Characterization of the insulin sensitivity of ghrelin receptor KO mice using glycemic clamps.

BACKGROUND: We and others have demonstrated previously that ghrelin receptor (GhrR) knock out (KO) mice fed a high fat diet (HFD) have increased insulin sensitivity and metabolic flexibility relative to WT littermates. A striking feature of the HFD-fed GhrR KO mouse is the dramatic decrease in hepatic steatosis. To characterize further the underlying mechanisms of glucose homeostasis in GhrR KO mice, we conducted both hyperglycemic (HG) and hyperinsulinemic-euglycemic (HI-E) clamps. Additionally, we investigated tissue glucose uptake and specifically examined liver insulin sensitivity. RESULTS: Consistent with glucose tolerance-test data, in HG clamp experiments, GhrR KO mice showed a reduction in glucose-stimulated insulin release relative to WT littermates. Nevertheless, a robust 1st phase insulin secretion was still achieved, indicating that a healthy ß-cell response is maintained. Additionally, GhrR KO mice demonstrated both a significantly increased glucose infusion rate and significantly reduced insulin requirement for maintenance of the HG clamp, consistent with their relative insulin sensitivity. In HI-E clamps, both LFD-fed and HFD-fed GhrR KO mice showed higher peripheral insulin sensitivity relative to WT littermates as indicated by a significant increase in insulin-stimulated glucose disposal (Rd), and decreased hepatic glucose production (HGP). HFD-fed GhrR KO mice showed a marked increase in peripheral tissue glucose uptake in a variety of tissues, including skeletal muscle, brown adipose tissue and white adipose tissue. GhrR KO mice fed a HFD also showed a modest, but significant decrease in conversion of pyruvate to glucose, as would be anticipated if these mice displayed increased liver insulin sensitivity. Additionally, the levels of UCP2 and UCP1 were reduced in the liver and BAT, respectively, in GhrR KO mice relative to WT mice. CONCLUSIONS: These results indicate that improved glucose homeostasis of GhrR KO mice is characterized by robust improvements of glucose disposal in both normal and metabolically challenged states, relative to WT controls. GhrR KO mice have an intact 1st phase insulin response but require significantly less insulin for glucose disposal. Our experiments reveal that the insulin sensitivity of GhrR KO mice is due to both BW independent and dependent factors. We also provide several lines of evidence that a key feature of the GhrR KO mouse is maintenance of hepatic insulin sensitivity during metabolic challenge.

Training emergency medicine doctors for rural and regional Australia: can we learn from other countries?

INTRODUCTION: Australia is a country with a relatively small rural population dispersed over an enormous area. Issues similar to how best to deliver health services and recruit health professionals to rural areas exist in other countries. For professional and lifestyle reasons, most specialist doctors (including emergency medicine specialists), choose to live and work in major metropolitan centres. Outside the major Australian cities, most presentations to emergency departments are dealt with by 'non-specialist' doctors, often with limited specialist back up. Recruitment of suitably trained medical staff is increasingly difficult. There is increasing reliance on overseas trained doctors from widely varying backgrounds. In Canada and New Zealand, family medicine trained emergency medicine doctors are a significant proportion of the workforce in rural and regional emergency departments. AIM: To undertake a detailed investigation of the non-specialist emergency medicine doctors in Australia, and examine strategies to secure a more highly trained emergency medicine workforce for rural and regional Australia. METHODS: A survey was undertaken of 230 doctors working in 57 rural and regional Australian emergency departments. Consultations and interviews were held with 53 key clinicians, educators and administrators. RESULTS: There were no training or education standards for doctors working in smaller Australian emergency departments. There was considerable instability in the workforce with many planning to leave their current position or reduce their involvement in emergency medicine. The vast majority felt a need to undertake further emergency medicine training. There was little agreement among stakeholders as to how emergency medicine should be taught, or services delivered in rural and regional Australia. CONCLUSIONS: There is need in Australia to offer a specific postgraduate qualification in emergency medicine for doctors wishing to practise emergency medicine outside major city hospitals. Ideally, such a course would be largely taught in rural and regional hospitals and would contain additional elements relevant to rural practice. The Canadian and New Zealand emergency medicine qualifications may be useful models.

The AMP-activated protein kinase AAK-2 links energy levels and insulin-like signals to lifespan in C. elegans.

Although limiting energy availability extends lifespan in many organisms, it is not understood how lifespan is coupled to energy levels. We find that the AMP:ATP ratio, a measure of energy levels, increases with age in Caenorhabditis elegans and can be used to predict life expectancy. The C. elegans AMP-activated protein kinase alpha subunit AAK-2 is activated by AMP and functions to extend lifespan. In addition, either an environmental stressor that increases the AMP:ATP ratio or mutations that lower insulin-like signaling extend lifespan in an aak-2-dependent manner. Thus, AAK-2 is a sensor that couples lifespan to information about energy levels and insulin-like signals.