Obesity dysregulates fasting-induced changes in glucagon secretion

in Journal of Endocrinology
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  • 1 Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA
  • 2 Center for Human Nutrition, Washington University School of Medicine, Saint Louis, Missouri, USA

Correspondence should be addressed to P E Scherer: philipp.scherer@utsouthwestern.edu

(J H Stern is now at Division of Endocrinology, University of Arizona, College of Medicine, Tucson, Arizona, USA)

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Hyperglucagonemia, a hallmark in obesity and insulin resistance promotes hepatic glucose output, exacerbating hyperglycemia and thus predisposing to the development type 2 diabetes. As such, glucagon signaling is a key target for new therapeutics to manage insulin resistance. We evaluated glucagon homeostasis in lean and obese mice and people. In lean mice, fasting for 24 h caused a rise in glucagon. In contrast, a decrease in serum glucagon compared to baseline was observed in diet-induced obese mice between 8 and 24 h of fasting. Fasting decreased serum insulin in both lean and obese mice. Accordingly, the glucagon:insulin ratio was unaffected by fasting in obese mice but increased in lean mice. Re-feeding (2 h) restored hyperglucagonemia in obese mice. Pancreatic perfusion studies confirm that fasting (16 h) decreases pancreatic glucagon secretion in obese mice. Consistent with our findings in the mouse, a mixed meal increased serum glucagon and insulin concentrations in obese humans, both of which decreased with time after a meal. Consequently, fasting and re-feeding less robustly affected glucagon:insulin ratios in obese compared to lean participants. The glucoregulatory disturbance in obesity may be driven by inappropriate regulation of glucagon by fasting and a static glucagon:insulin ratio.

 

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  • Aguilar-Parada E, Eisentraut AM & Unger RH 1969 Effects of starvation on plasma pancreatic glucagon in normal man. Diabetes 717723. (https://doi.org/10.2337/diab.18.11.717)

    • Search Google Scholar
    • Export Citation
  • Andrikopoulos S, Blair AR, Deluca N, Fam BC & Proietto J 2008 Evaluating the glucose tolerance test in mice. American Journal of Physiology: Endocrinology and Metabolism E1323E1332. (https://doi.org/10.1152/ajpendo.90617.2008)

    • Search Google Scholar
    • Export Citation
  • Ayala JE, Samuel VT, Morton GJ, Obici S, Croniger CM, Shulman GI, Wasserman DH, Mcguinness OP & NIH Mouse Metabolic Phenotyping Center Consortium 2010 Standard operating procedures for describing and performing metabolic tests of glucose homeostasis in mice. Disease Models and Mechanisms 525534. (https://doi.org/10.1242/dmm.006239)

    • Search Google Scholar
    • Export Citation
  • Bagger JI, Knop FK, Lund A, Holst JJ & Vilsboll T 2014 Glucagon responses to increasing oral loads of glucose and corresponding isoglycaemic intravenous glucose infusions in patients with type 2 diabetes and healthy individuals. Diabetologia 17201725. (https://doi.org/10.1007/s00125-014-3264-2)

    • Search Google Scholar
    • Export Citation
  • Baron AD, Schaeffer L, Shragg P & Kolterman OG 1987 Role of hyperglucagonemia in maintenance of increased rates of hepatic glucose output in type II diabetics. Diabetes 274283. (https://doi.org/10.2337/diab.36.3.274)

    • Search Google Scholar
    • Export Citation
  • Beer SF, Bircham PM, Bloom SR, Clark PM, Hales CN, Hughes CM, Jones CT, Marsh DR, Raggatt PR & Findlay AL 1989 The effect of a 72-h fast on plasma levels of pituitary, adrenal, thyroid, pancreatic and gastrointestinal hormones in healthy men and women. Journal of Endocrinology 337350. (https://doi.org/10.1677/joe.0.1200337)

    • Search Google Scholar
    • Export Citation
  • Belfiore F, Iannello S, Rabuazzo AM & Campione R 1987 Metabolic effects of short-term fasting in obese hyperglycaemic humans and mice. International Journal of Obesity 631640.

