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Insulin Pharmacokinetics

Article  in  Diabetes Care · March 1984

DOI: 10.2337/diacare.7.2.188 · Source: PubMed

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 Review

i nsulin Pharmacokinetics
CHRISTIAN BINDER, M.D., TORSTEN LAURITZEN, M.D., OLE FABER, M.D., AND STIG PRAMMING, M.D.

Where adjustments of diet, physical activity, and dosage of insulin are well known to diabetologists
and diabetic patients, present-day knowledge of factors of importance to the pharmacokinetics of insulin
is frequently ignored. The pharmacokinetics of insulin comprise the absorption process, the distribution
including binding to circulating insulin antibodies, if present, and to insulin receptors, and its ultimate
degradation and excretion. The distribution and metabolism of absorbed insulin follow that of endog'
enous insulin. The distribution and metabolism cannot be actively changed, except in the case of
circulating insulin antibodies, which in rare cases also may cause insulin resistance. The use of insulin
preparation of low immunogeneity will avoid or reduce this course of variation in action. The absorption
process, the detailed mechanisms of which are still unknown, is influenced by many variables where
some can be controlled, thereby reducing the intrapatient variability in insulin absorption, which may
reach 35%, causing a corresponding metabolic lability. Besides the known differences in timing among
different preparations, the size of dose, the injected volume, and the insulin concentration are deter-
minants of absorption role. Fortuitous injection technique contributes to variance, as do changes in
blood flow of the injected tissue. This may be induced by changes in ambient temperature, exercise of
injected limb, or local massage. Regional differences are also due to differences in blood flow. Serum
insulin peaks may peak up to 1 h after injection of soluble insulin into the thigh versus into the
abdominal wall. Local degradation of insulin seems of less importance but may, in rare cases, be the
cause of high insulin "requirements." Available evidence is reviewed and the importance of imple-
menting the consequences in the daily care of the insulin-treated patient is emphasized, DIABETES CARE
7: 188-199, MARCH-APRIL 1984.

N
ormoglycemia throughout 24 h has become a
major objective of treatment of patients with
diabetes mellitus. This is based on the assump-
tion that long-term good control of blood glu-
cose may help prevent or delay the development of the late
complications of the disease.
In the treatment of diabetes mellitus the fully automatic
control of the healthy subject has to be replaced by manual
external control. The success of this depends, at least par-
tially, on a knowledge of the factors causing variability in
the effect of the various parts of treatment. The effect of
various adjustments of diet and of physical exercise is gen-
erally known to physicians and patients. However, present-
day knowledge of factors of importance to insulin pharma-
cokinetics, such as types of preparation, injection site and
injection technique, ambient temperature, and exercise, is
frequently ignored.
The pharmacokinetics of injected insulin are governed by
a series of processes. Some of these processes are controllable;
others are unknown (Figure 1).
Choice of type, dose, and concentration of insulin, syringe
and needle, mixing of fast- and prolonged-acting insulin,
injection technique, and site of injection are all controllable
factors influencing the pharmacokinetics.
After the injection, the absorption process (not fully
understood) conveys insulin to the blood stream by which it
reaches its target tissue and its sites of degradation; degra-
dation, however, may already start at the site of injection.
Then, insulin in blood will be in a free and bound form
in an equilibrium determined by the binding characteristics

188 DIABETES CARE, VOL. 7 NO. 2, MARCH-APRIL 1984

 INSULIN PHARMACOKINETICS/CHRISTIAN BINDER AND ASSOCIATES

RESISTANCE- DIET
INSULIN
PREP.
B-GLUCOSE
CONTROL

I U-GLUCOSE

FIG. I. Factors of importance to the phax

macokinetics and action of injected insulin.

of the antibodies. The presence of antibodies prolongs the from previous injections will confuse the interpretation of
data. The test is still in use.2
biologic half-life of circulating insulin, but only the free frac-
tion is considered biologically active, diffusing freely through Another recent technique has overcome the problem of
the interstitial spaces from where it is bound to insulin re- hypoglycemia by infusing glucose to keep blood glucose at a
ceptors of the cell surface. The liver and the kidneys are constant level by means of the Biostator (Ames Division,
major sites of insulin degradation, but degradation also takes Miles Laboratories, Elkhart, Indiana).3 This technique has
place in the individual cells after internalization of the in- been further improved to enable clamping the blood glucose
sulin/insulin-receptor complex. Residual B-cell function may at higher levels.3a The time course and amount of glucose
also contribute to the circulating pool of insulin. Thus, var- infusion reflect the timing of acting. If combined with meas-
ious partly unknown pharmacokinetic factors influence the urements of free insulin,45 plasma C-peptide, and preferably
bioavailability of insulin. with determination of local clearance, this approach will give
the most complete picture of the pharmacokinetics of in-
It is the purpose of this article to critically review available
data on insulin pharmacokinetics with special emphasis on jected insulin6"13 that can be obtained even in diabetic pa-
what can lead to improvement of metabolic control in the tients.14
insulin-treated patient. Direct methods. A precise determination of the amount of
insulin cleared from the injection site per unit time requires
measurement of the blood and lymph flow through the tissue
EVALUATION OF INSULIN TIMING
and of the arteriovenous concentration difference. This is
Indirect methods. Until radiolabeled insulin and sensitive in- impracticable in man and difficult in animal models.
sulin assays became available, the timing of insulin action By labeling the insulin with a 7-emitting isotope, the re-
could only be evaluated from the time course of its metabolic maining amount of insulin at the injection site can be in-
effects. In practical terms this is synonymous with the effect directly determined by external counting of the nonabsorbed
on blood glucose concentration after the injection. Time to radioactivity, provided that in every respect the labeled sub-
blood glucose minimum (time-to-peak), blood glucose con- stance is absorbed like the unlabeled, and that the radio-
centration at that time (peak), and time of return to fasting activity counted externally is proportional to the nonab-
level (time of action) are common expressions of the outcome sorbed amount of radioactivity. All such absorption studies
of this test. In normal subjects as in diabetic patients, diet, in man have been performed by employing insulin labeled
physical activity, and counterregulatory mechanisms to hy- with radioactive iodide,15"55 but only part of them2325"55 have
poglycemia will exert an unverifiable effect on the time course used pharmaceutical preparations of iodine-labeled insulin.
of blood glucose leading to an underestimate of the time of Furthermore, the validity of the tracer preparation had been
action. The latter is only partly counteracted in the Gerritzen demonstrated in vitro.25'35'53
test1 where 10 g of carbohydrate is given every hour. By its In vivo examinations as to whether conditions were ful-
glucose equivalents it will tend to return blood glucose to a filled for employing iodine-labeled insulin to study insulin
fasting level earlier if not disturbed by release of endogenous absorption have been carried out in sheep2553 and pigs. 44>
insulin via the gastrointestinal insular axis. Furthermore, re- Although a few percent local degradation of the labeled in-
sidual endogenous insulin secretion and remaining insulin sulin compared with carrier insulin could not be excluded,

