Insulin
Insulin is a hormone produced by the beta cells of
the islets of Langerhans of the pancreas and consists
of 2 chains of amino acids ,the A and B chains, con-
nected by 2 disulphide bridges. Insulin produced by
different species conforms to the same basic struc-
ture but has different sequences of amino acids in
the chains. Porcine insulin differs from human insulin
in only one amino acid in the B chain whereas bovine insulin differs
from human insulin not only in this same amino acid in the B chain but
also in 2 amino acids in the A chain.
The precursor of insulin in the pancreas is proinsulin
which is a single polypeptide chain incorporating
both the A and .B chains of insulin connected by a
peptide termed the C-peptide (or connecting peptide).
Although the insulins of various species may
be similar in composition the proinsulins are not, in
that the sequence and number of amino acids in the
C-peptide may vary considerably.
Insulin (Ph. Eur„ USP 23) is of either bovine or por-
cine origin; the USP also allows mixed bovine and
porcine origin. Human Insulin (Ph. Eur.) is pro-
duced either by the enzymatic modification and suit-
able purification of porcine insulin or by
recombinant DNA technology in micro-organisms.
Insulin Human (USP 23) is produced similarly.
Early commercial insulins were obtained by extrac-
tion from bovine or porcine or mixed bovine and
porcine pancreases and were purified by recrystalli-
sation only. Insulins obtained by such methods were
often termed 'conventional insulins' to distinguish
them from insulins which have undergone further
purification processes. An extract which has been
recrystallised only once can be separated into 3
components or fractions termed the 'a', 'b', and 'c'
components. The 'a' component consists of high
molecular weight substances and is only usually
found in very impure preparations since repeated re-
crystallisation will remove most of it. The 'b' com-
ponent consists largely of proinsulin and insulin
dimers, and the 'c' component consists of insulin,
insulin esters, arginine insulin, and desamidoinsu-
lin. Other pancreatic peptides such as glucagon,
pancreatic polypeptide. somatostatin, and vasoac-
tive intestinal peptide are also usually found in prod-
ucts which have not undergone further purification.
Gel filtration will substantially reduce the content of
proinsulin but will not significantly reduce the con-
tent of insulin derivatives or pancreatic peptides;
products purified by gel filtration are often termed
'single-peak insulins'. Addition of ion-exchange
chromatography to the purification methods will
further reduce the proinsulin content and also reduce
the contamination by insulin derivatives and pancre-
atic peptides. In the UK 'highly purified insulins'
and 'monocomponent insulins' are terms some-
times applied to insulins which have undergone both
gel filtration and ion-exchange chromatography. In
the USA the Food and Drugs Administration (PDA)
has designated the term 'purified insulins' for prep-
arations similarly prepared and containing less than
10 ppm of proinsulin.
Much of the insulin now produced has an amino-
acid sequence identical to that of human insulin.
Human insulin (emp) is produced by the enzymatic
modification of insulin obtained from the porcine
pancreas; it is also sometimes called semisynthetic
human insulin. The term human insulin (crb) is
used for insulin produced by the chemical combina-
tion of A and B chains which have been obtained
from bacteria genetically modified by recombinant
DNA technology. Human insulin (prb) is produced
from proinsulin obtained from bacteria genetically
modified by recombinant DNA technology. Human
insulin (pyr) is insulin produced from a precursor
obtained from a yeast genetically modified by re-
combinant DNA technology. Human insulin ob-
tained by recombinant DNA technology is
sometimes termed biosynthetic human insulin.
Insulin or human insulin is supplied in a variety of
forms in solution or suspension for injection .
Crystalline insulin may be prepared for
therapeutic use merely by making a solution, either
of acidic or neutral pH. Soluble insulin or 'neutral
insulin' is a short-acting preparation that can be giv-
en intravenously if necessary to cover emergencies.
Soluble formulations are sometimes referred to as
'regular insulin' or 'unmodified insulin': these
names reflect the fact that the preparation has not
been formulated in order to prolong the duration of
action of the insulin.
In order to prolong the duration of action of insulin,
preparations may be formulated as suspensions in 2
general ways. The first involves complexing insulin
with a protein from which it is slowly released; ex-
amples are protemine zinc insulin, which contains
an excess of protamine, and isophane insulin,
which contains equimolecular amounts of insulin
and protamine. The second method of prolonging
the action of insulin is to modify the particle size and
the various insulin zinc suspensions are in this cat-
egory.
Biphasic insulins are mixtures providing for both
immediate and prolonged action.
Chemical modification of the insulin molecule has
resulted in insulins such as dalanated insulin (pre-
pared by the removal of the C-terminal alanine from
the B chain of insulin), insclin defalan (prepared by
the removal of the terminal phenylalanine), and sul-
phated insulin, but these insulins have not been
widely used. Insulin argine and insulin lispro have
been developed recently; insulin lispro, in which the
B28 and B29 amino acid residues of human insulin
are replaced with lysine and proline, is now availa-
ble as a rapidly acting alternative to soluble insulin.
Recombinant DNA technology has enabled produc-
tion of other insulin analogues with altered pharma-
cokinetic profiles; some of these are being evaluated
clinically (see Insulin Analogues and Proinsulin un-
der Uses, below).
Stability and Storage
Insulin in powder form should be stored in airtight containers
and protected from light. Storage at a low temperature is also
recommended. The Ph. Eur. advises storage at a temperature
not exceeding -20° while the USP requires storage at-10° to
-25°. It is stressed that this temperature is for the powder and
not for the preparations: preparations should not be subjected
to storage conditions that lead to freezing.
Both the Ph. Eur. and the USP recommend that insulin prep-
arations be stored in a refrigerator at 2° to 8°, protected from
light, and not be allowed to freeze. It is recognised that pa-
tients may not follow such stringent storage guidelines and
most manufacturers of commercial insulin preparations con-
sider that storage by the patient at a temperature of up to 25°
would be acceptable for up to one month. Patients should still
be advised not to expose their vials or cartridges to excessive
heat or sunlight.
It is advisable to shake suspensions gently before a dose is
withdrawn.
Adsorption. The adsorption of insulin onto glass and plas-
tics used in administration sets has been decreased by the ad-
dition of albumin or polygeline to insulin solutions. Some
workers consider this to be unnecessary since in practice in-
sulin adsorption is not a major problem. Running approxi-
mately 10 mL of the insulin solution through the intravenous
tubing before beginning the infusion has been suggested by
some.
Aggregation. For discussion of the problems of insulin ag-
gregation, see Intensive Administration Regimens under
Uses, below.
Units
One unit of bovine insulin is contained in
0.03891 mg of the first International Standard
(1986). One unit of porcine insulin is contained in
0.03846 mg of the first International Standard
(1986). One unit of human insulin is contained in
0.03846 mg of the first International Standard
(1986).