    • Search Google Scholar
    • Export Citation
  • Benelli C, Desbuquois B & De Galle B 1986 Acute in vivo stimulation of low-Km cyclic AMP phosphodiesterase activity by insulin in rat-liver Golgi fractions. European Journal of Biochemistry 211220. (https://doi.org/10.1111/j.1432-1033.1986.tb09570.x)

    • Search Google Scholar
    • Export Citation
  • Boyle PJ, Shah SD & Cryer PE 1989 Insulin, glucagon, and catecholamines in prevention of hypoglycemia during fasting. American Journal of Physiology E651E661. (https://doi.org/10.1152/ajpendo.1989.256.5.E651)

    • Search Google Scholar
    • Export Citation
  • Cheng-Xue R, Gomez-Ruiz A, Antoine N, Noel LA, Chae HY, Ravier MA, Chimienti F, Schuit FC & Gilon P 2013 Tolbutamide controls glucagon release from mouse islets differently than glucose: involvement of K(ATP) channels from both alpha-cells and delta-cells. Diabetes 16121622. (https://doi.org/10.2337/db12-0347)

    • Search Google Scholar
    • Export Citation
  • Elliott AD, Ustione A & Piston DW 2015 Somatostatin and insulin mediate glucose-inhibited glucagon secretion in the pancreatic alpha-cell by lowering cAMP. American Journal of Physiology: Endocrinology and Metabolism E130E143. (https://doi.org/10.1152/ajpendo.00344.2014)

    • Search Google Scholar
    • Export Citation
  • Elvert R, Herling AW, Bossart M, Weiss T, Zhang B, Wenski P, Wandschneider J, Kleutsch S, Butty U, Kannt A, et al. 2018 Running on mixed fuel-dual agonistic approach of GLP-1 and GCG receptors leads to beneficial impact on body weight and blood glucose control: a comparative study between mice and non-human primates. Diabetes, Obesity and Metabolism 18361851. (https://doi.org/10.1111/dom.13212)

    • Search Google Scholar
    • Export Citation
  • Felig P, Gusberg R, Hendler R, Gump FE, Kinney JM & Mulrow PJ 1974 Concentrations of glucagon and the insulin:glucagon ratio in the portal and peripheral circulation. Proceedings of the Society for Experimental Biology and Medicine 8890. (https://doi.org/10.3181/00379727-147-38286)

    • Search Google Scholar
    • Export Citation
  • Glinsmann WH & Mortimore GE 1968 Influence of glucagon and 3′,5′-AMP on insulin responsiveness of the perfused rat liver. American Journal of Physiology 553559. (https://doi.org/10.1152/ajplegacy.1968.215.3.553)

    • Search Google Scholar
    • Export Citation
  • Guerrero-Romero F & Rodriguez-Moran M 2001 Glucose intolerance is predicted by the high fasting insulin-to-glucose ratio. Diabetes and Metabolism 117121.

    • Search Google Scholar
    • Export Citation
  • Hare KJ, Vilsboll T, Asmar M, Deacon CF, Knop FK & Holst JJ 2010 The glucagonostatic and insulinotropic effects of glucagon-like peptide 1 contribute equally to its glucose-lowering action. Diabetes 17651770. (https://doi.org/10.2337/db09-1414)

    • Search Google Scholar
    • Export Citation
  • Hauge-Evans AC, King AJ, Carmignac D, Richardson CC, Robinson IC, Low MJ, Christie MR, Persaud SJ & Jones PM 2009 Somatostatin secreted by islet delta-cells fulfills multiple roles as a paracrine regulator of islet function. Diabetes 403411. (https://doi.org/10.2337/db08-0792)