DIABETES CARE, VOL. 7 NO. 2, MARCH-APRIL 1984 189

 INSULIN PHARMACOKINETICS/CHRISTIAN BINDER AND ASSOCIATES
excised amounts of radioactivity corresponded to the exter-
nally counted radioactivity at time of excision. The exter-
nally determined remaining fraction of insulin also corre-
sponded with the excised amount of insulin, which showed
no significant change of specific radioactivity. That substan-
tial degradation of some radiolabeled insulins can take place
has, however, been demonstrated by the extensive studies
by one group of a tritiated semisynthetic biologically active
insulin57 injected subcutaneously (s.c.) into rats,57"63 pigs,64
and man.63
The reliability of using iodinated insulin for local clearance
determinations can also be judged indirectly. Combined stud-
ies of local clearance and time course of blood glucose25'29'33'38-39'40
and plasma insulin concentrations have shown strong co-
variation between disappearance rate of radioactivity, changes
in plasma immunoreactive insulin, and blood glucose.46'48'50'53
Moreover, a calculated half-time of insulin in serum was
comparable to values found by direct measures.48
In most cases external measurements have been carried
out by means of a carefully collimated Nal (Tl)-crystal at-
tached to a photomultiplier. Others have used portable min-
iature Geiger-Miiller tubes with telemetrical transfer of counts.30
A comparison between the two methods has shown them to
be equally efficient, although the results from the Geiger-
Miiller method seem more vulnerable to minor changes in
counting geometry.47
Therefore, provided that the insulin is carefully labeled
and taken together with carrier insulin through the chemical
and pharmaceutical processes,25'35153'56 external monitoring of
the radioactivity remaining at the site of injection provides
a reliable measure of the amount of insulin remaining in that
tissue.
MECHANISMS OF INSULIN ABSORPTION
I
nsulin seems to be absorbed directly into the blood
stream rather than via the lymphatics irrespective of
whether the insulin is injected in a dissolved, amor-
phous, or crystalline state. 25 Insulin was injected s.c.
into the forearm. A t varying intervals blood was collected
from the vein draining the region chosen for the determi-
nation of insulin. The insulin concentration was considerably
higher than that found in venous blood from the correspond-
ing contralateral region and reached values of up to several
thousand microunits per milliliter. It must be assumed that
there is no route from the lymphatic system to the blood
distal to the cubital fossa. Consequently, the results can mean
nothing except insulin being absorbed directly from tissue to
blood.
Absorption rate depends on the physical state of insulin,
the injection volume, the insulin concentration, the blood
flow, and the presence or absence of degradation at the in-
jection site.
In one study neutrally dissolved insulin (Actrapid, Novo
Industry, Bagsvaerd, Denmark) was found to be ab-
sorbed faster than acidly dissolved insulin using 125I-insulin
as a tracer in a crossover study.25'52 However, Galloway et
al. 65 were unable to confirm the existence of such a difference
190 DIABETES CARE, VOL. 7 NO. 2, MARCH-APRIL 1984
using the time course of blood glucose and plasma insulin as
expressions of the absorption kinetics. Differences in com-
position of vehicles might be an explanation as the Zn 2 +
content of regular insulin seems to be of no importance. 25
It was a characteristic and consistent feature of the course
of absorption for regular insulin in more than 200 patients
studied that the relative absorption rate rose during the first
hours after the injection, and then remained constant. 25
Similar initial delay has been observed by one group, 20 but
not by others.18>19'52 This initial delay disappears by reducing
the concentration tenfold from 40 U / m l or by increasing the
volume from 0.01 to 1 ml. T h e absorption rate decreased
with increasing concentration as well as with increasing vol-
ume. 25 Similar concentration dependency evaluated from blood
glucose and serum insulin concentrations has also been found.66
From available data on insulin absorption and on capillary
physiology it seems likely that soluble insulin reaches the
capillaries by diffusion to be absorbed probably in a mono-
meric or dimeric state. 25 ' 67 When the insulin molecules have
reached a space in the injected tissue within which the chance
of hitting a capillary surface during a unit diffusion time is
infinitely larger than the chance of passing outside the space,
then a state of constant absorption rate is reached. 67 This
explains the dependency on concentration, but not that on
volume. T h e latter might be due to local depression of the
microcirculation. 68
No certain conclusions can be reached on the absorption
mechanisms in the case of preparations with protracted ac-
tion. Presumably, zinc insulins are dissolved in situ and pro-
tamine insulin split69 before absorption takes place.
A suspension of an amorphous porcine insulin prepara-
tion (Semilente, Novo) showed similar course of absorp-
tion as that for dissolved insulin except for its considerably
longer duration. 25 When insulin was injected as a suspen-
sion of crystals (Isophane [Nordisk, Gentofte, Denmark],
Lente [Novo], Monotard [Novo], N P H [Nordisk], Rapitard
[Novo], Insulatard [Nordisk], or Ultralente [Novo]), the
absorption curves had in general a monoexponential
form 25^8-33-35-39'46'48-51'52'56
The absorption rate of dissolved as well as of insulin sus-
pensions is significantly correlated to the blood flow whether
injected s . c . 25 ' 36 ' 38 ' 51i69a or intramuscularly (i.m.). 2 5 However,
at high 133Xe-flow rates no further increase in absorption rate
seemed to take place 70 supporting the hypothesis that avail-
able capillary surface area is the rate-limiting factor and not
the flow of blood. 67 This might explain why Ferrannini et
al. 55 could not demonstrate a correlation between flow and
absorption rate of insulin.
The slowing effect of smoking on the absorption of regular
insulin is presumably also related to peripheral vasoconstric-
tion induced by smoking. 45
INSULIN DEGRADATION AT INJECTION SITE
After the injection, insulin remains for an appreciable time
in a micromilieu at 35-37°C containing all sorts of enzymes,
buffers, and ions—the influence of which on insulin is more
or less unknown. It has been postulated that these conditions
 INSULIN PHARMACOKINETICS/CHRISTIAN BINDER AND ASSOCIATES
are conducive to polymerization of especially the longer-
acting insulins.71
Subcutaneous enzymes play an important role for the split-
ting of isophane into protamine and insulin.69
In 1978 it was reported that i.v. infusion of 50-62 IU of
regular insulin restored metabolic control in six patients pre-
viously requiring up to 3000 IU per day by the s.c. route.72
It was suggested that local degradation at the injection site
was the possible cause, a concept that was supported by
others.73"76 Later evidence was given that in such cases of
severe insulin resistance a high level of insulin-degrading
activity could be demonstrated in extracts of serum77 and of
adipose and muscle tissue.74'7879 In vitro insulin-degrading
enzyme activities were increased in muscle and fat biopsies
from three obese insulin-resistant and two insulin-treated
subjects.80 The difficulty in establishing a diagnosis of sub-
cutaneous insulin malabsorption has recently been empha-
sized.803 Of 20 brittle patients referred, 19 responded to in-
traperitoneal insulin. Noteworthy was the observation that
eight patients demonstrated abnormal behavior.
Direct studies in rats59"62 and pigs64 by means of a fully
biologically active semisynthetic insulin have shown exten-
sive insulin degradation at the site of s.c. injection. This was
indirectly confirmed (in rats) using a new technique of pro-
grammed infusion aiming at imitation of the magnitude and
time course of biologic responses obtained by the s.c. route.81
The total amount of insulin infused i.v. was only 50% of
that required when injected s.c.
Comparisons between the ability of closed-loop i.v. in-
fusion, open-loop continuous s.c. infusion, and conventional
insulin therapy to obtain comparable degrees of metabolic
control have shown similar doses in most studies.32-82"84 In-
asmuch as this speaks against substantial local degradation,
the report that injection of aprotinin together with insulin
greatly increased the absorption rate favored it.85"88 However,
others have not been able to confirm this, 4489 and severe side
reactions to aprotinin with nausea and difficulty in breathing
have been observed necessitating i.v. chlorpheniramine.89
Intravenous, but not s.c. administration of aprotinin reversed
excessive insulin degradation in adipose and muscle tissue in
a patient who developed insensitivity to s.c. injected insu-
lin.90 In a recent study aprotinin was shown to cause local
hyperemia.91'9'3
Using the area under the serum insulin curve after an i.v.
dose of insulin as denominator and the area under the serum
insulin curve after s.c. or i.m. injection of the same dose, a
"bioavailability index" was computed.66 Provided that dis-
tribution and systemic metabolic degradation are constant,
that no endogenous secretion takes place, and that the plasma
insulin concentration is followed until its return to prein-
jection level, this index may reflect the fraction reaching the
circulation from the injection site. However, a comparison
between s.c. and i.v. administration is only valid if the in-
sulin is delivered in both cases by comparable continuous
infusion techniques aimed at the same biologic responses.81'92
Various models have been applied on the time course of
plasma insulin after s.c. injection and infusion in man1393
and dog.94 The half-time of absorption was calculated to be
DIABETES CARE, VOL. 7 NO. 2, MARCH-APRIL 1984
shorter than found by local clearance methods. This might
be explained in part by an effect of a smaller concentration
or dose. Also, as judged from the plasma insulin profile in
these articles, absorption time seems longer than can be
explained by the calculated half-time of absorption.
As can be understood, local degradation of insulin is still
an open question. In a few cases requiring huge amounts
of s.c. or i.m. insulin but "normal" amounts i.v. to be in
metabolic control, degradation is the most likely cause.
DISTRIBUTION AND INSULIN ANTIBODIES
I
f no circulating insulin-binding antibodies are present,
insulin will distribute as free insulin in the plasma and
then diffuse into other compartments. The plasma con-
centration of insulin then becomes a function of four
variables: absorption rate, endogenous insulin secretion, dis-
tribution volume, and catabolism.
If circulating insulin-binding antibodies are present, the
pharmacokinetics of insulin are considerably more compli-
cated.95'96
The affinity constant and binding capacity may in rare
cases be so high that practically no free insulin is available
for biologic action.97 This condition has been named insulin
resistance. It should not be confused with insulin resistance
due to insulin receptor antibodies, or receptor and postre-
ceptor defects.
The circulating insulin antibodies only seem to act as a
carrier protein. The antibodies are heterogenous and of IgG-
type comprising a mixed population of high-affinity and low-
affinity antibodies.97 This division is somewhat arbitrary, the
distribution of insulin to antibodies being complex with a
large variation between patients.97 Even within the same
patient considerable time-to-time variations are seen,98 pre-
sumably related to the quality of the insulin preparation.
The antibody-bound insulin is in equilibrium with the free
insulin. It clearly prolongs the biologic lifetime.9899 This
might cause hypoglycemia at unexpected times,97100 but can
also protect against fast development of ketosis in situations
of insulin deprivation.101
In case of change-over from less to higher purified insulin,
a substantial dose reduction is often experienced.98102 This
is explained by a reduction or change of antibodies and by
a lesser affinity of the purified insulin to existing antibodies.
This is especially the case if the change includes a shift from
bovine to porcine insulin102103 and might also be expected
when shifting from bovine to human insulin. However, no
direct relationship between insulin antibodies and daily in-
sulin dose has been found,14104"106 and it is far from all cases
of metabolic instability, given high doses of insulin, that can
be explained by the binding properties of insulin antibod-
106,107
ies.
For more detailed information readers are referred to a
recent review.71
CONVENTIONAL INSULIN THERAPY
The diurnal blood glucose profile varies considerably in di-
abetic patients, even in those who follow optimal dietary
191
 INSULIN PHARMACOKINETICS/CHRISTIAN BINDER AND ASSOCIATES
instructions, take one or two daily injections of insulin, and
pursue a fairly regulated life. Some profiles exhibit little var-
iation and stay within the range where no hypoglycemic
reactions or hyperglycemia/glucosuria occur. In other pa-
tients there is unpredictable variability ranging from severe
hypoglycemia to hyperglycemia and ketonuria. In addition,
variations occur in the individual reproducibility of this diur-
nal profile. In patients whose regimen is carefully planned
to coordinate meals, exercise, and other activities with the
hypothetical action of injected insulin, variations in insulin
absorption and insulin sensitivity become major determinants
of fluctuations in blood glucose levels.
Variation in absorption rate correlated with plasma con-
centration of free insulin38'46'48'541078 and with changes in blood
glucose concentration. 29'39i4°'46'48'50 Up to 80% of the day-to-
day fluctuations in blood glucose concentrations can be ac-
counted for by variation in the absorption of the interme-
diate-acting insulin preparations.3948
Insulin preparations. The absorption kinetics of the most
commonly used insulin preparations are now well
k n o w n . •3.23,25,26,28.33-35,37,38,46,47,49,52,66,108 p i g u r e J g[ves
and range of the absorption courses of neutrally dissolved
insulin (regular insulin) and the intermediate-acting iso-
phane (NPH) and lente insulins after s.c. injection into the
femoral region. While the average absorption follows a simple
exponential course, irregularity is a most striking feature.
Coefficients of variation for the time until 50% of the insulin
dose is absorbed (T50) are approximately 25% within and up
to 50% between patients25'33-50'51'66 for all insulins studied. A
major part of the variation is related to changes in blood
flow .»,36,38,51
The average absorption curve for ultralente insulin is also
monoexponential with half-times about 30-40 h and with a
similar variability from day-to-day than the other insulins
studied.25'26-38
FAST
SBOLGNTE
MTERMEDMTE
« 24 30 36
HOURS AFTER SM0LE S.C NflCTDN
FIG. 2. Mean and range of the disappearance ofs. c. injected nH-labeled
pharmaceutical insulin preparations. Illlllllllll, Regular insulin (N = 12);
, semilente (N = 9); nun, intermediate-acting Zn 2+ insulins and
isophane (N = 36).
192 DIABETES CARE, VOL. 7 NO. 2, MARCH-APRIL 1984
TABLE 1
Regional differences in absorption of regular insulin injected s.c. or i.m.
into various regions
T50% regular insulin (12 IU)
s.c. Region i.m.
141 ± 23' Deltoid 69 ± 12*
87 ± 12 Abdominal
155 ± 28 Gluteal
164 ± 15 Femoral 89 ±31
' Data given in minutes.
Regional differences. The relationship to blood flow also
explains the regional differences in absorption, with higher
rates from abdominal s.c. depots when compared with those
from the femoral regiOn.12-13'23'25'42-66 Within the same region,
absorption rates from an i.m. depot are higher than those
from an s.c. depot.25'66
the mean Table 1 gives the mean T50% and standard error of the
mean absorption after s.c. injection of 12 IU of regular insulin
from various commonly used regions and tissue. After s.c.
injection into the thigh it took almost 3 h before 50% of the
dose was absorbed compared with only H h after s.c. injection
into the abdominal region. This can be used therapeutically,
whereas nothing more can be gained by i.m. injection, which
is much more painful to the patient than s.c. injections.
There is disagreement as to whether s.c. adiposity influ-
ences the absorption of insulin. 1O7a'1O8a
The regional differences in absorption of insulin prepa-
rations with prolonged action are much less pronounced and
seem of only little therapeutical importance.25 However, the
results clearly speak against random rotation of injection
between regions from day-to-day.
Insulin dose and concentration. As is the case with the phar-
12) macokinetics of all other drugs, the dose and time of action
9) are related. The higher the dose, the longer the biologic
(n 36) action. Figure 3 illustrates this in its extreme. The full lines
show the hour-to-hour insulin absorption rate and plasma
insulin after a certain dose of intermediate-acting insulin.
The broken lines show the absorption rates when the dose
was increased by a factor of three on the following day.
Corresponding blood glucose values are also shown.
On the face of it the time of maximal activity was the
same, but the duration of significant activity was longer.
Furthermore, only 75% of the increase of dose was absorbed
within the first 24 h.
In practice this means that it takes from 2 to 5 days after
a certain dose change of intermediate-acting insulin before
a new "steady" state is achieved between daily injected and
daily absorbed insulin.
The absorption rate of regular insulin correlates inversely
with the concentration of the s.c. injected insulin25-52-66 and
directly with the injection volume.25 These two factors seem
to balance each other since blood glucose profiles after s.c.
injection of identical doses of U40 and U100 are similar.109'110
 INSULIN PHARMAC0KINET1CS/CHR1STIAN BINDER AND ASSOCIATES

