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“Twincretins”: Two Is Better than One

Despite obesity-linked diabetes approaching worldwide epidemic proportions and the growing recognition of it as a global health challenge, safe and effective medicines have remained largely elusive. Pharmacological options targeting multiple obesity and diabetes signaling pathways offer greater therapeutic potential compared to molecules targeting a single pathway. Finan et al. now report the discovery, characterization, and translational efficacy of a single molecule that acts equally on the receptors for the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). In rodent models of obesity and diabetes, this dual incretin co-agonist more effectively lowered body fat and corrected hyperglycemia than selective mono-agonists for the GLP-1 and GIP receptors. An enhanced insulinotropic effect translated from rodents to monkeys and humans, with substantially improved levels of glycosylated hemoglobin A1c (HbA1c) in humans with type 2 diabetes. The dual incretin was engineered with selective chemical modifications to enhance pharmacokinetics. This, in combination with its inherent mixed agonism, lowered the drug dose and ameliorated the dose-limiting nausea that has plagued selective GLP-1 therapies. These dual incretin co-agonists signify a new direction for unimolecular combination therapy and represent a new class of drug candidates for the treatment of metabolic diseases.

Abstract

We report the discovery and translational therapeutic efficacy of a peptide with potent, balanced co-agonism at both of the receptors for the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). This unimolecular dual incretin is derived from an intermixed sequence of GLP-1 and GIP, and demonstrated enhanced antihyperglycemic and insulinotropic efficacy relative to selective GLP-1 agonists. Notably, this superior efficacy translated across rodent models of obesity and diabetes, including db/db mice and ZDF rats, to primates (cynomolgus monkeys and humans). Furthermore, this co-agonist exhibited synergism in reducing fat mass in obese rodents, whereas a selective GIP agonist demonstrated negligible weight-lowering efficacy. The unimolecular dual incretins corrected two causal mechanisms of diabesity, adiposity-induced insulin resistance and pancreatic insulin deficiency, more effectively than did selective mono-agonists. The duration of action of the unimolecular dual incretins was refined through site-specific lipidation or PEGylation to support less frequent administration. These peptides provide comparable pharmacology to the native peptides and enhanced efficacy relative to similarly modified selective GLP-1 agonists. The pharmacokinetic enhancement lessened peak drug exposure and, in combination with less dependence on GLP-1–mediated pharmacology, avoided the adverse gastrointestinal effects that typify selective GLP-1–based agonists. This discovery and validation of a balanced and high-potency dual incretin agonist enables a more physiological approach to management of diseases associated with impaired glucose tolerance.

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Supplementary Material

Summary

Fig. S1. Sequences of native hormones and engineered analogs.
Fig. S2. Indirect calorimetry analysis in DIO mice.
Fig. S3. Pair-feeding comparison in DIO mice.
Fig. S4. Genomic profile of white adipose tissue, liver, and quadriceps.
Fig. S5. Comparison in GLP-1RKO mice.
Fig. S6. Effects on hepatic damage and steatosis in DIO mice.
Fig. S7. Effects on glycemia and islet cytoarchitecture in ZDF rats.