    • Search Google Scholar
    • Export Citation
  • Henderson SJ, Konkar A, Hornigold DC, Trevaskis JL, Jackson R, Fritsch Fredin M, Jansson-Lofmark R, Naylor J, Rossi A, Bednarek MA, et al. 2016 Robust anti-obesity and metabolic effects of a dual GLP-1/glucagon receptor peptide agonist in rodents and non-human primates. Diabetes, Obesity and Metabolism 11761190. (https://doi.org/10.1111/dom.12735)

    • Search Google Scholar
    • Export Citation
  • Hojlund K, Wildner-Christensen M, Eshoj O, Skjaerbaek C, Holst JJ, Koldkjaer O, Moller Jensen D & Beck-Nielsen H 2001 Reference intervals for glucose, beta-cell polypeptides, and counterregulatory factors during prolonged fasting. American Journal of Physiology: Endocrinology and Metabolism E50E58. (https://doi.org/10.1152/ajpendo.2001.280.1.E50)

    • Search Google Scholar
    • Export Citation
  • Ipp E 2000 Impaired glucose tolerance: the irrepressible alpha-cell? Diabetes Care 569570. (https://doi.org/10.2337/diacare.23.5.569)

  • Jelinek LJ, Lok S, Rosenberg GB, Smith RA, Grant FJ, Biggs S, Bensch PA, Kuijper JL, Sheppard PO & Sprecher CA 1993 Expression cloning and signaling properties of the rat glucagon receptor. Science 16141616. (https://doi.org/10.1126/science.8384375)

    • Search Google Scholar
    • Export Citation
  • Jensen TL, Kiersgaard MK, Sorensen DB & Mikkelsen LF 2013 Fasting of mice: a review. Laboratory Animals 225240. (https://doi.org/10.1177/0023677213501659)

    • Search Google Scholar
    • Export Citation
  • Jewell JL, Fu V, Hong AW, Yu FX, Meng D, Melick CH, Wang H, Lam WM, Yuan HX, Taylor SS, et al. 2019 GPCR signaling inhibits mTORC1 via PKA phosphorylation of raptor. eLife e43038. (https://doi.org/10.7554/eLife.43038)

    • Search Google Scholar
    • Export Citation
  • Kawamori D, Kurpad AJ, Hu J, Liew CW, Shih JL, Ford EL, Herrera PL, Polonsky KS, Mcguinness OP & Kulkarni RN 2009 Insulin signaling in alpha cells modulates glucagon secretion in vivo. Cell Metabolism 350361. (https://doi.org/10.1016/j.cmet.2009.02.007)

    • Search Google Scholar
    • Export Citation
  • Kazda CM, Ding Y, Kelly RP, Garhyan P, Shi C, Lim CN, Fu H, Watson DE, Lewin AJ, Landschulz WH, et al. 2016 Evaluation of efficacy and safety of the glucagon receptor antagonist LY2409021 in patients with type 2 diabetes: 12- and 24-week phase 2 studies. Diabetes Care 12411249. (https://doi.org/10.2337/dc15-1643)

    • Search Google Scholar
    • Export Citation
  • Knop FK, Vilsboll T, Madsbad S, Holst JJ & Krarup T 2007 Inappropriate suppression of glucagon during OGTT but not during isoglycaemic i.v. glucose infusion contributes to the reduced incretin effect in type 2 diabetes mellitus. Diabetologia 797805. (https://doi.org/10.1007/s00125-006-0566-z)

    • Search Google Scholar
    • Export Citation
  • Koo SH, Flechner L, Qi L, Zhang X, Screaton RA, Jeffries S, Hedrick S, Xu W, Boussouar F, Brindle P, et al. 2005 The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature 11091111. (https://doi.org/10.1038/nature03967)

    • Search Google Scholar
    • Export Citation
  • Kostic A, King TA, Yang F, Chan KC, Yancopoulos GD, Gromada J & Harp JB 2018 A first-in-human pharmacodynamic and pharmacokinetic study of a fully human anti-glucagon receptor monoclonal antibody in normal healthy volunteers. Diabetes, Obesity and Metabolism 283291. (https://doi.org/10.1111/dom.13075)

