Improvement of basal hepatic glucose production and fasting hyperglycemia of type I diabetic patients treated with human recombinant ultralente insulin.
OBJECTIVE
To test whether a suppertime injection of human ultralente insulin in patients with type I diabetes would result in a larger inhibition of basal hepatic glucose production (HGP) and improvement in fasting and mean daily plasma glucose levels.


METHODS
We studied 16 type I diabetic patients (41 +/- 4 years of age; body mass index [BMI] = 23.3 +/- 0.3 kg/m2; diabetes duration > 3 years) with a crossover protocol of therapy with an intermediate and ultralente insulin. All patients were already treated with three injections per day of regular insulin in addition to intermediate-acting (NPH) insulin at suppertime. After a 14-day run-in period, patients were randomly assigned to treatment with equivalent doses (10.8 +/- 0.8 U, at 1900) of intermediate (Humulin I) or ultralente (Humulin U) insulin. After 1 month of treatment, patients were crossed over. No change of the insulin dosage was performed during the study period. Basal HGP was measured by D-(6,6-2H2)-glucose infusion. Plasma glucose concentration was measured in the fasting state and monitored during the day.


RESULTS
Before starting the study period, fasting plasma glucose was 13.4 +/- 1.1 mM and plasma free-insulin was 48.0 +/- 4.8 pM. Daily plasma glucose concentration averaged 10.3 +/- 0.3 mM and the area under the curve (AUC) was 1.41 +/- 0.05 mol/14 h. NPH insulin, given at suppertime for a month, did not induce significant changes in fasting plasma insulin (40.2 +/- 4.8 pM), glucose concentration (14.0 +/- 0.9 mM) or HGP (20.2 +/- 2.2 mumol.kg-1.min-1). Accordingly, no change occurred in the average daily plasma glucose (10.3 +/- 0.3 mM) or AUC (1.41 +/- 0.9 mol/14 h). Glycated hemoglobin also was not affected (8.2 +/- 0.4 vs. 8.2 +/- 0.3%). On the contrary, a 4-week treatment with ultralente insulin, also given at suppertime, was associated with a decline in the basal HGP (16.0 +/- 1.3 mumol.kg-1.min-1), fasting (11.3 +/- 0.9 mM) and average daily (9.4 +/- 0.3 mM) plasma glucose concentrations, and AUC (1.29 +/- 0.07 mol/14 h) of plasma glucose level (all P < 0.05). Glycated hemoglobin was reduced (7.9 +/- 0.4%). In each condition, fasting plasma glucose concentration was correlated with the average daily plasma glucose level (basal = 0.78; intermediate = 0.89; ultralente = 0.62; all P < 0.05), which suggests that ultralente insulin likely induces the improvements of metabolic control through reducing fasting plasma glucose.


CONCLUSIONS
Our results suggest that treating type I diabetic patients with ultralente insulin at suppertime provides a better modulation of basal HGP so that lower fasting plasma glucose levels are ensured. The reduction of fasting hyperglycemia is likely to affect positively daily plasma glucose control.
Riccio
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A
Cattedra di Malattie del Metabolismo, University of Padova, Padua, Italy.
Avogaro
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A
Valerio
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A
Zappella
A
A
Tiengo
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A
Del Prato
S
S
D000328:Adult; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005215:Fasting; D005260:Female; D005947:Glucose / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia; D007328:Insulin / Q000097:blood / Q000627:therapeutic use*; D007336:Insulin, Isophane / Q000627:therapeutic use; D049528:Insulin, Long-Acting / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D011994:Recombinant Proteins / Q000627:therapeutic use
D001786:Blood Glucose; D007328:Insulin; D049528:Insulin, Long-Acting; D011994:Recombinant Proteins; D007336:Insulin, Isophane; D005947:Glucose