Review Article

Med Sci Monit, 2001; 7(4): 848-859

How recombinant insulin analogs improve insulin therapy of

diabetes mellitus: pathophysiology, clinical practice and
recommendations
Jan Tato1, Zvonko Milicevic2, Barbara Moejko-Pastewka3, Magorzata Bernas1, Anna Czech1
Department and Clinic of Internal Diseases and Diabetology, Medical University of Warsaw, Warsaw, Poland
Eli Lilly and Company, Vienna, Austria
3 Eli Lilly Poland, Warsaw, Poland
1
2

key words: diabetes mellitus, type 2 diabetes, insulin therapy, insulin mixtures, insulin analogs, humalog

SUMMARY
According to the latest prognoses, 300 million people are expected to suffer from diabetes (particularly type 2) in 2025; diabetes will become a new epidemics of the coming century. Therefore it is so important to get acquainted with the pathomechanism of diabetes-related disorders and the possibilities of effective treatment. During the last decade, numerous prospective
epidemiological studies have been completed, which have considerably extended our knowledge of the pathomechanism of
disturbances and their effect on late complications of diabetes. Resistance to insulin has an important role in the etiology of
type 2 diabetes. However, there is substantial evidence indicating that impairment or regression of rapid insulin secretion phase at the early stage of the disease is a factor of no lesser importance. The lack of appropriate insulin concentration after the
stimulation by food ingestion (first 30 min after the meal), leads to permanent, treatment-resistant hyperglycemia. The postulated attempts to obtain a nearly normoglycemic condition, as well as the results of prospective epidemiological studies proving that achieving this aim improves the prognosis of diabetic patients, prompt the researchers to search for the drugs or treatment schedules, which could effectively restore the impaired insulin secretion, and its early phase in particular, in type 2 diabetes. Human insulin analogs and their pre-formulated commercially available mixtures seem very promising in this respect.

BACKGROUND
The year 2001 is the 80th anniversary of reporting the discovery of insulin by Frederick Grant Banting, Charles
Herbert Best and John James Richard Macleod in the
program of local medical society in Toronto (Canada).
It was a successful ending of a long efforts made with less
success before by numerous European researchers. The
first patient whose life was saved owing to that discovery
was 14-year-old Leonard Thompson, admitted in January 1922 to Hospital for Sick Children in Toronto with
diabetic ketosis [1].
During the 80 years that have elapsed since that time,
insulin has saved the lives of millions of diabetics, numerous studies in the field of insulin therapy have been
carried out, and the foundations have been laid for furReceived: 2001.04.01
Accepted: 2001.05.07

848

ther improvements. The discovery of insulin and insulin

therapy was an achievement of utmost importance in
the history of medicine and society of the 20th century,
Parallel progress in physiological and clinical studies is
particularly important in this field. This allows to make
progress in insulin therapy by the way of evidence-based
medicine (Evidence Based Medicine Diabetology).
The aim of this paper is to present the advances and recommendations with respect to insulin therapy utilizing
insulin analogs on the basis of pathophysiological, pharmacological and clinical studies. The following problems
are discussed:
1. Physiological standards for insulin therapy,
2. Disadvantages of traditional native (non-modified) insulin preparations,
3. Modification of insulin molecule for therapeutic purposes insulin analogs,

Correspondence address: Prof. Jan Tato, Department and Clinic of Internal Diseases and Diabetology, Medical University of Warsaw,
Kondratowicza 8, 03-242 Warsaw, Poland, tel./fax +48 22 811 67 52

Tato J et al How recombinant insulin analogs improve insulin therapy

4. New objectives of treatment of type 1 and type 2

diabetes the necessity to propagate intensive insulin therapy,
5. Practical aspects of treatment with insulin analogs,
6. Special groups of diabetic patients,
7. Special clinical circumstances,
8. Summary and conclusions.

1. PHYSIOLOGICAL STANDARDS FOR INSULIN

THERAPY
Baseline and reactive (postprandial) insulin
secretion
Insulin is an alimentary signal. This signal is sent from the gastrointestinal tract by absorbable molecules of glucose and
some amino acids, as well as directly by hormones secreted
by the gastric and duodenal mucosa, such as: secretin, pancreozymin, enteroglucagon, to the beta islet cells of the
pancreas, which release insulin to the bloodstream in response to this signal (intestino-pancreatic axis). This hormone reaches all systemic tissues involved in metabolism. The
presence of insulin in blood and tissue fluids signals that the
organism is saturated with nutrients, whereas the lack of insulin or decrease of its level signals the state of hunger.
Thus, insulin constitutes a signal correlating the intensity
of digestion and absorption of nutrients with the general
metabolic demand of the organism and the function of
its different energetic reserves.
Insulin exerts a direct or indirect effect on all stages of
metabolism. For this reason, probably, the biosynthesis
and secretion of this hormone is regulated by numerous
factors which integrate this process closely with the organisms needs. [2] These factors include:
1. neural stimuli stimulation of insulin secretion: cholinergic and adrenergic receptors, inhibition: adrenergic receptors,
2. hormonal stimuli stimulation: pancreozymin, enteroglucagon and some other intestinal hormones, as
well as pancreatic glucagon, inhibition: catecholamines, somatostatin and exogenous insulin,
3. substrate stimuli stimulation: increased blood concentrations of glucose, some aminoacids, ketones,
low-molecule fatty acids, some electrolytes such as
Ca2+, Mg2+, inhibition: hunger, exertion.
Insulin exerts its effect on the cells by:
1. binding of its molecule and stimulation of insulin-specific receptor and
2. release of cellular biochemical excitatory transmitters
from the receptor to effector enzymes and
3. modification of effector enzyme activity (metabolism,
proliferation).

