Effect of NPH Insulin, Insulin Detemir and Insulin Glargine on GH-IGF-IGFBP Axis

Diabetes Mellitus, Type 1 Clinical Trial

Official title:

Effect of NPH Insulin, Insulin Detemir and Insulin Glargine on IGFBP-1 Production and Serum IGF-I in Subjects With Type 1 Diabetes Mellitus: An Open-label, Randomised, Triple Cross-over Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01461616
• Other study ID #: NPH-Detemir-Glargine-2011
• Status: Completed
• Phase: Phase 3
• First received: October 24, 2011
• Last updated: December 3, 2012
• Start date: February 2012
• Est. completion date: November 2012

Study information

• Verified date: December 2012
• Source: University of Aarhus
• Contact: n/a
• Is FDA regulated: No
• Health authority: Denmark: Danish Dataprotection AgencyDenmark: Danish Medicines AgencyDenmark: The Regional Committee on Biomedical Research Ethics
• Study type: Interventional

Clinical Trial Summary

The objective is to describe the interaction of equal doses of NPH insulin (Neutral Protamine Hagedorn), insulin Detemir and insulin glargine on IGFBP-1 (Insulin-like Growth Factor Binding Protein-1) production as well as immunoreactive and bioactive IGF-I (Insulin-like Growth Factor-I) after once-daily injection on three separate visits in type 1 diabetic subjects.

Description:

Because of the importance of receptors activation and potential effects on the IGF system, a head-to-head comparison of the eventual differential impact of intermediate-acting human insulin (NPH), insulin detemir and insulin glargine on the growth hormone—insulin-like growth factor—insulin-like growth factor binding protein (GH-IGF-IGFBP) axis is relevant to be conducted for the safety assurance of insulin analogues. Therefore, this study aims to investigate whether the serum insulin profile obtained by once-daily injection of long-acting insulin analog, insulin detemir or insulin glargine, has a different impact on IGFBPs production and IGF-I concentrations (total IGF-I) bioactivity and tissue-availability as compared to that seen during treatment with intermediate-acting human insulin, NPH insulin.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 19
• Est. completion date: November 2012
• Est. primary completion date: November 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

1. Informed consent obtained before any trial-related activities.

2. Diagnosis of diabetes mellitus according to WHO criteria; history and clinical course consistent with type 1 diabetes mellitus.

3. Diagnosed with diabetes for more than 6 years and using continuous subcutaneous insulin infusion (CSII) at least 6 months at time of inclusion.

4. Total daily insulin dose between 0.4 and 1.4 units/kg (both values included)

5. HbA1c between 6% and 9% (both values included).

6. Age = 18 years.

7. BMI between 18.5 and 28 kg /m2 (including both values).

Exclusion Criteria:

1. Known or suspected allergy to trial product(s) or related products.

2. Recurrent major hypoglycaemic episodes.

3. Heart: Unstable Angina Pectoris, AMI < 12 months or heart insufficiency classified according to NYHA III-IV

4. Blood Pressure: Severe uncontrolled hypertension with BP > 180/110 mmHg, sitting

5. Liver: Impaired hepatic function corresponding to serum-ALAT or basic phosphatase > 2 x upper reference limit of the local laboratory.

6. Kidneys: Impaired renal function corresponding to serum-creatinin > 150 µmol/l according to the local laboratory.

7. Any disease judged by the investigator to affect the trial.

8. Pregnancy, breast-feeding or the intention of becoming pregnant or fertile women not using adequate contraceptive measures - adequate contraceptive method is sterilisation, hysterectomy or current use of contraceptive pills or intra uterine device.

Study Design

Allocation: Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 1

Intervention

Drug:
• NPH
equal doses of NPH insulin, insulin Detemir and insulin glargine injection
• Detemir
equal doses of NPH insulin, insulin Detemir and insulin glargine injection
• Glargine
equal doses of NPH insulin, insulin Detemir and insulin glargine injection

Locations

Country	Name	City	State
Denmark	Department of Endocrinology and Internal Medicine, Aarhus University Hospital	Aarhus

Sponsors (1)

Lead Sponsor	Collaborator
University of Aarhus

Country where clinical trial is conducted

Denmark, 

References & Publications (16)

Bereket A, Lang CH, Wilson TA. Alterations in the growth hormone-insulin-like growth factor axis in insulin dependent diabetes mellitus. Horm Metab Res. 1999 Feb-Mar;31(2-3):172-81. Review. — View Citation

Bolli GB, Owens DR. Insulin glargine. Lancet. 2000 Aug 5;356(9228):443-5. — View Citation

Brismar K, Fernqvist-Forbes E, Wahren J, Hall K. Effect of insulin on the hepatic production of insulin-like growth factor-binding protein-1 (IGFBP-1), IGFBP-3, and IGF-I in insulin-dependent diabetes. J Clin Endocrinol Metab. 1994 Sep;79(3):872-8. — View Citation

