Glukos, även kallat blodsocker, är en viktig energikälla för kroppen. Högt blodsocker är emellertid skadligt för kroppen och kan leda till att komplikat- ioner utvecklas över tid. Sjukdomen där man har högt blodsocker kallas dia- betes. Det finns många olika bakomliggande orsaker till det höga blodsockret och diabetes är därför indelat i flera olika typer. Det har uppskattats att 5 mil- joner dödsfall årligen i världen kan kopplas till komplikationer till följd av diabetes. Hos en frisk person reglerar kroppen blodsockernivåerna väldigt noggrant i ett smalt koncentrationsfönster. Många olika hormoner och fysio- logiska faktorer är inblandade i denna reglering, kallad glukoshomeostas. För att utvärdera olika aspekter av glukoshomeostasen och effekten av intervent- ioner, såsom läkemedel, kan man utföra glukostoleranstest. I dessa tester ger man glukos antingen oralt eller intravenöst och mäter koncentrationen av glu- kos och andra viktiga faktorer i blodet.
Matematiska modeller är värdefulla verktyg i läkemedelsutveckling och kan användas för att öka förståelsen för komplexa system såsom glukosho- meostasen, kvantifiera läkemedelseffekter och göra läkemedelsutvecklings processen mer effektiv. I denna avhandling har en ny omfattande matematisk modell utvecklats som beskriver de viktigaste aspekterna av glukoshomeostas under glukostoleranstest i båda friska individer och patienter med typ 2 diabe- tes. Modellen kan simultant beskriva reglering av magtömning och glukos- absorption, reglering av två hormoner som ökar utsöndringen av insulin efter oralt intag av glukos, den ökade insulinsekretionen efter oralt intag av glukos, leverns upptag av nyligen framställt insulin, regleringen av hormonet gluka- gon som i motsats till insulin ökar blodsockernivåerna, samt regleringen av kroppseget bildande av blodsocker. Därutöver beskriver denna avhandling hur man kan skala en tidigare utvecklad modell för människa så den kan beskriva glukoshomeostas även i mus, råtta, gris, hund och apa.
Sammanfattningsvis så ökar de utvecklade modellerna i denna avhandling kunskapen om regleringen av glukoshomeostas under glukostoleranstest. De kan användas för att undersöka kombinationsbehandlingar och läkemedel med flera olika effekter, samt att de öppnar upp möjligheten att effektivt skala lä- kemedelseffekter mellan arter, vilket kan leda till förbättrad läkemedelsut- veckling och i förlängningen nya läkemedel mot typ 2 diabetes.
Acknowledgements
The work presented in this thesis was carried out at the Department of Phar- maceutical Biosciences, Faculty of Pharmacy, Uppsala University. I am grate- ful to DDMoRe for funding parts of this work, and additional travel grants from Apotekarsocieteten and the Anna-Maria Lundin foundation at Smålands nation who provided the opportunity for me to attend international confer- ences.
I would like to express my sincerer gratitude to all who have contributed, di- rectly or indirectly, to this thesis and especially to:
My main supervisor Associate Professor Maria Kjellsson, for sharing knowledge, guidance and supporting me with positive encouragement. My co-supervisor Professor Mats Karlsson for being a brilliant scientist and sharing your enthusiasm for the science of pharmacometrics.
Diabetes group members through time: Steve, Rikke, Siti, Moustafa, Gustav and Kanji for our scientific discussions during weekly meetings.
I would also like to thank all PhD-students, post-docs, administrators, teachers past and present who have contributed to the kind and inspirational atmos- phere at the department. Special thanks to Oskar C, Jörgen, Anders K and Sofia.
Master student Sara Ericsson for doing awesome work with the glucagon model.
Agneta for formatting and proofreading of the manuscripts in this thesis. My collaborators and co-authors who contributed with data and knowledge, making this thesis possible.
The most important thing, my family! Linda, Edith and Majken without you this thesis would not matter.