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REFERENCES AND NOTES

1
Barrera J. G., Sandoval D. A., D’Alessio D. A., Seeley R. J., GLP-1 and energy balance: An integrated model of short-term and long-term control. Nat. Rev. Endocrinol. 7, 507–516 (2011).
2
Drucker D. J., The biology of incretin hormones. Cell Metab. 3, 153–165 (2006).
3
Astrup A., Rössner S., Van Gaal L., Rissanen A., Niskanen L., Al Hakim M., Madsen J., Rasmussen M. F., Lean M. E.; NN8022-1807 Study Group, Effects of liraglutide in the treatment of obesity: A randomised, double-blind, placebo-controlled study. Lancet 374, 1606–1616 (2009).
4
Amori R. E., Lau J., Pittas A. G., Efficacy and safety of incretin therapy in type 2 diabetes: Systematic review and meta-analysis. JAMA 298, 194–206 (2007).
5
Kim S. J., Nian C., McIntosh C. H., Activation of lipoprotein lipase by glucose-dependent insulinotropic polypeptide in adipocytes. A role for a protein kinase B, LKB1, and AMP-activated protein kinase cascade. J. Biol. Chem. 282, 8557–8567 (2007).
6
Miyawaki K., Yamada Y., Yano H., Niwa H., Ban N., Ihara Y., Kubota A., Fujimoto S., Kajikawa M., Kuroe A., Tsuda K., Hashimoto H., Yamashita T., Jomori T., Tashiro F., Miyazaki J., Seino Y., Glucose intolerance caused by a defect in the entero-insular axis: A study in gastric inhibitory polypeptide receptor knockout mice. Proc. Natl. Acad. Sci. U.S.A. 96, 14843–14847 (1999).
7
Miyawaki K., Yamada Y., Ban N., Ihara Y., Tsukiyama K., Zhou H., Fujimoto S., Oku A., Tsuda K., Toyokuni S., Hiai H., Mizunoya W., Fushiki T., Holst J. J., Makino M., Tashita A., Kobara Y., Tsubamoto Y., Jinnouchi T., Jomori T., Seino Y., Inhibition of gastric inhibitory polypeptide signaling prevents obesity. Nat. Med. 8, 738–742 (2002).
8
Althage M. C., Ford E. L., Wang S., Tso P., Polonsky K. S., Wice B. M., Targeted ablation of glucose-dependent insulinotropic polypeptide-producing cells in transgenic mice reduces obesity and insulin resistance induced by a high fat diet. J. Biol. Chem. 283, 18365–18376 (2008).
9
Gault V. A., O’Harte F. P., Harriott P., Flatt P. R., Characterization of the cellular and metabolic effects of a novel enzyme-resistant antagonist of glucose-dependent insulinotropic polypeptide. Biochem. Biophys. Res. Commun. 290, 1420–1426 (2002).
10
Gault V. A., O’Harte F. P., Harriott P., Mooney M. H., Green B. D., Flatt P. R., Effects of the novel (Pro3)GIP antagonist and exendin(9–39)amide on GIP- and GLP-1-induced cyclic AMP generation, insulin secretion and postprandial insulin release in obese diabetic (ob/ob) mice: Evidence that GIP is the major physiological incretin. Diabetologia 46, 222–230 (2003).
11
McClean P. L., Irwin N., Cassidy R. S., Holst J. J., Gault V. A., Flatt P. R., GIP receptor antagonism reverses obesity, insulin resistance, and associated metabolic disturbances induced in mice by prolonged consumption of high-fat diet. Aml J. Physiol. Endocrinol. Metab. 293, E1746–E1755 (2007).
12
Nauck M. A., Heimesaat M. M., Orskov C., Holst J. J., Ebert R., Creutzfeldt W., Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J. Clin. Invest. 91, 301–307 (1993).
13
Vilsbøll T., Knop F. K., Krarup T., Johansen A., Madsbad S., Larsen S., Hansen T., Pedersen O., Holst J. J., The pathophysiology of diabetes involves a defective amplification of the late-phase insulin response to glucose by glucose-dependent insulinotropic polypeptide—Regardless of etiology and phenotype. J. Clin. Endocrinol. Metab. 88, 4897–4903 (2003).
14
Kim S. J., Nian C., Karunakaran S., Clee S. M., Isales C. M., McIntosh C. H., GIP-overexpressing mice demonstrate reduced diet-induced obesity and steatosis, and improved glucose homeostasis. PLoS One 7, e40156 (2012).
15
