• Diabetes mellitus and insulin • Insulins in current use including choice, formulations, adverse effects, hypoglycaemia, insulin resistance Oral antidiabetes drugs Treatment of diabetes
Trang 1Diabetes mellitus, insulin, oral
antidiabetes agents, obesity
SYNOPSIS
Diabetes mellitus affects 1-2% of many
national populations Its successful management
requires close collaboration between the
patient and the doctor.
• Diabetes mellitus and insulin
• Insulins in current use (including choice,
formulations, adverse effects, hypoglycaemia,
insulin resistance)
Oral antidiabetes drugs
Treatment of diabetes mellitus
Diabetic ketoacidosis
Surgery in diabetic patients
Obesity and overweight
Diabetes mellitus and
insulin
HISTORY
Insulin (as pancreatic islet cell extract) was first
ad-ministered to a 14-year-old insulin-deficient patient
on 11 January 1922 in Toronto, Canada An adult
sufferer from diabetes who developed the disease
in 1920 and who, because of insulin, lived until
1968, has told how:
Many doctors, after they have developed a disease, take up the speciality in it But that was not so with me I was studying for surgery when diabetes took me up The great book of Joslin said that by starving you might live four years with luck [He went to Italy and, whilst his health was declining there, he received a letter from a biochemist friend which said] there was something called 'insulin' appearing with a good name in Canada, what about going there and getting it I said 'No thank you; I've tried too many quackeries for diabetes; I'll wait and see' Then I got peripheral neuritis
So when [the friend] cabled me and said, 'I've got insulin — it works — come back quick', I responded, arrived at King's College Hospital, London, and went to the laboratory as soon as it opened It was all experimental for [neither of us] knew a thing about it So we decided to have
20 units a nice round figure I had a nice breakfast
I had bacon and eggs and toast made on the Bunsen I hadn't eaten bread for months and months by 3 o'clock in the afternoon my urine was quite sugar free That hadn't happened for many months So we gave a cheer for Banting and Best.1
But at 4 pm I had a terrible shaky feeling and a terrible sweat and hunger pain That was my first experience of hypoglycaemia We remembered that
1 F G Banting and C H Best of Toronto, Canada (see also Journal of Laboratory and Clinical Medicine 1922 7: 251).
679
Trang 2Banting and Best had described an overdose of
insulin in dogs So I had some sugar and a biscuit
and soon got quite well, thank you.2
Type I (formerly, insulin dependent diabetes mellitus,
IDDM) which typically occurs in younger people who
cannot secrete insulin
Type 2 (formerly, non-insulin dependent diabetes mellitus,
NIDDM), which typically occurs in older, often obese
people who retain capacity to secrete insulin but who are
resistant to its action.These terms and abbreviations are
used in this chapter.
Sources of insulin
Insulin is synthesised and stored (bound to zinc) in
granules in the (Hslet cells of the pancreas Daily
secretion amounts to 30-40 units, which is about
25% of total pancreatic insulin content The principal
factor that evokes insulin secretion is a high blood
glucose concentration
Insulin is a polypeptide with two peptide chains
(A chain, 21 amino acids and B chain, 30) linked by
two disulphide bridges The basic structure having
metabolic activity is common to all mammalian
species but there are minor species differences,
which result in the development of antibodies in all
patients treated with animal insulins, as well as to
unavoidable impurities in the preparations, minimal
though these now are
• Bovine insulin differs from human insulin by
three amino acids and is more antigenic to man
than is
• Porcine insulin differs from human by only one
amino acid
• Human insulin (1980) is made either by enzyme
modification of porcine insulin, or by using
recombinant DNA to synthesise the proinsulin,
precursor molecule for insulin This is done by
artificially introducing the DNA into either
Escherichia coli or yeast.
The three forms of human insulin have the same
amino acid sequence, but are separately designated
2 Abbreviated from Lawrence R D 1961 King's College
Hospital Gazette 40: 220 Transcript from a recorded after
dinner talk to students' Historical Society.
