Targeting appetite and satiety in diabetes and obesity, via G protein-coupled receptors.

Type 2 diabetes and obesity have reached pandemic proportions throughout the world, so much so that the World Health Organisation coined the term "Globesity" to help encapsulate the magnitude of the problem. G protein-coupled receptors (GPCRs) are highly tractable drug targets due to their wide involvement in all aspects of physiology and pathophysiology, indeed, GPCRs are the targets of approximately 30% of the currently approved drugs. GPCRs are also broadly involved in key physiologies that underlie type 2 diabetes and obesity including feeding reward, appetite and satiety, regulation of blood glucose levels, energy homeostasis and adipose function. Despite this, only two GPCRs are the target of approved pharmaceuticals for treatment of type 2 diabetes and obesity. In this review we discuss the role of these, and select other candidate GPCRs, involved in various facets of type 2 diabetic or obese pathophysiology, how they might be targeted and the potential reasons why pharmaceuticals against these targets have not progressed to clinical use. Finally, we provide a perspective on the current development pipeline of anti-obesity drugs that target GPCRs.

Dopamine and ghrelin receptor co-expression and interaction in the spinal defecation centers.

BACKGROUND: Dopamine receptor 2 (DRD2) and ghrelin receptor (GHSR1a) agonists both stimulate defecation by actions at the lumbosacral defecation center. Dopamine is in nerve terminals surrounding autonomic neurons of the defecation center, whereas ghrelin is not present in the spinal cord. Dopamine at D2 receptors generally inhibits neurons, but at the defecation center, its effect is excitatory. METHODS: In vivo recording of defecation and colorectal propulsion was used to investigate interaction between DRD2 and GHSR1a. Localization studies were used to determine sites of receptor expression in rat and human spinal cord. KEY RESULTS: Dopamine, and the DRD2 agonist, quinpirole, directly applied to the lumbosacral cord, caused defecation. The effect of intrathecal dopamine was inhibited by the GHSR1a antagonist, YIL781, given systemically, but YIL781 was not an antagonist at DRD2. The DRD2 agonist, pramipexole, administered systemically caused colorectal propulsion that was prevented when the pelvic nerves were cut. Drd2 and Ghsr were expressed together in autonomic preganglionic neurons at the level of the defecation centers in rat and human. Behaviorally induced defecation (caused by water avoidance stress) was reduced by the DRD2 antagonist, sulpiride. We had previously shown it is reduced by YIL781. CONCLUSIONS AND INFERENCES: Our observations imply that dopamine is a transmitter of the defecation pathways whose actions are exerted through interacting dopamine (D2) and ghrelin receptors on lumbosacral autonomic neurons that project to the colorectum. The results explain the excitation by dopamine agonists and the conservation of GHSR1a in the absence of ghrelin.

Design, synthesis and characterization of a fluorescently labeled functional analog of full-length human ghrelin.

Human ghrelin receptor (GHSR) is a recognized prospective target in the diagnosis and therapy of multiple cancer types. To gain a better understanding of this receptor signaling system, we have synthesized a novel full-length ghrelin analog that is fluorescently labeled at the side-chain of a C-terminal cysteine extension. This analog exhibited nanomolar affinity and potency for the ghrelin receptor. It shows comparable efficacy with that of endogenous ghrelin. The fluorescently-labeled ghrelin analog is a valuable tool for in vitro imaging of cell lines that express ghrelin receptor.

Medical foster home is less costly than traditional nursing home care.