Adverse Effects
The most frequent complication of insulin therapy is
hypoglycaemia, the speed of onset and duration of
which may vary according to the type of preparation
used and the route of administration. It is usually as-
sociated with an excessive dosage of insulin, the
omission of a meal by the patient, or increased phys-
ical activity.Patients,especially the elderly or those
with tightly controlled diabetes or diabetes of long
standing,may not experience the typical early warn-
ing symptoms of a hypoglycaemic attack. There
have been reports of hypoglycaemia, sometimes
with decreased warning symptoms, in patients
changing from animal (especially bovine) to human
insulin (see under Hypoglycaemia. below). Symp-
toms of hypoglycaemia resulting from increased
sympathetic activity include hunger, pallor, sweat-
ing, palpitations, anxiety, and tremulousness. Other
symptoms include headache, visual disturbances
such as blurred or double vision, slurred speech,
paraesthesia of the mouth and fingers, alterations in
behaviour, and impaired mental or intellectual abil-
ity. If untreated, hypoglycaemia may lead to convul-
sions and coma which should not be confused with
hyperglycaemic coma.
Insulin, administered subcutaneously. may cause ei-
ther lipoatrophy or lipohypertrophy. Lipoatrophy
appears to occur less frequently with purified insu-
lins than with conventional insulins: if it has oc-
curred, it may be reversed by the injection of a purer
animal insulin or human insulin into and around the
atrophied site. Lipohypertrophy is usually associat-
ed with repeated injections at the same site and may
usually be overcome by rotating the site of injection.
although it should be remembered that absorption of
insulin may vary from different anatomical areas.
Prolonged insulin therapy may result in weight gain.
Insulin may occasionally cause local or systemic hy-
persensitivity reactions. Local reactions, character-
ised by erythema and pruritus at the injection site.
usually disappear with continued treatment. Gener-
alised hypersensitivity may produce urticaria. an-
gioedema. and very rarely anaphylactic reactions: if
continued therapy with insulin is essential hyposen-
sitisation procedures may need to be performed.
Again, hypersensitivity reactions are observed less
frequently with purified than with conventional in-
sulins and porcine insulin is less immunogenic than
bovine insulin. Although hypersensitivity reactions
have been reported in patients transferred from ani-
mal to human insulins, there are only isolated re-
ports of such reactions in patients treated
exclusively with human insulin.
Many patients treated with insulin, either animal or
human insulin, develop antibodies but the signifi-
cance of such antibody formation with regard to the
clinical management of the patient is not entirely
clear.
Of patients who received intensive insulin therapy for type I
diabetes as part of the Diabetes Control and Complications
Trial, those who experienced the greatest weight gain also had
increased blood concentrations of triglycerides and low-den-
sity-lipoprotein cholesterol. and lowered high-density-lipo-
protein cholesterol. These lipid changes, together with
higher blood pressure, increased waist-to-hip ratio, and great-
er insulin requirements, were held to be similar to the symp-
toms of insulin resistance and to indicate a possible increased
risk of macrovascular disease. Results from the UK Prospec-
tive Diabetes Study indicated that type 2 diabetic patients
treated with insulin had greater weight gain than those man-
aged with other therapies. but demonstrated no evidence of
harmful cardiovascular effects.
For discussion of some of the specific problems associated
with continuous infusion of insulin, see Intensive Administra-
tion Regimens under Uses. below.
Antibody formation. A review of Human insulin including
a discussion 6n the clinical importance of insulin antibodies'
Both pork and human insulin are definitely less immunogenic
than beef insulin producing fewer circulating insulin antibod-
ies. but several studies have indicated no detectable change in
antibody concentrations on switching from pork to human in-
sulin or vice versa. Antibodies cause lipoatrophy and are re-
sponsible for the substantial insulin resistance seen in some
patients, but with purified pork insulin in common use, both
events became rare. Interest has been revived in the possible
contribution of antibodies in modifying metabolic control. In
the short term and under hospital conditions, they are known
to prolong the intravenous half-life of injected insulin and to
delay the appearance in the circulation of a subcutaneously
administered bolus dose. Patients with moderate concentra-
tions of antibodies are also reported to show delay in recovery
from induced hypoglycaemia , but on the other hand to lose
control less quickly after insulin withdrawal and thus may be
relatively protected from ketoacidosis,
Effects on the liver. For a report of hepatomegaly occurring
after insulin overdosage, see under Abuse, in Precautions, be-
low.
Effects on the skin. Delayed pressure urticaria. in the form
of large wheals occurring 4 to 6 hours after prolonged pres-
sure. and lasting for up to 24 hours, was seen in a patient with
type I diabetes within 6 months of changing from animal to
human insulin.' The condition improved following a switch
back to insulin of animal origin, and became aggravated again
following a second attempt to switch to human insulin.
Hypersensitivity. Hypersensitivity reactions to insulin
preparations may be caused not only by the insulin itself, but
also by other components of the formulation such as zinc' or
protamine.
See also under Antibody Formation, above and under Precau-
tions below.
HYPOSENSITISATION. Following failure of standard hyposensiti
sation measures in a patient with cutaneous hypersensitivity
to insulin, hyposensitisation was attempted by giving insuiln
by mouth.' Aspirin 1.3 g three times daily by mouth was also
given to antagonise vascular mediators of the reaction . After
one week subsequent hyposensitisation using insulin by in-
jection was successful. When the patient stopped taking aspi-
rin after 6 months the original hypersensitivity reaction
recurred: aspirin was then given permanently in a dose of
1.3 g twice daily.
Hypoglycaemia. Hypoglycaemia is the major adverse ef-
fect of insulin treatment with severe hypoglycaemic episodes
in up to a third of all insulin-treated patients at some point in
their lives. Moves towards more intensive insulin therapy, in
order to reduce the development of diabetic complications.
increase the risk of hypoglycaemic episodes.' This may be
connected with the fact that patients maintaining strict gly-
caemic control are prone to 'hypoglycaemia unawareness' in
which the normal adrenergic counter-response to hypogly-
caemia (characterised by symptoms such as pallor, sweating,
and tremor) is reduced or lost.' so that hypoglycaemia can
develop without warning. 'Such a loss of awareness of im-
pending hypoglycaemia also seems to develop in diabetics as
disease duration increases.-* One of the primary factors in re-
ducing awareness of hypoglycaemia is that repeated hypogly-
caemic episodes seem to trigger an adaptive conservation of
glucose concentrations in the brain, resulting in higher central
than peripheral blood glucose values:' avoidance of hypogly-
caemia helps restore awareness.
When recombinant human insulin became generally available
in the late 1980s a number of patients complained of a loss of
awareness of impending hypoglycaemia following transfer to
human insulin.' h and there were reports of severe or even fa-
tal hypoglycaemia occurring in patients who had been well
stabilised on animal insulins."