as insulin emp (Enzyme Modified Porcine), prb (Proinsulin Recombinant in Bacteria) and pyr
(Precursor insulin Yeast Recombinant) Although one of the incentives for introducing human insulin was avoidance of insulin antibody production, the allergies to older insulins were largely caused by impurities in the preparations, and are avoided equally well by using the highly purified, mono-component porcine and bovine insulins Other preparations have been withdrawn There is no systematic difference in activity between human and animal insulin, but any change in preparation prescribed to a patient should be monitored with care (see below)
Insulin receptors
Insulin binds to the a subunit of its receptor The (3 subunit is a tyrosine kinase which is activated by insulin binding and is autophosphorylated Tyrosine kinase also phosphorylates other substrates so that
a signalling cascade is initiated and biological response ensues Insulin receptors are present on the surface of the target cells (mostly liver, muscle, fat) Receptors vary in number inversely with the insulin concentration to which they are exposed, i.e with high insulin concentration the number of
receptors declines (down-regulation) and
responsive-ness to insulin also declines (insulin resistance); with low insulin concentration the number of
receptors increases (up-regulation) and
responsive-ness to insulin increases Type 2 diabetes patients have insulin resistance
Hyperinsulinaemia predates the onset of diabetes and the resistance is thought to be secondary to down-regulation of insulin receptors as well as postreceptor, intracellular events Obesity is a major factor in the development of insulin resistance Patients may recover insulin responsiveness as
a result of dieting so that the insulin secretion decreases, cellular receptors increase and insulin sensitivity is restored
Actions of insulin
The effects of stimulation of the insulin receptors include activation of glucokinase and glucose phos-phatase Insulin also increases glucose transport
Trang 3as well as its utilisation, especially by muscle and
adipose tissue Its effects include:
• Reduction in blood glucose due to increased
glucose uptake in the peripheral tissues (which
convert it into glycogen or fat), and reduction of
hepatic output of glucose (diminished
breakdown of glycogen and diminished
gluconeogenesis) When the blood glucose
concentration falls below the renal threshold (10
mmol/1 or 180 mg/100 ml) glycosuria ceases, as
does the osmotic diuresis of water and
electrolytes Polyuria with dehydration and
excessive thirst are thus alleviated As the blood
glucose falls, appetite is stimulated
• Other metabolic effects In addition to enabling
glucose to pass across cell membranes, the
transit of amino acids and potassium into the cell
is enhanced Insulin regulates carbohydrate
utilisation and energy production It enhances
protein synthesis It inhibits breakdown of fats
(lipolysis) An insulin-deficient diabetic (Type 1)
becomes dehydrated due to osmotic diuresis,
and is ketotic because fats break down faster
than the ketoacid metabolites can be
metabolised
D I A B E T E S M E L L I T U S A N D I N S U L I N
This difference may have clinical importance and this is why some continous infusion pumps (see below) deliver insulin intraperitoneally rather than subcutaneously
In conventional use, insulin is injected (s.c., i.m
or i.v.) as it is digested if swallowed It is absorbed into the blood3 and is inactivated in the liver and kidney; about 10% appears in the urine The t1/, is
5 min.
In addition to needles and syringes, alternative techniques for insulin administration have been developed, some availing themselves of the kinetics
of insulin: insulin pens (supplied preloaded or with replaceable cartridges), external infusions and implantable pumps These latter are convenient for
an accurately controlled continuously functioning biofeedback system, but pose difficulties for rou-tine replacement in insulin deficiency Therefore sustained-release (depot) formulations are used to provide an approach reasonably near to natural function and compatible with the convenience of daily living An even closer approach is provided by the development of (at present inevitably expensive) miniaturised infusion pumps which can be used by reliable patients
Uses
• Diabetes mellitus is the main indication
• Insulin promotes the passage of potassium
simultaneously with glucose into cells, and this
effect is utilised to correct hyperkalaemia (see
p 537)
• Insulin-induced hypoglycaemia can also be used
as a test of anterior pituitary function (growth
hormone and corticotropin are released)
Pharmacokinetics
• Insulin, naturally secreted by the pancreas,
enters the portal vein and passes straight to the
liver, where half of it is taken up The rest enters
and is distributed in the systemic circulation so
that its concentration (in fasting subjects) is only
about 15% of that entering the liver
• When insulin is injected s.c it enters the systemic
circulation and both liver and other peripheral
organs receive the same concentration
DIFFERENCES BETWEEN HUMAN AND ANIMAL INSULINS
Human insulin is absorbed from subcutaneous tissue slightly more rapidly than animal insulins and it has a slightly shorter duration of action Human insulin is less immunogenic than bovine, but not porcine, insulin When changing from animal to human insulin, patients taking < 100 units
of animal insulin are likely to require 10% less human insulin, and if taking > 100 units animal insulin, 25% less human insulin
There has been concern that patients taking human insulin may experience more frequent and more severe hypoglycaemic attacks, especially when
3 Peak plasma insulin (s.c.) concentration is attained in 60-90 min Absorption is slower if there is peripheral vascular disease or smoking, and faster if the patient takes a hot bath or uses an ultraviolet light sunbed (which may induce a hypoglycaemic fit) or exercises The effects are due
to changes in peripheral blood flow.