References
1. Aronoff SL, Berkowitz K, Shreiner B, Want L. Glucose metabolism and reg- ulation: beyond insulin and glucagon. Diabetes Spectrum 2004, 17(3): 183- 190.
2. Silverthorn DU. Human Physiology: An Integrated Approach, Media Update:
International Edition. Pearson Education, 2008.
3. LeRoith D. β-cell dysfunction and insulin resistance in type 2 diabetes: role of metabolic and genetic abnormalities. The American journal of medicine 2002, 113(6): 3-11.
4. Jones A, Hattersley A. The clinical utility of C‐peptide measurement in the care of patients with diabetes. Diabetic Medicine 2013, 30(7): 803-817. 5. Lund A, Bagger JI, Christensen M, Knop FK, Vilsbøll T. Glucagon and type 2
diabetes: the return of the alpha cell. Current diabetes reports 2014, 14(12): 555.
6. Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterol-
ogy 2007, 132(6): 2131-2157.
7. Holst JJ. The physiology of glucagon-like peptide 1. Physiological reviews 2007, 87(4): 1409-1439.
8. Kim W, Egan JM. The role of incretins in glucose homeostasis and diabetes treatment. Pharmacological reviews 2008, 60(4): 470-512.
9. Brener W, Hendrix TR, McHugh PR. Regulation of the gastric emptying of glucose. Gastroenterology 1983, 85(1): 76-82.
10. Hellström PM, Grybäck P, Jacobsson H. The physiology of gastric emptying.
Best Practice & Research Clinical Anaesthesiology 2006, 20(3): 397-407.
11. Muniyappa R, Madan R, Quon MJ. Assessing insulin sensitivity and resistance in humans. 2015.
12. Myers GB, McKean RM. The oral glucose tolerance test: A review of the lit- erature. American Journal of Clinical Pathology 1935, 5(4): 299-312. 13. Association AD. 2. Classification and Diagnosis of Diabetes: Standards of
Medical Care in Diabetes—2018. Diabetes Care 2018, 41(Supplement 1): S13-S27.
14. Creutzfeldt W, Ebert R. New developments in the incretin concept. Diabeto-
logia 1985, 28(8): 565-573.
15. Perley MJ, Kipnis DM. Plasma insulin responses to oral and intravenous glu- cose: studies in normal and diabetic subjects. The Journal of clinical investi-
gation 1967, 46(12): 1954-1962.
16. Brodovicz KG, Girman CJ, Simonis-Bik AM, Rijkelijkhuizen JM, Zelis M, Bunck MC, et al. Postprandial metabolic responses to mixed versus liquid meal tests in healthy men and men with type 2 diabetes. Diabetes research and clin-
ical practice 2011, 94(3): 449-455.
17. DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. American Journal of Physiology-
18. Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circula-
tion research 2010, 107(9): 1058-1070.
19. Rask-Madsen C, King GL. Vascular complications of diabetes: mechanisms of injury and protective factors. Cell metabolism 2013, 17(1): 20-33.
20. Vlassara H, Uribarri J. Advanced glycation end products (AGE) and diabetes: cause, effect, or both? Current diabetes reports 2014, 14(1): 453.
21. Ogurtsova K, da Rocha Fernandes J, Huang Y, Linnenkamp U, Guariguata L, Cho N, et al. IDF Diabetes Atlas: Global estimates for the prevalence of dia- betes for 2015 and 2040. Diabetes research and clinical practice 2017, 128: 40-50.
22. Forouzanfar MH, Alexander L, Anderson HR, Bachman VF, Biryukov S, Brauer M, et al. Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clus- ters of risks in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. The Lancet 2015, 386(10010): 2287-2323. 23. Organization WH. Global report on diabetes. World Health Organization,
2016.
24. Weir GC, Bonner-Weir S. Five stages of evolving beta-cell dysfunction during progression to diabetes. Diabetes 2004, 53(suppl 3): S16-S21.