insulin by dividing the insulin dose into several smaller de-

2<H pots.116
Reflux from the injected depot may in rare cases become
a problem.
Exercise and ambient temperature. Simultaneous measure-
ments of s.c. clearance of insulin and of a blood flow indicator
have shown a high degree of correlation between insulin
clearance and blood flow. 25,36,38.51,55 However, it is important
2 0.10
to notice that the impact of a certain change in blood flow
3
(0 is many times greater on the absorption of regular insulin
z than on the absorption of insulin suspensions. This explains
why moderate-to-heavy exercise of the injected limb13'29'63'117
and change of local or ambient temperature induce marked
alterations in absorption13-41'43 on fast-acting insulin,1329'63
but not measurable on intermediate-acting insulin.13 The
effect seems most pronounced just after the injection.13'29
Local massage in the form of gentle rubbing of the injection
site seems to accelerate the absorption of soluble as well as
7a.m.
of intermediate-acting insulin preparations.13118
F/G. 3. Average time course of insulin absorption rate, plasma insulin, Combinations of insulin preparations. The preinjection mix-
and blood glucose concentration after a single s.c. injection of interme- ing of regular and intermediate-acting insulins in proportions
diate-acting insulin into the femoral region. Full lines represent one-third adjusted to the need of the individual patient has become
of the dose corresponding with the broken line (N = 6). regular practice.
Combinations of regular insulin and NPH insulin did not
change the absorption course of regular insulin.13'52 This is
The accuracy of drawing up insulin does not influence the in slight contrast with another group.66 The discrepancy might
pharmacokinetics, but can be a substantial part of the error be due to a higher protamine content (0.4 versus 0.3 mg/
of dosage. Intrapatient variation has been found to range 100 IU) of the NPH insulin studied.52
between 0.5% and 10.2%. lll "" 3a Varying dead space of the When mixing regular with lente insulins the excess of Zn2 +
syringes may also cause serious errors in insulin dose. ll3a " 4 of the latter will modify and prolong the action of the for-
Injection technique. In one large series of absorption stud- mer.26'66119 However, provided the fraction of regular com-
jes?o-37,46,47,52 ^ i n s u | j n w a s injected perpendicularly to the prises more than 40-50% and provided the injection is given
skin with the tip of the needle reaching 10 mm below the immediately after mixing in the syringe, the clinical effect
surface. In the other large series a 45° oblique injection was seems less important.13
given into a lifted semifold with a 25-gauge one-inch
n e e d l e 25,25,26.28,38,39,48,50 furthermore, the two groups used dif-
ferent techniques of measuring the local insulin clearance. FRACTION AT INJECTION SITE
Despite these discrepancies comparable absorption charac- 1.0
teristics were obtained. However, Figure 4 illustrates what
might happen if the injection is given with the needle in-
serted in a too narrow angle to the skin, the depot being
0.75
placed close to or into the richly perfused layer between s.c.
and cutaneous tissue.
It is important to teach the patient and let him use a
reproducible injection technique, to place the insulin depot 0.50
deeply into the s.c. tissue.
Jet injection. Insulin can also be delivered by a fine stream
that penetrates the skin at high velocity, causing insulin to
be deposited s.c. in a more dispersed fashion."5 Such an 0.25
injection results in more rapid absorption of insulin without 1
initial delay and significant differences in plasma insulin and - 9
in the response of blood glucose and 3-hydroxybutyrate lev- —4
5 12 24 36 48
els. The increased absorption rate may be explained partly
HOURS AFTER SINGLE INJECTION
by the insulin being divided into multiple minute depots and
partly by being placed close to the highly perfused layer FIG. 4. Mean and SEM of the disappearance of intermediate-acting
between skin and s.c. tissue (rete cutaneum). insulin after deep (N = JO) and superficial s. c. injection into the femoral
It is also possible to accelerate the absorption of regular region.