681
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transferring from animal insulins Such occurrences
are likely to be due to management problems rather
than to pharmacological differences
There is some evidence of a lessened
aware-ness of hypoglycaemia with human insulin, i.e
the counter-regulatory physiological responses to
animal and human insulin may differ It is claimed
that with human insulin patients experience less
adrenergic symptoms (sweating, tremor,
palpita-tions), which are such a useful warning, although
the neurological (neuroglycopenic) symptoms
(dizziness, headache, inability to concentrate) are
unchanged It now seems likely that the reduced
awareness is a paradoxical response to improved
glycaemic control Thus patients with a normal
level of glycosylated haemoglobin (HbAlc) show
no reduction in glucose uptake in the brain during
episodes of hypoglycaemia that trigger a
sympto-matic and neuroendocrine response in patients with
elevated levels of HbAlc (see Boyle et al 1995, in
Guide to Further Reading)
PREPARATIONS OF INSULIN (Fig 35.1)
There are three major factors:
• Strength (concentration)
• Source (human, porcine, bovine)
• Formulation
— short-acting solution of insulin for use s.c.,
i.m or i.v
— intermediate and longer acting (sustained
release) preparations in which the insulin has
been physically modified by combination with
protamine or zinc to give an amorphous or
crystalline suspension; this is given s.c and
slowly dissociates to release insulin in its
soluble form (given i.m., which is not advised,
the time course of release would be different)
Dosage is measured in international units now
standardised by chemical assay
Diabetes mellitus may be managed from a choice
of four types of insulin (animal or human)
prep-arations, having:
1 Short duration of action (and rapid onset):
Soluble Insulin (neutral insulin) The most
recent addition to this class of insulin, insulin
lispro (Humalog), is a modified human insulin
in which the reversing of two amino acids has
resulted in a very rapid onset of action (within
15 minutes of injection) Insulin aspart is similar
2 Intermediate duration of action (and slower
onset): Isophane Insulin, a suspension with protamine; Insulin Zinc Suspensions, amorphous or a mixture of amorphous and crystalline
3 Longer duration of action: Insulin Zinc
Suspension, crystalline, or Protamine Zinc Insulin (insulin in suspension with both zinc and protamine)
4 A mixture of soluble and isophane insulins, officially called biphasic insulins The
short-acting analogue insulins are now also available
in mixtures Other mixtures are available, but infrequently used
Insulin nomenclature
This is potentially confusing The problems have arisen because insulin is a naturally occuring mol-ecule (differing slightly among species), which has been formulated in many ways — partly catering for differing patient requirements, and partly reflect-ing a variety of manufacturreflect-ing processes used by pharmaceutical companies Fortunately, there has been considerable rationalisation of the preparations but it may be helpful to explain some remaining ambiguities
• Soluble and neutral insulin are the same; the
British National Formulary favours the former term, but neutral is the INN (internationally approved) name, dating back to when there were acid and neutral pH formulations of soluble insulin Human, porcine and beef are available
• Isophane insulin is the only approved name for
suspensions of insulin with protamine Human, porcine and beef are available; the latter is rarely used
• Biphasic insulins are, with one exception,
proprietary mixtures of soluble (neutral) insulin and isophane insulin, which provide soluble (neutral) insulin at concentrations between 10% and 50% of the total insulin concentration Human, porcine and beef are available, but most preparations in this group are of human insulin These preparations remove the need for patients
to mix soluble and isophane insulins, without
Trang 5D I A B E T E S M E L L I T U S A N D I N S U L I N 35
Preparation Onset, peak activity and duration of action in hours (approx)
Species 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 Neutral insulin Humalog
injection (insulin lispro)
Human actrapid
(pyr)
Human velosulin (emp)
Humulin S (prb)
Hypurin neutral
Pork velosulin Biphasic insulin Human mixtard
injection 10, 20, 30, 40, or 50 (pyr)
The numbers refer to Humulin
the proportion of Ml, 2 3, 4 or 5 {pyr)
soluble insulin in the
mixture, between Pork mixtard 30
10 and 50%
Rapitard MC Insulin zinc suspension
Semitard MC (amorphous)
Isophane insulin Human insulatard
injection (pry)
Humulin 1 (prb)
Hypurin isophane
Pork insulatard Insulin zinc Human monotard
suspension (mixed) (pyr)
Humulin lente (prb) Hypurin lente
Lentard MC Insulin zinc suspension Human ultratard
(cystalline) (pry)
Humulin zn (prb) Protamine zinc Hypurin protamine
insulin injection zinc
(prb) - produced from prc insulin synthesised by bacteria using recombinant DNA technology;
(pyr) - produced from a precursor synthesised by yeast using recombinant DNA technology;
(emp) - produced by enzymatic modification of porcine insulin.
