Differential effects of insulin detemir and neutral protamine Hagedorn (NPH) insulin on hepatic glucose production and peripheral glucose uptake during hypoglycaemia in type 1 diabetes.
OBJECTIVE
We compared the symptoms of hypoglycaemia induced by insulin detemir (NN304) (B29Lys(epsilon-tetradecanoyl),desB30 human insulin) and equally effective doses of neutral protamine Hagedorn (NPH) insulin in relation to possible differential effects on hepatic glucose production and peripheral glucose uptake.


METHODS
After overnight intravenous infusion of soluble human insulin 18 participants with type 1 diabetes received subcutaneous injections of NPH insulin or insulin detemir (0.5 U/kg body weight) on separate occasions in random order. During the ensuing gradual development of hypoglycaemia cognitive function and levels of counter-regulatory hormones were measured and rates of endogenous glucose production and peripheral glucose uptake continuously evaluated using a primed constant infusion of [6,6-(2)H(2)]glucose. The study was terminated when plasma glucose concentration had fallen to 2.4 mmol/l or had reached a minimum at a higher concentration.


RESULTS
During the development of hypoglycaemia no difference between the two insulin preparations was observed in symptoms or hormonal responses. Significant differences were seen in rates of glucose flux. At and below plasma glucose concentrations of 3.5 mmol/l suppression of endogenous glucose production was greater with insulin detemir than with NPH insulin, whereas stimulation of peripheral glucose uptake was greater with NPH insulin than with insulin detemir.


CONCLUSIONS
In participants with type 1 diabetes subcutaneously injected insulin detemir exhibits relative hepatoselectivity compared with NPH insulin, but symptoms of hypoglycaemia and hormonal counter-regulation are similar.


BACKGROUND
ClinicalTrials.gov NCT00760448.
Smeeton
F
F
Department of Medicine, Nevill Hall Hospital, Abergavenny, Monmouthshire, UK.
Shojaee Moradie
F
F
Jones
R H
RH
Westergaard
L
L
Haahr
H
H
Umpleby
A M
AM
Russell-Jones
D L
DL
D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D001794:Blood Pressure / Q000187:drug effects; D018592:Cross-Over Studies; D003922:Diabetes Mellitus, Type 1 / Q000097:blood* / Q000188:drug therapy* / Q000503:physiopathology; D004311:Double-Blind Method; D004837:Epinephrine / Q000097:blood; D005947:Glucose / Q000378:metabolism; D013006:Growth Hormone / Q000097:blood; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007003:Hypoglycemia / Q000097:blood*; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007262:Infusions, Intravenous; D007328:Insulin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000069057:Insulin Detemir; D007336:Insulin, Isophane / Q000008:administration & dosage / Q000627:therapeutic use*; D049528:Insulin, Long-Acting; D008099:Liver / Q000378:metabolism*; D018579:Patient Selection; D011930:Reaction Time
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D049528:Insulin, Long-Acting; D000069057:Insulin Detemir; D007336:Insulin, Isophane; D013006:Growth Hormone; D005947:Glucose; D004837:Epinephrine
Am J Physiol. 1997 Aug;273(2 Pt 1):E438-47
9277399
Diabetes. 1998 Apr;47(4):523-9
9568682
Am J Physiol. 1956 Sep;187(1):15-24
13362583
Clin Ther. 2004 May;26(5):724-36
15220016
Diabetes Care. 2001 Feb;24(2):296-301
11213882
Diabet Med. 2001 Sep;18(9):690-705
11606166
Diabetes. 2008 Mar;57(3):746-56
18083783
Exp Clin Endocrinol Diabetes. 2000;108(2):100-5
10826516
Pharm Res. 2004 Aug;21(8):1498-504
15359587
Diabet Med. 2006 Jul;23(7):729-35
16842476
Comput Methods Programs Biomed. 1988 May-Jun;26(3):289-99
3383567
Diabetes Care. 2000 Aug;23(8):1124-9
10937509
Diabet Med. 1999 Apr;16(4):332-8
10220208
Diabetes. 1987 Aug;36(8):914-24
3297886
Diabetes. 2003 Jan;52(1):133-7
12502503
Am J Physiol. 1987 Feb;252(2 Pt 1):E209-17
3548421
Biochem J. 1995 Dec 15;312 ( Pt 3):725-31
8554512
Diabet Med. 2003 Mar;20(3):231-7
12675669
Eur J Pharm Sci. 2009 Jan 31;36(1):78-90
19028573
Diabetes Care. 2003 Mar;26(3):590-6
12610006
Diabetologia. 2005 Mar;48(3):420-6
15729576