The Alan D. Cherrington Lab

 The Alan D. Cherrington Lab
Education:
1967 BS, Univ of New Brunswick, Fredericton, New Brunswick, Canada
1969 MS, Dept of Physiology, Univ of Toronto, Toronto, Ontario, Canada
1973 PhD, Dept of Physiology, Univ of Toronto, Toronto, Ontario, Canada

Positions:
1967-68 Biologist, Food & Drug Directorate, Dept of National Health & Welfare, Ottawa, Canada
1973-75 Postdoctoral Fellow in Physiology, Vanderbilt Univ Sch of Med, Nashville, TN
1975-78 Assistant Professor of Physiology, VUMC
1977-94 Assistant Professor of Medicine, VUMC
1978-82 Associate Professor of Physiology, VUMC
1982-85 Professor of Physiology, VUMC
1986-98 Vice Chairman of Molecular Physiology & Biophysics, VUMC
1987-91 Director of Graduate Studies for Molecular Physiology & Biophysics, VUMC
1979-present Associate Director of Diabetes Research and Training Center, VUMC
1985-present Professor of Molecular Physiology & Biophysics, VUMC
1994-present Professor of Medicine; Director of DRTC Analytical Services Core; and Charles H. Best Professor of Diabetes Research, VUMC
1998-present Chairman of Molecular Physiology & Biophysics, VUMC
2004-2005 President of American Diabetes Association

Alan Cherrington's Biography
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Vanderbilt University Medical Center

Awards:
1976 Solomon A. Berson Award for Science from the American Diabetes Association
1984 Lilly Award for Outstanding Scientific Achievement from the American Diabetes Association
1989 David Rumbough Award for Scientific Achievement from the Juvenile Diabetes Foundation
1989 Rachmeal Levine Award for Service from the American Diabetes Association
1992 R.E. Haist Award for Research Achievement from the University of Toronto
1997 Frederick Banting Award for Career Scientific Achievement from the American Diabetes Association
1997 Award for Scientific Achievement from the Mizuno Co., Japan
2000 Alumni Award, Davidson Lecture, University of Toronto
2002 Josiah Kirby Lilly, Sr. Distinguished Service Award from the American Diabetes Association Heartland Region, Indianapolis, IN
2004 MDRF-ADA Gold Medal from the Madras Diabetes Research Foundation, India
2005 Charles R. Park Faculty Award for Research, Vanderbilt University School of Medicine
2005 Frederick Banting Medal for Service from the American Diabetes Association
2005 David Murdock-Dole Lectureship from the Mayo Karolinska Foundation, Stockholm, Sweden




 

DiCostanzo CA, Dardevet D, Neal D, Hastings JR, Neal DW, Williams PE, Lautz M, and Cherrington AD. The effect of vagal cooling on canine hepatic glucose metabolism in the presence of peripheral hyperglycemia. Metabolism 56:814-824, 2007.

Rivera N, Everett, CA, Edgerton DS, Rodewald T, Neal DW, Nishimura E, Larsen MP, Jacobsen LO, Kristensen K, Brand CL, and Cherrington AD. A novel glucagon receptor antagonist, NCC 25-0926, blunts hepatic glucose production in the conscious dog. Journal of Pharmacology and experimental Therapeutics 321:743-752, 2007.

Edgerton DS, Cherrington AD, Neal DW, Scott M, Bowen L, Wilson W, Hobbs CH, Leach C, Kuo M-C, and Strack TR. Inhalation of human insulin (Exubera®) augments the efficiency of muscle glucose uptake in vivo. Diabetes 55(12):36094-1610, 2006.

Edgerton DS, Stettler KM, Neal DW, Scott M, Bowen L, Wilson W, Hobbs CH, Leach C, Sivakumaran S, Strack TR, and Cherrington AD. Inhalation of insulin (Exubera®) is associated with improved insulin action compartion with subcutaneous injection and endogenous secretion in dog. J of Applied Physiol. 319:1258-1264, 2006.

Edgerton DS, Jacobson PB, Opgennorth TJ, Zinker B, Beno D, von Geldern T, Ohman L, Scott M, Neal D and Cherrington AD. Reduction of hepatic glucose production by a liver-selective glucocorticoid receptor antagonist (A-348441). Metabolism 55(9):1255-1262, 2006.