25. Kahn S. The relative contributions of insulin resistance and beta-cell dysfunc- tion to the pathophysiology of type 2 diabetes. Diabetologia 2003, 46(1): 3- 19.
26. Chatterjee S, Khunti K, Davies MJ. Type 2 diabetes. The Lancet 2017, 389(10085): 2239-2251.
27. Nolan CJ, Damm P, Prentki M. Type 2 diabetes across generations: from path- ophysiology to prevention and management. The Lancet 2011, 378(9786): 169-181.
28. Ette EI, Williams PJ. Pharmacometrics: the science of quantitative pharma-
cology. John Wiley & Sons, 2013.
29. EFPIA M, Marshall S, Burghaus R, Cosson V, Cheung S, Chenel M, et al. Good Practices in Model-Informed Drug Discovery and Development: Prac- tice, Application, and Documentation. CPT: pharmacometrics & systems
pharmacology 2016, 5(3): 93.
30. Ajmera I, Swat M, Laibe C, Le Novere N, Chelliah V. The impact of mathe- matical modeling on the understanding of diabetes and related complications.
CPT: pharmacometrics & systems pharmacology 2013, 2(7): 1-14.
31. Landersdorfer CB, Jusko WJ. Pharmacokinetic/pharmacodynamic modelling in diabetes mellitus. Clinical pharmacokinetics 2008, 47(7): 417-448. 32. Silber HE, Jauslin PM, Frey N, Gieschke R, Simonsson US, Karlsson MO. An
integrated model for glucose and insulin regulation in healthy volunteers and type 2 diabetic patients following intravenous glucose provocations. The Jour-
nal of Clinical Pharmacology 2007, 47(9): 1159-1171.
33. Silber HE, Frey N, Karlsson MO. An integrated glucose‐insulin model to de- scribe oral glucose tolerance test data in healthy volunteers. The Journal of
Clinical Pharmacology 2010, 50(3): 246-256.
34. Jauslin PM, Silber HE, Frey N, Gieschke R, Simonsson US, Jorga K, et al. An integrated glucose‐insulin model to describe oral glucose tolerance test data in type 2 diabetics. The Journal of Clinical Pharmacology 2007, 47(10): 1244- 1255.
35. Jauslin PM, Frey N, Karlsson MO. Modeling of 24‐hour glucose and insulin profiles of patients with type 2 diabetes. The Journal of Clinical Pharmacology 2011, 51(2): 153-164.
36. Alonso LC, Watanabe Y, Stefanovski D, Lee EJ, Singamsetty S, Romano LC,
et al. Simultaneous measurement of insulin sensitivity, insulin secretion, and
the disposition index in conscious unhandled mice. Obesity 2012, 20(7): 1403- 1412.
37. Frangioudakis G, Gyte AC, Loxham SJ, Poucher SM. The intravenous glucose tolerance test in cannulated Wistar rats: a robust method for the in vivo assess- ment of glucose-stimulated insulin secretion. Journal of pharmacological and
toxicological methods 2008, 57(2): 106-113.
38. Hara H, Lin YJ, Zhu X, Tai H-C, Ezzelarab M, Balamurugan A, et al. Safe induction of diabetes by high-dose streptozotocin in pigs. Pancreas 2008, 36(1): 31-38.
39. Ionut V, Liu H, Mooradian V, Castro AVB, Kabir M, Stefanovski D, et al. Novel canine models of obese prediabetes and mild type 2 diabetes. American
Journal of Physiology-Endocrinology and Metabolism 2009, 298(1): E38-
E48.
40. Vicini P, Caumo A, Cobelli C. The hot IVGTT two-compartment minimal model: indexes of glucose effectiveness and insulin sensitivity. American
Journal of Physiology-Endocrinology And Metabolism 1997, 273(5): E1024-
E1032.
