Metabolic Regulation of Inflammation and Its Resolution: Current Status, Clinical Needs, Challenges, and Opportunities.

Metabolism and inflammation have been viewed as two separate processes with distinct but critical functions for our survival: metabolism regulates the utilization of nutrients, and inflammation is responsible for defense and repair. Both respond to an organism's stressors to restore homeostasis. The interplay between metabolic status and immune response (immunometabolism) plays an important role in maintaining health or promoting disease development. Understanding these interactions is critical in developing tools for facilitating novel preventative and therapeutic approaches for diseases, including cancer. This trans-National Institutes of Health workshop brought together basic scientists, technology developers, and clinicians to discuss state-of-the-art, innovative approaches, challenges, and opportunities to understand and harness immunometabolism in modulating inflammation and its resolution.

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.

Molecular Transducers of Physical Activity Consortium (MoTrPAC): Human Studies Design and Protocol.

Physical activity, including structured exercise, is associated with favorable health-related chronic disease outcomes. While there is evidence of various molecular pathways that affect these responses, a comprehensive molecular map of these molecular responses to exercise has not been developed. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) is a multi-center study designed to isolate the effects of structured exercise training on the molecular mechanisms underlying the health benefits of exercise and physical activity. MoTrPAC contains both a pre-clinical and human component. The details of the human studies component of MoTrPAC that include the design and methods are presented here. The human studies contain both an adult and pediatric component. In the adult component, sedentary participants are randomized to 12 weeks of Control, Endurance Exercise Training, or Resistance Exercise Training with outcomes measures completed before and following the 12 weeks. The adult component also includes recruitment of highly active endurance trained or resistance trained participants who only complete measures once. A similar design is used for the pediatric component; however, only endurance exercise is examined. Phenotyping measures include weight, body composition, vital signs, cardiorespiratory fitness, muscular strength, physical activity and diet, and other questionnaires. Participants also complete an acute rest period (adults only) or exercise session (adults, pediatrics) with collection of biospecimens (blood only for pediatrics) to allow for examination of the molecular responses. The design and methods of MoTrPAC may inform other studies. Moreover, MoTrPAC will provide a repository of data that can be used broadly across the scientific community.

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.

Type 1 Diabetes in Acute Pancreatitis Consortium: From Concept to Reality.

ABSTRACT: Acute pancreatitis (AP), resulting from inflammation of the pancreas, accounts for more than 300,000 US hospital discharges per year. Although glucose intolerance has been known as a complication of severe AP, this effect was thought to be transient. Recently, cohort studies and meta-analysis of 24 published studies of 1100 patients who survived one or more episodes of AP revealed that 30% to 40% of patients developed diabetes or impaired glucose tolerance within 3 to 4 years of even a single episode of AP. The National Institute of Diabetes and Digestive and Kidney Diseases funded the Type 1 Diabetes in Acute Pancreatitis Consortium (T1DAPC) to undertake a prospective observational study of the occurrence of diabetes during an AP episode or subsequently, with emphasis on type 1 diabetes. Key factors for funding T1DAPC are the increasing incidence and prevalence of AP, its association with the development of type 1 diabetes and other forms of diabetes after AP, its complications, and associated health care cost. The T1DAPC structure, governance, and research objectives are described in this article. The DREAM (Diabetes RElated to Acute pancreatitis and its Mechanisms) studies to be undertaken by the T1DAPC are described in other articles in this journal's issue.

Rationale and Development of a Data Coordinating Center to Support the Type 1 Diabetes in Acute Pancreatitis Consortium.

ABSTRACT: A data coordinating center (DCC) is a critical member of any multicenter research undertaking, and that is especially true for the Type 1 Diabetes in Acute Pancreatitis Consortium (T1DAPC). We describe how the T1DAPC DCC supports the consortium via its experience and expertise in project management, administration, financial management, regulatory compliance, scientific coordination, data management, research computing, and biostatistics and in facilitating scientific publications. The DCC's matrix management system has been extremely effective in managing all of its responsibilities. The first 16 months in the life of the T1DAPC have been dedicated to the development of its first protocol, titled Diabetes RElated to Acute pancreatitis and its Mechanisms (DREAM), addressing the institutional review board and regulatory components, developing the T1DAPC data management system, and providing training and certification of clinical center staff. As a result of its efforts, the DCC was a major contributor to the T1DAPC being able to initiate recruitment for the DREAM study in January 2022.