DIABETES CARE, VOL. 7 NO. 2, MARCH-APRIL 1984 193

 INSULIN PHARMACOKINETICS/CHRISTIAN BINDER AND ASSOCIATES

SIZE OF DEPOT AT STEADY STATE

40 IU PER DAY

INTERMEDIATE b.d.
t,,, : 15 hrs

FIG. 5. Calculated diurnal variation in the total

amount remaining in s.c. depots at steady state
with a daily dose of 40 ID assuming a T50 of
absorption of IS h for intermediate-acting insulin
REGULAR t . d . s . * INTERMED and 2\ h for regular insulin. Upper curve corre-
t 1 / 2 -2 1/2 hrs sponds to intermediate b. d.; middle curve to reg-
CSII • ON-DEMAND ular t.d.s. plus intermediate at bedtime; lower
curve shows CSU, basal rate 0.5 IVIh plus bolus
8 NOON 11 8a.m. injections as indicated.

Species. At present only a few controlled studies have been
carried out comparing the pharmacokinetics of equimolar
preparations of human, porcine, and bovine insulins. The
results are conflicting: some found no difference in absorption49
while others found a faster absorption rate of human insu-
lin.108120 However, the difference does not seem to be big,
and is therefore not likely to be of clinical importance.
It should be borne in mind that the small number of pa-
tients included in these studies gives a high risk of statistical
error of the second type. Considering a coefficient of inter-
patient variation of 30%, a total number of about 40 paired
experiments are necessary to make a difference in T50% of 30
min significant (2 a = 0.05, 3 = 0.20).
CHOICE OF INSULIN REGIMEN
Figure 5 shows the diurnal profiles of the calculated size of
s.c. insulin depot by three treatment regimens: intermediate-
acting insulin b.i.d.; regular insulin t.i.d. plus intermediate-
acting insulin at night; and CSII with 0.5 IU/h as the basal
infusion rate. The amount of insulin injected is shown, with
the dose of intermediate-acting insulin represented as the
circular number.
The size of the depot varies from 22 to 56 IU with the
intermediate-acting insulin b.i.d. regimen, from 12 to 21 IU
with the multiple-dose regimen, but only from 1 to 14 IU
with CSII. This difference in the size of the depot has very
different consequences if the absorption rate varies. For ex-

CONTINUOUS SUBCUTANEOUS INSULIN INFUSION (CSII) INSULIN SENSITIVITY DURING NIGHT HOURS

T
he pharmacokinetics of continuous s.c. infused B-GLUCOSE
insulin follow the same principles as for bolus in- mmol/l
jections of regular insulin.50 Steady-state size of 2O-i
the depot is achieved about 6-8 h after a constant
basal infusion has been started.693 There is a day-to-day coef-
ficient of within-patient variation of about 30%. The ab-
sorption of the s.c. bolus injection given through the pump
follows the same absorption pattern as seen after s.c. injection
of regular insulin given with syringe and needle. If the bolus 10-
dose is infused and not injected, the absorption is slower.116
It seems that the timing of administration of preprandial
insulin bolus infusion is of importance. If the infusion was
started 60 min before a meal, plasma glucose and free insulin
profiles came close to normal when compared with admin-
istration 30 min or immediately before meal ingestion.121122 0 50 100 150
In accordance with the expected kinetics for s.c. injected
insulin, a constant basal flow rate delivering the insulin either "Free" IRI pmol/l
continuously or intermittently as pulses spaced up to 120 min FIG. 6. Range of regression lines between free insulin and blood glucose
showed no significant differences in overnight blood glucose, concentrations from 4 to 7 a.m. in seven insulin-dependent diabetic
plasma free insulin, and plasma glucagon profiles.123 patients without endogenous insulin secretion.

