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

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ClinicalTrials.gov Identifier: NCT01461616

Recruitment Status : Completed

First Posted : October 28, 2011

Last Update Posted : December 4, 2012

Sponsor:

Information provided by (Responsible Party):

University of Aarhus

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Diabetes Mellitus, Type 1	Drug: NPH Drug: Detemir Drug: Glargine	Phase 3

Detailed 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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	19 participants
Allocation:	Randomized
Intervention Model:	Crossover Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
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
Study Start Date :	February 2012
Actual Primary Completion Date :	November 2012
Actual Study Completion Date :	November 2012

Resource links provided by the National Library of Medicine

Genetics Home Reference related topics: Type 1 diabetes

MedlinePlus related topics: Diabetes Type 1

Drug Information available for: Insulin Insulin human Insulin, isophane Insulin glargine Insulin detemir

Genetic and Rare Diseases Information Center resources: Oculocerebral Syndrome With Hypopigmentation

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Experimental: NPH insulin injection NPH insulin will be injected in random order in one of three seperated visit days.	Drug: NPH equal doses of NPH insulin, insulin Detemir and insulin glargine injection Other Name: NPH insulin: Insulatard
Experimental: detemir insulin injection insulin detemir will be injected in random order in one of three seperated visit days.	Drug: Detemir equal doses of NPH insulin, insulin Detemir and insulin glargine injection Other Name: insulin Detemir: Levemir
Experimental: glargine insulin injection insulin glargine will be injected in random order in one of three seperated visit days.	Drug: Glargine equal doses of NPH insulin, insulin Detemir and insulin glargine injection Other Name: insulin glargine: Lamtus

Outcome Measures

Primary Outcome Measures :

IGF-I(ng/ml) [ Time Frame: 16 hours (from 18:00 to 10:00 next day) ]
Hourly samples will be taken from 18:00 to 10:00 next day.
IGFBP-1(ng/ml) [ Time Frame: 16 hours (from 18:00 to 10:00 next day) ]
Hourly samples will be taken from 18:00 to 10:00 next day.
IGFBP-2(ng/ml) [ Time Frame: 16 hours (from 18:00 to 10:00 next day) ]
Hourly samples will be taken from 18:00 to 10:00 next day.
IGFBP-3(ng/ml) [ Time Frame: 16 hours (from 18:00 to 10:00 next day) ]
Hourly samples will be taken from 18:00 to 10:00 next day.
Growth Hormone(ng/ml) [ Time Frame: 16 hours (from 18:00 to 10:00 next day) ]
Hourly samples will be taken from 18:00 to 10:00 next day.

Secondary Outcome Measures :

plasma glucose concentration (mmol/L) after a single injection of either NPH insulin, insulin Detemir or insulin glargine [ Time Frame: 16 hours (from 18:00 to 10:00 next day) ]
Hourly samples will be taken from 18:00 to 10:00 next day.
insulin concentration (mmol/L) after a single injection of either NPH insulin, insulin Detemir or insulin glargine [ Time Frame: 16 hours (from 18:00 to 10:00 next day) ]
Hourly samples will be taken from 18:00 to 10:00 next day.

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:	18 Years to 65 Years (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Informed consent obtained before any trial-related activities.
Diagnosis of diabetes mellitus according to WHO criteria; history and clinical course consistent with type 1 diabetes mellitus.
Diagnosed with diabetes for more than 6 years and using continuous subcutaneous insulin infusion (CSII) at least 6 months at time of inclusion.
Total daily insulin dose between 0.4 and 1.4 units/kg (both values included)
HbA1c between 6% and 9% (both values included).
Age ≥ 18 years.
BMI between 18.5 and 28 kg /m2 (including both values).

Exclusion Criteria:

Known or suspected allergy to trial product(s) or related products.
Recurrent major hypoglycaemic episodes.
Heart: Unstable Angina Pectoris, AMI < 12 months or heart insufficiency classified according to NYHA III-IV
Blood Pressure: Severe uncontrolled hypertension with BP > 180/110 mmHg, sitting
Liver: Impaired hepatic function corresponding to serum-ALAT or basic phosphatase > 2 x upper reference limit of the local laboratory.
Kidneys: Impaired renal function corresponding to serum-creatinin > 150 μmol/l according to the local laboratory.
Any disease judged by the investigator to affect the trial.
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.

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01461616

Locations

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Denmark
Department of Endocrinology and Internal Medicine, Aarhus University Hospital
Aarhus, Denmark, 8000

Sponsors and Collaborators

University of Aarhus

Investigators

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Principal Investigator:	Jens Sandahl Christiansen, M.D.	Department of Endocrinology and Internal Medicine, Aarhus University Hospital

More Information

Publications:

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.

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.

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.

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.

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.

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.

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.

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.

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

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

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.

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.

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.

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.

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.

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.

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Responsible Party:	University of Aarhus
ClinicalTrials.gov Identifier:	NCT01461616
Other Study ID Numbers:	NPH-Detemir-Glargine-2011
First Posted:	October 28, 2011 Key Record Dates
Last Update Posted:	December 4, 2012
Last Verified:	December 2012

Keywords provided by University of Aarhus:


Diabetes Mellitus, Type 1

Additional relevant MeSH terms:

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Diabetes Mellitus Diabetes Mellitus, Type 1 Glucose Metabolism Disorders Metabolic Diseases Endocrine System Diseases Autoimmune Diseases Immune System Diseases	Insulin Insulin, Globin Zinc Insulin Glargine Insulin Detemir Hypoglycemic Agents Physiological Effects of Drugs

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