This was. and remains, a somewhat controversial area. De-
spite some small studies suggesting a problem. others
failed to find evidence of a difference between animal and hu-
man insulins.However, most commentators appear to
consider that patients should continue to have access to ani-
mal insulins if desired, and that those well maintained on an-
imal insulin should not be transferred to human insulin
without appropriate clinical grounds,and then only
with careful monitoring.
There has also been concern about possible long-term seque-
lae of hypoglycaemic episodes on the CNS. However, a re-
cent report on patients participating in the Diabetes Control
and Complications Trial (DCCT) suggested that the increased
risk of hypoglycaemia seen with intensive therapy was not
associated with neuropsychological impairment.'
For the treatment of insulin-induced hypoglycaemia, see be-
low.
Oedema. Severe, acute oedema is a rare adverse effect of
insulin treatment, occurring most often at the initiation of
therapy. It should be distinguished from chronic and suba-
cute forms of oedema which may be complications of the di-
abetic disease process. Possible mechanisms of acute
oedema are sodium retention resulting from a direct action of
insulin on the renal tubule or an effect of insulin on vascular
permeability. The oedema usually responds to a decrease in
insulin dosage.
Treatment of Insulin-induced Hypoglycae-
mia
In the conscious and cooperative patient hypogly-
caemia is treated by the oral administration of a
readily absorbable form of carbohydrate, such as
sugar lumps or a glucose-based drink and all diabet-
ics should always carry a suitable sugar source by
way of precaution.
If hypoglycaemic coma occurs, up to 50 mL of a
50% solution of glucose should be given intrave-
nously. Glucose 10 or 20% may be used but larger
volumes are required. Occasionally this may need to
be repeated and an intravenous infusion of glucose
initiated. If after about one hour. blood-glucose con-
centrations are normal and the patient has failed to
regain consciousness, the possibility of cerebral-
oedema should be considered. In situations where
the intravenous administration of glucose is imprac-
tical or not feasible, glucagon 0.5 to I mg by subcu-
taneous, intramuscular, or intravenous injection may
arouse the patient sufficiently to allow oral glucose
to be given. If the patient fails to respond to gluca-
gon within about 10 to 15 minutes, then glucose has
to be given intravenously despite any impracticali-
ties.
Following a return to consciousness, carbohydrates
by mouth may need to be given until the action of
insulin has ceased which, for preparations with a rel-
atively long duration of action such as isophane in-
sulin. some insulin zinc suspensions, and protamine
zinc insulin, may be several hours.
Carbohydrate. A comparative study' of 7 different prepa-
rations of oral carbohydrate for the treatment of hypoglycae-
mia in the conscious patient found no significant difference in
effectiveness between glucose or sucrose in solution or tablet
form; a hydrolysed polysaccharide solution containing glu-
cose, maltose, and various more complex saccharides (Gluci-
dex 19) was also roughly comparable. However, a glucose gel
and orange juice were each less effective in treating hypoply-
caemia.
Glueagon. A discussion of the relative merits of parenteral
glucose and glucagon in unconscious hypoglycaemic
patients' suggested that glucagon should be encouraged as
first-line treatment, although in practice (see above) parenter-
al glucose is usually preferred. The effect of glucagon relies
upon the patient having adequate liver glycogen stores, which
may not always be the case.
Surgical excision. Reports of the treatment of insulin
overdosage by excision of tissue at the site of injection.
Precautions
Dosage requirements of insulin may be altered by
many factors. Increased doses are usually necessary
during infection, emotional stress, accidental or sur-
gical trauma, puberty, and the latter two trimesters
of pregnancy, and decreased doses are usually nec-
essary in patients with impaired renal or liver func-
tion or during the first trimester of pregnancy.
Following initiation and stabilisation of therapy in
newly diagnosed diabetic patients, a temporary de-
crease in requirements may also occur (the so-called
honeymoon period )
Because of the possibility of differing responses to
insulins from different species, care is recommend-
ed to avoid the inadvertent change from insulin of
one species to another. Reduction in insulin dosage
may be required on transfer from animal (especially
bovine insulin) to human insulin. Hypoglycaemic
problems associated with a change to human insulin
are discussed under Adverse Effects, above. Care is
also necessary during excessive exercise; hypogly-
caemia caused by metabolic effects and increased
insulin absorption is the usual response, but hyperg-
lycaerflia may sometimes occur.
The use of insulin necessitates monitoring of thera-
py, such as the testing of blood or urine for glucose
concentrations and the urine for ketones, by the pa-
tient.
Drugs which have an effect on blood-glucose con-
centrations may alter glycaemic control with conse-
quent need for a change in insulin dose (see under
Interactions, below).
CAUTION. Biphasic insulin, insulin zinc suspensions, isophane
insulin, and protamine zinc insulin should never be given in-
travenously and they are not suitable for the emergency treat-
ment of diabetic ketoacidosis.
Abuse. Transient recurrent hepatomegaly associated with
hypoglycaemia was associated with the surreptitious admin-
istration of additional insulin injections in an insulin-depend-
ent diabetic. Increased storage of glycogen in the liver
resulting from insulin excess was considered responsible for
the hepatomegaly.
Decreased plasma C-peptide concentrations or the presence
of anti-insulin antibodies may be used to confirm insulin
abuse as a cause of hypoglycaemia in patients who have never
been treated with insulin medically. Insulin has been abused
by bodybuilders and other sportspersons, severe brain dam-
age after prolonged neuroglycopenia has resulted.
Accelerated absorption. Factors such as a hot bath, sauna.
or use of a sunbed have been reported to accelerate the ab-
sorption of subcutaneous injection, presumably by an in-
crease in skin blood flow. There may, therefore, be a risk of
hypoglycaemia.
Adrenocortical Insufficiency. A report of 2 cases of recur-
rent severe hypoglycaemia in type I diabetics which persisted
despite a reduction in insulin doses and proved to be due to
Addison's disease. Insulin requirements rose again in both
patients following replacement therapy with fludrocortisone
and hydrocortisone.
Driving. Patients in the UK with diabetes mellitus are re-
quired to declare their condition lo the vehicle licensing cen-
tre who then assess their fitness to drive. The law treats
hypoglycaemic episodes as being under the influence of a
drug and patients taking insulin are generally not permitted to
drive vocationally.' Driving is not permitted when hypogly-
caemic awareness has been lost. Drivers should normally
check their blood-glucose concentration before setting out,
and. on long journeys, at intervals of about 2 hours. If hy-
poglycaemia occurs, the driver should stop until recovery is
complete.
Regulations in other countries differ widely.
Exercise. A discussion of the metabolic effects of exercise
and the precautions to be taken by the exercising type I dia-
betic.