Secretory reaction
A characteristic feature of secretory reaction of pancreatic beta cells to glucose is its biphasic nature: the first,

rapid secretion phase is initiated during 1 min. from the

glucose stimulus, reaches its peak during 25 min. and
subsides during the next 35 min. The second, slow phase starts after that time and lasts for ca. 1 h. Protein synthesis inhibitors, such as puromycin, do not affect the
first phase, whereas they attenuate the second one.
On that basis it has been presumed that 2 insulin pools
are present in the beta cells. One of them is stored and
easily released in response to stimuli, accounting for the
first phase of the secretory reaction. The second one
comprises insulin synthesized de novo in response to the
stimuli with admixture of small amounts of proinsulin,
which are secreted during the second phase of the secretory reaction.
The first symptom of disturbed insulin secretion in impaired glucose tolerance and type 2 diabetes is total or partial loss of the first postprandial glucose release [3], leading to prandial hyperglycemia and other secondary disorders of angiotoxic character [4].
Thus, insulin is a potent and quick-acting regulator of
metabolism. It stimulates the processes of energy generation, assimilation and storage on continuous basis (baseline levels) and periodically, according to the supply of
nutrients (reactive, postprandial levels).

Baseline insulin level

Baseline insulin levels in venous or arterial blood plasma
of healthy subjects most frequently amounts, after overnight fasting, to 515 U/ml. (0.250.75 g/ml) [4]. The
change of baseline plasma insulin concentration is coupled in an inversely proportional manner with the level
of sensitivity of peripheral cells to insulin. It increases in
obese subjects and decreases in hunger. The intensity of
insulin secretion in a healthy subject of 70 kg body weight is estimated at 0.51.5 jU/h. During 24 h, a healthy
adult secretes 2040 U insulin.

Reactive insulin secretion

It is a precisely functioning mechanism ensuring glucose
homeostasis both after meals and during fasting periods.
The main signal altering insulin secretion in mammals is
glucose concentration in arterial blood perfusing the
pancreatic islets.
The concentrations of amino acids and some other metabolites, as well as those of glucagon and somatostatin
in blood are also important signals regulating insulin secretion. The secretory reaction is determined by calcium
ions availability for the cell.
Insulin level rises rapidly after meals. Maximum postprandial insulin levels are usually 3 8, and even 10-fold
higher than before the meal. Besides the value of postprandial insulin concentration, the rate of its secretion is
also very important the more rapidly insulin level in-

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creases, the less pronounced postprandial hyperglycemia

is. Delayed insulin secretion may be manifested as
excessive postprandial hyperglycemia and subsequent
hypoglycemia, which can be observed 35 h after the
meal. Therefore, rapid decrease of insulin level to the
baseline values during e.g. 60120 min. is of equal importance. Schema of physiological insulin secretion as
a reaction of the meal stimuli is ilustrated by Fig. 1.

Insulin catabolism

10

20

40

60

80

100

120

140

Time (minutes)

Insulin leaves the pancreas via the pancreatic vein an

lymphatic vessels. For this reason, considerable amounts
of insulin are present in the lymph of the gastrointestinal
tract. Analysis of the elimination curves for human, porcine and bovine insulin after i. v. injection of their small
amounts demonstrated that the half-life period of this
hormone is ca. 58 min. This index has not been determined more accurately. The liver rapidly eliminates insulin from the blood. After a single passage of blood through this organ, it retains 4060% of insulin, most of
which is degraded by the insulinase system. This term
has been used to refer to the system of insulin-degrading
enzymes [2,4]

Selection of insulin therapy method

Insulin is a drug used in each case of diabetes, in which
other methods are not effective enough to attain the
optimal criteria of therapeutic compensation of metabolic disorders and prevention of chronic complication of
diabetes. According to the type of diabetes, there are
two essential objectives of insulin therapy:
1. it is used as natural substitution for absolute insulin
deficiency in subjects with type 1 diabetes and diabetes due to pancreotomy, as well as in subjects with
type 2 diabetes with absolute insulin deficiency (e.g.
at late stages of type 2 diabetes),
2. it supplements relative endogenous insulin deficiency
and helps to overcome resistance to insulin in patients with type 2 diabetes (non-insulin-dependent)
as well as in some types of secondary diabetes.
In selection of the method of insulin therapy the following factors should be taken into consideration:
a. metabolic needs resulting from the individual pathophysiological characteristics of diabetes,
b. the patients lifestyle,
c. therapeutic objectives in children, adolescent and
young patients the aim of the therapy is to restore
a nearly normoglycemic state; in patients over 75, it
is sufficient to maintain the levels of glycemia below
the renal threshold values,
d. technical factors, such as the type of insulin preparation and equipment used for injections,
e. cost-effectiveness of the therapy, taking into account
first of all the medical benefits and individual benefits for the patient.

