Profile

The focus of my research is to better understand the regulation of glucose metabolism. Hepatic glucose production is determined by gluconeogenesis and glycogenolysis, which are regulated, to a large extent, by insulin and glucagon. I have spent the last 19 years studying the physiologic role of this hormone in controlling these processes. It is clear that insulin exerts both direct and indirect effects on the liver. Following the binding of insulin to its hepatic receptor there is rapid suppression of hepatic glucose production due to the suppression of glycogenolysis. Although insulin also directly inhibits the release of gluconeogenically derived glucose into the blood stream, gluconeogenic flux (through phosphoenolpyruvate carboxykinase to glucose-6-phosphate) is not reduced at physiologic insulin concentrations; instead gluconeogenic carbon is diverted into glycogen stores. Insulin can reduce hepatic extraction and circulating availability of gluconeogenic precursors, but only at high concentrations of the hormone. Although the direct effects of insulin on the suppression of hepatic glucose production are dominant, insulin also has critical indirect effects; including inhibition of lipolysis, suppression of glucagon secretion, and potential effects on the central nervous system. Recently we sought to understand the relative importance of brain insulin action in regulating liver glucose metabolism. We found that while insulin in the brain has no apparent effect on the suppression of glucose production under physiologic insulin conditions (when insulin is elevated by the same fold at the liver and the brain), glycogen synthesis is augmented by the central effects of insulin. Additional research is necessary to determine the relevance of this effect under hyperglycemic conditions (at the time when insulin is typically elevated and when glycogen synthesis is most important). It is also critical to understand how these processes may be dysregulated in insulin resistance, allowing for improved treatment of individuals with diabetes.

Publications

The following timeline graph is generated from all co-authored publications.

Featured publications are shown below:

  1. Insulin Delivery Into the Peripheral Circulation: A Key Contributor to Hypoglycemia in Type 1 Diabetes. Gregory JM, Kraft G, Scott MF, Neal DW, Farmer B, Smith MS, Hastings JR, Allen EJ, Donahue EP, Rivera N, Winnick JJ, Edgerton DS, Nishimura E, Fledelius C, Brand CL, Cherrington AD (2015) Diabetes 64(10): 3439-51
    › Primary publication · 26085570 (PubMed) · PMC4587648 (PubMed Central)
  2. Is brain insulin action relevant to the control of plasma glucose in humans? Edgerton DS, Cherrington AD (2015) Diabetes 64(3): 696-9
    › Primary publication · 25713193 (PubMed) · PMC4876740 (PubMed Central)
  3. Biologic comparison of inhaled insulin formulations: Exubera™ and novel spray-dried engineered particles of dextran-10. Kuehl PJ, Cherrington A, Dobry DE, Edgerton D, Friesen DT, Hobbs C, Leach CL, Murri B, Neal D, Lyon DK, Vodak DT, Reed MD (2014) AAPS PharmSciTech 15(6): 1545-50
    › Primary publication · 25106135 (PubMed) · PMC4245427 (PubMed Central)
  4. Changes in glucose and fat metabolism in response to the administration of a hepato-preferential insulin analog. Edgerton DS, Moore MC, Winnick JJ, Scott M, Farmer B, Naver H, Jeppesen CB, Madsen P, Kjeldsen TB, Nishimura E, Brand CL, Cherrington AD (2014) Diabetes 63(11): 3946-54
