Weight and Glucose Reduction Observed with a Combination of Nutritional Agents in Rodent Models Does Not Translate to Humans in a Randomized Clinical Trial with Healthy Volunteers and Subjects with Type 2 Diabetes
Rebecca J Hodge, Mark A Paulik, Ann Walker, Joyce A Boucheron, Susan L McMullen, Dawn S Gillmor, Derek J Nunez, Rebecca J Hodge, Mark A Paulik, Ann Walker, Joyce A Boucheron, Susan L McMullen, Dawn S Gillmor, Derek J Nunez
Abstract
Background: Nutritional agents have modest efficacy in reducing weight and blood glucose in animal models and humans, but combinations are less well characterized. GSK2890457 (GSK457) is a combination of 4 nutritional agents, discovered by the systematic assessment of 16 potential components using the diet-induced obese mouse model, which was subsequently evaluated in a human study.
Nonclinical results: In the diet-induced obese mouse model, GSK457 (15% w/w in chow) given with a long-acting glucagon-like peptide -1 receptor agonist, exendin-4 AlbudAb, produced weight loss of 30.8% after 28 days of treatment. In db/db mice, a model of diabetes, GSK457 (10% w/w) combined with the exendin-4 AlbudAb reduced glucose by 217 mg/dL and HbA1c by 1.2% after 14 days.
Clinical results: GSK457 was evaluated in a 6 week randomized, placebo-controlled study that enrolled healthy subjects and subjects with type 2 diabetes to investigate changes in weight and glucose. In healthy subjects, GSK457 well tolerated when titrated up to 40 g/day, and it reduced systemic exposure of metformin by ~ 30%. In subjects with diabetes taking liraglutide 1.8 mg/day, GSK457 did not reduce weight, but it slightly decreased mean glucose by 0.356 mmol/L (95% CI: -1.409, 0.698) and HbAlc by 0.065% (95% CI: -0.495, 0.365), compared to placebo. In subjects with diabetes taking metformin, weight increased in the GSK457-treated group [adjusted mean % increase from baseline: 1.26% (95% CI: -0.24, 2.75)], and mean glucose and HbA1c were decreased slightly compared to placebo [adjusted mean glucose change from baseline: -1.22 mmol/L (95% CI: -2.45, 0.01); adjusted mean HbA1c change from baseline: -0.219% (95% CI: -0.910, 0.472)].
Conclusions: Our data demonstrate remarkable effects of GSK457 in rodent models of obesity and diabetes, but a marked lack of translation to humans. Caution should be exercised with nutritional agents when predicting human efficacy from rodent models of obesity and diabetes.
Trial registration: ClinicalTrials.gov NCT01725126.
Conflict of interest statement
Competing Interests: RJH, MAP, AW, JAB, SLM, DSG, and DJN are employees or former employees and shareholders of GlaxoSmithKline, and as such act as representatives of GlaxoSmithKline in the performing of this work. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.
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References
- Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C., et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2014;384(9945):766–81.
- NIH Publication No. 98–4083. Health Risks of Overweight and Obesity. Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults—The Evidence Report. Sep 1998: 12–25.
- Cani PD, Everard A, Duparc T. Gut microbiota, enteroendocrine functions and metabolism. Curt Opin Pharmacol. 2013;13;935–40.
- Everard A, Cani PD, Diabetes, obesity, and gut microbiota. Best Prac Res Clin Gastroenterol. 2013;27(1):73–83.
- Ley RE, Blackhed F, Turnbaugh P, Lozupone CA, Knight RD, Gordon JI. Obesity alters gut microbial ecology. Proc Nat Acad Sci. 2005;102(31):11070–75.
- Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, Delzenne NM, et al. Changes in Gut Microbiota Control Metabolic Endotoxemia-Induced Inflammation in High-Fat Diet-Induced Obesity and Diabetes in Mice. Diabetes. 2008;57(6):1470–81. 10.2337/db07-1403
- Cani PD, Possemiers S, Van de WT, Guiot Y, Everard A, Rottier O, et al. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut. 2009;58:1091–1103. 10.1136/gut.2008.165886
- Janssen S, Deportere I. Nutrient sensing in the gut: new roads to therapeutics? Trends Endocrinol Metab. 2013;24(2):92–100. 10.1016/j.tem.2012.11.006
- Den Besten G, van Eunen K, Groen AK, Venema K, Reijingoud D-J, Bakker BM. The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. J Lipid Res. 2013;54:2325–40. 10.1194/jlr.R036012
- Puddu A, Sanguineti R, Montecucco F, Viviani GL. Evidence for the Gut Microbiota Short-Chain Fatty Acids as Key Pathophysiological Molecules Improving Diabetes. Mediators Inflamm. 2014: Article ID 162021, 9 pages, 2014. 10.1155/2014/162021
- Moran TH. Gut peptides in the control of food intake. Int J Obes. 2009;33:S7–S10.
- Karra E, Batterham RL. The role of gut hormones in the regulation of body weight and energy homeostasis. Mol Cell Endocrinol. 2010;316(2):120–8. 10.1016/j.mce.2009.06.010
- Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferranini E. Nauck M, et al. Management of Hyperglycemia in Type 2 Diabetes 2015 –A Patient-Centered Approach. Diabetes Care. 2015;38:140–9.