194 DIABETES CARE, VOL. 7 NO. 2, MARCH-APRIL 1984

 INSULIN PHARMAC0K1NETICS/CHR1STIAN BINDER AND ASSOCIATES
TABLE 2
Summary of factors of major importance for the fate of injected insulin
Variable Present knowledge indicates that:
Insulin Regular insulin Tw% ~ 2-4 h
preparation Intermediate-acting insulin T50% ~ 16-20 h
Prolonged-acting insulin T50% ~ =36 h
Intraindividual variation in absorption up to 50%
Interindividual variation from day to day up to 25%
Insulin Of minimal importance
species
Fortuitous Contributes to variance
injection
technique
Injected Absorption faster from abdominal region than from
region femoral and gluteal region. Exercising injected
limb speeds up absorption. Applies especially to
regular insulin
Subcutaneous Major determinant for absorption rate and clini-
blood flow cally significant for regular insulin (influenced by
smoking, ambient temperature, exercise, local
massage, etc.)
Subcutaneous Usually of no clinical significance. In rare cases
degradation after insulin need exceeds 120 IU it might ex-
of insulin plain brittleness
Insulin Increase unpredictably the circulating part of insu-
antibodies lin and prolong its half-life. Rare cause of insu-
lin resistance
ample, during the time interval from 4:00 a.m. to 6:00 a.m.,
a change of T50 of 30% in either direction of insulin absorp-
tion will give the following ranges for the calculated amount
of insulin absorbed: for the intermediate-acting insulin b.i.d.
regimen, 2-4.2 IU; for the regimen of regular insulin t.i.d.
plus intermediate-acting insulin at bedtime, 1-1.9 IU; and
for CSII plus on-demand boluses, 0.7-1.8 IU. In the period
immediately after injections, these differences between treat-
ment regimens still exist, but are less pronounced. These
differences seem to serve a purpose, however, since the doses
are adjusted depending upon meals and physical activity for
the two latter regimens.
The frequent occurrence of night-time hypoglycemia dur-
ing conventional treatment is easily explained by the large
fluctuations in insulin absorption in absolute terms. The cal-
culations also indicate a smaller risk of prolonged hypogly-
cemia during CSII if the dosage of insulin is properly designed
to the needs of the patient.
Differences in insulin sensitivity are another source of var-
iation in blood glucose levels when comparing patients seem-
ingly otherwise alike in overall treatment regimen. In a re-
cent study of the absorption of NPH insulin, we showed that
the blood glucose values from 4:00 a.m. to 7:00 a.m. cor-
related closely with the insulin absorption rate and with the
plasma free insulin concentration.48 In all but one of the
eight patients studied there was a significant correlation be-
tween the plasma free insulin level and the blood glucose
DIABETES CARE, VOL. 7 NO. 2, MARCH-APRIL 1984
concentration.124 In this small group of patients, the range
of sensitivity varied from a change in blood glucose concen-
tration of 1-5 mmol/L to a 10 pmol/L change in free insulin
level (Figure 6). The patient who showed no correlation had
a decreased but significant capacity for endogenous insulin
secretion. This is in contrast to the others who were all
without demonstrable beta cell function.
A patient who is relatively insensitive to changes in plasma
free insulin concentration might therefore be less prone to
fluctuations in blood glucose levels. The individual could
better tolerate the large absolute variations inherent in con-
ventional therapy when compared with the more insulin-
sensitive patient. In circumstances where insulin absorption
studies have proved to be of no practical value in the planning
of the dose of insulin, the determination of an individual
patient's insulin sensitivity may be valuable in selecting those
patients who will benefit from a multiple-dose regimen, and
also help to design a CSII program for the patient.
CONCLUSIONS
A
lthough the detailed mechanisms of insulin ab-
sorption from s.c. and i.m. depots are still un-
known, results from the studies carried out so far
can be implemented in the daily care of the
insulin-treated patient. The major variables are listed in
Table 2.
The absorption time of an average dose of insulin is about
8-10 h for regular insulin and 24-36 h for intermediate-
acting insulins. Increase in dose prolongs the absorption time,
and decrease shortens it. The long absorption time of the
intermediate-acting insulins implies that it takes several days
from a change in dose before a new steady state is attained.
The intrapatient variability in insulin absorption may reach
35% causing in itself metabolic lability. In such cases a change
to multiple daily injections or CSII may reduce the problem
considerably.
Reproducible injection technique is important, and re-
gional differences in absorption rates should lead to the avoid-
ance of random shifts of injections between regions. On the
other hand, used intentionally, it may improve metabolic
control. The effect will be most significant with regular in-
sulin.
Finally, it is important to remember that insulin therapy
is no precision tool. Concurrent adjustments of food intake
are still necessary even in the best controlled cases on CSII.
For maximal benefit it is important to teach the patient
these basic facts about insulin pharmacokinetics, so that mis-
takes can be avoided or used to enhance the patient's quality
of life.
From the Steno Memorial Hospital and Hagedorn Research
Laboratory (C.B., T.L., S.P.)» Gentofte, Denmark, and the H0r-
sholm Hospital (O.F.), H0rsholm, Denmark.
195
 INSULIN PHARMAC0K1NETICS/CHRISTIAN BINDER AND ASSOCIATES
REFERENCES
' Gerritzen, R: The duration of the action of different insulins.
Br. Med. J. 1952; 1:249-50.
2
Weinges, K., Ehrhardt, M., and Enzmann, F.: Comparison of
biosynthetic human insulin and pork insulin in the Gerritzen test.
Diabetes Care 1981; 4:180-82.
' Bottermann, P., Gyaram, H., Wahl, K., Ermler, R., and Le-
bender, A.: Pharmacokinetics of biosynthetic human insulin and
characteristics of its effect. Diabetes Care 1981; 4:168-69.
3a
Clemens, A. H., Hough, D. L , and D'Orazio, P. A.: Devel-
opment of the Biostator glucose clamping algorithm. Clin. Chem.
1982; 28:1899-1904.
4
Bottermann, P., Gyaram, H., Wahl, K., Ermler, R., and Le-
bender, A.: Verhalten der Insulinkonzentration im peripher-ven-
osen Blut nach intraperitonealer Bolusgabe von Insulin. Klin.
Wochenschr. 1981; 59:157-63.
5
Taylor, R., Home, P. H., and Alberti, K. G. M. M.: Plasma
free insulin profiles after administration of insulin by jet and con-
ventional syringe injection. Diabetes Care 1981; 4: 377-79.
6
Guerra, S. M. O., and Kitabchi, A. E.: Comparison of the
effectiveness of various routes of insulin injection: insulin levels
and glucose response in normal subjects. J. Clin. Endocrinol. Me-
tab. 1976; 42:869-74.
7
Slama, G., Buu, K. N. P., Tchobroutsky, G., Delage, A., and
Desplanque, N.: Plasma insulin and C-peptide levels during con-
tinuous subcutaneous insulin infusion. Diabetes Care 1979; 2:251-
55.
8 25
Chtsholm, D. J., Kraegen, E. W., and Zelenka, G. S.: Pro-
gramming of insulin delivery with meals during subcutaneous insulin
infusion. Diabetes Care 1981; 4:265-68.
9
Owens, D. R., Jones, M. K., Hayes, T. M., Heding, L. G.,
Alberti, K. G. M. M., Home, P. D., Burrin, J. M., andNewcombe,
R. G.: Human insulin: study of safety and efficacy in man. Br.
Med. J. 1981; 282:1264-66.
10
Owens, D. R., Jones, M. K., Hayes, T. M., Heding, L. G.,
Alberti, K. G. M. M., Home, P. D., and Burrin, J. M.: Comparative
study of subcutaneous, intramuscular, and intravenous administra-
tion of human insulin. Lancet 1981; 2:118-22.
11
Home, P. D., Alberti, K. G. M. M., and Owens, D. R.: Some
observations on insulin absorption and pharmacokinetics. In Insulin