    › Primary publication · 24947349 (PubMed) · PMC4392933 (PubMed Central)
  5. Biobehavioral profiles of arousal and social motivation in autism spectrum disorders. Corbett BA, Swain DM, Newsom C, Wang L, Song Y, Edgerton D (2014) J Child Psychol Psychiatry 55(8): 924-34
    › Primary publication · 24329926 (PubMed) · PMC4055549 (PubMed Central)
  6. Impact of hematopoietic cyclooxygenase-1 deficiency on obesity-linked adipose tissue inflammation and metabolic disorders in mice. Saraswathi V, Ramnanan CJ, Wilks AW, Desouza CV, Eller AA, Murali G, Ramalingam R, Milne GL, Coate KC, Edgerton DS (2013) Metabolism 62(11): 1673-85
    › Primary publication · 23987235 (PubMed) · PMC4845736 (PubMed Central)
  7. Glucagon's yin and yang effects on hepatic glucose production. Edgerton DS, Cherrington AD (2013) Nat Med 19(6): 674-5
    › Primary publication · 23744146 (PubMed) · PMC5407006 (PubMed Central)
  8. Effects of intraportal exenatide on hepatic glucose metabolism in the conscious dog. Edgerton DS, An Z, Johnson KM, Farmer T, Farmer B, Neal D, Cherrington AD (2013) Am J Physiol Endocrinol Metab 305(1): E132-9
    › Primary publication · 23673158 (PubMed) · PMC3725568 (PubMed Central)
  9. Effects of 11β-hydroxysteroid dehydrogenase-1 inhibition on hepatic glycogenolysis and gluconeogenesis. Winnick JJ, Ramnanan CJ, Saraswathi V, Roop J, Scott M, Jacobson P, Jung P, Basu R, Cherrington AD, Edgerton DS (2013) Am J Physiol Endocrinol Metab 304(7): E747-56
    › Primary publication · 23403942 (PubMed) · PMC3625750 (PubMed Central)
  10. Interaction between the central and peripheral effects of insulin in controlling hepatic glucose metabolism in the conscious dog. Ramnanan CJ, Kraft G, Smith MS, Farmer B, Neal D, Williams PE, Lautz M, Farmer T, Donahue EP, Cherrington AD, Edgerton DS (2013) Diabetes 62(1): 74-84
    › Primary publication · 23011594 (PubMed) · PMC3526039 (PubMed Central)
  11. Evidence against a physiologic role for acute changes in CNS insulin action in the rapid regulation of hepatic glucose production. Ramnanan CJ, Edgerton DS, Cherrington AD (2012) Cell Metab 15(5): 656-64
    › Primary publication · 22560218 (PubMed) · PMC3348512 (PubMed Central)
  12. Brain insulin action augments hepatic glycogen synthesis without suppressing glucose production or gluconeogenesis in dogs. Ramnanan CJ, Saraswathi V, Smith MS, Donahue EP, Farmer B, Farmer TD, Neal D, Williams PE, Lautz M, Mari A, Cherrington AD, Edgerton DS (2011) J Clin Invest 121(9): 3713-23
    › Primary publication · 21865644 (PubMed) · PMC3163950 (PubMed Central)
  13. Physiologic action of glucagon on liver glucose metabolism. Ramnanan CJ, Edgerton DS, Kraft G, Cherrington AD (2011) Diabetes Obes Metab : 118-25
    › Primary publication · 21824265 (PubMed) · PMC5371022 (PubMed Central)
  14. Glucagon as a critical factor in the pathology of diabetes. Edgerton DS, Cherrington AD (2011) Diabetes 60(2): 377-80
    › Primary publication · 21270249 (PubMed) · PMC3028334 (PubMed Central)
  15. Molecular characterization of insulin-mediated suppression of hepatic glucose production in vivo. Ramnanan CJ, Edgerton DS, Rivera N, Irimia-Dominguez J, Farmer B, Neal DW, Lautz M, Donahue EP, Meyer CM, Roach PJ, Cherrington AD (2010) Diabetes 59(6): 1302-11