- Astrup A, Rossner S, van Gaal L, Rissanen A, Niskanen L, al Hakim M, et al. Effects of liraglutide in the treatment of obesity: a randomized, double-blind, placebo-controlled study. Lancet. 2009;374(9701):1606–16.
- Therakan G, Tan T, Bloom S. Emerging therapies in the treatment of ‘diabesity’: beyond GLP-1. Trends Pharmacol Sci. 2011;32(1):8–15.
- Napolitano A, Miller S, Nicholls AW, Baker D, van Horn S. Thomas E, et al. Novel Gut-Based Pharmacology of Metformin in Patients with Type 2 Diabetes Mellitus. PLOS ONE. 2014;9(7): e100778 10.1371/journal.pone.0100778
- International Conference on Harmonisation (1996) ICH Harmonised Tripartite Guideline. Guideline for Good Clinical Practice. Version 10.
- World Medical Association (2000) Declaration of Helsinki: ethical principles for medical research involving human subjects. J Am Med Assoc. 284:3043–45.
- Svedlund J., Sjodin I, Dolevall G. GSRS—a clinical rating scale for gastrointestinal symptoms in patients with irritable bowel syndrome and peptic ulcer disease. Dig.Dis.Sci. 1988;33:129–134.
- Parnell JA, Reimer RA. Weight loss during oligofructose supplementation is associated with decreased ghrelin and increased peptide YY in overweight and obese adults. Am J Clin Nutr. 2009;89:1751–59. 10.3945/ajcn.2009.27465
- DiLorenzo C, Williams CM, Hajnal F, Valenzuela JE. Pectin delays Gastric Emptying and Increases Satiety in Obese Subjects. Gastroenterol. 1988:95(5):1211–15.
- Schwartz SE, Levine RA, Weinstock RS, Petokas S, Mills CA, Thomas FD. Sustained pectin ingestion: effect on gastric emptying and glucose tolerance in non-insulin-dependent diabetic patients. Am J Clin Nutr. 1988;48:1413–17.
- Carr RD, Larsen MO, Winzell MS, Jelic K, Lindgren O, Deacon CF, et al. Incretin and islet hormonal responses to fat and protein ingestion in healthy men. Am J Physiol Endocrinol Metab. 2008;295:E779–E784. 10.1152/ajpendo.90233.2008
- Teres S, Barcelo-Coblijn G, Benet M, Alvarez R, Bressani R, Halver JE, et al. Oleic acid content is responsible for the reduction in blood pressure induced by olive oil. PNAS. 2008;105(37):13811–16. 10.1073/pnas.0807500105
- Munir KM, Chandrasekaran S, Gao F, Quon MJ. Mechanisms for food polyphenols to ameliorate insulin resistance and endothelial dysfunction: therapeutic implications for diabetes and its cardiovascular complications. Am J Physiol Endorcinol Metab. 2013:305(6):E679–E686.
- Guo H, Xia M, Zou T, Ling W, Zhong R, Zhang W. Cyanidin 3-glucoside attenuates obesity-associated insulin resistance and hepatic steatosis in high-fat diet-fed and db/db mice via the transcription factor Fox01. J Nutr Biochem. 2012;23(4):349–60.
- Tsuda T. Regulation of Adipocyte Function by Anthocyanins; Possibility of Preventing the Metabolic Syndrome. J. Agric. Food Chem. 2008;56:642–46. 10.1021/jf073113b
- Delzenne NM, Cani PD, Daubioul C, Neyrinck AM. Impact of inulin and oligofructose on gastrointestinal peptides. Br J Nutr. 2005;93(Suppl. 1):S157–S161.
- Gibson GR, Beatty ER, Wang X, Cummings JH. Selective stimulation of bifidobacteria in the human colon by oligofructose and inulin. Gastroenterol. 1995;108(4):975–982.
- Howard M D, Gordon DT, Garleb KA, Kerley MS. Dietary fructooligosaccharide, xylooligosaccharide and gum arabic have variable effects on cecal and colonic microbiota and epithelial cell proliferation in mice and rats. J Nutr. 1995;125(10):2604–2609.
- Kleessen B, Hartmann L, Blaut M. Oligofructose and long-chain inulin: Influence on the gut microbial ecology of rats associated with a human faecal flora. Bri J Nutri. 2001;86(2):291–300.
- Sasaki R, Nishimura N, Hoshino H, Isa Y, Kadowaki M, Ichi T, et al. Cyanidin 3-glucoside ameliorates hyperglycemia and insulin sensitivity due to downregulation of retinol binding protein 4 expression in diabetic mice. Biochem Pharmacol. 2007;74:1619–1627.
- Burant CF. Activation of GPR40 as a Therapeutic Target for the Treatment of Type 2 Diabetes. Diabetes Care. 2013;36(S2):S175–S179.
- Zhang D, Leung PS. Potential roles of GPR120 and its agonists in the management of diabetes. Drug Des, Devel Ther. 2014;8:1013–1027.
- Chakravarthy MV, Lodhi IF, Yin L, Malapaka RRV, Xu HE, Turk J, et al. Identification of a Physiologically Relevant Endogenous Ligand for PPARα in Liver. Cell. 2009;138(3):476–488.
- Godlewski G, Offertaler L, Wagner JA, Kunos G. Receptors for acylethanoloamides—GPR55 and GPR119. Prostaglandins Other Lipid Mediat. 2009;89(3–4):105–111. 10.1016/j.prostaglandins.2009.07.001
Source: PubMed