    • Search Google Scholar
    • Export Citation
  • Krebs S, Fischaleck M & Blum H 2009 A simple and loss-free method to remove Trizol contaminations from minute RNA samples. Analytical Biochemistry 136138. (https://doi.org/10.1016/j.ab.2008.12.020)

    • Search Google Scholar
    • Export Citation
  • Larsson H & Ahren B 2000 Islet dysfunction in insulin resistance involves impaired insulin secretion and increased glucagon secretion in postmenopausal women with impaired glucose tolerance. Diabetes Care 650657. (https://doi.org/10.2337/diacare.23.5.650)

    • Search Google Scholar
    • Export Citation
  • Lavine RL, Voyles N, Perrino PV & Recant L 1975 The effect of fasting on tissue cyclic cAMP and plasma glucagon in the obese hyperglycemic mouse. Endocrinology 615620. (https://doi.org/10.1210/endo-97-3-615)

    • Search Google Scholar
    • Export Citation
  • Lee Y, Wang MY, Du XQ, Charron MJ & Unger RH 2011 Glucagon receptor knockout prevents insulin-deficient type 1 diabetes in mice. Diabetes 391397. (https://doi.org/10.2337/db10-0426)

    • Search Google Scholar
    • Export Citation
  • Lee Y, Berglund ED, Yu X, Wang MY, Evans MR, Scherer PE, Holland WL, Charron MJ, Roth MG & Unger RH 2014 Hyperglycemia in rodent models of type 2 diabetes requires insulin-resistant alpha cells. PNAS 1321713222. (https://doi.org/10.1073/pnas.1409638111)

    • Search Google Scholar
    • Export Citation
  • Legro RS, Finegood D & Dunaif A 1998 A fasting glucose to insulin ratio is a useful measure of insulin sensitivity in women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 26942698. (https://doi.org/10.1210/jcem.83.8.5054)

    • Search Google Scholar
    • Export Citation
  • Livak KJ & Schmittgen TD 2001 Analysis of relative gene expression data using real-time quantitative PCR and the 2(-delta delta C(T)) method. Methods 402408. (https://doi.org/10.1006/meth.2001.1262)

    • Search Google Scholar
    • Export Citation
  • Lo S, Russell JC & Taylor AW 1970 Determination of glycogen in small tissue samples. Journal of Applied Physiology 234236. (https://doi.org/10.1152/jappl.1970.28.2.234)

    • Search Google Scholar
    • Export Citation
  • Lu M, Wan M, Leavens KF, Chu Q, Monks BR, Fernandez S, Ahima RS, Ueki K, Kahn CR & Birnbaum MJ 2012 Insulin regulates liver metabolism in vivo in the absence of hepatic Akt and FoxO1. Nature Medicine 388395. (https://doi.org/10.1038/nm.2686)

    • Search Google Scholar
    • Export Citation
  • Mackrell DJ & Sokal JE 1969 Antagonism between the effects of insulin and glucagon on the isolated liver. Diabetes 724732. (https://doi.org/10.2337/diab.18.11.724)

    • Search Google Scholar
    • Export Citation
  • Marliss EB, Aoki TT, Unger RH, Soeldner JS & Cahill GF 1970 Glucagon levels and metabolic effects in fasting man. Journal of Clinical Investigation 22562270. (https://doi.org/10.1172/JCI106445)

    • Search Google Scholar
    • Export Citation
  • Maruyama H, Hisatomi A, Orci L, Grodsky GM & Unger RH 1984 Insulin within islets is a physiologic glucagon release inhibitor. Journal of Clinical Investigation 22962299. (https://doi.org/10.1172/JCI111658)

    • Search Google Scholar
    • Export Citation
  • Mifflin MD, St Jeor ST, Hill LA, Scott BJ, Daugherty SA & Koh YO 1990 A new predictive equation for resting energy expenditure in healthy individuals. American Journal of Clinical Nutrition 241247. (https://doi.org/10.1093/ajcn/51.2.241)