Renner S., Fehlings C., Herbach N., Hofmann A., von Waldthausen D. C., Kessler B., Ulrichs K., Chodnevskaja I., Moskalenko V., Amselgruber W., Göke B., Pfeifer A., Wanke R., Wolf E., Glucose intolerance and reduced proliferation of pancreatic β-cells in transgenic pigs with impaired glucose-dependent insulinotropic polypeptide function. Diabetes 59, 1228–1238 (2010).
16
Müller T. D., Sullivan L. M., Habegger K., Yi C. X., Kabra D., Grant E., Ottaway N., Krishna R., Holland J., Hembree J., Perez-Tilve D., Pfluger P. T., DeGuzman M. J., Siladi M. E., Kraynov V. S., Axelrod D. W., DiMarchi R., Pinkstaff J. K., Tschöp M. H., Restoration of leptin responsiveness in diet-induced obese mice using an optimized leptin analog in combination with exendin-4 or FGF21. J. Pept. Sci. 18, 383–393 (2012).
17
Neary N. M., Small C. J., Druce M. R., Park A. J., Ellis S. M., Semjonous N. M., Dakin C. L., Filipsson K., Wang F., Kent A. S., Frost G. S., Ghatei M. A., Bloom S. R., Peptide YY3–36 and glucagon-like peptide-17–36 inhibit food intake additively. Endocrinology 146, 5120–5127 (2005).
18
Talsania T., Anini Y., Siu S., Drucker D. J., Brubaker P. L., Peripheral exendin-4 and peptide YY3–36 synergistically reduce food intake through different mechanisms in mice. Endocrinology 146, 3748–3756 (2005).
19
Mentis N., Vardarli I., Köthe L. D., Holst J. J., Deacon C. F., Theodorakis M., Meier J. J., Nauck M. A., GIP does not potentiate the antidiabetic effects of GLP-1 in hyperglycemic patients with type 2 diabetes. Diabetes 60, 1270–1276 (2011).
20
Day J. W., Ottaway N., Patterson J. T., Gelfanov V., Smiley D., Gidda J., Findeisen H., Bruemmer D., Drucker D. J., Chaudhary N., Holland J., Hembree J., Abplanalp W., Grant E., Ruehl J., Wilson H., Kirchner H., Lockie S. H., Hofmann S., Woods S. C., Nogueiras R., Pfluger P. T., Perez-Tilve D., DiMarchi R., Tschöp M. H., A new glucagon and GLP-1 co-agonist eliminates obesity in rodents. Nat. Chem. Biol. 5, 749–757 (2009).
21
Wu J., Boström P., Sparks L. M., Ye L., Choi J. H., Giang A. H., Khandekar M., Virtanen K. A., Nuutila P., Schaart G., Huang K., Tu H., van Marken Lichtenbelt W. D., Hoeks J., Enerbäck S., Schrauwen P., Spiegelman B. M., Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 150, 366–376 (2012).
22
Hansotia T., Baggio L. L., Delmeire D., Hinke S. A., Yamada Y., Tsukiyama K., Seino Y., Holst J. J., Schuit F., Drucker D. J., Double incretin receptor knockout (DIRKO) mice reveal an essential role for the enteroinsular axis in transducing the glucoregulatory actions of DPP-IV inhibitors. Diabetes 53, 1326–1335 (2004).
23
Habegger K. M., Stemmer K., Cheng C., Müller T. D., Heppner K. M., Ottaway N., Holland J., Hembree J. L., Smiley D., Gelfanov V., Krishna R., Arafat A. M., Konkar A., Belli S., Kapps M., Woods S. C., Hofmann S. M., D’Alessio D., Pfluger P. T., Perez-Tilve D., Seeley R. J., Konishi M., Itoh N., Kharitonenkov A., Spranger J., DiMarchi R. D., Tschöp M. H., Fibroblast growth factor 21 mediates specific glucagon actions. Diabetes 62, 1453–1463 (2013).
24
Russell-Jones D., Gough S., Recent advances in incretin-based therapies. Clin. Endocrinol. 77, 489–499 (2012).
25
Finan B., Yang B., Ottaway N., Stemmer K., Müller T. D., Yi C. X., Habegger K., Schriever S. C., García-Cáceres C., Kabra D. G., Hembree J., Holland J., Raver C., Seeley R. J., Hans W., Irmler M., Beckers J., de Angelis M. H., Tiano J. P., Mauvais-Jarvis F., Perez-Tilve D., Pfluger P., Zhang L., Gelfanov V., DiMarchi R. D., Tschöp M. H., Targeted estrogen delivery reverses the metabolic syndrome. Nat. Med. 18, 1847–1856 (2012).
26
Day J. W., Li P., Patterson J. T., Chabenne J., Chabenne M. D., Gelfanov V. M., Dimarchi R. D., Charge inversion at position 68 of the glucagon and glucagon-like peptide-1 receptors supports selectivity in hormone action. J. Pept. Sci. 17, 218–225 (2011).