Everett-Grueter C, Edgerton DS, Donahue EP, Vaughan S, Chu CA, Sindelar DK, and Cherrington AD. The effect of an acute elevation of NEFA concentrations on glucagon-stimulated epatic glucose output. Am J Physiol 291:E449-E459, 2006.

Basu R, Edgerton DS, Singh RJ, Cherrington A, and Rizza RA. Splanchnic cortisol production in dogs occurs primarily in the liver: Evidence for substantial hepatic specific 11(beta) hydroxysteroid dehydrogenase type 1 activity. Diabetes 55:3013-3019, 2006.

Cherrington, AD. 2005 Presidential address: Diabetes: past, present, and future. Diabetes Care 29(9): 2158-2164, 2006

Edgerton D, Lautz M, Scott M, Everett C, Stettler K, Neal DW, Chu CA, and Cherrington, AD. Insulin’s direct effects on the liver dominate the control of hepatic glucose production. J Clin Invest 116(2):521-527, 2006.

DiCostanzo, CA Dardevet, D Neal, D Lautz, M Allen, E Snead W, and Cherrington AD. Role of the hepatic sympathetic nerves in the regulation of net hepatic glucose uptake and the mediation of the portal glucose signal. Am J Physiol 290(1):E9-E16, 2006.

Dardevet D, Moore MC, DiCostanzo CA, Farmer B, Neal D, Snead W Lautz, M and Cherrington, AD. Insulin secretion-independent effects of GLP-1 on canine liver glucose metabolism do not involve portal vein GLP-1 receptors. Am J Physiol 289:G806-G814, 2005.

Gustavson SM, Rajotte RV, Hunkeler D, Lakey JRT, Edgerton DS, Neal DW, Snead WL, Penaloza AR, and Cherrington AD. Islet auto-transplantation results into an omental or splenic site results in a normal beta cell but abnormal alpha cell response to mild non-insulin-induced hypoglycemia. Am J Transplantation 5:2368-2377, 2005.

Grubert JM, Lautz M, Lacy B, Moore MC, Farmer B, Penaloza A, Cherrington AD, and McGuinness OP. Impact of continuous and pulsatile insulin delivery on net hepatic glucose uptake. Am J Physiol 289:E232-E240, 2005.

Moore MC, Kimura K, Shibata H, Honjoh T, Saito M, Everett CA, Smith MS, and Cherrington AD. Portal 5-hydroxytryptophan unfusion enhances glucose disposal in conscious dogs. Am J Physiol 289:E225-E231, 2005.

Edgerton DS, Neal DW, Scott M, Bown L, Wilson W, Hobbs CH, Leach C, Sivakumara S, Strack T, and Cherrington AD. Inhalation of insulin (Exubera®) is associated with augmented disposal of portally infused glucose in dogs. Diabetes 54:E1164-E1170, 2005.

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, Barkham T, Marsh K, Beno D, Hickman B, Edgerton DS, Cherrington AD, Efendic S, and Opgenorth T. Hepatic glucocorticoid receptor antagonism is sufficient to reduce elevated hepatic glucose output and improve glucose control in animal models of type 2 diabetes. JPET 314:191-200, 2005.

DiCostanzo CA, Moore MC, Lautz M, Scott M, Farmer B, Everett CA, Still J, Higgins A, and Cherrington AD. Simulated first-phase insulin release using humulin or an insulin analogue HIM2 is associated with prolonged improvement in post-prandial glycemia. Am J Physiol 289:E46-E52, 2005.

Shiota M, Galassetti P, Igawa K, Neal DW, and Cherrington AD. Inclusion of low amounts of fructose with an intraportal glucose load increases net hepatic glucose uptake (NHGU) in the presence of relative insulin deficiency in the conscious dog. Am J Physiol 288:E1160-E1167, 2005.

Cherrington AD. The role of hepatic insulin receptors in the regulation of glucose production. J Clin Invest 115:1136-1139, 2005.

Moore MC, DiCostanzo CA, Dardevet D, Lautz M, Farmer B, and Cherrington AD. Interaction of a selective serotonin reuptake inhibitor with insulin in the control of hepatic glucose uptake in conscious dogs. Am J Physiol 288:E556-E563, 2005.

Moore MC, DiCostanzo CA, Dardevet D, Lautz M, Farmer B, Neal DW, and Cherrington AD. Portal infusion of a selective serotonin reuptake inhibitor enhances hepatic glucose disposal in conscious dogs. Am J Physiol 287:E1057-E1063, 2004.