    › Primary publication · 20185816 (PubMed) · PMC2874690 (PubMed Central)
  16. Effect of 11 beta-hydroxysteroid dehydrogenase-1 inhibition on hepatic glucose metabolism in the conscious dog. Edgerton DS, Basu R, Ramnanan CJ, Farmer TD, Neal D, Scott M, Jacobson P, Rizza RA, Cherrington AD (2010) Am J Physiol Endocrinol Metab 298(5): E1019-26
    › Primary publication · 20159854 (PubMed) · PMC2867371 (PubMed Central)
  17. Effects of insulin on the metabolic control of hepatic gluconeogenesis in vivo. Edgerton DS, Ramnanan CJ, Grueter CA, Johnson KM, Lautz M, Neal DW, Williams PE, Cherrington AD (2009) Diabetes 58(12): 2766-75
    › Primary publication · 19755527 (PubMed) · PMC2780867 (PubMed Central)
  18. Current strategies for the inhibition of hepatic glucose production in type 2 diabetes. Edgerton DS, Johnson KM, Cherrington AD (2009) Front Biosci (Landmark Ed) : 1169-81
    › Primary publication · 19273123 (PubMed)
  19. Inhaled insulin is associated with prolonged enhancement of glucose disposal in muscle and liver in the canine. Edgerton DS, Cherrington AD, Neal DW, Scott M, Lautz M, Brown N, Petro J, Hobbs CH, Leach C, Del Parigi A, Strack TR (2009) J Pharmacol Exp Ther 328(3): 970-5
    › Primary publication · 19098161 (PubMed) · PMC3202424 (PubMed Central)
  20. Inhibition of dipeptidyl peptidase-4 by vildagliptin during glucagon-like Peptide 1 infusion increases liver glucose uptake in the conscious dog. Edgerton DS, Johnson KM, Neal DW, Scott M, Hobbs CH, Zhang X, Duttaroy A, Cherrington AD (2009) Diabetes 58(1): 243-9
    › Primary publication · 18840785 (PubMed) · PMC2606880 (PubMed Central)
  21. Intraportally delivered GLP-1, in the presence of hyperglycemia induced via peripheral glucose infusion, does not change whole body glucose utilization. Johnson KM, Edgerton DS, Rodewald T, Scott M, Farmer B, Neal D, Cherrington AD (2008) Am J Physiol Endocrinol Metab 294(2): E380-4
    › Primary publication · 18056788 (PubMed)
  22. Effects of the nitric oxide donor SIN-1 on net hepatic glucose uptake in the conscious dog. An Z, DiCostanzo CA, Moore MC, Edgerton DS, Dardevet DP, Neal DW, Cherrington AD (2008) Am J Physiol Endocrinol Metab 294(2): E300-6
    › Primary publication · 18029444 (PubMed)
  23. Insulin action on the liver in vivo. Cherrington AD, Moore MC, Sindelar DK, Edgerton DS (2007) Biochem Soc Trans 35(Pt 5): 1171-4
    › Primary publication · 17956305 (PubMed)
  24. Intraportal GLP-1 infusion increases nonhepatic glucose utilization without changing pancreatic hormone levels. Johnson KM, Edgerton DS, Rodewald T, Scott M, Farmer B, Neal D, Cherrington AD (2007) Am J Physiol Endocrinol Metab 293(4): E1085-91
    › Primary publication · 17684104 (PubMed)
  25. Triglyceride uptake and lipoprotein lipase-generated fatty acid spillover in the splanchnic bed of dogs. Nelson RH, Edgerton DS, Basu R, Roesner JC, Cherrington AD, Miles JM (2007) Diabetes 56(7): 1850-5
    › Primary publication · 17416801 (PubMed)
  26. A novel glucagon receptor antagonist, NNC 25-0926, blunts hepatic glucose production in the conscious dog. Rivera N, Everett-Grueter CA, Edgerton DS, Rodewald T, Neal DW, Nishimura E, Larsen MO, Jacobsen LO, Kristensen K, Brand CL, Cherrington AD (2007) J Pharmacol Exp Ther 321(2): 743-52