27
Edwards K. L., Stapleton M., Weis J., Irons B. K., An update in incretin-based therapy: A focus on glucagon-like peptide-1 receptor agonists. Diabetes Technol. Ther. 14, 951–967 (2012).
28
Gier B., Matveyenko A. V., Kirakossian D., Dawson D., Dry S. M., Butler P. C., Chronic GLP-1 receptor activation by exendin-4 induces expansion of pancreatic duct glands in rats and accelerates formation of dysplastic lesions and chronic pancreatitis in the KrasG12D mouse model. Diabetes 61, 1250–1262 (2012).
29
Butler P. C., Elashoff M., Elashoff R., Gale E. A., A critical analysis of the clinical use of incretin-based therapies: Are the GLP-1 therapies safe? Diabetes Care 36, 2118–2125 (2013).
30
Nauck M. A., Baranov O., Ritzel R. A., Meier J. J., Do current incretin mimetics exploit the full therapeutic potential inherent in GLP-1 receptor stimulation? Diabetologia 56, 1878–1883 (2013).
31
Kulkarni R. N., GIP: No longer the neglected incretin twin? Sci. Transl. Med. 2, 49ps47 (2010).
32
McIntosh C. H., Widenmaier S., Kim S. J., Glucose-dependent insulinotropic polypeptide (gastric inhibitory polypeptide; GIP). Vitam. Horm. 80, 409–471 (2009).
33
Kim S. J., Nian C., McIntosh C. H., Resistin is a key mediator of glucose-dependent insulinotropic polypeptide (GIP) stimulation of lipoprotein lipase (LPL) activity in adipocytes. J. Biol. Chem. 282, 34139–34147 (2007).
34
Kim S. J., Nian C., McIntosh C. H., GIP increases human adipocyte LPL expression through CREB and TORC2-mediated trans-activation of the LPL gene. J. Lipid Res. 51, 3145–3157 (2010).
35
Hansotia T., Maida A., Flock G., Yamada Y., Tsukiyama K., Seino Y., Drucker D. J., Extrapancreatic incretin receptors modulate glucose homeostasis, body weight, and energy expenditure. J. Clin. Invest. 117, 143–152 (2007).
36
Widenmaier S. B., Kim S. J., Yang G. K., De Los Reyes T., Nian C., Asadi A., Seino Y., Kieffer T. J., Kwok Y. N., McIntosh C. H., A GIP receptor agonist exhibits β-cell anti-apoptotic actions in rat models of diabetes resulting in improved β-cell function and glycemic control. PLoS One 5, e9590 (2010).
37
Scrocchi L. A., Drucker D. J., Effects of aging and a high fat diet on body weight and glucose tolerance in glucagon-like peptide-1 receptor−/− mice. Endocrinology 139, 3127–3132 (1998).
38
Faivre E., Hamilton A., Hölscher C., Effects of acute and chronic administration of GIP analogues on cognition, synaptic plasticity and neurogenesis in mice. Eur. J. Pharmacol. 674, 294–306 (2012).
39
Schelshorn D., Joly F., Mutel S., Hampe C., Breton B., Mutel V., Lütjens R., Lateral allosterism in the glucagon receptor family: Glucagon-like peptide 1 induces G-protein-coupled receptor heteromer formation. Mol. Pharmacol. 81, 309–318 (2012).
40
Chia C. W., Carlson O. D., Kim W., Shin Y. K., Charles C. P., Kim H. S., Melvin D. L., Egan J. M., Exogenous glucose-dependent insulinotropic polypeptide worsens post prandial hyperglycemia in type 2 diabetes. Diabetes 58, 1342–1349 (2009).
41
Bénardeau A., Verry P., Atzpodien E. A., Funk J. M., Meyer M., Mizrahi J., Winter M., Wright M. B., Uhles S., Sebokova E., Effects of the dual PPAR-α/γ agonist aleglitazar on glycaemic control and organ protection in the Zucker diabetic fatty rat. Diabetes Obes. Metab. 15, 164–174 (2013).
42
Uhles S., Wang H., Bénardeau A., Prummer M., Brecheisen M., Sewing S., Tobalina L., Bosco D., Wollheim C. B., Migliorini C., Sebokova E., Taspoglutide, a novel human once-weekly GLP-1 analogue, protects pancreatic β-cells in vitro and preserves islet structure and function in the Zucker diabetic fatty rat in vivo. Diabetes Obes. Metab. 13, 326–336 (2011).