Hypersensitivity to protamine. A retrospective survey
has indicated that patients receiving isophane insulin, which
contains protamine. have an increased risk of severe reactions
simulating anaphylaxis when protamine is used to reverse
systemic heparinisation after cardiac catheterisation.' A
mechanism involving lgE and lgG antibodies lo protamine
has been proposed.
Sec also Hypersensitivity under Adverse Effects, above.
Infections. Decreased requirements of insulin, added to the
dialysale. occurred in 6 diabetic patients undergoing continu-
ous ambulatory peritoneal dialysis for chronic renal failure
during episodes of severe bacterial peritonitis. This was con-
trary lo the increased insulin requirements exhibited by most
diabetic patients during severe infections and probably result-
ed from increased absorption of insulin due to mesothelial
damage.
Menstruation. Discussion on (he control of diabetes during
the menstrual cycle and the possible need to adjust insulin
dosage regularly around the time of menstruation.
Morning hyperglycaemia. Morning hyperglycaemia may
be the result of mere waning of subcutaneously injected insu-
lin. It may also be rebound hyperglycaemia (posthypoglycae-
mic hyperglycaemia or the Somogyi phenomenon) occurring
after an episode of nocturnal hypoglycaemia. Morning hyper-
glycaemia has also been observed without antecedent hy-
poglycaemia even during constant intravenous infusion of
insulin, when the waning of previously injected insulin would
not be a factor and this is commonly referred lo as the dawn
phenomenon. Clinically, it is important to distinguish be-
tween the dawn phenomenon, simple waning of previously
injected insulin, and rebound hyperglycaemia as a cause of
early-morning hyperglycaemia because their treatment dif-
fers. Management of the dawn phenomenon and insulin wan-
ing generally consists of adjusting the evening dose of insulin
to provide additional coverage between 4 a.m. and 7 a.m.
Management of rebound hyperglycaemia consists of reducing
insulin doses or providing additional late-evening carbohy-
drate. or both, to avoid nocturnal hypoglycaemia. Mistaking
rebound hyperglycaemia for the dawn phenomenon or mere
waning of injected insulin could result in more serious noc-
turnal hypoglycaemia, if evening doses of insulin were in-
creased.
Pregnancy. For discussion of the precautions necessary in
the management of diabetes mellitus during pregnancy.
There has been a report of 2 cases of fetal malformation in the
offspring of well-controlled diabetic women who received in-
sulin lispro. However, the incidence of fetal malformation is
increased in infants of women with diabetes. Although the
use of insulin lispro is not recommended during pregnancy
the manufacturers were aware of 19 live births among women
treated with insulin lispro, 1 of which exhibited a congenital
abnormality.
Renal impairment. See under Infections, above.
Smoking. Smoking has been reported to decrease the ab-
sorption of insulin and may contribute to metabolic instability
in diabetic patients.' Dosage adjustment may be necessary.
Smoking is of course highly undesirable in diabetic patients.
who already have an increased risk of cardiovascular disease.
Surgery: For a discussion «f the management of diabetes
mellitus during surgery.
Transmission of prion disease. Studies of cattle with
proven bovine spongiform encephalopathy (BSE) have not
detected infectivity in the pancreas, from which bovine insu-
lin is derived.'
Travelling. Advice for the diabetic patient when travelling,
including adjustment of insulin dosage when crossing time
zones. Since insulin solution or suspension must not be fro-
zen. it should not be carried in the luggage hold of an aircraft.
Interactions
Many drugs have an effect on blood-glucose con-
centrations and may alter insulin requirements.
Drugs with hypoglycaemic activity or which may
decrease insulin requirements include ACE inhibi-
tors, alcohol, anabolic steroids. aspirin, beta block-
ers (which may also mask the warning signs of
hypoglycaemia). disopyramide, fenfluramine,
guanethidine. some monoamine oxidase inhibitors,
mebendazole. octreotide, some tetracyclines. and
the tricyclic antidepressant amitriptyline.
On the other hand. increased requirements of insulin
may possibly be seen with chlordiazepoxide. chlo-
rpromazine, some calcium-channel blockers such as
diltiazem or nifedipine, corticosteroids, diazoxide,
lithium , thiazide diuretics, and thyroid hormones.
Both increased and decreased requirements may oc-
cur with cyclophosphamide, isoniazid, and oral con-
traceptives.
ACE Inhibitors. Although ACE inhibitors are favoured for
use in diabetic patients with hypertension or evidence of in-
cipient nephropathy or both. they may increase insulin sensi-
tivity and thus decrease insulin requirements when given
concomitantly. The need for oral hypoglycaemics may also
be decreased.
Alcohol. Severe hypoglycaemic episodes have been reported
in type I diabetics following heavy drinking episodes. Al-
cohol inhibits gluconeogenesis, and its effects are therefore
likely to be greatest if taken without food: however, it seems
to be generally agreed that diabetics need not abstain from a
moderate alcohol intake with meals.
Aspirin. Aspirin produces a modest decrease in blood-glu-
cose concentrations but a significant interaction at conven-
tional analgesic doses appears to be unlikely. One study in
children with type I diabetes found an average 15% decrease
in blood glucose values following treatment with aspirin 1.2
to 2.4 g daily for 3 days, but there were no significant changes
in insulin requirements. However, high doses of aspirin can
reduce or even replace the insulin dose required. Other sali-
cylates might be expected to have similar properties.
Beta blockers. There are a few reports of severe hypogly-
caemia in patients, including insulin-treated diabetics, who
were given propranolol or pindolol;l-3 there is also a report of
an interaction with timolol given as eye drops. Some evi-
dence exists of an interaction with metoprolol, but little evi-
dence for some of the more selective beta blockers. Because
of the effects of beta blockers on the sympathetic nervous sys-
tem the usual premonitory signs of hypoglycaemia may not
occur, allowing a severe episode to develop before the patient
is aware and able to counter it.
Cilclum-channel blockers. Diabetes worsened in an insu-
lin-treated diabetic when given diltiazem.' The resultant in-
tractable hyperglycaemia improved when the drug was
withdrawn, and recurred, although at a more manageable lev-
el, when diltiazern was restarted at a lower dose. There are
also reports of a diabetogenic effect of nifedipine . However.
reports of significant disturbances of metabolic control ap-
pear to be uncommon.
Interferons. A report of markedly increased insulin require-
ments developing in a previously well controlled diabetic fol-
lowing treatment with interferon alfa 2a.' Insulin
requirements rapidly fell once interferon therapy was discon-
tinued.
Oral contraceptives. Both increases and decreases (main-
ly the former) in insulin requirements have been reported in
insulin-dependent diabetics given various oral contracep-
tives. However, it appears that in most cases the effects of a
hormonal contraceptive on diabetic control are modest or
insignificant: one study suggests that progestogen-only and
combined oral contraceptives in general have little effect.