850

Figure 1. Model of insulin secretion in healthy people. There are two

clearly visible phases of insulin secretion: first phase (early)
secretion of insulin stored in cell B of pancreas and
second phase secretion of insulin produced de novo by
cell B of pancreas.

Selection of algorithm and insulin preparations

This issue is totally subordinated to the therapeutic objectives, i.e. the attempt to obtain the nearly normoglycemic state and the prevention of chronic complications
of diabetes, trying at the same time to optimize the quality of life of diabetic patients and their social emancipation. The factors influencing the decision in individual
cases include:
a. detailed determination of the magnitude of insulin
deficiency and sensitivity to insulin,
b. clinical assessment of other characteristics of diabetes
and conditions of treatment.
An intensive approach to insulin therapy, including the
selection of appropriate insulin analogs, is definitely preferable.

Selection of dose
There is no method of calculation of insulin doses delivered in individual injections or of daily doses, which would priori prove appropriate in practice. The accuracy
of dose estimation is largely dependent on the physicians experience. Usually the initially prescribed dose is
later adjusted according to the results of determination
of circadian glycemia levels. The average daily dose of
insulin or insulin analogs usually necessary in case of treatment schedules involving four injections a day is
0.30.5 IU/kg b.w. but the required daily doses may range from e.g. 4 IU to 100 IU. In the morning the patient
usually receives ca. 3040% of the daily dose, at noon
1520%, in the evening 1520% and 2030% before
supper and going to bed. In practice, the adjustment of
LisPro insulin doses to the character of the meal should
follow the same principles as those for short-acting insulin. Approximately 2 IU of Humalog should be administered for each carbohydrate equivalent. Moreover, for
every 30 mg/dl of excessive blood glucose 12 IU should
be added to the planned Humalog dosage.

Tato J et al How recombinant insulin analogs improve insulin therapy

At the beginning of treatment, when self-control and adjustment of dosage by the patients themselves is very important, glycemia should be measured after overnight fasting, before each of the main meals, as well as two hours after the meals. Hyperglycemia after overnight fasting
exceeding 120 mg/dl often requires increasing the dose
of long-acting insulin administered in the evening. Too
high glucose levels before meals during the day require
increasing insulin doses or more frequent injections of
short-acting insulin (e.g. Humalog), whereas too low glucose levels require opposite decisions.

ations of glycemic levels. The main disadvantages of traditional short-acting human insulin preparations include:
slow onset of effect
necessity to observe a 30-45 min. interval between
insulin injection and the meal (inconvenient for the
patient)
difficulty in attaining quick reduction of postprandial
glycemia (considerable fluctuations of glycemia)
relatively prolonged effect
risk of postprandial hypoglycemia (46 h after the
meals, snacks between meals necessary)

Attempt to simulate physiological regulation in

the therapy

Insulin preparations with intermediate or prolonged activity injected in the form of crystal suspensions (NPH) or
amorphic particles (zinc insulins), require shaking before
use in order to ensure appropriate absorption, but this
method is not sufficient to obtain homogenecity of the
suspension. Individual variations of absorption may lead
to variability of glycemia (differences amounting even to
80% of the area under the circadian glycemic profile curve) manifested on subsequent days of treatment [5].
Thus, they are not very effective at ensuring a uniform,
baseline insulin levels. Hypoglycemic episodes are common at night, as well as hyperglycemic ones in the morning.

Insulin secretion in healthy subjects occurs as follows:

1. on a continuous basis, ensuring constant baseline insulin levels in the serum between meals and at night,
2. according to reactive, postprandial patterns, involving rapid and short-lasting increases of insulin levels
appropriate for postprandial hyperglycemia. Owing
to these secretion patterns, hyperglycemia after meals in healthy subjects is short-lasting and does not
exceed the renal threshold.
Simulation of the physiological, circadian profile of changes in insulin secretion by pancreatic islet beta cells and
the corresponding changes in regulation of the hormone
activity should be treated as the primary objective of insulin therapy.
Flexibility and effectiveness, as well as adjustability to the
changing needs of the patient should be the characteristics distinguishing good insulin therapy. For this reason,
for instance, it cannot be assumed that intensive treatment using an infusion pump will be better than the
schedule involving several insulin injections during 24
h or two injections a day of mixed preparations containing both rapidly and slowly absorbed insulin. The decisive factors are the degree of beta cell function impairment and clinical character of the disease.
In practice, insulin therapy is oriented towards realization of the therapeutic objectives, including the postulated restoration of nearly normoglycemic state in young
patients. It means attaining the values <110 mg/dl after
overnight fasting and <140 mg/dl after the meals. In elderly patients, maintaining the values of circadian glycemic profile at a 10% higher level is recommended because of the risk of hypoglycemia.