    › Primary publication · 17308040 (PubMed)
  27. Inhalation of human insulin (exubera) augments the efficiency of muscle glucose uptake in vivo. Edgerton DS, Cherrington AD, Williams P, Neal DW, Scott M, Bowen L, Wilson W, Hobbs CH, Leach C, Kuo MC, Strack TR (2006) Diabetes 55(12): 3604-10
    › Primary publication · 17130510 (PubMed)
  28. Splanchnic cortisol production in dogs occurs primarily in the liver: evidence for substantial hepatic specific 11beta hydroxysteroid dehydrogenase type 1 activity. Basu R, Edgerton DS, Singh RJ, Cherrington A, Rizza RA (2006) Diabetes 55(11): 3013-9
    › Primary publication · 17065337 (PubMed)
  29. Inhalation of human insulin is associated with improved insulin action compared with subcutaneous injection and endogenous secretion in dogs. Edgerton DS, Stettler KM, Neal DW, Scott M, Bowen L, Wilson W, Hobbs CH, Leach C, Strack TR, Cherrington AD (2006) J Pharmacol Exp Ther 319(3): 1258-64
    › Primary publication · 16963622 (PubMed)
  30. Selective antagonism of the hepatic glucocorticoid receptor reduces hepatic glucose production. Edgerton DS, Jacobson PB, Opgenorth TJ, Zinker B, Beno D, von Geldern T, Ohman L, Scott M, Neal D, Cherrington AD (2006) Metabolism 55(9): 1255-62
    › Primary publication · 16919547 (PubMed)
  31. The effect of an acute elevation of NEFA concentrations on glucagon-stimulated hepatic glucose output. Everett-Grueter C, Edgerton DS, Donahue EP, Vaughan S, Chu CA, Sindelar DK, Cherrington AD (2006) Am J Physiol Endocrinol Metab 291(3): E449-59
    › Primary publication · 16608886 (PubMed)
  32. Insulin's direct effects on the liver dominate the control of hepatic glucose production. Edgerton DS, Lautz M, Scott M, Everett CA, Stettler KM, Neal DW, Chu CA, Cherrington AD (2006) J Clin Invest 116(2): 521-7
    › Primary publication · 16453026 (PubMed) · PMC1359060 (PubMed Central)
  33. Islet auto-transplantation into an omental or splenic site results in a normal beta cell but abnormal alpha cell response to mild non-insulin-induced hypoglycemia. Gustavson SM, Rajotte RV, Hunkeler D, Lakey JR, Edgerton DS, Neal DW, Snead WL, Penaloza AR, Cherrington AD (2005) Am J Transplant 5(10): 2368-77
    › Primary publication · 16162184 (PubMed)
  34. Inhalation of insulin (Exubera) is associated with augmented disposal of portally infused glucose in dogs. Edgerton DS, Neal DW, Scott M, Bowen L, Wilson W, Hobbs CH, Leach C, Sivakumaran S, Strack TR, Cherrington AD (2005) Diabetes 54(4): 1164-70
    › Primary publication · 15793257 (PubMed)
  35. Hepatic glucocorticoid receptor antagonism is sufficient to reduce elevated hepatic glucose output and improve glucose control in animal models of type 2 diabetes. Jacobson PB, von Geldern TW, Ohman L, Osterland M, Wang J, Zinker B, Wilcox D, Nguyen PT, Mika A, Fung S, Fey T, Goos-Nilsson A, Grynfarb M, Barkhem T, Marsh K, Beno DW, Nga-Nguyen B, Kym PR, Link JT, Tu N, Edgerton DS, Cherrington A, Efendic S, Lane BC, Opgenorth TJ (2005) J Pharmacol Exp Ther 314(1): 191-200
    › Primary publication · 15784656 (PubMed)
  36. Vagal cooling and concomitant portal norepinephrine infusion do not reduce net hepatic glucose uptake in conscious dogs. Cardin S, Pagliassotti MJ, Moore MC, Edgerton DS, Lautz M, Farmer B, Neal DW, Cherrington AD (2004) Am J Physiol Regul Integr Comp Physiol 287(4): R742-8