Fig 35.1 Insulin chart Reproduced with permission of the Monthly Index of Medical Specialities.This chart is subject to change as
companies develop their products.
683
Trang 6losing the flexible administration of the right
amount of soluble (neutral) insulin to cover the
meal following the dose
• Mixed insulin zinc suspension is, confusingly, the
approved name for proprietary mixtures of
crystalline and amorphous zinc suspension
Mixed insulins are not, therefore, the same as
biphasic insulins While the different proprietary
formulations in this group do have differing time
courses of action (see Fig 35.1) depending on
their (unstated) proportions of amorphous and
crystalline suspension, it is not expected that
doctors or patients would vary the formulation
prescribed
The important thing is for the doctor to get to
know well a range that will serve most patients
(For insulin regimens and injection techniques, see
p 691.)
NOTES FOR PRESCRIBING INSULIN
There is no need to change a stabilised diabetic
from animal to human insulin Unexplained
require-ment of above 100 units/d is usually due to
non-compliance and less often to antibodies since the
withdrawal of the older insulin preparations
Allergy still occurs to additives (protamine), to the
preservative, e.g phenol, cresol, or to insulin itself
It may take the form of local reactions
(inflam-matory or fat atrophy) or of insulin resistance
Antibodies to insulin, provided they are moderate
in amount, may be actually advantageous They act
as a carrier or store, binding insulin after injection
and releasing it slowly as the free insulin in the
plasma declines In this way they smooth and
pro-long insulin action But too high antibody
concen-trations cause insulin resistance
4 An adverse effect of easy self-monitoring is that a minority
of obsessional patients, told of the desirability of blood
glucose concentrations being kept in the normal range to
prevent diabetic complications, become obsessed with
monitoring, and experience great anxiety when they find
what are, in fact, normal fluctuations They then anxiously
change their insulin doses daily and as a result induce
frequent hypoglycaemia, e.g one patient had 33 episodes in
44 days, many with loss of consciousness (Beer S F et al 1989
British Medical Journal 298: 362).
Compatibility Soluble insulin may be mixed in the syringe with insulin zinc suspensions (amorphous, crystalline) and with isophane and mixed (biphasic) insulin, and used at once: but there are insulins in which protamine is used as a carrier, and spare protamine will bind some of the short-acting neutral insulin, thus blunting its effects
Intravenous insulin Only Soluble (neutral, clear) Insulin Inj should be used
The standard strength of insulin preparations is
100 units per ml in a large and growing number of countries Even very low doses can be accurately measured with modern special syringes Solutions
of 40 units and 80 units remain available in many countries, and healthcare providers should be aware of this
Insulins in current use CHOICE OF PREPARATION
That insulin preparations should be both precise and of uniform strength all over the world is vital
to the health and safety of millions of diabetics Advances in technology now allow biological standardisation in animal insulin to be replaced by physicochemical methods (high performance liquid chromatography: HPLC)
Soluble insulin inj (neutral, regular insulin) is an aqueous solution of insulin It is simple to use, being given s.c 2-3 times a day, 30 min before meals There is little risk of serious hypoglycaemic reaction
if it is used sensibly If a meal must be delayed, then the insulin injection should be delayed The dose can easily be adjusted according to self-performed blood glucose measurements.4 For these reasons it
is often used initially to balance diabetics needing insulin and always for the treatment of diabetic ketoacidosis The biggest disadvantages of soluble insulin for long-term use are the need for frequent injections, and the occurrence of high blood glucose before breakfast
Soluble insulin is neutral, adjusted to pH 7.0 Acid formulations of soluble insulin are no longer available
Trang 7Intravenous soluble (neutral) insulin is used in
diabetic ketoacidosis It may be given intermittently
(i.v or i.m.) but continous infusion is preferred If
the insulin is infused by drip in physiological saline
(40 units/1) as much as 60-80% can be lost due
to binding to the fluid container and tubing It is
necessary to take this into account in dosing
Polygeline (Haemaccel) may be added to bind the
insulin in competition with the apparatus and so
carry it into the body
Use of a slow-infusion pump with a
concen-trated solution (insulin 1.0 unit/ml) is recommended
Insulin loss is minimised and control of dose is
more accurate than when more dilute solutions are
used (For i.v doses see diabetic ketoacidosis, below.)
