Involvement of Steatosis-induced Glucagon Resistance in Hyperglucagonaemia
NCT ID: NCT02337660
Last Updated: 2018-11-16
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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COMPLETED
NA
30 participants
INTERVENTIONAL
2015-01-31
2016-01-31
Brief Summary
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Detailed Description
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Conditions
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Study Design
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NON_RANDOMIZED
PARALLEL
BASIC_SCIENCE
NONE
Study Groups
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Healthy, lean
15 healthy, lean subjects.
Will have a liver biopsy, and on the experimental day a pancreatic clamp will be performed.
Liver biopsy
One ultrasound guided liver biopsy
Pancreatic clamp
I.v. infusions of somatostatin and insulin (basal rate) for will be adminstered for 3 hours. Glucagon will administered for 3 hours in total with infusion rates at a basal and a high physiological rate for 1.5 hours each.
Obese, otherwise healthy
15 obese, otherwise healthy subjects
Will have a liver biopsy, and on the experimental day a pancreatic clamp will be performed.
Liver biopsy
One ultrasound guided liver biopsy
Pancreatic clamp
I.v. infusions of somatostatin and insulin (basal rate) for will be adminstered for 3 hours. Glucagon will administered for 3 hours in total with infusion rates at a basal and a high physiological rate for 1.5 hours each.
Interventions
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Liver biopsy
One ultrasound guided liver biopsy
Pancreatic clamp
I.v. infusions of somatostatin and insulin (basal rate) for will be adminstered for 3 hours. Glucagon will administered for 3 hours in total with infusion rates at a basal and a high physiological rate for 1.5 hours each.
Eligibility Criteria
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Inclusion Criteria
* Between 18.5 and 25 kg/m2 or between 30 and 40 kg/m2
* Normal haemoglobin
* Normal coagulation factor II, VII and X, INR and thrombocytes
* Age above 25 years
* Informed consent
Exclusion Criteria
* Prediabetes (impaired glucose tolerance and/or impaired fasting plasma glucose)
* First-degree relatives with diabetes
* Nephropathy (eGFR \< 60ml/min and/or albuminuria)
* Liver disease (ALAT and/or serum ASAT \>2x normal values)
* Use of anticoagulative medicine like Clopidogrel og Warfarin
* Pregnancy and/or breastfeeding
* Age above 80 years
* Any condition that the investigator feels would interfere with trial participation
25 Years
80 Years
ALL
Yes
Sponsors
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The Novo Nordisk Foundation Center for Basic Metabolic Research
OTHER
University Hospital, Gentofte, Copenhagen
OTHER
Responsible Party
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Malte Palm Suppli
Research year assistant
Locations
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Center for Diabetes Research
Gentofte Municipality, , Denmark
Countries
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References
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Mitrakou A, Kelley D, Veneman T, Jenssen T, Pangburn T, Reilly J, Gerich J. Contribution of abnormal muscle and liver glucose metabolism to postprandial hyperglycemia in NIDDM. Diabetes. 1990 Nov;39(11):1381-90. doi: 10.2337/diab.39.11.1381.
Gromada J, Franklin I, Wollheim CB. Alpha-cells of the endocrine pancreas: 35 years of research but the enigma remains. Endocr Rev. 2007 Feb;28(1):84-116. doi: 10.1210/er.2006-0007. Epub 2007 Jan 16.
Knop FK, Aaboe K, Vilsboll T, Volund A, Holst JJ, Krarup T, Madsbad S. Impaired incretin effect and fasting hyperglucagonaemia characterizing type 2 diabetic subjects are early signs of dysmetabolism in obesity. Diabetes Obes Metab. 2012 Jun;14(6):500-10. doi: 10.1111/j.1463-1326.2011.01549.x. Epub 2012 Jan 17.
Faerch K, Pilgaard K, Knop FK, Hansen T, Pedersen O, Jorgensen T, Holst JJ. Incretin and pancreatic hormone secretion in Caucasian non-diabetic carriers of the TCF7L2 rs7903146 risk T allele. Diabetes Obes Metab. 2013 Jan;15(1):91-5. doi: 10.1111/j.1463-1326.2012.01675.x. Epub 2012 Sep 9.
Mitrakou A, Kelley D, Mokan M, Veneman T, Pangburn T, Reilly J, Gerich J. Role of reduced suppression of glucose production and diminished early insulin release in impaired glucose tolerance. N Engl J Med. 1992 Jan 2;326(1):22-9. doi: 10.1056/NEJM199201023260104.
Unger RH, Orci L. The essential role of glucagon in the pathogenesis of diabetes mellitus. Lancet. 1975 Jan 4;1(7897):14-6. doi: 10.1016/s0140-6736(75)92375-2.
Liljenquist JE, Mueller GL, Cherrington AD, Keller U, Chiasson J-L, Perry JM, Lacy WW, Rabinowitz D. Evidence for an important role of glucagon in the regulation of hepatic glucose production in normal man. J Clin Invest. 1977 Feb;59(2):369-74. doi: 10.1172/JCI108649.