Evaluating the Immunopathogenesis of Diabetes After Acute Pancreatitis in the Diabetes RElated to Acute Pancreatitis and Its Mechanisms Study: From the Type 1 Diabetes in Acute Pancreatitis Consortium.

ABSTRACT: The association between acute pancreatitis (AP) and diabetes mellitus (DM) has long been established, with the initial descriptions of AP patients presenting with DM after a bout of AP published in the 1940s and 50s. However, the potential mechanisms involved, particularly those components related to the immune system, have not been well defined. The Diabetes RElated to Acute pancreatitis and its Mechanisms (DREAM) study is a multicenter clinical study designed to understand the frequency and phenotype of DM developing after AP. This article describes one objective of the DREAM study: to determine the immunologic mechanisms of DM after AP, including the contribution of ß-cell autoimmunity. This component of the study will assess the presence of islet autoimmunity, as well as the magnitude and kinetics of the innate and adaptive immune response at enrollment and during longitudinal follow-up after 1 or more episodes of AP. Finally, DREAM will evaluate the relationship between immune features, DM development, and pancreatitis etiology and severity.

Assessing the Pathophysiology of Hyperglycemia in the Diabetes RElated to Acute Pancreatitis and Its Mechanisms Study: From the Type 1 Diabetes in Acute Pancreatitis Consortium.

OBJECTIVES: The metabolic abnormalities that lead to diabetes mellitus (DM) after an episode of acute pancreatitis (AP) have not been extensively studied. This article describes the objectives, hypotheses, and methods of mechanistic studies of glucose metabolism that comprise secondary outcomes of the DREAM (Diabetes RElated to Acute pancreatitis and its Mechanisms) Study. METHODS: Three months after an index episode of AP, participants without preexisting DM will undergo baseline testing with an oral glucose tolerance test. Participants will be followed longitudinally in three subcohorts with distinct metabolic tests. In the first and largest subcohort, oral glucose tolerance tests will be repeated 12 months after AP and annually to assess changes in ß-cell function, insulin secretion, and insulin sensitivity. In the second, mixed meal tolerance tests will be performed at 3 and 12 months, then annually, and following incident DM to assess incretin and pancreatic polypeptide responses. In the third, frequently sampled intravenous glucose tolerance tests will be performed at 3 months and 12 months to assess the first-phase insulin response and more precisely measure ß-cell function and insulin sensitivity. CONCLUSIONS: The DREAM study will comprehensively assess the metabolic and endocrine changes that precede and lead to the development of DM after AP.

Design and Rationale for the Use of Magnetic Resonance Imaging Biomarkers to Predict Diabetes After Acute Pancreatitis in the Diabetes RElated to Acute Pancreatitis and Its Mechanisms Study: From the Type 1 Diabetes in Acute Pancreatitis Consortium.

ABSTRACT: This core component of the Diabetes RElated to Acute pancreatitis and its Mechanisms (DREAM) study will examine the hypothesis that advanced magnetic resonance imaging (MRI) techniques can reflect underlying pathophysiologic changes and provide imaging biomarkers that predict diabetes mellitus (DM) after acute pancreatitis (AP). A subset of participants in the DREAM study will enroll and undergo serial MRI examinations using a specific research protocol. The aim of the study is to differentiate at-risk individuals from those who remain euglycemic by identifying parenchymal features after AP. Performing longitudinal MRI will enable us to observe and understand the natural history of post-AP DM. We will compare MRI parameters obtained by interrogating tissue properties in euglycemic, prediabetic, and incident diabetes subjects and correlate them with metabolic, genetic, and immunological phenotypes. Differentiating imaging parameters will be combined to develop a quantitative composite risk score. This composite risk score will potentially have the ability to monitor the risk of DM in clinical practice or trials. We will use artificial intelligence, specifically deep learning, algorithms to optimize the predictive ability of MRI. In addition to the research MRI, the DREAM study will also correlate clinical computed tomography and MRI scans with DM development.