Pharmacokinetics
Insulin has no hypoglycaemic effect when adminis-
tered by mouth since it is inactivated in the gastro-
intestinal tract.
It is fairly rapidly absorbed from subcutaneous tis-
sue following injection and although the half-life of
unmodified insulin in blood is very short (being only
a matter of minutes), the duration of action of most
preparations is considerably longer due to their for-
mulation (for further details see Uses and Adminis-
tration, below). The rate of absorption from different
anatomical sites may be different depending on lo-
cal blood flow, with absorption from the abdomen
being faster than that from the arm, and that from the
arm faster than from buttock or thigh. Absorption
may also be increased by exercise. The absorption
of insulin after intramuscular administration is more
rapid than that following subcutaneous administra-
tion. Human insulin may be absorbed slightly faster
from subcutaneous tissue than porcine or bovine in-
sulin.
Insulin is rapidly metabolised, mainly in the liver
but also in the kidneys and muscle tissue. In the kid-
neys it is reabsorbed in the proximal tubule and ei-
ther returned to venous blood or metabolised. with
only a small amount excreted unchanged in the
urine.
For discussion of factors which may affect the absorption of
insulin, sec under Precautions. Accelerated Absorption.
above, and Uses, Administration Routes, below.
Resistance to Insulin
The term insulin resistance has traditionally been
used to describe a state in which diabetic patients
exhibit considerably increased insulin requirements.
It is now used in a much wider sense, and is for in-
stance also applied to patients in whom a subnormal
biological response to insulin can be demonstrated.
although many of these patients do not apparently
present difficulties in their clinical management. In-
sulin resistance is found particularly in obese pa-
tients; resistance to endogenous insulin is thought to
be linked to the development of type 2 diabetes in
such patients. Insulin resistance is frequently associ-
ated with lipid disorders, hypertension, and ischae-
mic heart disease. In women, it may also be linked
to polycystic ovary syndrome.
Insulin resistance of the type manifested by greatly
increased insulin requirements may be due to a vari-
ety of factors, including antibody formation and
inadequate absorption of insulin from subcutaneous
sites.
Uses and Administration
Insulin is a hormone that plays a key role in regulat-
ing carbohydrate, protein, and fat. metabolism. The
main stimulus for its secretion is glucose, although
many other factors including amino acids, catecho-
lamines, cortisol, glucagon, and growth hormone
and its hypothalamic release-inhibiting hormone
(somatostatin), are involved in its regulation. The
secretion of insulin is not constant and peaks occur
in response to the intake of food.
The major effects of insulin on carbohydrate ho-
moeostasis follow its binding to specific cell-surface
receptors on insulin-sensitive tissues, notably the
liver, muscles, and adipose tissue. It inhibits hepatic
glucose production and enhances peripheral glucose
disposal thereby reducing blood-glucose concentra-
tion. It also inhibits lipolysis thereby preventing the
formation of ketone bodies.
Therapy with insulin is essential for the long-term
survival of all patients with type I diabetes mellitus.
It may also be necessary in some patients with type
2 disease. The management of diabetes mellitus and
the role of insulin in type I and type 2 disease is
discussed on p.313. Insulin is generally the treat-
ment chosen for all types of diabetes mellitus during
pregnancy.
Choice of Insulin. The different types of insulin and
their formulations are described under Definitions.
above. In some countries including the UK the com-
mercially available preparations have been stand-
ardised to a single strength containing 100 units per
mL; a strength of 40 units per mL is still available in
some other countries, and in others concentrated in-
jections (500 units per mL) are available to enable
high doses to be given subcutaneously in a small
volume. All formulations can be given by subcuta-
neous injection, most by intramuscular injection,
but only soluble insulins can be given by the intrave-
nous route. The long-term management of diabetic
patients usually involves the subcutaneous route.
Syringes and needles for subcutaneous injection are
preferably disposable. Pen-injector devices which
hold the insulin in cartridge form and meter the re-
quired dose are becoming increasingly popular. Sol-
uble insulin is often given by the intraperitoneal
route to patients on continuous ambulatory perito-
neal dialysis.
The various formulations of insulin are classified,
according to their duration of action after subcutane-
ous injection, as short-, intermediate-, or long-act-
ing. The exact duration of action for any particular
preparation, however, is variable and may depend
upon factors such as interindividual variation, the
patient's antibody status, whether the insulin is of
human or animal origin, the dose, and the site of in-
jection. Short-acting insulins are the soluble insu-
lins, which have an onset after about 30 minutes to
I hour, a peak activity at about 2 to 5 hours, and a
duration of about 6 to 8 hours. Intermediate-acting
insulins include biphasic insulins, isophane insulins,
and amorphous insulin zinc suspensions. In general
these have an onset within about 2 hours, peak activ-
ity after about 4 to 12 hours, and a duration of up to
24 hours. Commercially available mixtures of solu-
ble insulins and isophane insulins have activities
which would normally place them within the inter-
mediate-acting category. Mixed insulin zinc suspen-
sions may be classified as either intermediate- or
long-acting as the duration of action may be up to 30
hours: the onset of action is generally 2 to 3 hours
and the time to peak activity 6 to 15 hours. Long-
acting insulins include crystalline insulin zinc sus-
pensions and protamine zinc insulins. These gener-
ally have an onset after about 4 hours, a peak activity
at about 10 to 20 hours, and a duration of up to 36
hours. Following intramuscular injection, the onset
of action of all insulins is generally more rapid and
the duration of action shorter.
The type of formulation, its dose. and the frequency
of administration are chosen to suit the needs of the
individual patient. Whatever the formulation, hu-
man insulin is generally used for all newly diag-
nosed diabetics.
Control. The dosage of insulin must be determined
for each patient and although a precise dose range
cannot be given a total dose in excess of about
80 units daily would be unusual and may indicate
the presence of a form of insulin resistance. The
dose should be adjusted as necessary according to
the results of regular monitoring of blood concentra-
tions (or occasionally urine concentrations) of glu-
cose by the patient.
