NCT02337660

Brief Summary

The purpose of this study is to examine whether non-alcoholic fatty liver disease (NAFLD) is associated with hepatic glucagon resistance and hyperglucagonemia.

Trial Health

87
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
30

participants targeted

Target at below P25 for not_applicable

Timeline
Completed

Started Jan 2015

Geographic Reach
1 country

1 active site

Status
completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

Study Start

First participant enrolled

January 1, 2015

Completed
7 days until next milestone

First Submitted

Initial submission to the registry

January 8, 2015

Completed
5 days until next milestone

First Posted

Study publicly available on registry

January 13, 2015

Completed
12 months until next milestone

Primary Completion

Last participant's last visit for primary outcome

January 1, 2016

Completed
Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

January 1, 2016

Completed
Last Updated

November 16, 2018

Status Verified

November 1, 2018

Enrollment Period

1 year

First QC Date

January 8, 2015

Last Update Submit

November 14, 2018

Conditions

Non-alcoholic Fatty Liver Disease

Outcome Measures

Primary Outcomes (2)

  • Endogenous glucose production

    0-180 min

  • Amino acid metabolism

    0-180 min

Secondary Outcomes (2)

  • Degree of steatosis

    baseline

  • Total RNA sequencing of liver biopsies

    baseline

Study Arms (2)

Healthy, lean

EXPERIMENTAL

15 healthy, lean subjects. Will have a liver biopsy, and on the experimental day a pancreatic clamp will be performed.

Procedure: Liver biopsyOther: Pancreatic clamp

Obese, otherwise healthy

EXPERIMENTAL

15 obese, otherwise healthy subjects Will have a liver biopsy, and on the experimental day a pancreatic clamp will be performed.

Procedure: Liver biopsyOther: Pancreatic clamp

Interventions

Liver biopsyPROCEDURE

One ultrasound guided liver biopsy

Healthy, leanObese, otherwise healthy
Pancreatic clampOTHER

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.

Healthy, leanObese, otherwise healthy

Eligibility Criteria

Age25 Years - 80 Years
Sexall
Healthy VolunteersYes
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • Normal fasting plasma glucose and HbA1c \< 6.0%
  • 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

You may not qualify if:

  • Diabetes
  • 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

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (1)

Center for Diabetes Research

Gentofte Municipality, 2900, Denmark

Location

Related Publications (20)

  • 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.

    PMID: 2121568BACKGROUND

  • 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.

    PMID: 17261637BACKGROUND

  • 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.

    PMID: 22171657BACKGROUND

  • 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.

    PMID: 22862926BACKGROUND

  • 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.

    PMID: 1727062BACKGROUND

  • 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.

    PMID: 46337BACKGROUND

  • 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.

    PMID: 833282BACKGROUND

  • 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.

    PMID: 17846745BACKGROUND

  • 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.

    PMID: 16037884BACKGROUND

  • 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.

    PMID: 23160527BACKGROUND

  • 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.

    PMID: 207737BACKGROUND

  • 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.

    PMID: 8405710BACKGROUND

  • 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.

    PMID: 16108839BACKGROUND

  • 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.

    PMID: 15242486BACKGROUND

  • 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.

    PMID: 14633828BACKGROUND

  • 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.

    PMID: 23064290BACKGROUND

  • 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.

    PMID: 20150286BACKGROUND

  • 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.

    PMID: 40004948DERIVED

  • 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.

    PMID: 34169247DERIVED

  • 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.

    PMID: 31974144DERIVED

MeSH Terms

Conditions

Non-alcoholic Fatty Liver Disease

Condition Hierarchy (Ancestors)

Fatty LiverLiver DiseasesDigestive System Diseases

Study Design

Study Type
interventional
Phase
not applicable
Allocation
NON RANDOMIZED
Masking
NONE
Purpose
BASIC SCIENCE
Intervention Model
PARALLEL
Sponsor Type
OTHER
Responsible Party
PRINCIPAL INVESTIGATOR
PI Title
Research year assistant

Study Record Dates

First Submitted

January 8, 2015

First Posted

January 13, 2015

Study Start

January 1, 2015

Primary Completion

January 1, 2016

Study Completion

January 1, 2016

Last Updated

November 16, 2018

Record last verified: 2018-11

Locations

DK(1)