Rationale and Design for the Diabetes RElated to Acute Pancreatitis and Its Mechanisms Study: A Prospective Cohort Study From the Type 1 Diabetes in Acute Pancreatitis Consortium.

ABSTRACT: Acute pancreatitis (AP) is a disease characterized by an acute inflammatory phase followed by a convalescent phase. Diabetes mellitus (DM) was historically felt to be a transient phenomenon related to acute inflammation; however, it is increasingly recognized as an important late and chronic complication. There are several challenges that have prevented precisely determining the incidence rate of DM after AP and understanding the underlying mechanisms. The DREAM (Diabetes RElated to Acute Pancreatitis and its Mechanisms) Study is a prospective cohort study designed to address these and other knowledge gaps to provide the evidence needed to screen for, prevent, and treat DM after AP. In the following article, we summarize literature regarding the epidemiology of DM after AP and provide the rationale and an overview of the DREAM study.

Physiology of the Weight-Reduced State: A Report from a National Institute of Diabetes and Digestive and Kidney Diseases Workshop.

Preventing regain of lost weight is the most difficult challenge in the treatment of obesity. The National Institute of Diabetes and Digestive and Kidney Diseases convened a workshop, "The Physiology of the Weight-Reduced State," on June 3 to 4, 2019, in order to explore the physiologic mechanisms of appetitive and metabolic adaptation that take place in the weight-reduced state and counter an individual's efforts to maintain reduced weight following weight loss.

Perspective: Dietary Biomarkers of Intake and Exposure-Exploration with Omics Approaches.

While conventional nutrition research has yielded biomarkers such as doubly labeled water for energy metabolism and 24-h urinary nitrogen for protein intake, a critical need exists for additional, equally robust biomarkers that allow for objective assessment of specific food intake and dietary exposure. Recent advances in high-throughput MS combined with improved metabolomics techniques and bioinformatic tools provide new opportunities for dietary biomarker development. In September 2018, the NIH organized a 2-d workshop to engage nutrition and omics researchers and explore the potential of multiomics approaches in nutritional biomarker research. The current Perspective summarizes key gaps and challenges identified, as well as the recommendations from the workshop that could serve as a guide for scientists interested in dietary biomarkers research. Topics addressed included study designs for biomarker development, analytical and bioinformatic considerations, and integration of dietary biomarkers with other omics techniques. Several clear needs were identified, including larger controlled feeding studies, testing a variety of foods and dietary patterns across diverse populations, improved reporting standards to support study replication, more chemical standards covering a broader range of food constituents and human metabolites, standardized approaches for biomarker validation, comprehensive and accessible food composition databases, a common ontology for dietary biomarker literature, and methodologic work on statistical procedures for intake biomarker discovery. Multidisciplinary research teams with appropriate expertise are critical to moving forward the field of dietary biomarkers and producing robust, reproducible biomarkers that can be used in public health and clinical research.

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.

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

BACKGROUND: 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. OBJECTIVES: The objective of the ADOPT biological domain subgroup is to create a list of high-priority biological measures for weight-loss studies that will advance the understanding of individual variability in response to adult obesity treatments. This list includes measures of body composition, energy homeostasis (energy intake and output), brain structure and function, and biomarkers, as well as biobanking procedures, which could feasibly be included in most, if not all, studies of obesity treatment. The recommended high-priority measures are selected to balance needs for sensitivity, specificity, and/or comprehensiveness with feasibility to achieve a commonality of usage and increase the breadth and impact of obesity research. SIGNIFICANCE: The accumulation of data on key biological factors, along with behavioral, psychosocial, and environmental factors, can generate a more precise description of the interplay and synergy among them and their impact on treatment responses, which can ultimately inform the design and delivery of effective, tailored obesity treatments.