41. Vicini P, Zachwieja JJ, Yarasheski KE, Bier DM, Caumo A, Cobelli C. Glu- cose production during an IVGTT by deconvolution: validation with the tracer- to-tracee clamp technique. American Journal of Physiology-Endocrinology
And Metabolism 1999, 276(2): E285-E294.
42. Mori A, Sato T, Lee P, Furuuchi M, Tazaki H, Katayama K, et al. Clinical significance of plasma mannose concentrations in healthy and diabetic dogs.
Veterinary research communications 2009, 33(5): 439-451.
43. Knop F, Vilsbøll T, Larsen S, Madsbad S, Holst JJ, Krarup T. Glucagon sup- pression during OGTT worsens while suppression during IVGTT sustains alongside development of glucose intolerance in patients with chronic pancre- atitis. Regulatory peptides 2010, 164(2-3): 144-150.
44. Casu A, Bottino R, Balamurugan A, Hara H, Van Der Windt D, Campanile N,
et al. Metabolic aspects of pig-to-monkey (Macaca fascicularis) islet transplan-
tation: implications for translation into clinical practice. Diabetologia 2008, 51(1): 120-129.
45. Dyson MC, Alloosh M, Vuchetich JP, Mokelke EA, Sturek M. Components of metabolic syndrome and coronary artery disease in female Ossabaw swine fed excess atherogenic diet. Comparative medicine 2006, 56(1): 35-45.
46. Brott DA, Diamond M, Campbell P, Zuvich A, Cheatham L, Bentley P, et al. An acute rat in vivo screening model to predict compounds that alter blood glucose and/or insulin regulation. Journal of pharmacological and toxicologi-
cal methods 2013, 68(2): 190-196.
47. Bagger JI, Knop FK, Lund A, Holst JJ, Vilsbøll T. Glucagon responses to in- creasing oral loads of glucose and corresponding isoglycaemic intravenous glucose infusions in patients with type 2 diabetes and healthy individuals. Di-
abetologia 2014, 57(8): 1720-1725.
48. Bagger JI, Knop FK, Lund A, Vestergaard H, Holst JJ, Vilsbøll T. Impaired regulation of the incretin effect in patients with type 2 diabetes. The Journal of
Clinical Endocrinology & Metabolism 2011, 96(3): 737-745.
49. Overgaard RV, Jelic K, Karlsson M, Henriksen JE, Madsen H. Mathematical beta cell model for insulin secretion following IVGTT and OGTT. Annals of
50. Adolph EF. Quantitative relations in the physiological constitutions of mam- mals. Science 1949, 109(2841): 579-585.
51. Anderson BJ, McKee AD, Holford NH. Size, myths and the clinical pharma- cokinetics of analgesia in paediatric patients. Clinical pharmacokinetics 1997, 33(5): 313-327.
52. Holford NH. A size standard for pharmacokinetics. Clinical pharmacokinetics 1996, 30(5): 329-332.
53. West GB, Brown JH, Enquist BJ. A general model for the origin of allometric scaling laws in biology. Science 1997, 276(5309): 122-126.
54. Beal S, Sheiner, L.B., Boeckmann, A., & Bauer, R.J.,. NONMEM User's Guides. (1989-2009). Ellicott City, MD, USA: Icon Development Solutions; 2009.
55. R Core Team. R: A language and environment for statistical computing. Vi- enna, Austria: R Foundation for Statistical Computing; 2015.
56. Jonsson EN, Karlsson MO. Xpose—an S-PLUS based population pharmaco- kinetic/pharmacodynamic model building aid for NONMEM. Computer meth-
ods and programs in biomedicine 1998, 58(1): 51-64.
57. H. Wickham. ggplot2: Elegant Graphics for Data Analysis. New York: Springer-Verlag; 2009.
58. Lindbom L, Pihlgren P, Jonsson N. PsN-Toolkit—a collection of computer in- tensive statistical methods for non-linear mixed effect modeling using NON- MEM. Computer methods and programs in biomedicine 2005, 79(3): 241-257. 59. Keizer RJ, Van Benten M, Beijnen JH, Schellens JH, Huitema AD. Pirana and PCluster: a modeling environment and cluster infrastructure for NONMEM.
