Eulogy for the Metabolic Clinical Investigator?

A recent editorial in the Journal of Clinical Investigation by Nathan et al. (1) dwelt on the decision to cease direct National Institutes of Health (NIH) funding of Clinical Research Centers (CRCs). As the authors rightly point out, the lack of extramural support for the CRC infrastructure will doom this valuable resource for human research at academic institutions without the wherewithal to support clinical research. CRCs as they currently exist might no longer require NIH support if we already knew the entirety of human physiology as it relates to disease or if entities such as industry would fund the studies needed to understand the primary mechanisms of complex human disease. We are certain the former is untrue and highly doubtful the latter will occur. The subsequent demise of the CRCs and our diminished ability to perform complex, mechanistic studies in humans will have both immediate and long-term adverse effects on biomedical research. Support obtained by the NIH Research Project Grant (R01) mechanism will be insufficient to maintain the necessary research infrastructure. Consequently, investigators will abandon comprehensive, mechanistic studies in humans because of the costs involved. The eventual fall in the number of investigators capable of designing, conducting, and interpreting such studies threatens to make the U.S. a second-tier biomedical research environment. This is especially important for the field of diabetes and metabolism where related human studies account for a significant proportion of CRC use. Certainly, rigorous metabolic research requires meticulous control of diet and activity prior to study. Moreover, ensuring participant safety with intensive monitoring often requires extended inpatient stays. The elimination of the NIH-supported CRC system will also substantially constrain the infrastructure necessary for intensive human studies, such as those requiring tissue biopsy, vascular catheterization, and frequent sampling of the arterial or venous circulation. Although basic bench research and clinical trials continue to be important, CRC-based investigation has certainly accelerated the translation of discoveries to clinical practice. In some cases, observations made during CRC-based clinical investigation have driven discovery and the development of novel therapeutics. For example, insulin resistance was first observed in metabolic studies of obese subjects, leading to substantial bench research to elucidate the pathogenesis of insulin resistance (2,3). Similarly, the observation that enteral glucose delivery stimulated greater insulin secretion than an equivalent parenteral glucose load (4) led to the discovery of incretin hormones (5,6) and, ultimately, to novel therapies for type 2 diabetes (7). Has biomedical science changed so much in the past decade that such work is no longer necessary or relevant? Multiple counterarguments could be made to suggest that this is not the case. Rodent models of human disease are critical to advancing our understanding of disease but are not substitutes for human experiments. Importantly, rodent life span is much shorter than that of humans, and rodents only live for a few months after their growth has ceased. In contrast, humans experience several decades of life after their full growth potential is achieved. Most diseases like type 2 diabetes occur in older people, and it is optimistic to assume that therapeutic or toxic effects shown in growing animals are relevant to humans “aged” over several decades. Recent carefully conducted studies in rodents and in tissue culture have shown that metformin, a major antidiabetes drug, acts by inhibiting the glucagon effect on hepatic glucose production (8). However, CRC-based human studies now demonstrate that, contrary to the preclinical data, glucagon in fact mitigates metformin’s effect on hepatic glucose production (9). Other examples abound where human reality has “failed” to live up to the expectations generated by preclinical models or epidemiological associations; we will highlight two to illustrate the importance of human studies in helping to focus drug development. Randle et al. (10) demonstrated that free fatty acids (FFAs) compete with glucose for substrate oxidation in isolates of rat heart muscle and rat diaphragm. This led to the postulate