2. DISADVANTAGES OF NATIVE
(NON-MODIFIED) INSULIN PREPARATIONS
The so-called short-acting insulin preparations available
at present, delivered subcutaneously, do not allow to obtain an appropriate correlation between glycemia and
insulin levels. This leads both to too high postprandial increases of glycemia and to its too low levels 57 h after
the meals, i.e. to very pronounced and harmful fluctu-

3. MODIFICATION OF INSULIN MOLECULE FOR

THERAPEUTIC PURPOSES INSULIN ANALOGS
Insulin molecule
An insulin molecule consists of two polypeptide chains,
A and B, connected by two disulfide bonds. The additional, third disulfide bond is formed between the amino
acid radicals at positions 6 and 11 of chain A. Altogether,
the insulin molecule consists of 51 amino acids (chain
A 21, chain B 30). The molecular weight of porcine
insulin amounts to 5778, bovine 5735 and human 5808
Da: its isoelectric point corresponds to pH 5, 35. The sequence of amino acids in the molecule is constant. It is
virtually identical in insulins produced by all animal species except for amino acids located at positions 4, 8, 9,
and 10 of chain A and 1, 2, 3, 27, 29 and 30 of B.
Genetic biotechnology makes it possible to obtain, besides biosynthesis of insulin molecules identical to human
insulin (e.g. by Escherichia coli), also modified insulin
molecules. By changing the sequence of nucleic acids in
synthetic insulin gene inoculated to bacteria, insulin-like,
appropriately modified molecules can be obtained. The
modification may involve reduction of the number of
amino acids, their addition or substitution. The properties of insulin molecules modified in this way i.e. insulin
analogs, such as polymerization ability, magnitude of
binding by the insulin receptor, growth-promoting activity, antigenicity, may be favorable from the therapeutic
point of view. An important reason for the development
of analogs is an attempt to obtain a physiological, simulating the natural one, profile of insulin activity. Insulin absorption rate is dependent on the size of polymer mole-

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cules, in which it is present. The monomeric form is absorbed very quickly, dimeric and hexameric forms slowly. Inclusion of amino acids whose charge causes repulsion of other molecules prevents polymerization. Such
an analog does not form polymers and remains in the
subcutaneous tissue in its monomeric form, so it can be
absorbed more quickly than classical polymerizing insulin. Analogs demonstrating an increased tendency to
form polymers are produced as well. Their absorption
from the subcutaneous tissue is slower than that of insulin. Delayed absorption effect can also be obtained by
forming an analog characterized by reduced solubility at
the pH values prevailing in the tissue fluid. An analog of
this type, which has a form of solution in the ampoule,
but it is precipitated in the tissue fluid, has been obtained. Unfortunately, its pharmacodynamics is subject to
considerable alterations due to differences in blood flow
and insulin degradation in the subcutaneous dept. Poor
bioavailability is a disadvantage of slowly absorbable preparations. Substitution of amino acids in insulin molecule
may also affect its growth-promoting activity. Short-acting insulin analogs are absorbed from the subcutaneous
tissue in basically the same way as human insulin. The

Figure 2. Insulin Lis(B28) Pro (B29) (Humalog) model of structure

Figure 3. Scheme of insulin dimer. Arrows show places of changes in

the section of B-chain [Lis(B28)Pro(B29)] compared to
human insulin. This change causes reduction of electrostatic
forces and lower tendency Lispro to association (adherence)
molecules exist in monomer form.

852

difference lies in the reduced period of transformation of

hexamers into dimers and monomers and time of diffusion into the bloodstream [68]. The presence of the
analog in monomeric form leads, after the establishment
of dynamic equilibrium, to an increase of absorption rate
in comparison with that of native (non-modified) insulin.
The profile of plasma levels of the analog depends not
only on the absorption rate, but also on the intensity of
metabolic clearance. Some analogs are characterized by
higher, and some by lower metabolic clearance. The intensity of this clearance depends, in turn, on binding of
insulin and its analogs by insulin receptors and intracellular metabolism of the insulin-receptor complex. Decreased metabolic clearance of the analog results in its higher extracellular concentration and, consequently, more potent regulatory effect. Thus, the dependencies between analog levels in tissue fluid, its regulatory activity
and metabolic clearance are correlated and may compensate one another.
Among different analogs, the one that has been used in
clinical practice (for 6 years) is a human insulin analog
insulin LisPro called Humalog. It is a molecule differing
from human insulin at position 28 of chain B, where it
has been substituted with lysine instead of proline, whereas at position 29 of chain B there is proline instead of
lysine. Owing to that modification, the tendency to form
polymers is considerably reduced in comparison with
traditional insulin molecule. This property allows very rapid absorption of the analog from the subcutaneous tissue, reaching the maximum serum level very quickly and
considerable shortening of the time of activity in comparison with classical insulin preparations [810]. The model of Humalog structure, as well as absorption, and reduced tendency to form plymers are illustrated by Fig.
24. Pharmacokinetic profile of Humalog in comparison
to regular short-acting insulin is illustrated by Fig. 5.
Insulin LisPro underwent numerous pre-clinical and clinical trials [1118]. No differences between the effects
of native insulin and Humalog on the growth of human
mammary gland cells and mutagenicity in these cells have been observed [18]. The analog also does not affect
immunogenicity in Rhesus monkeys [11]. The magnitude
of hypoglycemizing effect of this insulin analog is equivalent to that of native insulin [27]. However, it should be
emphasized that because of the specific pharmacokinetic and pharmacodynamic properties of Humalog, an increase of dose results mainly in potentiation of its immediate (maximum) effect, whereas no prolonged hypoglycemizing effect is observed, present in the case of traditional insulin preparations. [20]. Rapid absorption of
Humalog eliminates also the effect of injection site on
pharmacokinetic properties. The above characteristics of
insulin analogs administered as rapid- and short-acting
preparations make up for the pharmacodynamic shortcomings of traditional short-acting insulin preparations.
Humalog can be used as periprandial insulin, injected
on the average 3-4 times a day before the main meals.
There are also pre-formulated LisPro insulin mixtures ac-

