja AI-700 que se encuentra actualmente en fase III de investigación clínica. La ecocardiografía de contraste para perfusión miocárdica enfrenta varios retos que deberá resolver antes de que se establezca como una alternativa eficiente. Una limitante común es la aplicabilidad de este método en sujetos con mala ventana acústica, la creación de artefactos intrínsecos al sistema como son la atenuación distal y lateral, la inevitable curva de aprendizaje, y el establecimiento de criterios en la cuantificación de los defectos.

Advances in ultrasonic engineering have made possible the development of "intelligent" micro-particles with the capacity of passing through the pulmonary circulation in sufficient amount to acquire images of the left heart, making possible the evaluation of myocardial perfusión. Although the Food and Drug Administration of the United States has approved several contrast agents for use in ventricular opacification and visualization of endocardial borders in subjects that have sub-optimal studies, at this time, it has not approved any agent of contrast for use in myocardial perfusión. Currently, there are two multicenter studies on a great scale that were exclusively designed for myocardial perfusión in comparison with nuclear medicine and angiography. Our laboratory has had the opportunity to actively participate in both trials. This revision includes the design, interpretation criteria, and preliminary results of CARDIOsphere. As well, we are presenting the interpretation criteria of the AI-700 bubble, which is currently in phase III of clinical investigation. Myocardial perfusión assessment with contrast echocardiography faces several challenges that need to be addressed before it becomes established as an efficient alternative. A common limitation is the viability of this method in subjects with bad acoustic window, the creation of intrinsic artifacts to the system, as distal and lateral attenuation; the unavoidable learning curve, and the settlement of defect quantification criteria. (Arch Cardiol Mex 2005; 75: 197-209).