The WHO has recommended that the glucose con-
centration of venous whole blood under fasting con-
ditions should be kept within the range of 3.3 to
5.6 mmol per litre (60 to 100 mg per 100 mL) and
after meals should not be allowed to exceed
10 mmol per litre (180 mg per 100 mL); blood-glu-
cose concentrations should not be allowed to fall be-
low 3 mmol per litre (55 mg per 100 mL). In
practice it seems to be generally acceptable for pa-
tients to aim for blood-glucose concentrations be-
tween 4 and 10 mmol per litre, with the
understanding that occasional variations outside this
range may occur. It should be remembered that the
glucose concentrations in venous plasma, venous
whole blood, and capillary whole blood may be
slightly different. Control may also be determined
by monitoring of glycosylated haemoglobin con-
centrations; ideally the aim is an HbA1c level of less
than 7% or an HbA1 of less than 8.8%. compared
with normal ranges of 4 to 6% and 5 to 7.5% respec-
lively. Insulin requirements may be altered by vari-
ous factors (see Precautions, above). The aim of any
regimen should be to achieve the best possible con-
trol of blood glucose by attempting to mimic as
closely as possible the pattern of optimum endog-
enous insulin secretion. Many regimens involve the
use of a short-acting soluble insulin together with an
intermediate-acting insulin, such as isophane insulin
or mixed insulin zinc suspension. Such a combina-
tion is often given twice daily with about two-thirds
of the total daily requirement given before breakfast
and the remaining third before the evening meal. It
may sometimes be necessary, though, to give 3 or 4
injections daily to achieve good control and this typ-
ically involves the administration of a soluble insu-
lin before meals together with an intermediate- or
long-acting insulin given usually in the evening. A
once-daily injection of an intermediate- or long-act-
ing insulin is now generally considered to be accept-
able only for those patients with type 2 diabetes
mellitus who still retain some endogenous insulin
secretion but nevertheless require insulin therapy, or
for those patients with type I disease unable to cope
satisfactorily with more intensive regimens. If a
more intensive regimen is desired, continuous sub-
cutaneous infusion may be employed using soluble
insulin in an infusion pump. This delivers a constant
basal infusion of insulin supplying about half of the
total daily requirements, the remainder being pro-
vided by patient-activated bolus doses before each
meal. The technique has a limited place in the man-
agement of diabetes; patients using it need to be
well-motivated, reliable, and able to monitor their
own blood glucose, and must have access to expert
advice at all times. Formulations in which the insu-
lin is in suspension are not suitable for administra-
tion by continuous subcutaneous infusion.
Ketoacidosis. Insulin is also an essential part of the
emergency management of diabetic ketoacidosis.
see below. Only short-acting soluble insulins should
be used. Treatment includes adequate fluid replace-
ment, usually by infusing sodium chloride 0.9% in-
itially, and the administration of potassium salts to
prevent or correct hypokalaemia. If possible, insulin
should be given by continuous intravenous infusion
and typical initial infusion rates range between 5
and 10 units per hour; if facilities for intravenous in-
fusion are not available intramuscular injection may
be employed, typically with a loading dose of 10 to
20 units, followed by injection of 5 units every hour.
Since insulin normally corrects hyperglycaemia be-
fore ketosis it is usually necessary to continue ad-
ministration of insulin once normoglycaemia has
been achieved but to change the rehydration fluid to
glucose-saline so that the additional glucose pre-
vents the development of hypoglycaemia.
Administration. ADMINISTRATION ROUTES. The long-term
management of diabetic patients usually involves injection by
the subcutaneous route. The advice to diabetics has been to
inject their insulin using a full-depth perpendicular injection. '
In many non-obese patients, however, such a technique may
result in inadvertent intramuscular injection. Since insulin
is absorbed more rapidly after intramuscular than subcutane-
ous administration, such a change between routes may lead to
greater day to day variability in blood-glucose control. In
particular, overnight control may be inadequate if intermediate-
acting preparations such as isophane insulin arc used.' Some
workers therefore consider that extended-action insulins
should be injected at an angle into a raised skin fold. Al-
though injection of soluble insulin into muscle may produce
a more physiological action profile, until more data are avail-
able a technique that ensures subcutaneous administration
may be prudent with soluble insulins as well.'
The anatomic site of subcutaneous insulin injection is usually
rotated in an attempt to decrease local adverse effects (see
Adverse Effects, above). However, the rate of absorption var-
ies between sites and such a practice may also contribute to
day-to-day variability in blood-glucose concentrations' For
example, large variations in blood-glucose concentrations
have been reported following subcutaneous injection into the
thigh.* Some workers have suggested rotation of injection
sites within an anatomic region, or possibly use of the same
anatomic region for injections given at a specific time of day.
Jet injections deliver insulin at high pressure across the skin
into the subcutaneous tissue without use of a needle. The
greater dispersion obtained gives more rapid absorption of
short- and intermediate-acting insulins and consequently re-
duces the total duration of action."-" Delayed pain and bleed-
ing may be a problem. Despite having been available for
some years, there is little information about their benefits and
risks' and they are not widely used.7 However, results in a
small study in women with gestational diabetes have suggest-
ed that jet injection may be associated with less variation in
postprandial blood-glucose concentration and a lower inci-
dence of insulin antibodies'
Insulin preparations may also be administered by intramus-
cular injection. Absorption is more rapid than from a subcu-
taneous injection. However, exercise may produce
considerable variations in insulin absorption after intramus-
cular administration. Soluble insulins may be given intrave-
nonsly; this route is used in diabetic ketoacidosis. and also in
surgery and labour. Intermittent pulsed intravenous insulin
therapy added to a conventional subcutaneous regimen has
been reported to improve symptoms of postural
hypotension and hypertension.
The subcutaneous and intravenous routes, and. rarely, the in-
tramuscular route have all been used for the continuous ad-
ministration of insulin {see Intensive Administration
Regimens, below).
Formulations of insulin for intranasal administration are un-
der investigation. Absorption enhancers such as deoxy-
cholate or laureth 9 have been used to facilitate uptake of
insulin from the nasal mucosa. Studies in type 2 and type
I diabetes have investigated the use of intranasal insulin
given less than 30 minutes before a meal: in type I patients
this was as an adjunct to base-line subcutaneous insulin. Two
studies considered intranasal insulin to be promising.
However, one study found higher plasma-glucose concentra-
tions 120 to 150 minutes after intranasal than alter preprandi-
al subcutaneous insulin. Although local reactions such as
nasal irritation and chronic rhinitis have occurred, these
problems may be decreased by the development of less irri-
tant absorption enhancers.
Endogenous insulin is delivered into the portal venous sys-
tem. and then passes immediately to the liver where a large
fraction of the insulin is extracted. The above routes of ad-
ministration all deliver insulin into the peripheral circulation.
with the risk of peripheral hyperinsulinaemia which has been
considered a risk factor for atherosclerotic complications.
Administration of insulin via the intraperitoneal or oral
routes may overcome this problem to some extent. Peritoneal
insulin is used routinely in diabetics undergoing chronic am-
bulatory peritoneal dialysis, but has also been used for contin-
uous administration (see Intensive Administration Regimens.
below). Various formulations of insulin for oral delivery are
also under investigation." Some success in controlling blood-
glucose concentrations has been achieved in a limited number
of diabetics using a microemulsion of insulin in a lipid phase
of similar composition to chvlomicra. Rectal administra-
tion of insulin has also been tried, as has an aerosol for oral
inhalation.