Tato J et al How recombinant insulin analogs improve insulin therapy

Figure 4. Schematic presentation of the dissociation process of human

insulin and Lispro after subcutaneous application. The
differences consists in faster transformation of lispro
molecules into monomer form which easily passes through
the walls of the blood vessel and reaches a high
concentration in blood faster.

ting as so-called biphasic preparations, containing Humalog and isophanic suspension of crystalline LisPro insulin combined with protamine (NPL insulin) such as
Humalog Mix 25, Humalog Mix 50 or Humalog Mix 75.

4. NEW OBJECTIVES OF TREATMENT OF TYPE 1

AND TYPE 2 DIABETES THE NECESSITY TO
PROPAGATE INTENSIVE INSULIN THERAPY
Numerous clinical observations have indicated for a long
time the possibility of reducing the incidence of diabetic
angiopathic and neuropathic syndromes, improving the
prognosis and the patients quality of life by intensive hypoglycemizing treatment. Such possibility has been objectively and fully confirmed by long-term, prospective
studies such as Diabetes Control and Complications
Trial in type 1 diabetes, United Kingdom Prospective
Diabetes Study in type 2 diabetes, as well as by other
studies like Kumamoto Study Ohkubo. [2123]. The
general conclusion based on all these studies is that in all
the types and phases of the disease it is necessary to obtain the nearly normoglycemic state and to compensate
in this way other diabetes-related metabolic disorders,
leading to chronic complications. This postulate is closely
connected with the need to propagate intensive treatment of diabetes and objective, planned monitoring of
its results in order to introduce necessary modifications
improving the effects of hypoglycemizing therapy. It means in practice extending the indications for insulin therapy to include type 2 and secondary diabetes. The above applies also to subjects with elevated glycemia after
overnight fasting and increased postprandial glycemia,
detectable e.g. 1 or 2 h after glucose load or a meal.
Postprandial hyperglycemia, is, even in subjects with
normal fasting glycemic levels, a potent atherogenic factor. Persistent postprandial hyperglycemia result in increased hyperlipidemia after the meals, increased thrombotic activity, activation of blood platelets, increased secre-

Figure 5. Pharmacokinetics: Humalog compared to classic human

insulin reaches its highest concentration in serum earlier,
and after 3-5 hours insulin concentration returns to its initial
value.

tion of vasoconstrictors by the endothelium and increased oxidative stress [24] The significant role of these disturbances has been indicated, among others, by the
DECODE study (13 centers in Europe, investigated population of 26. 364 subjects, 10-year observation period). [25].
As it follows from these studies, abnormally elevated
postprandial glycemia (more than fasting glycemia) significantly correlates with increased risk of cardiovascular
diseases and related death.
In order to improve the prognosis and reduce the overall
risk of mortality, as well as that due specifically to cardiovascular diseases, it is necessary to normalize postprandial glycemia. This significantly extends the indications
for intensive pharmacotherapy, including prandial insulin
therapy. The above indication applies also to subjects
with impaired glucose tolerance. Toxic effects of hyperglycemia have also been observed by Marfell et al. [26]
They demonstrated that increased hyperglycemia leads
to an increase of the QTc interval (ECG) and QTc depression, even in healthy subjects. Such electrophysiological destabilization carries the risk of ventricular fibrillation and sudden cardiac death.

Postulate of normoglycemia possibility of approximating this postulate in the practice of

treatment with Humalog
Obtaining a nearly normoglycemic condition is a therapeutic measure significantly reducing the risk of diabetes-related complications. Thus, this postulate must be
widely propagated. Its practical realization depends on
application of such insulin preparations and analogs
which make it possible to simulate baseline and stimulated by food intake function of pancreatic islet beta cells.
It is characterized by an increase of insulinemia almost
simultaneous with the meal time, which reaches its peak
after 2030 min, and then returns to the baseline values