OBJECTIVE: To compare the costs of Community Nursing Homes (CNHs) to Medical Foster Homes (MFHs) at Veteran Health Administration (VHA) Medical Centers that established MFH programs. DATA SOURCES: Episode and costs data were derived from VA and Medicare files (inpatient, outpatient, emergency room, skilled nursing facility, dialysis, and hospice). STUDY DESIGN: Propensity scores matched 354 MFH to 1693 CNH Veterans on demographics, clinical characteristics, health care utilization, and costs. DATA EXTRACTION METHODS: Data were retrieved for years 2010-2011 from the VA Corporate Data Warehouse, VA Health Data Repository, and the VA MFH Program through the VA Informatics and Computing Infrastructure (VINCI). PRINCIPAL FINDINGS: After matching on unique characteristics of MFH Veterans, costs were $71.28 less per day alive compared to CNH care. Home-based and mental health care costs increased with savings largely attributable to avoiding CNH residential care. When average out-of-pocket payments by Veterans of $74/day are considered, MFH is at least cost neutral. Mortality was 12 percent higher among matched Veterans in CNHs. CONCLUSIONS: MFHs may serve as alternatives to traditional CNH care that do not increase total costs with mortality benefits. Future work should examine the differences for functional disability subgroups.

Medical Foster Homes: Can the Adult Foster Care Model Substitute for Nursing Home Care?

OBJECTIVE: To compare characteristics, healthcare use, and costs of care of veterans in the rapidly expanding Veterans Health Administration (VHA) medical foster home (MFH) with those of three other VHA long-term care (LTC) programs. DESIGN: Descriptive, unmatched study. SETTING: VHA MFHs, home-based primary care (HBPC), community living centers (CLCs), and community nursing homes (CNHs). PARTICIPANTS: Veterans newly enrolled in one of the four LTC settings in calendar years 2010 or 2011. MEASUREMENTS: Using VA and Medicare data from fiscal years 2010 and 2011, demographic characteristics, healthcare use, and costs of 388 veterans in MFHs were compared with 26,037 of those in HBPC, 5,355 in CLCs, and 5,517 in CNHs in the year before and the year after enrollment. RESULTS: Veterans enrolled in the MFH program were more likely to be unmarried than those in other LTC programs and had higher levels of comorbidity and frailty than veterans receiving HBPC but had similar levels of comorbidity, frailty, and healthcare use as those in CLCs and CNHs. MFH veterans incurred lower costs than those in CNHs and CLCs. CONCLUSION: MFHs served a distinct subset of veterans with levels of comorbidity and frailty similar to those of veterans cared for in CLCs and CNHs at costs that were comparable to or lower than those of the VHA. Propensity-matched comparisons will be necessary to confirm these findings.

Hospital Readmission From Post-Acute Care Facilities: Risk Factors, Timing, and Outcomes.

OBJECTIVES: Hospital discharges to post-acute care (PAC) facilities have increased rapidly. This increase may lead to more hospital readmissions from PAC facilities, which are common and poorly understood. We sought to determine the risk factors and timing for hospital readmission from PAC facilities and evaluate the impact of readmission on patient outcomes. DESIGN: Retrospective analysis of Medicare Current Beneficiary Survey (MCBS) from 2003-2009. SETTING: The MCBS is a nationally representative survey of beneficiaries matched with claims data. PARTICIPANTS: Community-dwelling beneficiaries who were hospitalized and discharged to a PAC facility for rehabilitation. INTERVENTION/EXPOSURE: Potential readmission risk factors included patient demographics, health utilization, active medical conditions at time of PAC admission, and PAC characteristics. MEASUREMENTS: Hospital readmission during the PAC stay, return to community residence, and all-cause mortality. RESULTS: Of 3246 acute hospitalizations followed by PAC facility stays, 739 (22.8%) included at least 1 hospital readmission. The strongest risk factors for readmission included impaired functional status (HR 4.78, 95% CI 3.21-7.10), markers of increased acuity such as need for intravenous medications in PAC (1.63, 1.39-1.92), and for-profit PAC ownership (1.43, 1.21-1.69). Readmitted patients had a higher mortality rate at both 30 days (18.9% vs 8.6%, P < .001) and 100 days (39.9% vs 14.5%, P < .001) even after adjusting for age, comorbidities, and prior health care utilization (30 days: OR 2.01, 95% CI 1.60-2.54; 100 days: OR 3.79, 95% CI 3.13-4.59). CONCLUSIONS: Hospital readmission from PAC facilities is common and associated with a high mortality rate. Readmission risk factors may signify inadequate transitional care processes or a mismatch between patient needs and PAC resources.