Computer methods and programs in biomedicine 2011, 101(1): 72-79.
60. Bergstrand M, Hooker AC, Wallin JE, Karlsson MO. Prediction-corrected vis- ual predictive checks for diagnosing nonlinear mixed-effects models. The
AAPS journal 2011, 13(2): 143-151.
61. Dosne A-G, Bergstrand M, Harling K, Karlsson MO. Improving the estimation of parameter uncertainty distributions in nonlinear mixed effects models using sampling importance resampling. Journal of pharmacokinetics and pharmaco-
dynamics 2016, 43(6): 583-596.
62. Mould D, Upton RN. Basic concepts in population modeling, simulation, and model‐based drug development—part 2: introduction to pharmacokinetic modeling methods. CPT: pharmacometrics & systems pharmacology 2013, 2(4): 1-14.
63. Deacon CF, Nauck MA, Meier J, Hücking K, Holst JJ. Degradation of endog- enous and exogenous gastric inhibitory polypeptide in healthy and in type 2 diabetic subjects as revealed using a new assay for the intact peptide. The Jour-
nal of Clinical Endocrinology & Metabolism 2000, 85(10): 3575-3581.
64. Holst JJ, Deacon C, TOFT‐NIELSEN MB, BJERRE‐KNUDSEN L. On the Treatment of Diabetes Mellitus with Glucagon‐like Peptide‐1. Annals of the
New York Academy of Sciences 1998, 865(1): 336-343.
65. Pontiroli A, Calderara A, Perfetti M, Bareggi S. Pharmacokinetics of intrana- sal, intramuscular and intravenous glucagon in healthy subjects and diabetic patients. European journal of clinical pharmacology 1993, 45(6): 555-558. 66. Samols E, Marri G, Marks V. Interrelationship of glucagon, insulin and glu-
cose: the insulinogenic effect of glucagon. Diabetes 1966, 15(12): 855-866. 67. Unger RH, Eisentraut AM, McCall M, Madison LL. Glucagon antibodies and
an immunoassay for glucagon. The Journal of clinical investigation 1961, 40(7): 1280-1289.
68. Snyder W, Cook M, Nasset E, Karhausen L, Howells GP, Tipton I. Report of the task group on reference man. International Commission on Radiological Protection no. 23. Pergamon Press, Oxford22 Rieth N et al (2009) Effects of
short-term corticoid ingestion on food intake and adipokines in healthy recre- ationally trained men Eur J Appl Physiol 1975, 105(2): 309313.
69. Clements J, Heading R, Nimmo W, Prescott L. Kinetics of acetaminophen ab- sorption and gastric emptying in man. Clinical Pharmacology & Therapeutics 1978, 24(4): 420-431.
70. Korsgren E, Korsgren O. Glucose effectiveness: the mouse trap in the devel- opment of novel ss-cell replacement therapies. Transplantation 2016, 100(1): 111-115.
71. McArthur MD, You D, Klapstein K, Finegood DT. Glucose effectiveness is the major determinant of intravenous glucose tolerance in the rat. American
Journal of Physiology-Endocrinology And Metabolism 1999, 276(4): E739-
E746.
72. Grodsky GM. A threshold distribution hypothesis for packet storage of insulin and its mathematical modeling. The Journal of clinical investigation 1972, 51(8): 2047-2059.
73. Van Cauter E, Mestrez F, Sturis J, Polonsky KS. Estimation of insulin secre- tion rates from C-peptide levels: comparison of individual and standard kinetic parameters for C-peptide clearance. Diabetes 1992, 41(3): 368-377.