Update. Skyler, J. S., Ed. Amsterdam, Excerpta Medica, 1982:120-
24.
12
Siisstrunk, H., Morell, B., Zieglef, W. H., and Froesch, E. R.:
Insulin absorption from the abdomen and the thigh in healthy
subjects during rest and exercise: blood glucose, plasma insulin,
growth hormone, adrenaline and noradrenaline levels. Diabetologia
1982; 22:171-74.
" Berger, M., Cuppers, H. J., Hegner, H., Jorgens, V., and
Berchtold, P.: Absorption kinetics and biologic effects ofsubcuta-
neously injected insulin preparations. Diabetes Care 1982; 5:77—
91.
14
Gerbitz, K.-D., Kemmler, W., Edelmann, A., Summer, J.,
Mehnert, H., and Wieland, O. H.: Free insulin, bound insulin,
C-peptide and the metabolic control in juvenile onset diabetics:
comparison of C-peptide secretors and non-secretors during 24 hours
conventional insulin therapy. Eur. J. Clin. Invest. 1979; 9:475-
83.
15
Reiner, L , Keston, A. S., and Green, M.: The absorption
and distribution of insulin labelled with radioactive iodine. Science
1942; 96:362-63.
16
Reiner, L , Lang, E. H., Irvine, J. W., Jr., Peacock, W., and
Evans, R. D.: The absorption rates of insulin, globin insulin and
196 DIABETES CARE, VOL. 7 NO. 2, MARCH-APRIL 1984
protamine zinc insulin labelled with radioactive iodine. J. Phar-
macol. Exp. Ther. 1943; 78:352-57.
17
Root, H. R, Irvine, J. W., Jr., Evans, R. D., Reiner, L , and
Carpenter, T. M.: Absorption of insulin labeled with radioactive
iodine in human diabetes. JAMA 1944; 124:84-90.
18
Joiner, C. L.: Rate of clearance of insulin labelled with '"I
from the subcutaneous tissues in normal and diabetic subjects. Lan-
cet 1959; 1:964-67.
19
Joiner, C. L., and Pearson, J. D.: V. Studies with insulin
labelled with iodine 131. Br. J. Radiol. 1959; 32:657-60.
20
Moore, E. W., Mitchell, M. L , and Chalmers, T. C : Vari-
ability in absorption of insulin-I131 in normal and diabetic subjects
after subcutaneous and intramuscular injection. J. Clin. Invest.
1959; 38:1222-27.
21
Balodimos, M. C., and Williams, R. H.: Absorption of insulin-
131
I from subcutaneous tissue in diabetic patients. Am. J. Med. Sci.
1962; 243:49-56.
22
Nora, J. J., Smith, D. W., and Cameron, J. R.: The route of
insulin administration in the management of diabetes mellitus. J.
Pediatr. 1964; 64:547-51.
23
Binder, C., Nielsen, Aa., and J0rgensen, K.: The absorption
of an acid and a neutral insulin solution after subcutaneous injection
into different regions in diabetic patients. Scand. J. Clin. Lab.
Invest. 1967; 19:156-63.
24
Dobson, H. L , Robbins, L , Johnsen, P. C , Mdalel, J., Odem,
D. D., Cornwall, G., and Davis, M. B.: Absorption of 131-1 labeled
modified insulin. Metabolism 1967; 16:723-32.
Binder, C : Absorption of injected insulin. Acta Pharmacol.
Toxicol. 1969; 27 (Suppl. 2): 1-84.
26
Schlichtkrull, J.: The absorption of insulin. Acta Paediatr.
Scand. 1977; 270:97-101.
27
Henry, D. A., Lowe, J. M., Citrin, D., and Manderson,
W. G.: Defective absorption of injected insulin. Lancet 1978; 2:741.
28
Faber, O. K., Lauritzen, T., Binder, C , Mouridsen, H. T.,
and V0lund, Aa.: Comparison of absorption and clinical effects of
Insulin Monotard and Insulin Novo Lente. Ugeskr. Laeger 1975;
137:2510-14.
29
Koivisto, V. A., and Felig, P.: Effects of leg exercise on insulin
absorption in diabetic patients. N. Engl. J. Med. 1978; 298:79-
83.
30
K0lendorf, K., Bojsen, J., andj0rgensen, K.: Storage telemetry
of subcutaneous absorption of 125I-NPH-insulin. In Biotelemetry IV.
Klewe, H.-J., and Kimmich, H. P., Eds. Braunschweig, Doring-
Druck, 1978:239-42.
31
K0lendorf, K., and Bojsen, J.: Storage telemetry for detection
subcutaneous absorption of protamine-125I-insulin in newly diag-
nosed, ketotic and non-ketotic insulin-dependent diabetes. Acta
Endocrinol. [Suppl.] (Copenh.) 1978; 88:51.
32
K0lendorf, K., Christiansen, J. S., Svendsen, P. Aa., Bojsen,
J., and Deckert, T.: Insulin absorption and insulin requirement.
Lancet 1978; 2:989.
33
K0lendorf, K., Aaby, P., Westergaard, S., and Deckert, T.:
Absorption, effectiveness and side effects of highly purified porcine
NPH-insulin preparations (Leo). Eur. J. Clin. Pharmacol. 1978;
14:117-24.
34
Petersen, H. D.: Absorption of NPH insulin labeled with 125I
from subcutaneous tissue. Ugeskr. Laeger 1978; 140:1760-64.
35
Hansen, B., Linde, S., K0lendorf, K., and Jensen, R: Ab-
sorption of protamine-insulin in diabetic patients. I. Preparation
and characterization of protamine-125I-insulin. Horm. Metab. Res.
1979; 11:85-90.
36
K0lendorf, K . , Bojsen, J . , a n d N i e l s e n , S . L.: A d i p o s e tissue
 INSULIN PHARMAC0KINETICS/CHRIST1AN BINDER AND ASSOCIATES
blood flow and insulin disappearance from subcutaneous tissue. Clin.
Pharmacol. Ther. 1979; 25:598-604.
37
Deckert, T.: Intermediate-acting insulin preparations: N P H
and lente. Diabetes Care 1980; 3:623-26.
38
Lauritzen, T . , Binder, C . , and Faber, O . K.: Importance of
insulin absorption, subcutaneous blood flow, and residual beta-cell
function in insulin therapy. Acta Paediatr. Scand. 1980; Suppl.
283:81-85.
39
Lauritzen, T . , Faber, O . K., and Binder, C : Variation in 125I-
insulin absorption and blood glucose concentration. Diabetologia
1979; 17:291-95.
40
Koivisto, V. A . : Sauna-induced acceleration in insulin ab-
sorption from subcutaneous injection site. Br. Med. J. 1980; 280:1411-
13.
41
Koivisto, V. A . : Sauna-induced acceleration in insulin ab-
sorption. Br. Med. J. 1980; 281:621-22.
42
Koivisto, V. A . , and Felig, P.: Alterations in insulin absorption
and in blood glucose control associated with varying insulin injec-
tion sites in diabetic patients. A n n . Intern. Med. 1980; 9 2 : 5 9 -
61.
43
Koivisto, V. A . , Fortney, S., Hendler, R., a n d Felig, P.: A
rise in ambient temperature augments insulin absorption in diabetic
patients. Metabolism 1981; 3 0 : 4 0 2 - 4 0 5 .
44
Deckert, T . , Hansen, B., Lauritzen, T . , a n d Christiansen,
J. S.: Subcutaneous degradation of insulin. Diabetologia 1981; 21:161-
62.
45
Klemp, P., Staberg, B., Madsbad, S., and K0lendorf, K.: Smoking
reduces insulin absorption from subcutaneous tissue. Br. Med. J.
1982; 284:237
46
K0lendorf, K., a n d Bojsen, J.: Kinetics of subcutaneous N P H
insulin in diabetics. Clin. Pharmacol. Ther. 1982; 31:494-500.
47
K0lendorf, K., and Bojsen, J.: Biotelemetric detection of the
disappearance rate of subcutaneously injected 125 I-NPH insulin in
diabetic patients. Clin. Physiol. 1982; 2:13-20.
48
Lauritzen, T., Pramming, S., Gale, E. A. M., Deckert, T.,
and Binder, C : Absorption of isophane (NPH) insulin and its
clinical implications. Br. Med. J. 1982; 285:159-62.
49
Sestoft, L., V0lund, Aa., Gammeltoft, S., Birch, K., and
Hildebrandt, P.: The biological properties of human insulin. Acta
Med. Scand. 1982; 212:21-28.
50
Lauritzen, T., Pramming, S., Deckert, T., and Binder, C :
Pharmacokinetics of continuous subcutaneous insulin infusion. Dia-
betologia 1983; 24:326-29.
51
K0lendorf, K., Bojsen, J., and Deckert, T.: Clinical factors
influencing the absorption of I25I-NPH insulin in diabetic patients.
Horm. Metab. Res. 1983; 15:274-78.
52
K0lendorf, K., Bojsen, J., and Deckert, T.: Absorption and
miscibility of regular porcine insulin after subcutaneous injection
of insulin-treated diabetic patients. Diabetes Care 1983; 6:6-9.
53
J0rgensen, K., and Binder, C : 125I-insulin as a tracer of insulin
in different chemical processes. In Labeled Proteins in Tracer Stud-
ies. Donato, L., Milhaud, G., and Sirchis, J., Eds. Brussels, EU-
RATOM, 1966:329-32.
54
Str0m, H., Lorentzen-Lund, S., Dahl-J0rgensen, K., Torjesen,
P., and Hanssen, K.: Insulin absorption kinetics: comparison of
disappearance of iodinated insulin and appearance of "free" insulin
in blood. Abstract. Diabetogia 1983; 25:196.