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after 23 h. This increase usually manifests as rapid and

transient rise of insulin level to 200300% of the baseline value. Between the meals, as well as at night, the values of insulinemia are low, allowing to maintain glycemia during that time at 60100 mg/dl level.
LisPro insulin analog, i.e Humalog, makes it possible to
approximate closely the physiological model of insulin
secretion (Fig. 6).
The dilemma faced by each classical insulin therapy utilizing native insulin preparations injected subcutaneously
is too late and too low increase of insulin level in periprandial periods and too persistent high insulin levels between the meals and at night. This means in practice insufficient control of postprandial hyperglycemia and
a hypoglycemic tendency between the meals and at night. As it has been described above, the rate of absorption of Humalog from the subcutaneous tissue, as well as
pharmacodynamic characteristics of the preparation, eliminate to a considerable extent these disadvantages of
classical insulin therapy, provided that the injections are
frequent enough to maintain the prandial effect of insulin and its baseline levels during the 24 h period. This is
particularly important with respect to too low blood levels of Humalog observed 5 hours after its administration, i.e. practically in the pre-prandial period. Therefore, a combination of prandial Humalog injections with
Humulin N injected in the morning and in the evening is
favorable. Such a need is eliminated by pre-formulated
mixtures of Humalog with so-called NPL insulin (Humalog combined with protamine) in 25/75, 50/50, and
75/25 proportions.
In conclusion, it can be stated that multiple injections of
Humalog, especially in combination with additional injections of isophanic protamine insulin (e.g. Humulin N)
or application of treatment schedules utilizing pre-formulated Humalog mixtures is a very important method
allowing to obtain nearly normoglycemia with the lowest possible risk of hypoglycemia, and, consequently,
unnecessary increase of body weight. Thus, detailed indications for the application of Humalog are very wide.
Their analysis has been presented below.

5. PRACTICAL ASPECTS OF TREATMENT WITH

INSULIN ANALOGS
Numerous studies carried out on patients with type 1
and 2 diabetes indicate in a reproducible way that Humalog injections delivered 015 min. periprandially reduce postprandial hyperglycemia more significantly than
the same doses of traditional short- acting insulin preparations administered 4060 min. before the meal [9,13]
Using LisPro insulin as compared with native insulin resulted in postprandial hyperglycemia reduction 1 h after
the meal by ca. 36% and after 2 h by 64%, in type 1 diabetes, and by 19% and 49%, respectively in patients
with type 2 diabetes. Similar results were obtained for
LisPro and NPH insulin combinations as compared with

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Bruttomesso D, Del Prato S. Diabetes, 1999; 48(1): 99-105

Figure 6. Effect of reproduction of early phase of insulin secretion by

means of application of Lispro in the oral glucose loading test
(OGTT) compared to human insulin application. A statistically
significant higher level of Lispro in venous blood plasma can
be observed during 1st hour after application. It causes lower
increase of glycaemia and lower level of C-peptide, which
may have protective influence onto B cell of pancreas.

those of native insulin and NPH [7]. Also a reduction of

the incidence of dangerous night hypoglycemia has been
observed in patients treated with Humalog [13,27].
Thus, administration of LisPro is more convenient for the
patients (injections immediately before the meal), reduces significantly postprandial hyperglycemia and incidence of night hypoglycemia. These aspects of treatment
with LisPro insulin or other quick-acting analogs, as well
as their mixtures, are very important. In order to obtain
a biphasic (fast and slow) hypoglycemizing effect, LisPro
can also be mixed with zinc insulins of the lente type.

Significance of HbA1c level as an index of glycemia

control
The level of glycated hemoglobin is the function of the
level and duration of hyperglycemia. It does not reflect
in any case the circadian variations of glycemic levels
(postprandial hyperglycemia and hypoglycemia), i.e. it
does not inform about these dangerous glycemic fluctuations. The administration of LisPro insulin eliminates
quick and high hyperglycemic peaks, which have less

Tato J et al How recombinant insulin analogs improve insulin therapy

significant influence on the HbA1 index than smaller,

but prolonged increases of glycemia. Changes of hyperglycemic values also do not affect the HbA1c value.
Thus, it seems that HbA1c cannot be the only index of
glycemia control, and that more indices reflecting the
glycemic fluctuations should be applied.
Reducing these fluctuations depends not only of prandial
LisPro doses, but also on appropriate selection of insulin
with prolonged activity, which maintains basal insulin levels. This has been demonstrated e.g. in insulin therapy
utilizing individual subcutaneous pumps. Insulin LisPro
delivered in this way caused constant, significantly more
pronounced decrease of HbA1c in comparison with native insulin [28]. This additionally indicates the importance of selection of basal insulin (acting between the meals
and at night) and unique periprandial activity of Humalog. LisPro and NPL insulin mixtures imitate this treatment schedule.