74. Meier JJ, Gallwitz B, Kask B, Deacon CF, Holst JJ, Schmidt WE, et al. Stim- ulation of insulin secretion by intravenous bolus injection and continuous in- fusion of gastric inhibitory polypeptide in patients with type 2 diabetes and healthy control subjects. Diabetes 2004, 53(suppl 3): S220-S224.
75. Nauck MA, Heimesaat MM, Orskov C, Holst JJ, Ebert R, Creutzfeldt W. Pre- served incretin activity of glucagon-like peptide 1 [7-36 amide] but not of syn- thetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. The Journal of clinical investigation 1993, 91(1): 301-307.
76. Vilsbøll T, Krarup T, Madsbad S, Holst J. Defective amplification of the late phase insulin response to glucose by GIP in obese type II diabetic patients.
Diabetologia 2002, 45(8): 1111-1119.
77. Schneck KB, Zhang X, Bauer R, Karlsson MO, Sinha VP. Assessment of gly- cemic response to an oral glucokinase activator in a proof of concept study: application of a semi-mechanistic, integrated glucose-insulin-glucagon model.
Journal of pharmacokinetics and pharmacodynamics 2013, 40(1): 67-80.
78. Pappenheimer J, Reiss KZ. Contribution of solvent drag through intercellular junctions to absorption of nutrients by the small intestine of the rat. The Jour-
nal of membrane biology 1987, 100(1): 123-136.
79. Anderwald C, Gastaldelli A, Tura A, Krebs M, Promintzer-Schifferl M, Kau- tzky-Willer A, et al. Mechanism and effects of glucose absorption during an oral glucose tolerance test among females and males. The Journal of Clinical
Endocrinology & Metabolism 2011, 96(2): 515-524.
80. Yoshikawa T, Inoue R, Matsumoto M, Yajima T, Ushida K, Iwanaga T. Com- parative expression of hexose transporters (SGLT1, GLUT1, GLUT2 and GLUT5) throughout the mouse gastrointestinal tract. Histochemistry and cell
biology 2011, 135(2): 183-194.
81. Siegel J, Urbain J, Adler L, Charkes N, Maurer A, Krevsky B, et al. Biphasic nature of gastric emptying. Gut 1988, 29(1): 85-89.
82. Collins P, Horowitz M, Cook D, Harding P, Shearman D. Gastric emptying in normal subjects--a reproducible technique using a single scintillation camera and computer system. Gut 1983, 24(12): 1117-1125.
83. Hunt J, Stubbs D. The volume and energy content of meals as determinants of gastric emptying. The Journal of physiology 1975, 245(1): 209-225.
84. Mudie DM, Murray K, Hoad CL, Pritchard SE, Garnett MC, Amidon GL, et
al. Quantification of gastrointestinal liquid volumes and distribution following
a 240 mL dose of water in the fasted state. Molecular pharmaceutics 2014, 11(9): 3039-3047.
85. Ritzel U, Fromme A, Ottleben M, Leonhardt U, Ramadori G. Release of glu- cagon-like peptide-1 (GLP-1) by carbohydrates in the perfused rat ileum. Acta
diabetologica 1997, 34(1): 18-21.
86. Shima K, Suda T, Nishimoto K, Yoshimoto S. Relationship between molecular structures of sugars and their ability to stimulate the release of glucagon-like peptide-1 from canine ileal loops. Acta endocrinologica 1990, 123(4): 464- 470.
87. Sugiyama K, Manaka H, Kato T, Yamatani K, Tominaga M, Sasaki H. Stimu- lation of truncated glucagon-like peptide-1 release from the isolated perfused canine ileum by glucose absorption. Digestion 1994, 55(1): 24-28.
88. Xu Z, Wang W, Nian X, Song G, Zhang X, Xiao H, et al. Dose-dependent effect of glucose on GLP-1 secretion involves sweet taste receptor in isolated perfused rat ileum [Rapid Communication]. Endocrine journal 2016, 63(12): 1141-1147.