    › Primary publication · 15166005 (PubMed)
  37. Inhalation of insulin in dogs: assessment of insulin levels and comparison to subcutaneous injection. Cherrington AD, Neal DW, Edgerton DS, Glass D, Bowen L, Hobbs CH, Leach C, Rosskamp R, Strack TR (2004) Diabetes 53(4): 877-81
    › Primary publication · 15047601 (PubMed)
  38. Selective stimulation of G-6-Pase catalytic subunit but not G-6-P transporter gene expression by glucagon in vivo and cAMP in situ. Hornbuckle LA, Everett CA, Martin CC, Gustavson SS, Svitek CA, Oeser JK, Neal DW, Cherrington AD, O'Brien RM (2004) Am J Physiol Endocrinol Metab 286(5): E795-808
    › Primary publication · 14722027 (PubMed)
  39. Effects of hyperglycemia on hepatic gluconeogenic flux during glycogen phosphorylase inhibition in the conscious dog. Edgerton DS, Cardin S, Neal D, Farmer B, Lautz M, Pan C, Cherrington AD (2004) Am J Physiol Endocrinol Metab 286(4): E510-22
    › Primary publication · 14644767 (PubMed)
  40. Unlike mice, dogs exhibit effective glucoregulation during low-dose portal and peripheral glucose infusion. Moore MC, Cardin S, Edgerton DS, Farmer B, Neal DW, Lautz M, Cherrington AD (2004) Am J Physiol Endocrinol Metab 286(2): E226-33
    › Primary publication · 14519598 (PubMed)
  41. Splanchnic free fatty acid kinetics. Jensen MD, Cardin S, Edgerton D, Cherrington A (2003) Am J Physiol Endocrinol Metab 284(6): E1140-8
    › Primary publication · 12736157 (PubMed)
  42. Effects of insulin deficiency or excess on hepatic gluconeogenic flux during glycogenolytic inhibition in the conscious dog. Edgerton DS, Cardin S, Pan C, Neal D, Farmer B, Converse M, Cherrington AD (2002) Diabetes 51(11): 3151-62
    › Primary publication · 12401705 (PubMed)
  43. Physiological consequences of phasic insulin release in the normal animal. Cherrington AD, Sindelar D, Edgerton D, Steiner K, McGuinness OP (2002) Diabetes : S103-8
    › Primary publication · 11815467 (PubMed)
  44. Selective tonic inhibition of G-6-Pase catalytic subunit, but not G-6-P transporter, gene expression by insulin in vivo. Hornbuckle LA, Edgerton DS, Ayala JE, Svitek CA, Oeser JK, Neal DW, Cardin S, Cherrington AD, O'Brien RM (2001) Am J Physiol Endocrinol Metab 281(4): E713-25
    › Primary publication · 11551847 (PubMed)
  45. Small increases in insulin inhibit hepatic glucose production solely caused by an effect on glycogen metabolism. Edgerton DS, Cardin S, Emshwiller M, Neal D, Chandramouli V, Schumann WC, Landau BR, Rossetti L, Cherrington AD (2001) Diabetes 50(8): 1872-82
    › Primary publication · 11473051 (PubMed)
  46. Effect of vagal cooling on the counterregulatory response to hypoglycemia induced by a low dose of insulin in the conscious dog. Cardin S, Jackson PA, Edgerton DS, Neal DW, Coffey CS, Cherrington AD (2001) Diabetes 50(3): 558-64
    › Primary publication · 11246875 (PubMed)
  47. Portal glucose infusion increases hepatic glycogen deposition in conscious unrestrained rats. Cardin S, Emshwiller M, Jackson PA, Snead WL, Hastings J, Edgerton DS, Cherrington AD (1999) J Appl Physiol (1985) 87(4): 1470-5
    › Primary publication · 10517780 (PubMed)
  48. The direct and indirect effects of insulin on hepatic glucose production in vivo. Cherrington AD, Edgerton D, Sindelar DK (1998) Diabetologia 41(9): 987-96
    › Primary publication · 9754815 (PubMed)