Postulate of attaining nearly normoglycemic

condition in type 2 diabetes
Proving that nearly normoglycemia reduces the risk of micro- and macroangiopathies in type 2 diabetes resulted in
propagation of intensive treatment of this type of diabetes.
This type of treatment includes all kinds of rational therapeutic measures allowing to obtain a nearly normoglycemic condition. They may involve modifications of lifestyle
and treatment with oral hypoglycemizing agents administered in monotherapy (sulphonylurea derivatives S, biguanides B, acarbosis A, glinides G) or in combinations
(S+B, S+A, S+G, B+A, B+G, A+G), as well as insulin
therapy. Various schedules of insulin therapy, individually
adjusted to the patients needs and utilizing traditional insulins as well as insulin analogs (I) or their combinations
with oral hypoglycemizing agents (I+B, I+A, I+G) are
used. Slow-acting insulins, e.g. NPH or Lente are often administered before supper, and oral drugs during the day.
Ca. 40% of patients with type 2 diabetes are currently treated with insulin only, most often administered 2 times
a day in the form of pre-formulated biphasic mixtures in
isophanic protamine NPH insulin solution or LisPro analog
in isophanic protamine analog insulin solution (NPL).
The essential pathogenetic disorder in type 2 diabetes is
the combination of insulin deficiency with resistance to
insulin. First the rapid phase of insulin secretion disappears, and later an impairment of the slow phase takes place as well. Therefore, the restoration of the first rapidly
attained postprandial peak of insulin level and activity is
considered most important to prevent excessive hyperglycemia after meals and later prolonged elevation of
glycemic levels. Mitrakou et al. demonstrated that the insulin level obtained during 30 min. correlates in inversely proportional manner with the level of glycemia reached two hours after the meal. It means that the lower
the insulin peak obtained at 30 min, the higher the glycemic level will be 2 h after food intake. [29]. In view of
the above, it would be logical to use in type 2 diabetes

a rapid- and short-acting insulin preparation (e.g. schedules involving the use of Humalog and its mixtures),
which would simulate the impaired early phase of insulin secretion. Basal insulin levels (between the meals)
may be maintained in these patients for a long time.

Pre-formulated commercial biphasic mixtures of

LisPro insulin analog
Industrial pre-formulation of quick-acting insulin analog
mixtures, e.g. LisPro with insulins characterized by prolonged absorption and activity period became possible owing
to the development of Neutral Protamine LisPro = NPL
preparation. It contains a suspension of crystals consisting
of protamine and LisPro molecules combined in constant
proportion. The crystallization process is conducted so
that after its completion there is no excess of either protamine or LisPro in the preparation. Such state is referred to
as isophanic. It allows to add to NPL insulin the LisPro
analog so that a mixture of two different insulins not interacting with each other in the solution will be formed. Injection of such a mixture is equivalent to administration of
2 insulin types in 2 separate injections. LisPro as it has
been mentioned above can be mixed with zinc insulins,
e.g. Lente, giving an additional early effect. Thus, such mixtures combine rapid and short-lasting postprandial hypoglycemizing effect characteristic of LisPro with the prolonged one resulting in maintaining baseline insulin activity
between the meals characteristic of NPL [3032].
In the LisPro and Lente insulin mix there is a slight additional effect delaying the activity of the first component.
Pharmacokinetics of LisPro is ilustrated on Fig. 7. In clinical trials, pre-formulated LisPro and NPL mixtures demonstrate significantly more pronounced postprandial
glycemia reduction than mixtures of native insulin with
NPH [16] This is an advantage of LisPro/NPL mixtures.
Fig. 8. Another important and positive characteristics is
the fact that treatment with LisPro/NPL mixtures injected
before breakfast and before dinner markedly reduces the
risk of night hypoglycemia (Fig. 9) [33].
For the above reasons, the introduction of pre-formulated analog mixtures into medical practice should be regarded as a very important achievement in insulin therapy of diabetes [33,38].

Other insulin analogs

Besides the LisPro insulin analog and its mixtures, in many centers works aiming to synthesize other analogs are
under way. [34] Those which have been subjected to clinical trials are presented below:

Rapidly acting monomeric

B28 Asp insulin analog

Slowly acting with increased isoelectric pH

GliA21, ArgB31, ArgB2 analog (Glargin, Hoe-901)
GliA21 AspB27, ThrB30 NH2 (Novosol Basal)

855

Review Article

Figure 7. Pharmacokinetics of Humalog and its ready mixtures.

Insulin acetylation
Acylation of LisB29 with ThrB30 removal
A strong bond with albumin is formed

Figure 8. Average variations of glycaemia after supper in patients with

type 2 diabetes. Statistically significant lower variations of
glycaemia (difference between glycaemia level before and
after supper) were observed in the group of patients treated
with Humalog Mix 25 compared to those treated with
traditional insulin mixture 30/70.

The quick-acting analog B28 Asp (NovoRapid) as well as

Glargin analog are currently being prepared for clinical
use.

Reducing the risk of post-insulin hypoglycemia

International studies including thousands of patients with
type 1 and type 2 diabetes have demonstrated that treatment with LisPro analog utilizing various algorithms of
administration, as well as treatment with pre-formulated
LisPro/NPL mixtures significantly reduces the frequency
of hypoglycemic episodes during the day, and, which is
particularly important, also at night [12,28,36]. The levels of insulin between the meals and at night is rarely
decreased in type 2 diabetes. From this observation it
follows that in type 2 diabetes the most common algorithm to be applied should involve multiple injections of
small doses of the quick-acting analog or biphasic, pre-formulated isophanic mixtures of the analog and protamine insulin. These studies have also demonstrated that
this kind of treatment significantly reduces postprandial
increases of glycemia in patients with type 2 diabetes
[3638]. A study carried out in a group of 2000 subjects
with type 1 diabetes, e.g. reduction of the incidence of
severe hypoglycemia even by 30% was observed [14].
Hypoglycemic symptoms and their hormonal control are
similar in treatment with LisPro analog and native insulin
[15].