Cardin S, Pagliassotti MJ, Moore MC, Edgerton DS, Lautz M, Farmer B, Neal DW, and Cherrington AD. Vagal cooling and concomitant portal norepinephrine infusion do not reduce net hepatic glucose uptake in the conscious dog. Am J Physiol 287:R742-R748, 2004.

Gustavson SM, Chu CA, Nishizawa M, Farmer B, Neal D, Farmer B, Yang Y, Donahue EP, Flakoll P, and Cherrington AD. Effects of hyperglycemia, glucagon and epinephrine on renal glucose release in the conscious dog. Metabolism 53:933-941, 2004.

Dardevet D, Moore MC, Neal D, DiCostanzo CA, Snead W, and Cherrington AD. Insulin-independent effects of GLP-1 on canine liver glucose metabolism: duration of infusion and involvement of hepatoportal region. Am J Physiol 287:E75-E81, 2004.

Chu CA, Fujimoto Y, Igawa K, Grimsby J, Grippo JF, Magnuson MA, Cherrington AD, and Shiota M. Rapid translocation of hepatic glucokinase in response to intraduodenal glucose infusion and changes in plasma glucose and insulin in conscious rat. Am J Physiol 286:G627-634, 2004.

Edgerton DS, Cardin S, Neal D, Farmer B, Lautz M, Pan C, and Cherrington AD. Effects of hyperglycemia on hepatic gluconeogenic flux during glycogen phosphorylase inhibition in the conscious dog. Am J Physiol 286:E510-522, 2004.

Hornbuckle LA, Everett CA, Martin CC, Gustavson SS, Svitek CA, Oeser JK, Neal DW, Cherrington AD, and O’Brien RM. Selective stimulation of G-6-Pase catalytic subunit but not G-6-P transporter gene expression by glucagon in vivo and cAMP in situ. Am J Physiol 286:E795-E808, 2004.

Cherrington AD, Neal DW, Edgerton DS, Glass D, Bowen L, Hobbs CH, Leach C, Rosskamp R, and Strack TR. Inhalation of insulin in dogs. Assessment of insulin levels and comparison to subcutaneous injection. Diabetes 53:877-881, 2004.

Moore MC, Cardin S, Edgerton DS, Farmer B, Neal DW, Lautz M and Cherrington, AD. Unlike mice, dogs exhibit glucoregulation during low-dose portal and peripheral glucose infusion. Am J Physiol 286:E226-E233, 2004.

Moore MC, Satake S, Lautz M, Soleimanpour SA, Neal DW, Smith M, and Cherrington AD. Nonesterified fatty acids and hepatic glucose metabolism in the conscious dog. Diabetes 53:32-40, 2004.

Moore MC, Geho WB Lautz M, Farmer B, Neal DW, and Cherrington AD. Portal serotonin infusion and glucose disposal in conscious dogs. Diabetes 53:14-20, 2004.

Chu CA, Fugimoto Y, Igawa K, Grimsby J, Grippo JF, Magnuson MA, Cherrington AD and Shiota M. Rapid translocation of heaptci glucoskinase in response to intraduodenal glucose infusion and changes in plasma glucose and insulin in conscious rats. Am J Physiol 286(4):G627-634, 2003.

Gustavson SM, Nishizawa M, Farmer B, Neal D, Brissova M, Powers AC, and Cherrington AD. A fall in portal vein insulin does not cause the alpha cell response to mild, non insulin-induced hypoglycemia in conscious dogs. Metabolism 52:1418-1425, 2003.

Gustavson SM, Chu CA, Nishizawa M, Farmer B, Neal D, Yang Y, Vaughan S, Donahue EP, Flakoll P, and Cherrington AD. Glucagon’s actions are modified by the combination of epinephrine and gluconeogenic precursor infusion. Am J Physiol 285:E534-E544, 2003.

Nishizawa, M., Moore, M.C., Shiota, M., Gustavson, S.M., Neal, D.W., Farmer, B., and Cherrington, A.D. Effect of intraportal glucagon-like peptide-1 on glucose metabolism in conscious dogs. Am. J. Physiol. 284:E1027-E1036, 2003.

Jensen, M.D., Cardin, S., Edgerton, D., and Cherrington, A. Splanchnic free fatty acid kinetics. Am. J. Physiol. 284:E1140-E1148, 2003.