Brown Adipose Reporting Criteria in Imaging STudies (BARCIST 1.0): Recommendations for Standardized FDG-PET/CT Experiments in Humans.

Human brown adipose tissue (BAT) presence, metabolic activity, and estimated mass are typically measured by imaging [18F]fluorodeoxyglucose (FDG) uptake in response to cold exposure in regions of the body expected to contain BAT, using positron emission tomography combined with X-ray computed tomography (FDG-PET/CT). Efforts to describe the epidemiology and biology of human BAT are hampered by diverse experimental practices, making it difficult to directly compare results among laboratories. An expert panel was assembled by the National Institute of Diabetes and Digestive and Kidney Diseases on November 4, 2014 to discuss minimal requirements for conducting FDG-PET/CT experiments of human BAT, data analysis, and publication of results. This resulted in Brown Adipose Reporting Criteria in Imaging STudies (BARCIST 1.0). Since there are no fully validated best practices at this time, panel recommendations are meant to enhance comparability across experiments, but not to constrain experimental design or the questions that can be asked.

Understanding the Cellular and Molecular Mechanisms of Physical Activity-Induced Health Benefits.

The beneficial effects of physical activity (PA) are well documented, yet the mechanisms by which PA prevents disease and improves health outcomes are poorly understood. To identify major gaps in knowledge and potential strategies for catalyzing progress in the field, the NIH convened a workshop in late October 2014 entitled "Understanding the Cellular and Molecular Mechanisms of Physical Activity-Induced Health Benefits." Presentations and discussions emphasized the challenges imposed by the integrative and intermittent nature of PA, the tremendous discovery potential of applying "-omics" technologies to understand interorgan crosstalk and biological networking systems during PA, and the need to establish an infrastructure of clinical trial sites with sufficient expertise to incorporate mechanistic outcome measures into adequately sized human PA trials. Identification of the mechanisms that underlie the link between PA and improved health holds extraordinary promise for discovery of novel therapeutic targets and development of personalized exercise medicine.

Toward development of imaging modalities for islets after transplantation: insights from the National Institutes of Health Workshop on Beta Cell Imaging.

BACKGROUND: Pancreatic islet transplantation can provide insulin independence and near normal glucose control in selected patients with type 1 diabetes mellitus. However, in most cases, achieving insulin independence necessitates the use of at least two donor pancreases per recipient and the rate of insulin independence may decline after transplantation. To better understand the fate of transplanted islets and the relationship between transplanted islet mass, graft function, and overall glucose homeostasis, an accurate and reproducible method of imaging islets in vivo is needed. METHODS: Recent advances in noninvasive imaging techniques such as magnetic resonance imaging, positron emission tomography, and other imaging modalities show great promise as potential tools to monitor islet number, mass, and function in the clinical setting. A recent international workshop, "Imaging the Pancreatic Beta Cell," sponsored by the National Institute of Biomedical Imaging and Bioengineering, the National Institute of Diabetes and Digestive and Kidney Diseases, and the Juvenile Diabetes Research Foundation International focused on these emerging efforts to develop novel ways of imaging pancreatic beta cells in vivo. RESULTS: Potential clinically applicable techniques include the use of directed magnetic resonance contrast agents such as lanthanides (Ln(3+)) and manganese (Mn(2+)) or magnetic resonance imaging probes such as superparamagnetic iron oxide nanoparticles. Potential techniques for positron emission tomography imaging include the use of beta cell-specific antibodies, or pharmacologic agents such as glyburide analogs, or d-mannoheptulose. Optical imaging techniques are also being used to evaluate various aspects of beta cell metabolism including intracellular Ca(2+) flux, glucokinase activity, and insulin granular exocytosis. CONCLUSIONS: The consensus among investigators at the imaging workshop was that an accurate and reproducible in vivo measure of functional islet mass is critically needed to further the strides that have been made in both islet transplantation and diabetes research as a whole. Such measures would potentially allow the assessment of islet engraftment and the early recognition of graft loss, leading to greater improvements in islet graft survival and function.

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.