Involvement of Steatosis-induced Glucagon Resistance in Hyperglucagonaemia

Non-alcoholic Fatty Liver Disease Clinical Trial

Official title:

Involvement of Steatosis-induced Glucagon Resistance in Hyperglucagonaemia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02337660
• Other study ID #: SIRG-1
• Status: Completed
• Phase: N/A
• Start date: January 2015
• Est. completion date: January 2016

Study information

• Verified date: November 2018
• Source: University Hospital, Gentofte, Copenhagen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Description:

Hyperglucagonemia is a common condition in obesity, prediabetes and type 2 diabetes. It increases the hepatic glucose production, thus contributing to type 2-diabetic hyperglycemia. In the current study we wish to examine whether non-alcoholic fatty disease (NAFLD) results in hepatic glucagon resistance. This could result in hyperglucagonemia through a feedback mechanism acting on the level of pancreatic alpha cells. Cirrhosis and type 1 diabetes, respectively, has previously been shown to be associated with hepatic glucagon resistance but it has not been examined in relation to NAFLD in humans so far.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 30
• Est. completion date: January 2016
• Est. primary completion date: January 2016
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 25 Years to 80 Years

Eligibility

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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

Related Conditions & MeSH terms

• Fatty Liver
• Liver Diseases
• Non-alcoholic Fatty Liver Disease

Intervention

Procedure:
• Liver biopsy
One ultrasound guided liver biopsy

Other:
• 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.

Locations

Country	Name	City	State
Denmark	Center for Diabetes Research	Gentofte

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital, Gentofte, Copenhagen	The Novo Nordisk Foundation Center for Basic Metabolic Research

Country where clinical trial is conducted

Denmark, 

References & Publications (17)

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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. — View Citation

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. — View Citation

Færch K, Pilgaard K, Knop FK, Hansen T, Pedersen O, Jørgensen 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. — View Citation

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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. Epub 2007 Jan 16. Review. — View Citation

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. — View Citation

Hare KJ, Vilsbøll 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. — View Citation

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. — View Citation

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. — View Citation

Knop FK, Aaboe K, Vilsbøll T, Vølund 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. — View Citation

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. — View Citation

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 a-cell hyperplasia: evidence for a circulating a-cell growth factor. Diabetes. 2013 Apr;62(4):1196-205. doi: 10.2337/db11-1605. Epub 2012 Nov 16. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Unger RH, Orci L. The essential role of glucagon in the pathogenesis of diabetes mellitus. Lancet. 1975 Jan 4;1(7897):14-6. — View Citation

* Note: There are 17 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Endogenous glucose production		0-180 min
Primary	Amino acid metabolism		0-180 min
Secondary	Degree of steatosis		baseline
Secondary	Total RNA sequencing of liver biopsies		baseline