Disruption of leptin receptor expression in the pancreas directly affects beta cell growth and function in mice

Obesity is characterized by hyperinsulinemia, hyperleptinemia, and an increase in islet volume. While the mechanisms that hasten the onset of diabetes in obese individuals are not known, it is possible that the adipose-derived hormone leptin plays a role. In addition to its central actions, leptin exerts biological effects by acting in peripheral tissues including the endocrine pancreas. To explore the impact of disrupting leptin signaling in the pancreas on beta cell growth and/or function, we created pancreas-specific leptin receptor (ObR) KOs using mice expressing Cre recombinase under the control of the pancreatic and duodenal homeobox 1 (Pdx1) promoter. The KOs exhibited improved glucose tolerance due to enhanced early-phase insulin secretion, and a greater beta cell mass secondary to increased beta cell size and enhanced expression and phosphorylation of p70S6K. Similar effects on p70S6K were observed in MIN6 beta cells with knockdown of the ObR gene, suggesting crosstalk between leptin and insulin signaling pathways. Surprisingly, challenging the KOs with a high-fat diet led to attenuated acute insulin secretory response to glucose, poor compensatory islet growth, and glucose intolerance. Together, these data provide direct genetic evidence, from a unique mouse model lacking ObRs only in the pancreas, for a critical role for leptin signaling in islet biology and suggest that altered leptin action in islets is one factor that contributes to obesity-associated diabetes.     

Transmyocardial revascularization: peril and potential

Transmyocardial laser revascularization is a technique for the treatment of patients with chronic angina pectoris that is refractory to medical therapy and who are not eligible for surgical intervention. Percutaneous myocardial revascularization is a less-invasive catheter-based procedure that has been adapted from transmyocardial laser revascularization. Six prospective randomized clinical trials have been performed with transmyocardial laser revascularization and 5 have been performed using percutaneous myocardial revascularization. All of the transmyocardial laser revascularization and 4 of the percutaneous myocardial revascularization studies showed a significant improvement in angina class; however, results for improved survival, increased exercise tolerance, improved ejection fraction, and improved myocardial perfusion were less definitive. Transmyocardial laser revascularization has significant potential for morbidity and mortality. This article summarizes the results of the randomized trials, explains the current theories for the mechanism of transmyocardial laser revascularization, and discusses its current role in treatment for patients, considering the evidence that currently exists.