    • Search Google Scholar
    • Export Citation
  • Muller WA, Faloona GR, Aguilar-Parada E & Unger RH 1970 Abnormal alpha-cell function in diabetes. Response to carbohydrate and protein ingestion. New England Journal of Medicine 109115. (https://doi.org/10.1056/NEJM197007162830301)

    • Search Google Scholar
    • Export Citation
  • Mutel E, Gautier-Stein A, Abdul-Wahed A, Amigo-Correig M, Zitoun C, Stefanutti A, Houberdon I, Tourette JA, Mithieux G & Rajas F 2011 Control of blood glucose in the absence of hepatic glucose production during prolonged fasting in mice: induction of renal and intestinal gluconeogenesis by glucagon. Diabetes 31213131. (https://doi.org/10.2337/db11-0571)

    • Search Google Scholar
    • Export Citation
  • Nair KS, Woolf PD, Welle SL & Matthews DE 1987 Leucine, glucose, and energy metabolism after 3 days of fasting in healthy human subjects. American Journal of Clinical Nutrition 557562. (https://doi.org/10.1093/ajcn/46.4.557)

    • Search Google Scholar
    • Export Citation
  • Nauck MA, Kleine N, Orskov C, Holst JJ, Willms B & Creutzfeldt W 1993 Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7–36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia 741744. (https://doi.org/10.1007/bf00401145)

    • Search Google Scholar
    • Export Citation
  • Nuttall FQ, Almokayyad RM & Gannon MC 2015 Comparison of a carbohydrate-free diet vs. fasting on plasma glucose, insulin and glucagon in type 2 diabetes. Metabolism: Clinical and Experimental 253262. (https://doi.org/10.1016/j.metabol.2014.10.004)

    • Search Google Scholar
    • Export Citation
  • Parrilla R, Goodman MN & Toews CJ 1974 Effect of glucagon: insulin ratios on hepatic metabolism. Diabetes 725731. (https://doi.org/10.2337/diab.23.9.725)

    • Search Google Scholar
    • Export Citation
  • Ramakers C, Ruijter JM, Deprez RH & Moorman AF 2003 Assumption-free analysis of quantitative real-time polymerase chain reaction (PCR) data. Neuroscience Letters 6266. (https://doi.org/10.1016/s0304-3940(02)01423-4)

    • Search Google Scholar
    • Export Citation
  • Rehfuss RP, Walton KM, Loriaux MM & Goodman RH 1991 The cAMP-regulated enhancer-binding protein ATF-1 activates transcription in response to cAMP-dependent protein kinase A. Journal of Biological Chemistry 1843118434.

    • Search Google Scholar
    • Export Citation
  • Rivero-Gutierrez B, Haller A, Holland J, Yates E, Khrisna R, Habegger K, Dimarchi R, D’Alessio D & Perez-Tilve D 2018 Deletion of the glucagon receptor gene before and after experimental diabetes reveals differential protection from hyperglycemia. Molecular Metabolism 2838. (https://doi.org/10.1016/j.molmet.2018.07.012)

    • Search Google Scholar
    • Export Citation
  • Salem V, Izzi-Engbeaya C, Coello C, Thomas DB, Chambers ES, Comninos AN, Buckley A, Win Z, Al-Nahhas A, Rabiner EA, et al. 2016 Glucagon increases energy expenditure independently of brown adipose tissue activation in humans. Diabetes, Obesity and Metabolism 7281. (https://doi.org/10.1111/dom.12585)

    • Search Google Scholar
    • Export Citation
  • Seitz HJ, Muller MJ, Krone W & Tarnowski W 1977 Coordinate control of intermediary metabolism in rat liver by the insulin/glucagon ratio during starvation and after glucose refeeding. Regulatory significance of long-chain acyl-CoA and cyclic AMP. Archives of Biochemistry and Biophysics 647663. (https://doi.org/10.1016/0003-9861(77)90399-x)