55
Ferrannini, E., Linde, B., and Faber, O . : Effect of bicycle
exercise o n insulin absorption and subcutaneous blood flow in the
normal subject. Clin. Physiol. 1982; 2:59-70.
56
Deckert, T . , Hansen, B., K0lendorf, K., Poulsen, J. S. D . ,
and Smith, M . : Absorption of NPH-insulin from subcutaneous tis-
DIABETES CARE, VOL. 7 NO. 2, MARCH-APRIL 1984
sue: a methodological study in pigs. Acta Pharmacol. Toxicol. 1982;
51:30-37.
57
Halban, P. A., and Offord, R. E.: The preparation of a sem-
isynthetic tritiated insulin with a specific radioactivity of up to 20
curies per millimole. Biochem. J. 1975; 151:219-25.
58
Duckworth, W. C , and Halban, P. A.: Comparison of 125I-
insulin and (Bl 3H-phenylalanine) insulin degradation by insulin
protease. In Insulin. Chemistry, Structure and Function of Insulin
and Related Hormones. Brandenburg, D., and Wollmer, A., Eds.
New York, Walter de Gruyter, 1980:509-16.
59
Davies, J. G., Offord, R. E., Halban, P. A., and Berger, M.:
The chemical characterization of the products of the processing of
subcutaneously injected insulin. In Insulin. Chemistry, Structure
and Function of Insulin and Related Hormones. Brandenburg, D.,
and Wollmer, A., Eds. New York, Walter de Gruyter, 1980:517-
23.
60
Halban, P., Berger, M., Gjinovci, A., Renold, A., Vranic,
M., and Offord, R.: Pharmacokinetics of subcutaneously injected
semisynthetic tritiated insulin in rats. In Semisynthetic peptides
and proteins. Offord, R. E., and DiBello, C , Eds. New York,
Academic Press, 1978:237-46.
61
Berger, M., Halban, P. A., Muller, W. A., Offord, R. E.,
Renold, A. E., and Vranic, M.: Mobilization of subcutaneously
injected tritiated insulin in rats: effects of muscular exercise. Dia-
betologia 1978; 15:133-40.
62
Halban, P. A., Berger, M., Gjinovci, A., and Renold, A. E.:
Biologic activity and pharmacokinetics of biosynthetic human in-
sulin in the rat. Diabetes Care 1981; 4:238-43.
63
Berger, M., Halban, P. A., Assal, J. P., Offord, R. E., Vranic,
M., and Renold, A. E.: Pharmacokinetics of subcutaneously in-
jected tritiated insulin: effects of exercise. Diabetes 1979; 28 (Suppl.
l):53-57.
64
B e r g e r , M . , H a l b a n , P. A . , G i r a r d i e r , L . , S e y d o u x , J . , Offord,
R. E., and Renold, A. E.: Absorption kinetics of subcutaneously
injected insulin. Evidence for degradation at the injection site.
Diabetologia 1979; 17:97-99.
65
Galloway, J. A., Root, M. A., Rathmacher, R. P., and Car-
michael, R. H.: A comparison of acid regular and neutral regular
insulin. Diabetes 1973; 22:471-79.
66
Galloway, J. A., Spradlin, C. T., Nelson, R. L., Wentworth,
S. M., Davidson, J. A., and Swarner, J. L.: Factors influencing
the absorption, serum insulin concentration, and blood glucose
responses after injections of regular insulin and various insulin mix-
tures. Diabetes Care 1981; 4:366-76.
67
Binder, C.: A theoretical model for the absorption of soluble
insulin. In Artificial Systems for Insulin Delivery. Brunetti, P.,
Alberti, K. G. M. M., Albisser, A. M., Hepp, K. D., and Massi-
Benedetti, M., Eds. New York, Raven Press, 1983:53-57.
68
Schou, J.: Subcutaneous and intramuscular injection of drugs.
In Handbook of Experimental Pharmacology. XXVII. Concepts in
Biochemical Pharmacology. Part 1. Brodie, B. B., and Gilette,
J. R., Eds. Berlin, Heidelberg, New York, Springer-Verlag, 1971:47—
66.
69
Hagedorn, H. C : Problems concerning the absorption of in-
sulin from human subcutaneous tissue. In Experimental Diabetes
and Its Relation to the Clinical Disease. Hoet, J. P., Young, F. G.,
Delafresnaye, J. F., and Smith, G. H., Eds. Oxford, Blackwell
Scientific Publications, 1954:279-90.
69a
Hildebrandt, P., Birch, K., Nielsen, S. L , and Sestoft, L :
Absorption of infused insulin: kinetics and relation to subcutaneous
blood flow. Abstract. Diabetologia 1983; 25:164.
70
Hildebrandt, P., Birch, K., Sestoft, L., and Nielsen, S. L :
197
 INSULIN PHARMACOKINETICS/CHRISTIAN BINDER AND ASSOCIATES
Non-linear relationship between subcutaneous blood flow and in-
sulin absorption. Abstract. Diabetologia 1982; 23:174-
71
Kurtz, A. B., andNabarro, J. D. N.: Circulating insulin-bind-
ing antibodies. Diabetologia 1980; 19:329-34.
72
Dandona, P., Foster, M., Healey, R, Greenbury, E., and Beck-
ett, A. G.: Low-dose insulin infusions in diabetic patients with high
insulin requirements. Lancet 1978; 2:283-85.
73
Henry, D. A., Lowe, J. M., Citrin, D., and Manderson,
W. G.: Defective absorption of injected insulin. Lancet 1978; 2:741.
74
Paulsen, E. P., Courtney, J. W., Ill, and Duckworth, W. C :
Insulin resistance caused by massive degradation of subcutaneous
insulin. Diabetes 1979; 28:640-45.
75
Freidenberg, G. R., White, N., Cataland, S., O'Dorisio,
T. M., Sotos, J. F., and Santiago, J. V.: Diabetes responsive to
intravenous but not subcutaneous insulin: effectiveness of aprotinin.
N. Engl. J. Med. 1981; 305:363-68.
76
Pickup, J. C , Home, P. D., Bilous, R. W., Keen, H., and
Alberti, K. G. M. M.: Management of severely brittle diabetes by
continuous subcutaneous and intramuscular insulin infusions: evi-
dence for a defect in subcutaneous insulin absorption. Br. Med. J.
1981; 282:347-50.
77
Misbin, R. I., Almira, E. C., and Cleman, M. W.: Insulin
degradation in serum of a patient with apparent insulin resistance.
J. Clin. Endocrinol. Metab. 1981; 52.177-80.
78
Kitabchi, A. E., Stentz, F. B., Cole, C , and Duckworth,
W. C : Accelerated insulin degradation: an alternate mechanism
for insulin resistance. Diabetes Care 1979; 2:414-17.
79
Maberly, G. E, Wait, G. A., Kilpatrick, J. A., Loten, E. G.,
Gain, K. R., Stewart, R. D. H., and Eastman, C. J.: Evidence for
insulin degradation by muscle and fat tissue in an insulin resistant
diabetic patient. Diabetologia 1982; 23:333-36.
80
Clarke, W. L., Thomas, L., and Santiago, J. V.: Clinical eval-
uation and preliminary studies on the use of an artificial pancreatic
beta cell in juvenile diabetes mellitus. J. Pediatr. 1977; 91:590-96.
803
Schade, D. S., and Eaton, R. P.: Brittle diabetes, subcutaneous
insulin malabsorption, and intraperitoneal insulin delivery. Ab-
stract. Diabetes 1983; 32 (Suppl. 1):4A.
81
Parsons, J. A., Pickup, J. C , Halban, P. A., Philippe, J.,
Offord, R. E., and Keen, H.: Pharmacokinetics of subcutaneously
infused insulin in rats and man. Abstract. Sixth International Con-
gress on Endocrinology, Melbourne, 1980:271.
82
Shahshahani, M. N., and Kitabchi, A. E.: Glucose-lowering
effect of insulin by different routes in obese and lean nonketotic
diabetic patients. J. Clin. Endocrinol. Metab. 1978; 47:34-40.
83
Rizza, R. A., Gerich, J. E., Haymond, M. W., Westland,
R. E., Hall, L. D., Clemens, A. H., and Service, F. J.: Control
of blood sugar in insulin-dependent diabetes: comparison of an
artificial endocrine pancreas, continuous subcutaneous insulin in-
fusion, and intensified conventional insulin therapy. N. Engl. J.
Med. 1980; 303:1313-18.
84
Lambert, A. E., Buysschaert, M., Marchand, E., Pierard, M.,
Wojcik, S., and Lambotte, L.: Determination of insulin require-
ments in brittle diabetic patients by the artificial pancreas. Diabetes
1978; 27:825-33.
85
Berger, M., Cuppers, H. J., Halban, P. A., and Offord, R. E.:
The effect of aprotinin on the absorption of subcutaneously injected
regular insulin in normal subjects. Diabetes 1980; 29:81-83.
86
Muller, W. A., Taillens, C , Le"reret, S., Berger, M., Philippe,
J., Halban, P. A., and Offord, R. E.: Resistance against subcuta-
neous insulin successfully managed with aprotinin. Lancet 1980;
1:1245-46.
87
Kasama, T., Oshiro, K., Uchida, M., Okubo, T., Kamiyama,
N., and Sugiura, M.: Studies on monocomponent insulin. IV. Sub-
198 DIABETES CARE, VOL. 7 NO. 2, MARCH-APRIL 1984