INSULIN ANALOGUES AND PROINSULIN. Recombinant-DNA tech-
nology has enabled the production of insulin analogues with
altered pharmacokinetic profiles.' Most of the insulin in
pharmaceutical preparations is in the form of hexamers,
which requires time to dissociate before absorption from a
subcutaneous site. Substitution of amino-acid residues at the
monomer-monomer interface has produced monomeric insu-
lin analogues that retain the biological activity of insulin.)
Good results have been reported with an analogue, insulin
lispro, in which the B28 and B29 residues are replaced with
lysine and proline. In comparative studies of insulin lispro
versus soluble insulin given before meals to patients also re-
ceiving a long-acting insulin, insulin lispro was reported lo
result in good glycaemic control and could be given imme-
diately before meals (5 TO 15 minutes) rather than 20 to 40
minutes before as with soluble insulin. There is a suggestion
that it may result in fewer hypoglycaemic episodes in such
regimens but it is not. in fact. clear that this is so, although
postprandial glycaemic control is improved. There is also a
report of benefit in a patient with severe insulin resistance.
Insulin lispro is commercially available and has been widely
reviewed.
Protein engineering has also been used to produce a range of
soluble insulins with absorption half-lives greater than 24
hours and hence a prolonged action. Development has how-
ever. been less impressive than with the rapid-acting ana-
logues.
Immunogenicity and possible unwanted metabolic effects of
insulin analogues must be studied in addition to metabolic ef-
ficacy before they can be introduced into clinical I
Proinsulin (the natural precursor of insulin) appears to be
more active than insulin in suppressing the hepatic production
rather than the peripheral uptake of glucose. It has there-
fore been studied particularly in patients with type 2 diabetes
mellitus. However, development by some manufacturers has
been suspended because of a higher rate of adverse
cardiac effects in patients treated with proinsulin than In controls.
Mecasermin (insulin-like growth factor) has been
observed to reverse hyperglycaemia and ketoacidosis in pa-
tients with insulin resistance.
INTENSIVE ADMINISTRATION REGIMENS. Intensive regimens for
insulin administration aim to mimic more closely the physio-
logical insulin pattern in which a basal insulin concentration
is supplemented by a preprandial boost of insulin. Such in-
tensive regimens are used to provide tight control in an at-
tempt to avoid long-term complications (see p.315).
In multiple-injection regimens, the basal insulin is provided
by an injection of intermediate- or long-acting insulin given
usually at night Soluble insulin is administered before each
main meal. perhaps with a pen-injector device." Systems for
continuous administration may be designed on an open-loop
or closed-loop delivery system. Open-loop systems comprise
an infusion pump with the infusion rate programmed or con-
trolled manually according to manual blood-glucose monitor-
ing. Closed-loop systems (the 'artiticial pancreas' ) consist of
an insulin pump. a glucose sensor, and a computer for analy-
sis of blood-glucose data. Systems for continuous administra-
tion have most commonly used the subcutaneous route, but
intraperitoneal, intravenous, or intramuscular infusion have
also been used.
The most extensively investigated open-loop system is con-
tinuous subcutaneous insulin infusion using an external
pump. A battery-powered pump infuses soluble insulin via a
subcutaneous catheter which is resited every I to 3 days. A
background infusion is given at a predetermined rate. and pre-
prandial bolus doses given using an override switch or manual
drive." Complications include erythema, abscess, or cellulitis
at the injection site and. rarely, systemic infection, hypersen-
sitivity reactions to components of the administration set.
pump malfunction, adsorption 'of insulin or preservative on to
the administration set. or catheter obstruction." If the pump
fails, the onset of ketoacidosis may be more rapid and more
likely to be associated with dangerous hyperkalaemia than
with conventional administration regimens because there is
no depot of insulin. Although improved glycaemic control in
intensive regimens may be associated with decreased hy-
poglycaemic awareness and more hypoglycaemic episodes,
one study has reported fewer severe hypoglycaemic episodes
in patients switched from multiple daily injections to contin-
uous subcutaneous infusion of insulin.'
Further development of open-loop delivery systems has been
in the design of implantable insulin pumps. The first pumps
delivered insulin at a constant basal rate. but variable-rate
models, such as the programmable implantable medication
system (PIMS) are now available. One of the major prob-
lems with implantable pumps has been the tendency for insu-
lin to aggregate on prolonged exposure lo body heat.
movement, and contact with hydrophobic surfaces' Insulin
aggregates may occlude pumps and tubing, and studies
have suggested that their prolonged infusion may induce
amyloidosis. Insulin aggregation has been decreased by the
development of insulin preparations containing calcium,
glycerol, bicarbonate, or most successfully, poloxamer. ln-
sulin pumps are implanted subcutaneously, usually in the ab-
domen. but the catheter is usually placed peritoneally or
intravenously. Glycaemic control has been good. A
French multicentre study involving 224 patients found that
glycosylated haemoglobin fell on average from 7.4 to 6.8%
in six months after implantation. Specific problems with hy-
poglycaemia or ketoacidosis do not appear to have been iden-
tified ,and indeed there is some evidence that the
postprandial insulin profile is better and hypoglycaemia less
frequent, in patients using implantable pumps for intraperito-
neal or intravenous delivery compared with those receiving
continuous subcutaneous infusion from an external pump.
Complications include mechanical failure of the system, in-
fection (particularly of the implantation site) and skin necro-
sis over the implant. Peritoneal catheters may become
obstructed by omental tissue.
Closed-loop continuous infusion systems are generally con-
fined to research and experimental work. External pumps are
used since no glucose sensor suitable for implantation has yet
been developed. (However, results in Animals have suggest-
ed that an alternative to such systems may be a vascularised
artificial pancreas containing islet cells.)
Intensified insulin ragimens have the advantage of improving
the patient's lifestyle and allowing flexibility in timing of
meals. However, careful dietary control must still be main-
tained and regular monitoring of blood-glucose concentra-
tions is an important component of such regimens. Therefore
patients must be well-motivated, reliable, and able to monitor
their own blood glucose, and must have access to expert 24-
hour help.'*'' Although there are reports of success with inten-
sive administration regimens in brittle (labile) diabetics,"
these patients are generally unlikely to benefit from such reg-
imens'
MIXING OF INSULINS. There are studies indicating that the rapid
effect of soluble insulin may be lost if mixed in the syringe
immediately prior to injection with insulins containing high
concentrations of free zinc. Insulin manufacturers recom-
mend immediate injection of mixtures prepared in the sy-
ringe; if delay is unavoidable a consistent routine is advised.
The shorter-acting insulin should be drawn into the syringe
first to prevent contamination of the vial by the longer-acting
preparation. Insulins from different manufacturers should not
be mixed since formulation differences, such as the buffer or
preservative used. may render them incompatible.
Diabetes mellitus. Insulin is the mainstay of the treatment
of type I diabetes mellitus.