    • Search Google Scholar
    • Export Citation
  • Shah P, Vella A, Basu A, Basu R, Schwenk WF & Rizza RA 2000 Lack of suppression of glucagon contributes to postprandial hyperglycemia in subjects with type 2 diabetes mellitus. Journal of Clinical Endocrinology and Metabolism 40534059. (https://doi.org/10.1210/jcem.85.11.6993)

    • Search Google Scholar
    • Export Citation
  • Singh V, Grotzinger C, Nowak KW, Zacharias S, Goncz E, Pless G, Sauer IM, Eichhorn I, Pfeiffer-Guglielmi B, Hamprecht B, et al. 2007 Somatostatin receptor subtype-2-deficient mice with diet-induced obesity have hyperglycemia, nonfasting hyperglucagonemia, and decreased hepatic glycogen deposition. Endocrinology 38873899. (https://doi.org/10.1210/en.2006-1659)

    • Search Google Scholar
    • Export Citation
  • Sun P, Lou L & Maurer RA 1996 Regulation of activating transcription factor-1 and the cAMP response element-binding protein by Ca2+/calmodulin-dependent protein kinases type I, II, and IV. Journal of Biological Chemistry 30663073. (https://doi.org/10.1074/jbc.271.6.3066)

    • Search Google Scholar
    • Export Citation
  • Townsend LK, Medak KD, Peppler WT, Meers GM, Rector RS, Leblanc PJ & Wright DC 2019 High-saturated-fat diet-induced obesity causes hepatic interleukin-6 resistance via endoplasmic reticulum stress. Journal of Lipid Research 12361249. (https://doi.org/10.1194/jlr.M092510)

    • Search Google Scholar
    • Export Citation
  • Unger RH 1971 Glucagon and the insulin: glucagon ratio in diabetes and other catabolic illnesses. Diabetes 834838. (https://doi.org/10.2337/diab.20.12.834)

    • Search Google Scholar
    • Export Citation
  • Unger RH & Orci L 1975 The essential role of glucagon in the pathogenesis of diabetes mellitus. Lancet 1416. (https://doi.org/10.1016/s0140-6736(75)92375-2)

    • Search Google Scholar
    • Export Citation
  • Unger RH, Madison LL & Muller WA 1972 Abnormal alpha cell function in diabetics response to insulin. Diabetes 301307. (https://doi.org/10.2337/diab.21.5.301)

    • Search Google Scholar
    • Export Citation
  • Vajda EG, Logan D, Lasseter K, Armas D, Plotkin DJ, Pipkin JD, Li YX, Zhou R, Klein D, Wei X, et al. 2017 Pharmacokinetics and pharmacodynamics of single and multiple doses of the glucagon receptor antagonist LGD-6972 in healthy subjects and subjects with type 2 diabetes mellitus. Diabetes, Obesity and Metabolism 2432. (https://doi.org/10.1111/dom.12752)

    • Search Google Scholar
    • Export Citation
  • Vuguin P, Saenger P & Dimartino-Nardi J 2001 Fasting glucose insulin ratio: a useful measure of insulin resistance in girls with premature adrenarche. Journal of Clinical Endocrinology and Metabolism 46184621. (https://doi.org/10.1210/jcem.86.10.7956)

    • Search Google Scholar
    • Export Citation
  • Wargent ET 2009 The measurement of insulin secretion using pancreas perfusion in the rodent. Methods in Molecular Biology 203219. (https://doi.org/10.1007/978-1-59745-448-3_14)

    • Search Google Scholar
    • Export Citation
  • Zhang X, Odom DT, Koo SH, Conkright MD, Canettieri G, Best J, Chen H, Jenner R, Herbolsheimer E, Jacobsen E, et al. 2005 Genome-wide analysis of cAMP-response element binding protein occupancy, phosphorylation, and target gene activation in human tissues. PNAS 44594464. (https://doi.org/10.1073/pnas.0501076102)

    • Search Google Scholar
    • Export Citation