Information & Authors

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Published In

Science Translational Medicine
Volume 5 | Issue 209
October 2013

Submission history

Received: 1 August 2013
Accepted: 11 October 2013

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Acknowledgments

We thank J. Levy for technical and chemical support of peptide synthesis; J. Ford for cell culture maintenance; J. Patterson, J. Day, B. Ward, and C. Ouyang for discussions on chemical structure–activity relationships; and C. Apfel for providing support with clinical chemistry measurements. Funding: Partial research funding was provided by Marcadia Biotech, which has been acquired by Roche Pharma, by the Helmholtz Alliance ICEMED (Imaging and Curing Environmental Metabolic Diseases) through the Initiative and Networking Fund of the Helmholtz Association, and by grants from the Deutsche Forschungsgesellschaft (TS226/1-1). Author contributions: B.F. designed and performed in vitro, in vivo, and ex vivo rodent experiments; synthesized and characterized compounds; analyzed and interpreted the data; and wrote the manuscript. T.M. designed, synthesized, and characterized compounds; performed in vitro experiments; and analyzed and interpreted the data. N.O. designed and led in vivo pharmacology and metabolism rodent studies and interpreted the data. T.D.M., K. M. Habegger, K. M. Heppner, H.K., S.H.L., S.H., P.T.P., and D.P.-T. designed, supervised, and performed in vivo experiments and interpreted the data. J. Holland, J. Hembree, and C.R. performed in vivo pharmacology and metabolism studies in rodents. D.L.S. and B.Y. synthesized and characterized compounds and interpreted the data. V.G. designed and performed in vitro experiments and interpreted the data. D.B. performed ex vivo analysis and interpreted the data. D.J.D. gave advice on experimental design and interpreted the data. J.G., L.V., and L.Z. designed in vivo rodent, primate, and human experiments and interpreted the data. J.B.H. and M.L. designed and performed human clinical experiments and interpreted the data. M.B., S.U., W.R., E.H., E.S., K.C.-K., and A.K. designed and performed in vitro, in vivo, and ex vivo analyses and interpreted the data. R.D.D. and M.H.T. conceptualized, designed, and interpreted all studies and wrote the manuscript. Competing interests: R.D.D. is a cofounder of Marcadia Biotech and is currently a research consultant to Roche that supports ongoing scientific collaborations. D.J.D. has served as an advisor or consultant within the past 12 months to Arisaph Pharmaceuticals Inc., Diartis Pharmaceuticals, Eli Lilly Inc., Intarcia Therapeutics, Merck Research Laboratories, Novo Nordisk Inc., NPS Pharmaceuticals Inc., Receptos, Sanofi, Takeda, and Transition Pharmaceuticals Inc. Neither D.J.D. nor his family members hold stock directly or indirectly in any of these companies. R.D.D. and T.M. are co-inventors on patent applications (US2011/0166062 A1; US 12/999,285; “GIP-based mixed agonists for treatment of metabolic disorders and obesity”) owned by Indiana University that pertain to the peptides in this paper that are licensed to Roche Pharmaceuticals (32993-214815). The other authors declare no competing interests.