6. SPECIAL GROUPS OF DIABETIC PATIENTS

Children and adolescents
Studies concerning the use of LisPro in algorithms involving 35 injections a day demonstrate in young patients
with type 1 diabetes much lower postprandial glycemia
combined with incidence of hypoglycemic episodes, inc-

856

Figure 9. Rate of hypoglycaemia occurring during night (22.3007.00) in patients with type 2 diabetes treated with Humalog
Mix25 or classic insulin mixture 30/70. The rate shows
number of hypoglycaemia episodes occurred during night per
one patient, within 3 months of observation.

luding those occurring during the night, reduced by ca.

50% [39]. LisPro administered before the meals to children, even those below 5, is effective and safe [40]. Particularly in the case of small children, the possibility of
Humalog administration in periprandial time 15 min.
before the meal to 20 min. from the beginning of the
meal is very important [41]. Small children often fail to
eat the whole planned meal, which is associated in case
of traditional insulin preparations administered 45 min.
before meals with the risk of postprandial hypoglycemia.

Elderly diabetic patients

It seems that reducing the risk of hypoglycemia might
encourage to use LisPro in the therapy of elderly pa-

Tato J et al How recombinant insulin analogs improve insulin therapy

tients. Herz et al. obtained a significant improvement of

postprandial glycemia and HbA1c values in elderly patients with type 2 diabetes poorly controlled with oral
drugs by two injections daily of Humalog Mix 25. No significant increase of hypoglycemia was observed in this
group [31].

Pregnancy
The most important disturbance in pregnant patients
with diabetes is postprandial hyperglycemia. Quick effect of LisPro on postprandial increases of glycemia could be beneficial for both the mother and the fetus. In
some clinical studies (mainly retrospective) available at
present, a favorable metabolic compensation has been
observed in comparison with traditional insulin [42,43].
No negative effect on the fetus has been observed. Further clinical verification is recommended [44].

creases the risk of hypoglycemia if exertion occurs immediately after the meal. However, this risk is markedly
reduced if exertion occurs 2-4 h after the meal, which is
more frequent in practice.
Thus, the subjects who expect intensive physical activity
immediately after LisPro injection and the meal, should
reduce the dose by ca. 10%, whereas exertion 24
h after LisPro administration and the meal is safer than in
the case of treatment with native insulin [46,47].

LisPro insulin analog in individual pumps

Jungmann et al. observed that intensive treatment with
LisPro insulin analogs delivered with subcutaneous
pumps in type 2 diabetes significantly lowered
HbA1c and eliminated microalbuminuria in comparison
with treatment utilizing native insulin. (IDF Congress,
Mexico City, 2000, P-456).

Resistance to insulin

8. SUMMARY AND CONCLUSIONS

There seem to be no differences of immunologic character between LisPro and native insulin. Some studies demonstrated that the administration of LisPro to subjects
with immunologically determined insulin resistance made it possible to reduce the doses [45]. There are also
observations that LisPro analog may allow to reduce the
insulin dose in tissue resistance to insulin, e.g. in obese
diabetic patients. This may be explained by specific
pharmacokinetics and pharmacodynamics of LisPro
shorter stimulation of impaired pancreatic B cell associated with more rapid decrease of postprandial glycemia
and shorter duration of high insulinemia.

7. SPECIAL CLINICAL CIRCUMSTANCES

1. In order to improve insulin therapy and to approximate nearly normoglycemic condition, human insulin analogs can be used in type 1 and type 2 diabetes, secondary diabetes and in patients with impaired
glucose tolerance.
2. Insulin LisPro can be mixed in one syringe with Ultralente and NPH insulin preparations.
3. Administration of LisPro insulin analog and its mixtures in multiple injection algorithms allows to simulate
more accurately the physiological rhythm of insulin
secretion (especially the first phase rapid postprandial insulin secretion)

Diet
Specific pharmacodynamics of LisPro analog is the reason that its administration can counteract hyperglycemizing effect of meals containing large amounts of carbohydrates. On the other hand, meals with higher fat
content, which is associated with delayed glucose absorption from food is an indication for LisPro administration after the meal (20 min from the beginning of the
meal) [41]. This allows to obtain better correlation between the effect of the meal and the analog on glycemia.
It has also been observed that short-lasting activity of
LisPro allows to eliminate from the diet so-called snacks
frequently used to prevent hypoglycemia 35 h after meals and administration of native insulin.

4. Modified profile of Humalog activity in comparison

with traditional insulin preparations is associated
with the following effects:
significant reduction of postprandial hyperglycemia,
reduced risk of hypoglycemia,
possibility to reduce the number of snacks,
elimination of the necessity to inject insulin 3060
min before the meal and wait for its effect.

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