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Administration of Neutral Protamine Hagedorn Insulin at Bedtime versus with Dinner in Type 1 Diabetes Mellitus To Avoid Nocturnal Hypoglycemia and Improve Control: A Randomized, Controlled Trial

Carmine G. Fanelli, MD, PhD; Simone Pampanelli, MD; Francesca Porcellati, MD, PhD; Paolo Rossetti, MD; Paolo Brunetti, MD; and Geremia B. Bolli, MD
[+] Article and Author Information

From University of Perugia, Perugia, Italy.


Acknowledgments: The authors thank Mad Judge Stout in Falkland Arms, Great Tew, United Kingdom, for his support.

Grant Support: By Juvenile Diabetes Research Foundation International (grant 1-2001-102).

Requests for Single Reprints: Geremia B. Bolli, MD, Department of Internal Medicine, University of Perugia, Via E. Dal Pozzo, I-06126 Perugia, Italy; e-mail, gbolli@dimisem.med.unipg.it.

Current Author Addresses: Drs. Fanelli, Pampanelli, Porcellati, Rossetti, Brunetti, and Bolli: Department of Internal Medicine, University of Perugia, Via E. Dal Pozzo, I-06126 Perugia, Italy.

Author Contributions: Conception and design: C.G. Fanelli, S. Pampanelli, F. Porcellati, P. Rossetti, P. Brunetti, G.B. Bolli.

Analysis and interpretation of the data: C.G. Fanelli, S. Pampanelli, F. Porcellati, P. Brunetti, G.B. Bolli.

Drafting of the article: C.G. Fanelli, S. Pampanelli, F. Porcellati, G.B. Bolli.

Critical revision of the article for important intellectual content: C.G. Fanelli, S. Pampanelli, F. Porcellati, P. Brunetti, G.B. Bolli.

Final approval of the article: C.G. Fanelli, S. Pampanelli, F. Porcellati, P. Rossetti, P. Brunetti, G.B. Bolli.

Provision of study materials or patients: S. Pampanelli, F. Porcellati, P. Rossetti, G.B. Bolli.

Statistical expertise: C.G. Fanelli, G.B. Bolli.

Obtaining of funding: C.G. Fanelli, F. Porcellati, P. Brunetti, G.B. Bolli.

Administrative, technical, or logistic support: P. Brunetti.

Collection and assembly of data: C.G. Fanelli, S. Pampanelli, P. Rossetti.


Ann Intern Med. 2002;136(7):504-514. doi:10.7326/0003-4819-136-7-200204020-00007
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First, these data demonstrate that in intensive treatment of type 1 diabetes, splitting the evening administration of insulin to short-acting insulin at dinner and NPH insulin at bedtime has several advantages over simultaneous (mixed) administration of short-acting and NPH insulins at dinner. Compared with mixed treatment, evening split treatment reduced by more than 60% the risk for nocturnal hypoglycemia; improved long-term control of blood glucose levels (hemoglobin A1c levels were approximately 0.5% lower); decreased variability of blood glucose levels in the fasting state; and preserved better hormonal, symptom, and cognitive function responses to hypoglycemia. We conclude that, whenever possible, patients with type 1 diabetes should be given the split insulin regimen in the evening.

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Figures

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Figure 1.
Mean (±SE) daily blood glucose levels in 22 patients during insulin regimens of evening split administration ( squares ) and evening mixed administration ( circles ).

The figure shows overall data from home monitoring during the final month of treatments.

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Grahic Jump Location
Figure 2.
Number of nocturnal hypoglycemia episodes in each patient ( n = 22) during the final month of each treatment period—mixed ( white bars ) versus split ( shaded bars ) administration of evening insulin.
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Grahic Jump Location
Figure 3.
Mean (±SE) daily blood glucose levels (home-monitored during the final month of both treatments).CHOTop.nnnBottom.nnn

The daily glucose levels are categorized according to hypoglycemia status and resultant snack consumption at the 3:00-a.m. measurement: no hypoglycemia (glucose level > 4.0 mmol/L [>72 mg/dL]) with no snack; hypoglycemia (glucose level ≤ 4.0 mmol/L [≤ 72 mg/dL]) with 20-g carbohydrate ( ) snack; or hypoglycemia with 40-g CHO snack. Evening mixed-treatment period: Patients received a mixture of human regular insulin and neutral protamine Hagedorn (NPH) insulin before dinner. During this treatment period, the following numbers of nocturnal glucose measurements were obtained: for nonhypoglycemia nights with no snack, = 218; for hypoglycemia nights with 20-g CHO snack, = 36; for hypoglycemia nights with 40-g CHO snack, = 54. Evening split-treatment period: Patients split the evening insulin regimen into human regular insulin administration before dinner and NPH insulin administration at bedtime. During this treatment period, patients recorded the following numbers of nocturnal glucose measurements: for nonhypoglycemia nights with no snack, = 273; for hypoglycemia nights with 20-g CHO snack, = 16; for hypoglycemia nights with 40-g CHO snack, = 12.

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Grahic Jump Location
Figure 4.
Mean (±SE) levels of plasma glucose ( top ) and insulin ( bottom ) during overnight hospitalization with evening regimen of split insulin ( squares ) versus mixed insulin ( circles ) administration.

Fifteen patients during the mixed-treatment period required glucose infusion between 2:00 a.m. and 4:00 a.m. to prevent a decrease in plasma glucose level to 4.0 mmol/L or less (≤ 72 mg/dL).

Grahic Jump Location
Grahic Jump Location
Figure 5.
Various assessments during stepwise, insulin-induced, clamped hypoglycemia in patients with type 1 diabetes mellitus ( n = 22) during two treatment periods—evening split insulin administration ( squares , shaded bars ) and evening mixed administration ( circles , white bars ). A.B.C.ZD.

Plasma adrenaline concentration. Score of autonomic symptoms. Mean of scores of cognitive function. Score of neuroglycopenic symptoms. Standard error bars are shown. To convert the top x-axis values (in mmol/L)—which represent induced, approximate target levels of plasma glucose—to mg/dL, divide by 0.0555.

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Summary for Patients

Splitting the Evening Insulin Dose To Avoid Low Blood Sugar Levels and To Improve Sugar Control in Patients with Type 1 Diabetes

The summary below is from the full report titled “Administration of Neutral Protamine Hagedorn Insulin at Bedtime versus with Dinner in Type 1 Diabetes Mellitus To Avoid Nocturnal Hypoglycemia and Improve Control. A Randomized, Controlled Trial.” It is in the 2 April 2002 issue of Annals of Internal Medicine (volume 136, pages 504-514). The authors are CG Fanelli, S Pampanelli, F Porcellati, P Rossetti, P Brunetti, and GB Bolli. The summaries may be reproduced for not-for-profit educational purposes only. Any other uses must be approved by the American College of Physicians-American Society of Internal Medicine.

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