Clemmons DR. Modifying IGF1 activity: an approach to treat endocrine disorders, atherosclerosis and cancer. Nat Rev Drug Discov. 2007 Oct;6(10):821-33. Review. — View Citation

Ekman B, Nyström F, Arnqvist HJ. Circulating IGF-I concentrations are low and not correlated to glycaemic control in adults with type 1 diabetes. Eur J Endocrinol. 2000 Oct;143(4):505-10. — View Citation

Hanaire-Broutin H, Sallerin-Caute B, Poncet MF, Tauber M, Bastide R, Rosenfeld R, Tauber JP. Insulin therapy and GH-IGF-I axis disorders in diabetes: impact of glycaemic control and hepatic insulinization. Diabetes Metab. 1996 Jul;22(4):245-50. Review. — View Citation

Heinemann L, Sinha K, Weyer C, Loftager M, Hirschberger S, Heise T. Time-action profile of the soluble, fatty acid acylated, long-acting insulin analogue NN304. Diabet Med. 1999 Apr;16(4):332-8. — View Citation

Hirsch IB. Insulin analogues. N Engl J Med. 2005 Jan 13;352(2):174-83. Review. — View Citation

Janssen JA, Jacobs ML, Derkx FH, Weber RF, van der Lely AJ, Lamberts SW. Free and total insulin-like growth factor I (IGF-I), IGF-binding protein-1 (IGFBP-1), and IGFBP-3 and their relationships to the presence of diabetic retinopathy and glomerular hyperfiltration in insulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 1997 Sep;82(9):2809-15. — View Citation

Kurtzhals P, Schäffer L, Sørensen A, Kristensen C, Jonassen I, Schmid C, Trüb T. Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes. 2000 Jun;49(6):999-1005. — View Citation

LeRoith D, Yakar S. Mechanisms of disease: metabolic effects of growth hormone and insulin-like growth factor 1. Nat Clin Pract Endocrinol Metab. 2007 Mar;3(3):302-10. Review. — View Citation

Porcellati F, Rossetti P, Candeloro P, Lucidi P, Cioli P, Andreoli AM, Ghigo E, Bolli GB, Fanelli CG. Short-term effects of the long-acting insulin analog detemir and human insulin on plasma levels of insulin-like growth factor-I and its binding proteins in humans. J Clin Endocrinol Metab. 2009 Aug;94(8):3017-24. doi: 10.1210/jc.2008-2838. Epub 2009 May 26. — View Citation

Slawik M, Schories M, Busse Grawitz A, Reincke M, Petersen KG. Treatment with insulin glargine does not suppress serum IGF-1. Diabet Med. 2006 Jul;23(7):814-7. — View Citation

Thrailkill KM. Insulin-like growth factor-I in diabetes mellitus: its physiology, metabolic effects, and potential clinical utility. Diabetes Technol Ther. 2000 Spring;2(1):69-80. Review. — View Citation

Varewijck AJ, Goudzwaard JA, Brugts MP, Lamberts SW, Hofland LJ, Janssen JA. Insulin glargine is more potent in activating the human IGF-I receptor than human insulin and insulin detemir. Growth Horm IGF Res. 2010 Dec;20(6):427-31. doi: 10.1016/j.ghir.2010.10.002. Epub 2010 Nov 4. — View Citation

Vigneri R, Squatrito S, Sciacca L. Insulin and its analogs: actions via insulin and IGF receptors. Acta Diabetol. 2010 Dec;47(4):271-8. doi: 10.1007/s00592-010-0215-3. Epub 2010 Aug 21. Review. — View Citation

* Note: There are 16 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	IGF-I(ng/ml)	Hourly samples will be taken from 18:00 to 10:00 next day.	16 hours (from 18:00 to 10:00 next day)	No
Primary	IGFBP-1(ng/ml)	Hourly samples will be taken from 18:00 to 10:00 next day.	16 hours (from 18:00 to 10:00 next day)	No
Primary	IGFBP-2(ng/ml)	Hourly samples will be taken from 18:00 to 10:00 next day.	16 hours (from 18:00 to 10:00 next day)	No
Primary	IGFBP-3(ng/ml)	Hourly samples will be taken from 18:00 to 10:00 next day.	16 hours (from 18:00 to 10:00 next day)	No
Primary	Growth Hormone(ng/ml)	Hourly samples will be taken from 18:00 to 10:00 next day.	16 hours (from 18:00 to 10:00 next day)	No
Secondary	plasma glucose concentration (mmol/L) after a single injection of either NPH insulin, insulin Detemir or insulin glargine	Hourly samples will be taken from 18:00 to 10:00 next day.	16 hours (from 18:00 to 10:00 next day)	No
Secondary	insulin concentration (mmol/L) after a single injection of either NPH insulin, insulin Detemir or insulin glargine	Hourly samples will be taken from 18:00 to 10:00 next day.	16 hours (from 18:00 to 10:00 next day)	No