Authors

Affiliations

Brian Finan*
Institute for Diabetes and Obesity, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg 85764, Germany.
Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Munich 80333, Germany.
Department of Chemistry, Indiana University, Bloomington, IN 47405, USA.
Tao Ma*
Department of Chemistry, Indiana University, Bloomington, IN 47405, USA.
Research Center, Beijing Hanmi Pharmaceutical, Beijing 10131, China.
Nickki Ottaway
Metabolic Diseases Institute, Division of Endocrinology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA.
Timo D. Müller
Institute for Diabetes and Obesity, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg 85764, Germany.
Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Munich 80333, Germany.
Kirk M. Habegger
Metabolic Diseases Institute, Division of Endocrinology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA.
Kristy M. Heppner
Metabolic Diseases Institute, Division of Endocrinology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA.
Henriette Kirchner
Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm 17177, Sweden.
Jenna Holland
Metabolic Diseases Institute, Division of Endocrinology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA.
Jazzminn Hembree
Metabolic Diseases Institute, Division of Endocrinology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA.
Christine Raver
Metabolic Diseases Institute, Division of Endocrinology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA.
Sarah H. Lockie
Department of Physiology, Monash University, Melbourne, Victoria 3800, Australia.
David L. Smiley
Department of Chemistry, Indiana University, Bloomington, IN 47405, USA.
Vasily Gelfanov
Department of Chemistry, Indiana University, Bloomington, IN 47405, USA.
Bin Yang
Department of Chemistry, Indiana University, Bloomington, IN 47405, USA.
Marcadia Biotech, Carmel, IN 46032, USA.
Susanna Hofmann
Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Munich 80333, Germany.
Dennis Bruemmer
Saha Cardiovascular Research Center, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
Daniel J. Drucker
Department of Medicine, Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, Ontario M5G 1X5, Canada.
Paul T. Pfluger
Institute for Diabetes and Obesity, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg 85764, Germany.
Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Munich 80333, Germany.
Metabolic Diseases Institute, Division of Endocrinology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA.
Diego Perez-Tilve
Metabolic Diseases Institute, Division of Endocrinology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA.
Jaswant Gidda
Marcadia Biotech, Carmel, IN 46032, USA.
Louis Vignati
Marcadia Biotech, Carmel, IN 46032, USA.
Lianshan Zhang
Marcadia Biotech, Carmel, IN 46032, USA.
Jonathan B. Hauptman
F. Hoffmann–La Roche Ltd., Basel 4070, Switzerland.
Michele Lau
F. Hoffmann–La Roche Ltd., Basel 4070, Switzerland.
Mathieu Brecheisen
F. Hoffmann–La Roche Ltd., Basel 4070, Switzerland.
Sabine Uhles
F. Hoffmann–La Roche Ltd., Basel 4070, Switzerland.
William Riboulet
F. Hoffmann–La Roche Ltd., Basel 4070, Switzerland.
Emmanuelle Hainaut
F. Hoffmann–La Roche Ltd., Basel 4070, Switzerland.
Elena Sebokova
F. Hoffmann–La Roche Ltd., Basel 4070, Switzerland.
Karin Conde-Knape
F. Hoffmann–La Roche Ltd., Basel 4070, Switzerland.
Anish Konkar
F. Hoffmann–La Roche Ltd., Basel 4070, Switzerland.
Richard D. DiMarchi [email protected]
Department of Chemistry, Indiana University, Bloomington, IN 47405, USA.
Matthias H. Tschöp [email protected]
Institute for Diabetes and Obesity, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg 85764, Germany.
Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Munich 80333, Germany.
Metabolic Diseases Institute, Division of Endocrinology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA.

Notes

*
These authors contributed equally to this work.
†Corresponding author. E-mail: [email protected] (R.D.D.); [email protected] (M.H.T.)

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