DIABETIC EMERGENCIES. Diabetic ketoac-
idosis is a medical emergency and should be treated immedi-
ately with fluid replacement and insulin . Potassium, and
possibly phosphate, replacement may also be required, but bi-
carbonate should not be given unless acidaemia is very se-
vere.
Soluble insulin is the form used in diabetic ketoacidosis. ide-
ally by the intravenous route. Large doses were formerly used
because of the presence of insulin resistance in diabetic ke-
toacidosis. probably related to the effects of acidaemia. Low-
er-dose regimens have since been shown to provide adequate
insulin concentrations and are now used routinely. Adults
are sometimes given an initial bolus injection of soluble insu-
lin 5 to 20 units. Soluble insulin, diluted to a concentration
of 1 unit per mL. is then administered continuously via an
infusion pump at a rate of 5 to 10 units per hour. Children
have been given insulin intravenously as a bolus of 0.1 unit
per kg body weight followed by an infusion of 0.1 unit per kg
per hour.
Insulin may be given by the intramuscular route provided the
circulatory stale of the patient is satisfactory. Adults may be
given a bolus injection of 20 units followed by 5 units per
hour. Children may be given 0.25 unit per kg as a bolus
followed by O.I unit per kg per hour.
Lack of response to insulin is generally a result of inadequate
hydration but may occasionally be caused by genuine insulin
resistance.l2 In this case the intravenous route is essential'
and the insulin dose needs to be doubled on a one- to two-
hourly basis until an adequate response has been obtained.' A
case report has suggested that mecasermin may be useful if
there is insulin resistance.
When the blood-glucose concentration has fallen to less than
10 mmol per litre the dose of insulin may be reduced by about
half and glucose administered intravenously. (A recent study
reported benefit, however, from continuing insulin infusion at
a rate of 5 units per hour until resolution of hyperketonae-
mia.) Glucose is usually given in a strength of 5% with
saline?·3 although some have advocated a glucose strength of
10%. The administration of 'glucose enables insulin to be
continued in order to clear ketone bodies, without inducing
hypoglycaemia: this is essential if a recurrence of ketoacido-
sis is to be avoided. Once glucose concentrations have been
controlled and acidosis has completely cleared, subcutaneous
injections of insulin can be started but intravenous infusion
should be continued at a reduced rate for an hour during the
change-over.
Hyperosmolar hyperglycaemic nonketotic coma (HONK) is
much less common in type I diabetics than diabetic ketoaci-
dosis. It occurs mainly in elderly patients with type 2 dia-
betes and has a much higher mortality than diabetic
ketoacidosis. Patients may present in coma or be very drow-
sy with severe hyperglycaemia but without significant keto-
sis; dehydration and renal impairment are also major features
and hypernatraemia is more common. Treatment is similar to
diabetic ketoacidosis ;bicarbonate is not required and potassium
requirements are lower. Less insulin but more fluid is
usually required and some have advocated the use of hypot-
onic fluids.
TYPE 2 DIABETES MELLITUS. Traditionally the use of insulin in pa-
tients with type 2 diabetes has tended to be reserved for those
who cannot be controlled by diet and oral hypoglycaemics
alone. Given the possible association between circulating
insulin and atherosclerotic cardiovascular symptoms' there
has been some concern about the administration of exogenous
insulin to insulin-resistant patients who are already hyperin-
sulinaemic. Furthermore, patients switched to insulin tend to
gain weight2 which is undesirable in a frequently obese pa-
tient group.
Although it is still the consensus that insulin should be re-
served for those poorly controlled on diet and oral hypogly-
caemic drugs, insulin is nonetheless being used more
frequently in type 2 patients. This is largely because of a trend
toward more intensive regimens designed to produce tighter
glycaemic control, on the hypothesis that. as in patients with
type I disease, this will reduce the development and progression of
diabetic complications. Results from the UK Prospec-
tive Diabetes Study show that insulin is an effective option
in type 2 diabetes, and confirm the value of intensive therapy
in retarding microvascular complications'
In order to minimise the dose of insulin required, and any
risks it may entail, it has been suggested that insulin therapy
in type 2 diabetes should be combined with other measures
including oral hypoglycaemic drugs." There has long been
debate about the value of combined therapy, but a recent
meta-analysis indicated that glycaemic control was better.
and insulin requirements lower, in type 2 diabetics who re-
ceived insulin with a sulphonylurea.
Diagnosis and testing. PITUITARY FUNCTION. Insulin-in
duced hypoglycaemia has been used to provide a stressful
stimulus in order to assess hypothalamic-pituitary function
The insulin stress or insulin tolerance test has been used as
standard test for assessment of growth hormone or cortico-
trophin deficiency. However, it is unpleasant, expensive, an
not without risk, and is contra-indicated in patients with angi
na. heart failure, cerebrovascular disease, or epilepsy; some
workers recommend its use only when results of alternative
tests are equivocal, and it should only be performed in spe-
cialist units under strict surveillance.
Hyperkalaemia. Insulin promotes the intracellular uptake
of potassium. It is therefore used in the management of mod-
erate to severe hyperkalaemia. when it is given with glucose.
Liver disorders. References to the use of insulin and glu-
cagon in the treatment of liver disorders based on their report-
ed hepatotrophic effect. However, a small randomised study
found no benefit from insulin and glucagon infusions in ful-
minant hepatic failure.
Myocardial infarction. Recent discussions on the effects of
insulin with glucose and potassium in the ischaemic heart in-
cluding its effect in reducing blood free fatty acids have em-
phasised its potential benefits in left ventricular failure and
cardiogenic shock, Glucose-insulin-potassium solutions
have been investigated in only small numbers of patients with
acute myocardial infarction although a meta-analysis of ran-
demised controlled studies performed before the widespread
use of thrombolytics found a reduction in mortality in recipi-
ents of these solutions and suggests that further investigation
of its value in acute myocardial infarction may be warranted.
Insulin-glucose infusion followed by multiple daily subcuta-
neous insulin injections has been reported to reduce mortality
in diabetics who suffered a myocardial infarction.
Neonatal hyperglycaemia. Hyperglycaemia is common
in very immature neonates. although hypoglycaemia is more
common in neonates born to diabetic mothers. Neonatal hy-
perglycaemia has been treated by glucose restriction until
glucose tolerance improves. However, the use of an insulin
infusion can allow normal glucose administration to contin-
ue.' It was suggested that insulin was best administered intra-
venously in a separate, easily titratable solution because of
the frequent fluctuations of requirement in these infants. An
alternative approach, namely subcutaneous injection of a
long-acting insulin, has been reported to result in less fluctu-
ation of blood-glucose concentrations' and hence easier.
management.
Organ and tissue transplantation. Brief discussion of
the possibility that administration of hormones, including in-
sulin, to 'brain-dead' patients could improve the function of
donated organs.