89. Alenkvist I, Gandasi NR, Barg S, Tengholm A. Recruitment of Epac2A to in- sulin granule docking sites regulates priming for exocytosis. Diabetes 2017, 66(10): 2610-2622.
90. Pratley R, Weyer C. The role of impaired early insulin secretion in the patho- genesis of type II diabetes mellitus. Diabetologia 2001, 44(8): 929-945. 91. Campioni M, Toffolo G, Basu R, Rizza RA, Cobelli C. Minimal model assess-
ment of hepatic insulin extraction during an oral test from standard insulin ki- netic parameters. American Journal of Physiology-Endocrinology and Metab-
olism 2009, 297(4): E941-E948.
92. Samols E, Ryder JA. Studies on tissue uptake of insulin in man using a differ- ential immunoassay for endogenous and exogenous insulin. The Journal of
clinical investigation 1961, 40(11): 2092-2102.
93. Eaton RP, Allen RC, Schade DS. Hepatic removal of insulin in normal man: dose response to endogenous insulin secretion. The Journal of Clinical Endo-
crinology & Metabolism 1983, 56(6): 1294-1300.
94. Meloni A, DeYoung M, Lowe C, Parkes D. GLP‐1 receptor activated insulin secretion from pancreatic β‐cells: mechanism and glucose dependence. Diabe-
tes, Obesity and Metabolism 2013, 15(1): 15-27.
95. Yabe D, Seino Y. Two incretin hormones GLP-1 and GIP: comparison of their actions in insulin secretion and β cell preservation. Progress in biophysics and
molecular biology 2011, 107(2): 248-256.
96. Campbell JE, Drucker DJ. Pharmacology, physiology, and mechanisms of in- cretin hormone action. Cell metabolism 2013, 17(6): 819-837.
97. Knop F, Vilsbøll T, Madsbad S, Holst JJ, Krarup T. Inappropriate suppression of glucagon during OGTT but not during isoglycaemic iv glucose infusion contributes to the reduced incretin effect in type 2 diabetes mellitus. Diabeto-
logia 2007, 50(4): 797-805.
98. Lund A, Vilsbøll T, Bagger JI, Holst JJ, Knop FK. The separate and combined impact of the intestinal hormones, GIP, GLP-1, and GLP-2, on glucagon se- cretion in type 2 diabetes. American Journal of Physiology-Endocrinology and
99. Hare KJ, Vilsbøll T, Holst JJ, Knop FK. Inappropriate glucagon response after oral compared with isoglycemic intravenous glucose administration in patients with type 1 diabetes. American Journal of Physiology-Endocrinology and Me-
tabolism 2010, 298(4): E832-E837.
100. Gaisano H, MacDonald PE, Vranic M. Glucagon secretion and signaling in the development of diabetes. Frontiers in physiology 2012, 3: 349.
101. Bak MJ, Albrechtsen NW, Pedersen J, Hartmann B, Christensen M, Vilsbøll T, et al. Specificity and sensitivity of commercially available assays for gluca- gon and oxyntomodulin measurement in humans. European Journal of Endo-
crinology 2014, 170(4): 529-538.
102. Dunning BE, Gerich JE. The role of α-cell dysregulation in fasting and post- prandial hyperglycemia in type 2 diabetes and therapeutic implications. Endo-
crine reviews 2007, 28(3): 253-283.
103. Firth R, Bell P, Marsh H, Hansen I, Rizza RA. Postprandial hyperglycemia in patients with noninsulin-dependent diabetes mellitus. Role of hepatic and ex- trahepatic tissues. The Journal of clinical investigation 1986, 77(5): 1525- 1532.
104. Lund A, Bagger JI, Christensen M, Grøndahl M, van Hall G, Holst JJ, et al. Higher Endogenous Glucose Production During OGTT vs Isoglycemic Intra- venous Glucose Infusion. The Journal of Clinical Endocrinology & Metabo-