Ferrannini E, Muscelli E, Natali A, Gabriel R, Mitrakou A, Flyvbjerg A, Golay A, Hojlund K; Relationship between Insulin Sensitivity and Cardiovascular Disease Risk (RISC) Project Investigators. Association of fasting glucagon and proinsulin concentrations with insulin resistance. Diabetologia. 2007 Nov;50(11):2342-7. doi: 10.1007/s00125-007-0806-x. Epub 2007 Sep 11.
Charbonneau A, Couturier K, Gauthier MS, Lavoie JM. Evidence of hepatic glucagon resistance associated with hepatic steatosis: reversal effect of training. Int J Sports Med. 2005 Jul-Aug;26(6):432-41. doi: 10.1055/s-2004-821225.
Longuet C, Robledo AM, Dean ED, Dai C, Ali S, McGuinness I, de Chavez V, Vuguin PM, Charron MJ, Powers AC, Drucker DJ. Liver-specific disruption of the murine glucagon receptor produces alpha-cell hyperplasia: evidence for a circulating alpha-cell growth factor. Diabetes. 2013 Apr;62(4):1196-205. doi: 10.2337/db11-1605. Epub 2012 Nov 16.
Bhathena SJ, Voyles NR, Smith S, Recant L. Decreased glucagon receptors in diabetic rat hepatocytes. Evidence for regulation of glucagon receptors by hyperglucagonemia. J Clin Invest. 1978 Jun;61(6):1488-97. doi: 10.1172/JCI109069.
Kahn SE, Prigeon RL, McCulloch DK, Boyko EJ, Bergman RN, Schwartz MW, Neifing JL, Ward WK, Beard JC, Palmer JP, et al. Quantification of the relationship between insulin sensitivity and beta-cell function in human subjects. Evidence for a hyperbolic function. Diabetes. 1993 Nov;42(11):1663-72. doi: 10.2337/diab.42.11.1663.
Jimba S, Nakagami T, Takahashi M, Wakamatsu T, Hirota Y, Iwamoto Y, Wasada T. Prevalence of non-alcoholic fatty liver disease and its association with impaired glucose metabolism in Japanese adults. Diabet Med. 2005 Sep;22(9):1141-5. doi: 10.1111/j.1464-5491.2005.01582.x.
Gupte P, Amarapurkar D, Agal S, Baijal R, Kulshrestha P, Pramanik S, Patel N, Madan A, Amarapurkar A, Hafeezunnisa. Non-alcoholic steatohepatitis in type 2 diabetes mellitus. J Gastroenterol Hepatol. 2004 Aug;19(8):854-8. doi: 10.1111/j.1440-1746.2004.03312.x.
Akbar DH, Kawther AH. Nonalcoholic fatty liver disease in Saudi type 2 diabetic subjects attending a medical outpatient clinic: prevalence and general characteristics. Diabetes Care. 2003 Dec;26(12):3351-2. doi: 10.2337/diacare.26.12.3351-a. No abstract available.
Seghieri M, Rebelos E, Gastaldelli A, Astiarraga BD, Casolaro A, Barsotti E, Pocai A, Nauck M, Muscelli E, Ferrannini E. Direct effect of GLP-1 infusion on endogenous glucose production in humans. Diabetologia. 2013 Jan;56(1):156-61. doi: 10.1007/s00125-012-2738-3. Epub 2012 Oct 12.
Hare KJ, Vilsboll T, Asmar M, Deacon CF, Knop FK, Holst JJ. The glucagonostatic and insulinotropic effects of glucagon-like peptide 1 contribute equally to its glucose-lowering action. Diabetes. 2010 Jul;59(7):1765-70. doi: 10.2337/db09-1414. Epub 2010 Feb 11.
Gilliam-Vigh H, Suppli MP, Heimburger SMN, Lund AB, Knop FK, Ellegaard AM. Cholesin mRNA Expression in Human Intestinal, Liver, and Adipose Tissues. Nutrients. 2025 Feb 8;17(4):619. doi: 10.3390/nu17040619.
Suppli MP, Bagger JI, Lelouvier B, Broha A, Demant M, Konig MJ, Strandberg C, Lund A, Vilsboll T, Knop FK. Hepatic microbiome in healthy lean and obese humans. JHEP Rep. 2021 Apr 27;3(4):100299. doi: 10.1016/j.jhepr.2021.100299. eCollection 2021 Aug.
Suppli MP, Bagger JI, Lund A, Demant M, van Hall G, Strandberg C, Konig MJ, Rigbolt K, Langhoff JL, Wewer Albrechtsen NJ, Holst JJ, Vilsboll T, Knop FK. Glucagon Resistance at the Level of Amino Acid Turnover in Obese Subjects With Hepatic Steatosis. Diabetes. 2020 Jun;69(6):1090-1099. doi: 10.2337/db19-0715. Epub 2020 Jan 23.
Other Identifiers
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SIRG-1
Identifier Type: -
Identifier Source: org_study_id
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