Applied nutritional investigationTargeting insulin inhibition as a metabolic therapy in advanced cancer: A pilot safety and feasibility dietary trial in 10 patients
Introduction
Persistent aerobic glycolysis is a feature of many cancers, although not as universal as originally proposed by Warburg [1]. A glycolytic phenotype nonetheless can be identified in diverse malignancies [2], [3]. Overexpression of the insulin-independent glucose transporter-1 (GLUT-1) [4], [5], [6] and hexokinase [7], [8] facilitates the increased glucose uptake needed to supply the energy needs of these cancers. 18F-2- fluoro-2-deoxyglucose (FDG) undergoes a similar transport and phosphorylation as glucose, its congener. The FDG uptake can be demonstrated on positron emission tomographic (PET) scans of glycolytic cancers, providing a useful tool for the diagnosis, staging, prognosis, and management of numerous aggressive malignancies [9], [10], [11], [12], [13].
The role of insulin in cancer is currently of research interest, and hyperinsulinemia has been described as a risk factor for many cancers [14], [15], [16], [17]. Conversely, we proposed previously that insulin inhibition (INSINH), by altering the metabolic microenvironment, may inhibit many human cancers evolutionarily adapted to a markedly different, specifically hyperinsulinemic, state [18]. We also previously reported on the growth and adenosine triphosphate inhibition in multiple aggressive cancer cell lines when grown in supplemental ketone body medium that are not seen in control fibroblasts [19]. The hypothesis also bears on recent interest in calorie restriction because studies by Kalaany and Sabatini [21] and Sengupta et al. [22], for example, have shown that calorie restriction shares many of the downstream signaling pathways of the insulin receptor.
Mechanistically, the binding of insulin to the insulin receptor activates the mitogen-activated protein (MAP) kinase and phosphatidylinositol-3-kinase pathways in normal cells and different tumor cell lines [22]. Other insulin receptor ligands, including insulin-like growth factor-1 (IGF-1) and IGF-2, share extensive homology and downstream signaling pathways with insulin, but have more potent mitogenic and antiapoptotic effects. In addition to the insulin receptor, IGF-1 receptor, a transmembrane receptor for IGF-1, is upregulated in different human cancers. Ligand binding to the IGF-1 receptor activates its tyrosine kinase, resulting in downstream signaling cascades in the insulin receptor substrate-1(IRS-1)/phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and Ras/Raf/mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) pathways, ultimately promoting proliferation, survival, transformation, metastases, and angiogenesis in many cancers, but especially colorectal and breast cancers. Conversely, decreased insulin secretion induces metabolic and molecular responses, including the inhibition and downregulation of the mammalian target of rapamycin, phosphatidylinositol-3-kinase/Akt, hypoxia-inducible factor (HIF)-1α, fatty acid synthase, and vascular endothelial growth factor (VEGF) and the upregulation of adenosine monophosphate–activated protein kinase (AMPK), all proposed cancer therapy targets [7], [20], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45] of drugs such as rapamycin, wortmannin, bevacizumab, metformin, among many others.
Insulin secretion is inhibited most simply by restricting carbohydrate (CHO) ingestion, thus decreasing the dietary sources of glucose, the principal secretagogue for pancreatic insulin release [46], [47], [48], [49]. The regulation of GLUT-1 translocation by insulin levels has been reported in cancer [50], which can decrease the nutrient supply for glucose-dependent cancers [7], [20], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45]. Ketosis alone and the increased lipolysis that accompany the disinhibition by insulin have been reported to inhibit cancer growth [18], [19], [51], [52], [53], [54], [55], [56], [57], with recent studies demonstrating in vitro [19] and in vivo [54], [58], [59], [60], [61] mechanisms. Further, the adverse effects of CHO-restricted diets have not been demonstrated in normal subjects [62], diabetics [49], [63], or individuals seeking weight loss in studies ranging from 3 mo to 2 y [64], [65], [66], [67], [68] or in patients with cancer over a duration of a 3 mo [69]. Humans with cancer have exhibited a normal nitrogen balance after 1 wk of dietary CHO restriction [52].
Dietary change alone is unlikely to be useful as a cancer therapy, but adding current or developing metabolic, endocrine, and molecular treatments can plausibly increase its effectiveness. Therefore, we initiated a prospective safety and feasibility trial of an INSINH CHO-restricted diet in patients with advanced glucose-dependent PET-FDG–positive cancers. The diets were designed to be eucaloric and weight stable. A change in FDG tumor uptake on a PET scan was chosen as a surrogate marker of a biologic effect [70].
Section snippets
Eligibility criteria
Eligible patients had incurable, advanced cancer with FDG-avid tumors detected by PET scanning, with progressive disease after at least two conventional anticancer treatments. The exclusion criteria included a body mass index lower than 20 kg/m2, a weight loss exceeding 5% of body weight within 3 mo of enrollment, a history of diabetes on hypoglycemic medications, intestinal obstruction, and abnormal liver function (increase in total or direct bilirubin to 1.1 or 0.3 mg/dL, respectively, and
Patient characteristics, dietary adherence, and adverse effects
Twelve patients with advanced cancer were recruited. For reasons unrelated to the intervention, two patients discontinued the study in less than 14 d and therefore were not evaluated. Of these two patients, one withdrew because of symptomatic chest wall disease on day 2 of the diet, requiring hospitalization and chemotherapy; the second patient withdrew after 1 wk because of clinical depression. The remaining 10 patients were included in the results; of these, five patients completed all 28 d
Discussion
The metabolic effects caused by the insulin inhibitory response to CHO restriction may result in disease stabilization in selected cancer types. Cancers cultured in glucose medium in vitro have been inhibited by supplemental ketone bodies [19], [51], [53] and the inhibition of tumor growth in a xenograft model has been associated with ketosis [56] and in non-ketotic rodent models limiting CHO ingestion [53], [54], [58], [59]. In human case reports, glioblastoma demonstrated partial remission on
Conclusion
Insulin inhibition effected by dietary CHO restriction was found safe and feasible in 10 patients with advanced cancer. The three-fold higher ketosis, demonstrated in patients with SD or PR compared with those with continued PD, must be interpreted cautiously in this small pilot study.
Acknowledgments
We are grateful for the consistent support of Dr. Shalom Kalnicki.
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This work was supported by the State University of New York Research Foundation and the Robert and Veronica Atkins Foundation. This publication also was supported in part by CTSA grants UL1RR025750, KL2RR025749, and TL1RR025748 from the National Center for Research Resources, a component of the National Institutes of Health, and the National Institutes of Health Roadmap for Medical Research.