Insulin is suitable for adimistration by continuous
i.v infusion because its short i l / 2 (5 min) means that
the plasma concentration rapidly reaches steady
state after initiating the infusion or altering its rate
(5 x t1/,, see p 101) Long-acting (sustained-release)
preparations must not be given i.v
Insulin zinc suspensions and isophane insulin
(see Fig 35.1) are sustained-release formulations in
which rate of release is controlled by modifying
particle size Neutral pH, soluble insulin can be
mixed with them without altering the time course
of effect of either and these formulations can be a
great convenience
Duration of action Patients live by a 24-hour cycle
and plainly insulins having a duration of action
exceeding 24 hours can cause problems, especially
early morning hypoglycaemia
DOSE AND USAGE
The total daily output of endogenous insulin from
pancreatic islet cells is 30-40 units (determined
by the needs of completely pancreatectomised
patients), and most insulin-deficient diabetics will
need 30-50 unit/day (0.5-0.8 units/kg) of insulin
(two-thirds in the morning and one-third in the
evening)
Initial treatment for a Type 1 (IDDM) patient, who
does not present with ketoacidosis, will usually be
outside hospital with two injections of
intermediate-acting insulin, or a mixed insulin Other
permu-tations, including soluble insulin before each meal,
I N S U L I N S I N C U R R E N T U S E
and an intermediate-acting insulin at bedtime, can follow later The following is a guide to initial daily dose requirements:
• 0.3 units/kg (16-20 units daily)
• increasing to 0.5 units/kg
The dose is adjusted according to the usual
moni-toring of blood5 glucose (or urine, if glucose meters are unavailable) Daily (total) dose increments should
be 4 units at 3-4-day intervals
If it is decided to give the patient only one injection per day, then 10-14 units of an intermediate-acting isophane suspension may be given Dose increments (4 units) may be made on alternate days Soluble insulin (neutral) may be added, or mixed (biphasic) insulins may be used, according to the patient's response
When stable, patients usually receive either a
biphasic insulin or a mixture of soluble, short-acting human insulin, and a longer-acting suspension of insulin with protamine or zinc
Excessive dose of insulin leads to overeating and obesity; it also leads to hypoglycaemia (especially nocturnal), that may be followed by rebound morning hyperglycaemia that is mistakenly treated
by increased insulin, thus establishing a vicious cycle (Somogyi effect)
Physical activity increases carbohydrate utilis-ation and insulin sensitivity, so that hypoglycaemia
is likely if a well-stabilised patient changes suddenly from an inactive existence to a vigorous life If this
is likely to happen the carbohydrate in the diet may
be increased and/or the dose of insulin reduced by
up to one-third and then readjusted according to need This is less marked in patients on oral agents See also Selection of therapy and Ketoacidosis (below)
ADVERSE EFFECTS OF INSULIN
Adverse effects of insulin are mainly those of overdose.6 Because the brain relies on glucose as its
5 The normal (fasting) blood glucose range is 3.9-5.8 mmol/1 (70-105 mg/100 ml).
6 Suicidal overdose (in diabetics) is well recorded Surgical excision of the skin and subcutaneous tissue at the injection site of an enormous dose of long-acting insulin has been used effectively.