cutaneous absorption of insulin from preparations with protracted
action. Chem. Pharm. Bull. 1980; 28:379-86.
88
Freidenberg, G., White, N., Cataland, S., O'Dorisio, T., So-
tos, J., and Santiago, J.: Effectiveness of aprotinin (Trasylol) in
protease-mediated insulin (In.) resistance. Abstract. Diabetes 1980;
29 (Suppl. 2):23A.
89
Pickup, J. C , Keen, H., Stevenson, R. W , Parsons, J. A.,
Alberti, K. G. M. M., White, M., and Kohner, E. M.: Insulin via
continuous subcutaneous infusion. Lancet 1978; 2:988-89.
90
Maberly, G. E, Wait, G. A., Kilpatrick, J. A., Loten, E. G.,
Gain, K. R., Stewart, R. D. H., and Eastman, C. J.: Evidence for
insulin degradation by muscle and fat tissue in an insulin resistant
diabetic patient. Diabetologia 1982; 23:333-36.
91
Williams, G., Pickup, J. C , Bowcock, S., Cooke, E., and
Keen, H.: Subcutaneous aprotinin causes local hyperaemia. A pos-
sible mechanism by which aprotinin improves control in some di-
abetic patients. Diabetologia 1983; 24:91-94-
9la
Linde, B., and Gunnarsson, R.: Effects of aprotinin on insulin
absorption and subcutaneous blood flow in insulin-treated diabetic
patients. Abstract. Diabetologia 1983; 25:175.
92
Stevenson, R. W , Tsakok, T. I., and Parsons, J. A.: Matched
glucose responses to insulin administered subcutaneously and in-
travenously. Evidence for subcutaneous inactivation of insulin. Dia-
betologia 1980; 18:423-26.
93
Kobayashi, T., Sawano, S., Itoh, T., Kosaka, K., Hirayama,
H., and Kasuya, Y.: The pharmacokinetics of insulin after contin-
uous subcutaneous infusion or bolus subcutaneous injection in di-
abetic patients. Diabetes 1983; 32:331-36.
94
Fischer, U., Freyse, E.-J., Jutzi, E., Besch, W , Raschke, M.,
Hofer, S., and Albrecht, G.: Absorption rates of subcutaneously
injected insulin in the dog as calculated from the plasma insulin
levels by means of a simple mathematical model. Diabetologia 1983;
24:196-201.
95
Berson, S. A., Yalow, R. S., Bauman, M. A., Rothschild, A.,
and Newerly, K.: Insulin 13II metabolism in human subjects: dem-
onstration of insulin binding globulin in the circulation of insulin
treated subjects. J. Clin. Invest. 1956; 35:170-90.
96
Bollinger, R. E., Morris, J. H., McKnight, F. G., and Diedrich,
D. A.: Disappearance of l31I-labeled insulin from plasma as a guide
to management of diabetes: N. Engl. J. Med. 1964; 270:767-70.
97
Berson, S. A., and Yalow, R. S.: Quantitative aspects of the
reaction between insulin and insulin binding antibody. J. Clin.
Invest. 1959; 38:1996-2016.
98
Dixon, K.: Measurement of antibodies to insulin in serum.
Clin. Chem. 1974; 20:1275-81.
99
Kurtz, A. B., Matthews, J. A., andNabarro, J. D. N.: Insulin
binding antibody: reaction differences with bovine and porcine in-
sulins. Diabetologia 1978; 15:19-22.
100
Asplin, C. M., and Hartog, M.: Serum free insulin concen-
trations during the treatment of diabetic coma and pre-coma with
low dose intramuscular insulin. Diabetologia 1977; 13:475-80.
101
Madsbad, S., Alberti, K. G. M. M., Binder, C , Burrin,
J. M., Faber, O. K., Krarup, T., and Regeur, L.: Role of residual
insulin secretion in protecting against ketoacidosis in insulin-de-
pendent diabetes. Br. Med. J. 1979; 2:1257-59.
102
Asplin, C. M., Hartog, M., and Goldie, D. J.: Change of
insulin dosage, circulating free and bound insulin and insulin an-
tibodies on transferring diabetics from conventional to highly pur-
ified porcine insulin. Diabetologia 1978; 14:99-105.
103
Mustaffa, B. E., Daggett, P. R., and Nabarro, J. D. N.: Insulin
binding capacity in patients changed from conventional to highly
purified insulins. Diabetologia 1977; 13:311-15.
104
Daggett, P., Mustaffa, B. E., and Nabarro, J. D. N.: Effects
 INSULIN PHARMACOKINET1CS/CHRISTIAN BINDER AND ASSOCIATES
of highly purified insulin on dosage requirements. Practitioner 1977;
218:563-68.
l05
Asplin, C. M., Hartog, M., Goldie, D. J., Alberti,
K. G. M. M., Smythe, P., Binder, C , and Faber, O. K.: A com-
parison between diabetics receiving a high or low daily insulin
dosage. Horm. Metab. Res. 1978; 10:365-69.
106
Asplin, C. M., Hartog, M., and Goldie, D. J.: The relation-
ship between circulating free and bound insulin, insulin antibodies,
insulin dosage and diabetic control in insulin treated diabetics. Acta
Endocrinol. 1978; 87:330-38.
107
Baxter, R. C., Yue, D. K., and Turtle, J. R.: Equilibrium
binding studies of insulin antibodies in diabetic subjects. Clin. Chem.
1976; 22:1089-94.
107a
Birtwell, A. J., Owens, D. R., Luzio, S., Jones, I. R., Hayes,
T. M., and V0lund, A.: Subcutaneous adiposity influences the
absorption of radiolabeled Actrapid insulin. Abstract. Diabetologia
1983; 25:141.
108
Sonnenberg, G. E., Kemmer, F. W., Cuppers, H.-J., and
Berger, M.: Subcutaneous use of regular human insulin (Novo):
pharmacokinetics and continuous insulin infusion therapy. Diabetes
Care 1983; 6 (Suppl. l):35-39.
io8a Ni e l s e n ) Aa. V., and Binder, C : The absorption of soluble
insulin correlated to the diabetic state. Acta Med. Scand. 1967;
181:521-27.
109
Swift, P. G. E, Kennedy, J. D., and Gerlis, L. S.: Change to
U-100 insulin does not appear to affect insulin absorption. Br. Med.
J. 1983; 286:1015.
110
Davis, T. M. E.: Letter to the Editor. Br. Med. J. 1983;
286:1438.
111
Nielsen, V. M.: Dosage of insulin. Ugeskr. Laeger 1980; 142:225—
28.
112
Kesson, C. M., and Bailie, G. R.: Do diabetic patients inject
accurate doses of insulin? Diabetes Care 1981; 4:333.
113
Wright, S., Morris, J. T., and Hartog, M.: The accuracy of
drawing up insulin by insulin treated diabetics. Diabetes Metab.
1982; 8:7-8.
113a
Skodda, H., Warzecha, P., Miihlhauser, I., Kemmer, F. W.,
DIABETES CARE, VOL. 7 NO. 2, MARCH-APRIL 1984
and Jorgens, V.: The quality of different insulin syringes. Abstract.
Diabetologia 1983; 25:194.
114
Shainfeld, F. J.: Errors in insulin doses due to the design of
insulin syringes. Pediatrics 1975; 56:302-303.
115
Cohn, L , Chez, R. A., Hingson, R. A., Szelman, A. E, and
Trimmer, M.: Use of jet insulin injection in diabetes mellitus ther-
apy. Diabetes 1972; 21:39-44.
116
Lauritzen, T., and Deckert, T.: Personal communication, 1983.
117
Kemmer, F. W., Berchtold, P., Berger, M., Starke, A., Cup-
pers, H. J., Gries, F. A., and Zimmermann, H.: Exercise-induced
fall of blood glucose in insulin-treated diabetics unrelated to alter-
ation of insulin mobilization. Diabetes 1979; 28:1131-37.
118
Dillon, R. S.: Improved serum insulin profiles in diabetic
individuals who massaged their insulin injection sites. Diabetes Care
1983; 6:399-401.
119
Schlichtkrull, J., Pingel, M., Heding, L. G., Brange, J., and
J0rgensen, K. H.: Insulin preparations with prolonged effect. In
Handbook of Experimental Pharmacology. Insulin II. Hasselblatt,
E., and Burchhausen, F. V., Eds. Berlin, Heidelberg, New York,
Springer, 1975:729-77.
120
Pramming, S., Lauritzen, T., Thorsteinsson, B., Johansen,
K., and Binder, C.: Absorption of soluble and isophane semi-syn-
thetic human and porcine insulin in insulin-dependent diabetic
subjects. Acta Endocrinol. 1983; 105:215-29.
121
Dimitriadis, G. D., and Gerich, J. E.: Importance of timing
of preprandial subcutaneous insulin administration in the manage-
ment of diabetes mellitus. Diabetes Care 1983; 6:374-77.
122
Kinmonth, A. L., and Baum, J. D.: Timing of pre-breakfast
insulin injection and postprandial metabolic control in diabetic
children. Br. Med. J. 1980; 280:604-606.
123
Levy-Marchal, C , Albisser, A. M., and Zinman, B.: Over-
night metabolic control with pulsed intermittent versus continuous
subcutaneous insulin infusion. Diabetes Care 1983; 6:356-60.
124
Binder, C , Lauritzen, T., Pramming, S., and Deckert, T.:
Pharmacokinetics of insulin. In Diabetes 1982. Mngola, E. N., Ed.
Amsterdam-Oxford-Princeton, Excerpta Medica, 1983:277-79.
199