Moore, M.C., Burish, M.J., Farmer, B, Neal, D.W., Pan , D., and Cherrington, A.D. Chronic hepatic artery ligation does not prevent the liver from differentiating portal vs. peripheral glucose delivery. Am. J. Physiol. 285:E845-E853, 2003.

Gustavson, S.M., Chu, C.A., Nishizawa, M., Farmer, B., Neal, D., Yang, Y., Donahue, E.P., Flakoll, P., and Cherrington, A.D. Interaction of glucagon and epinephrine in the control of hepatic glucose production in the conscious dogs. Am. J. Physiol. 284:E291-E301, 2003.

Chu, C.A., Galassetti, P., Igawa, K., Sindelar D.K., Neal, D.W., Burish M., and Cherrington, A.D. Interaction of free fatty acids and epinephrine in regulating hepatic glucose production in conscious dogs. Am. J. Physiol. 283:E958-E964, 2002.

Cardin, S., Walmsley, K., Neal, D.W., Williams, P.E. and Cherrington, A.D. Involvement of the vagus nerves in the regulation of basal hepatic glucose production in conscious dog. Am. J. Physiol.283:E958-E964, 2002.

Goldstein, R.E, Rossetti, L., Palmer, B., Liu, R., Massillon, D., Scott, M., Neal, D., Peeler, B., and Cherrington, A.D. The effects of fasting and glucocorticoids on hepatic gluconeogenesis assessed using two independent methods in vivo. Am. J. Physiol. 283:E946-E957, 2002.

Edgerton, D.S., Cardin, S., Pan, C., Neal, D., Farmer, B., Converse, M., and Cherrington, A.D. The effects of insulin deficiency or excess on hepatic gluconeogenic flux during glycogenolytic inhibition in the conscious dog. Diabetes 51, 3151-3162, 2002.

Igawa, K., Mugavero, M., Shiota, M., Neal, D.W., and Cherrington, A.D. Insulin sensitively controls the alpha cell response to hypoglycemia in the dog. Diabetes 50, 3033-3042, 2002.

Dunning, B.E., Moore, M.C., Ikeda T., Neal, D.W., Scott, M.F., and Cherrington, A.D. Evidence for a neurally-mediated incretin effect of portal vs peripheral glucose infusion in conscious dogs. Metabolism 51, 1324-1330, 2002.

Moore, M.C., Cherrington, A.D., Palmer, B., Lacy, D.B., and Goldstein, R.E. Effects of cyclosporine A and prednisone treatment on mixed meal disposition in dogs with hepatic denervation. JPEN 26, 42-50, 2002.

Chu, C.A., Sherck, S., Igawa, K., Sindelar, D.K., Neal, D.W., Emshwiller, M., and Cherrington, A.D. Effects of free fatty acids on hepatic glycogenolysis and gluconeogenesis in conscious dog. Am. J. Physiol. 282, E402-E411, 2002.

Satake, S., Moore, M.C., Shiota, M., Igawa, K., Converse, M., Farmer B., Neal, D.W., and Cherrington, A.D. Direct and indirect effects of insulin on glucose uptake and storage by the liver. Diabetes 51, 1663-1671, 2002.

Shiota, M., Moore, M.C., Galassetti, P, Monohan, M., Neal, D.W., Shulman, G.I., and Cherrington, A.D. Inclusion of low amount of fructose with an intraduodenal glucose load markedly reduces postprandial hyperglycemia and hyperinsulinemia in the conscious dog. Diabetes 51, 469-478, 2002.

Cherrington, A.D., Sindelar, D., Edgerton, D., Steiner, K., and McGuinness, O.P. Physiological consequences of phasic insulin release in the normal animal. Diabetes 51, S103-S108, 2002.

Moore, M.C., Satake, S., Baranowski, B., Hsieh, P-S., Neal, D.W., and Cherrington, A.D. Effect of hepatic denervation on peripheral insulin sensitivity in conscious dogs. Am. J. Physiol. 282, E286-E296, 2002.

Jetton, TL, Shiota, M, Knobel, SM, Piston, DW, Cherrington, AD, and Magnuson, MA. Substrate-induced nuclear export and peripheral compartmentalization of hepatic glucokinase correlates with glycogen deposition. Int. Jnl. Experimental Diab. Res. 2, 173-186, 2001.

Moore, MC, Davis, SN, Mann, SL, and Cherrington, AD. Acute fructose administration improves oral glucose tolerance in adults with type 2 diabetes. Diabetes Care 24, 1882-1887, 2001.

