Maren R. Laughlin

NIH experiment in centralized mouse phenotyping: the Vanderbilt experience and recommendations for evaluating glucose homeostasis in the mouse

This article addresses two topics. We provide an overview of the National Institutes of Health Mouse Metabolic Phenotyping Center (MMPC) Program. We then discuss some observations we have made during the first eight years of the Vanderbilt MMPC regarding common phenotyping practices. We include specific recommendations to improve phenotyping practices for tests of glucose tolerance and insulin action. We recommend that methods for experiments in vivo be described in manuscripts. We make specific recommendations for data presentation, interpretation, and experimental design for each test. To facilitate and maximize the exchange of scientific information, we suggest that guidelines be developed for methods used to assess glucose tolerance and insulin action in vivo.

Normal Roles for Dietary Fructose in Carbohydrate Metabolism

Although there are many well-documented metabolic effects linked to the fructose component of a very high sugar diet, a healthy diet is also likely to contain appreciable fructose, even if confined to that found in fruits and vegetables. These normal levels of fructose are metabolized in specialized pathways that synergize with glucose at several metabolic steps. Glucose potentiates fructose absorption from the gut, while fructose catalyzes glucose uptake and storage in the liver. Fructose accelerates carbohydrate oxidation after a meal. In addition, emerging evidence suggests that fructose may also play a role in the secretion of insulin and GLP-1, and in the maturation of preadipocytes to increase fat storage capacity. Therefore, fructose undergoing its normal metabolism has the interesting property of potentiating the disposal of a dietary carbohydrate load through several routes.

In vivo imaging of beta cells with radiotracers: state of the art, prospects and recommendations for development and use

Radiotracer imaging is characterised by high in vivo sensitivity, with a detection limit in the lower picomolar range. Therefore, radiotracers represent a valuable tool for imaging pancreatic beta cells. High demands are made of radiotracers for in vivo imaging of beta cells. Beta cells represent only a small fraction of the volume of the pancreas (usually 1–3%) and are scattered in the tiny islets of Langerhans throughout the organ. In order to be able to measure a beta cell-specific signal, one has to rely on highly specific tracer molecules because current in vivo imaging technologies do not allow the resolution of single islets in humans non-invasively. Currently, a considerable amount of preclinical data are available for several radiotracers and three are under clinical evaluation. We summarise the current status of the evaluation of these tracer molecules and put forward recommendations for their further evaluation.

NIH Mouse Metabolic Phenotyping Centers: the power of centralized phenotyping

The Mouse Metabolic Phenotyping Centers (MMPCs) were founded in 2001 by the National Institutes of Health (NIH) to advance biomedical research by providing the scientific community with standardized, high-quality phenotyping services for mouse models of diabetes, obesity, and their complications. The intent is to allow researchers to take optimum advantage of the many new mouse models produced in labs and in high-throughput public efforts. The six MMPCs are located at universities around the country and perform complex metabolic tests in intact mice and hormone and analyte assays in tissues on a fee-for-service basis. Testing is subsidized by the NIH in order to reduce the barriers for mouse researchers. Although data derived from these tests belong to the researcher submitting mice or tissues, these data are archived after publication in a public database run by the MMPC Coordinating and Bioinformatics Unit. It is hoped that data from experiments performed in many mouse models of metabolic diseases, using standard protocols, will be useful in understanding the nature of these complex disorders. The current areas of expertise include energy balance and body composition, insulin action and secretion, whole-body and tissue carbohydrate and lipid metabolism, cardiovascular and renal function, and metabolic pathway kinetics. In addition to providing services, the MMPC staff provides expertise and advice to researchers, and works to develop and refine test protocols to best meet the community’s needs in light of current scientific developments. Test technology is disseminated by publications and through annual courses.

Tracer Theory and 13C NMR

The in vivo 13C NMR technique opens up a rich new landscape for metabolic research, providing the ability to detect the flow of label in real time from one metabolite pool to the next in living tissue. However, the abundance of data that is gleaned from these experiments yields up useful results only in via the process of mathematical modeling. The use of tracer kinetics in biological systems has a rich history dating back at least fifty years, and the body of theory expands as each new tracer, detection methodology, or biological system requires a new collection of models tailored to particular strengths and limitations. With 13C NMR, we have been able to monitor multiple intracellular compounds in time, allowing the use of far more detailed and complex models than ever before (Chance et al., 1983). The challenge presented to the investigator now is to use the particular strengths of 13C NMR, those of in situ, time-dependent, and compound-specific detection, to investigate those aspects of biological systems that have constituted the black boxes of assumptions made for other tracer methodologies.

Research needs and prioritizations for studies linking dietary sugars and potentially related health outcomes

BackgroundRelationships among dietary sugars and a variety of chronic diseases have spawned interest in investigating the metabolic effects of dietary sugars. An approach developed by the Agency for Healthcare Research and Quality (AHRQ) for assessing Future Research Needs (FRN) was implemented with modifications that integrated an evidence mapping process.MethodsA panel of 14 stakeholders across 7 pre-defined areas of expertise (lay audience, policy makers, health providers, research funders, evidence-based methodologists, product makers, and researchers) was assembled to prioritize research needs. The panel was facilitated by an independent research team. A total of 213 studies were analyzed descriptively for evidence mapping, and the results were used to inform the stakeholder panel discussions on research needs.ResultsThe stakeholder panel identified and prioritized 14 sets of research questions. The top three high-priority FRN questions selected by the stakeholder panel focused on the effects of dietary sugars on body weight or body composition, fat deposition, and satiety and appetite. Research considerations for the top three research questions and crosscutting research design issues are discussed.ConclusionInvolving a multidisciplinary stakeholder panel to prioritize the direction of future research in this or other content areas has potential to add diverse perspectives to the determination of research needs, and to the development of public health policy.

Accumulating Data to Optimally Predict Obesity Treatment (ADOPT): Recommendations from the Biological Domain

The responses to behavioral, pharmacological, or surgical obesity treatments are highly individualized. The Accumulating Data to Optimally Predict obesity Treatment (ADOPT) project provides a framework for how obesity researchers, working collectively, can generate the evidence base needed to guide the development of tailored, and potentially more effective, strategies for obesity treatment.

β-cell biology in the 21st century

Abstract The NIDDK Workshop: β-Cell Biology in the 21st Century: Engineering a Pathway to Greater Understanding was held at the National Institutes of Health, Bethesda, MD, USA from 26 to 28 November 2001.