Sherck, SM, Shiota, M, Saccomando, J, Cardin, S, Allen, EJ, Hastings, JR, Neal, DW, Williams PE, and Cherrington, AD. The pancreatic response to mild non insulin-induced hypoglycemia does not involve extrinsic neural input. Diabetes 50, 2487-2496,2001.

Hornbuckle, LA, Edgerton, DS, Ayala, JE, Svitek, CA, Oeser, JK, Neal, DW, Cardin, S, Cherrington, AD, and O 'Brien, RM. Selective, tonic inhibition of G6Pase catalytic subunit but not G6P transporter gene expression by insulin in vivo. Am. J. Physiol. 281, E713-E725, 2001.

Edgerton, DS, Emshwiller, M, Cardin, S, Neal, D, Landau, B, Rossetti, L, and Cherrington, AD. Small increases in insulin inhibit hepatic glucose production solely due to an effect on glycogen metabolism. Diabetes 50, 1872-1882, 2001.

Shiota, M, Postic, C, Fujimoto, U, Jetton, TL, Dixon, K, Pan, D, Grimsby, J, Grippo, JF, Magnuson, MA, and Cherrington, AD. Glucokinase gene locus transgenic mice are resistant to the development of obesity-induced type 2 diabetes mellitus. Diabetes 50, 622-629, 2001.

Cardin, S, Jackson, PA, Edgerton, DS, Neal, DW, and Cherrington, AD. Effect of vagal cooling on the counterregulatory response to hypoglycemia induced by a low dose of insulin in the conscious dog. Diabetes 50, 558-564, 2001.

Flattem, N, Igawa, K, Shiota, M, Emshwiller, MG, Neal, DW, and Cherrington, AD. Alpha and beta cell responses to mild non-insulin induced hypoglycemia in the conscious dog. Diabetes 50, 367-375, 2001.



 

Research Faculties:

Mary(Genie) Moore
Dale Edgerton

Research Fellows:

Chris Ramnanan
Jason Winnick

Graduate Students: Kathryn Johnson
Zhibo An
Noelia Rivera

Technical Staff: Jon Hastings
Doss Neal
Ben Farmer
Maggie Lautz
Tiffany Rodewald
Melanie Scott
Marta Smith




 
Drug Action

One of the most sought after advances in the treatment of diabetes is to non-invasively measure blood glucose. The goals of our studies are to optimize a method, which uses near infrared light to allow glucose measurement without the need to sample blood.

Treatment of type 1 diabetes requires the delivery of insulin through injections or pumps. Regardless of which approach is used, it results in an overinsulinization of muscle or underinsulinization of the liver. This in turn overrules a metabolic cost. We are working with pharmaceutical companies to develop and test insulin analogues, which can be administered by mouth or inhalation. In addition, we are testing insulin vesicles that can be targeted to the liver.

GLP-1 is a peptide released from the gut which stimulates and inhibits glucagon release. It may also have direct metabolic effects on muscle. In view of its therapeutic potential we are investigating its metabolic actions in vivo.

The Portal Signal

Glucose distribution to muscle and liver following feeding is controlled by hormonal, substrate, and neural factors. Of particular importance are the plasma insulin and glucose levels and an unknown signal arising from the brain as a result of a comparison of the arterial system and the portal vein. Little is known about the nature of this signal (its origin, it mechanism of action). Likewise, it is not clear whether other metabolic substrate (i.e. free fatty acids, amino acids) can modify the effect on the liver. We are currently exploring these interactions.

Metabolic Action of Hormones

The plasma glucose level is precisely controlled by the balance between glucose production and glucose utilization. In turn each of these two rates are regulated by potent glucoregulatory feedback loops. The plasma glucose level can be sensed by the hepatocyte directly, by pancreatic a and b cells, and by neural sensors in the portal vein and hypothalamus. Hormonal and neural mediators are released in response to these sensors and they interact to control glucose uptake by muscle and fat and glucose production by the liver. We have studied the effects of the agonists and antagonists shown above on liver glucose production. We are now investigating these effects further and we are beginning to evaluate the interaction of these mediators in controlling liver glucose output.



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 Lab Links

American Diabetes Association

National Institute of Diabetes and Digestive and Kidney Diseases

Vanderbilt Diabetes Research and Training Center

Vanderbilt University Medical Center

Vanderbilt Medical Center Department of Molecular Physiology and Biophysics