685
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source of energy, an adequate blood glucose
con-centration is just as essential as an adequate supply
of oxygen, and hypoglycaemia may lead to coma,
convulsions and even death (in 4% of diabetics
under 50 years of age)
It is usually easier to differentiate
hypogly-caemia from severe diabetic ketosis than from other
causes of coma, which are as likely in a diabetic as
in anyone else It is unsound to advocate blind
administration of i.v glucose to comatose diabetics
on the basis that it will revive them if they are
hypoglycaemic and do no harm if they are
hyper-glycaemic A minority of comatose insulin-dependent
diabetics have hyperkalaemia and added glucose
can cause a brisk and potentially hazardous rise in
serum potassium (mechanism uncertain), in contrast
to nondiabetics in whom glucose causes a fall in
serum potassium
Hypoglycaemia may manifest itself as disturbed
sleep (nightmares) and morning headache For
details of treatment see below
Other adverse reactions to insulin are lipodystrophy
(atrophy or hypertrophy) at the injection sites (rare
with purified pork and human insulin), after they
have been used repeatedly These are unsightly, but
otherwise harmless The site should not be used
further, for absorption can be erratic, but the patient
may be tempted to continue if local anaesthesia has
developed, as it sometimes does Lipoatrophy is
probably allergic and lipohypertrophy is due to a
local metabolic action of insulin Local allergy also
is manifested as itching or painful red lumps
Generalised allergic reactions are very rare, but
may occur to any insulin (including human) and to
any constituent of the formulation Change of brand
of insulin, especially to highly purified preparations
(or to one with a different mode of manufacture)
may rectify allergic problems But zinc occurs in all
insulins (though very little in soluble insulin) and
can be the allergen
TREATMENT OF A HYPOGLYCAEMIC
ATTACK
Prevention depends very largely upon patient
education, but it is an unavoidable aspect of
inten-sive glycaemic control Patients should not miss
meals, must know the early symptoms of an attack,
and always carry glucose with them.7 Treatment is
to give sugar, either by mouth if the patient can still swallow or glucose (dextrose) i.v (20-50 ml of 50% solution, i.e 10-25 g; this concentration is irritant especially if extravasation occurs and the veins of diabetics are precious, so compress the vein immediately after completion of injection; adminis-tration of 50-125 ml of 20% glucose is less throm-botic, if available The response is usually dramatic The patient should be given a meal to avoid relapse But if the patient does not respond within 30 min,
it may be because of cerebral oedema, which re-covers slowly and may require treatment with i.v dexamethasone If the patient has been severely hypoglycaemic or if very large amounts of insulin
or sulphonylurea have been taken, then 20% glucose should be given by i.v infusion Very severe attacks sometimes damage the central nervous system permanently (See also use of glucagon, below.) After recovery from a severe attack and eluci-dation of the cause, the patient's treatment regimen should be carefully reviewed with appropriate educational input
Hypoglycaemia due to other causes, e.g alcohol,
is treated similarly
INSULIN RESISTANCE AND HORMONES THAT INCREASE BLOOD GLUCOSE
Insulin resistance may be due to a decline in number and/or affinity of receptors (see above) or to defects
in postreceptor mechanisms
A diabetic patient requiring more than 200 units/day is rare and regarded as insulin resistant (occasional patients have needed as much as 5000 units/day) Insulin resistance has become much less frequent with the wide availability of purified, mono-component and human insulins If the requirement is acquired and genuine, it is due to antibodies binding insulin in a biologically inactive complex (though it can dissociate as with protein binding of drugs) De novo insulin resistance occurs
in a small number of genetic syndromes, e.g in combination with the skin condition acanthosis nigricans
7 In the early stages of insulin treatment, it can be very useful training to allow a patient to experience hypoglycaemia once
by delaying a meal.
Trang 9Where animal insulins are still in use, change to
a highly purified pork or human insulin may be
successful in reducing resistance Responsiveness
to insulin may sometimes be restored by
immuno-suppression, e.g an adrenocortical steroid
(pred-nisolone 20-40 mg/d) over weeks (or a few months),
to suppress antibody production Obviously, if this
is successful, insulin dosage will have to be reduced
in accordance with the unpredictable reduction in
antibodies Patients need to be carefully monitored
to avoid severe hypoglycaemia Ketoacidosis also
reduces the effect of insulin
Glucagon (i l / 2 4min) is a polypeptide hormone
(29 amino acids) from the a-islet cells of the
pan-creas It is released in response to hypoglycaemia
and is a physiological regulator of insulin effect,
acting by causing the release of liver glycogen as
glucose Glucagon has been used to treat
insulin-induced hypoglycaemia, but in about 45 min from
onset of coma the hepatic glycogen will anyway be
exhausted and glucagon will be useless Its chief
advantage is that, as it can be given s.c or i.m
(1.0 mg), glucagon can be used in a severe
hypoglycaemic attack by somebody, e.g a member
of the patient's family, who is unable to give an i.v
injection of glucose If a comatose patient does not
recover sufficiently in 20 min to allow oral therapy,
i.v glucose is essential Glucagon is ineffective in
substantial hepatic insufficiency
Glucagon has a positive cardiac inotropic effect
by stimulating adenylyl cyclase; it appears to have
value in acute overdose of (3-adrenoceptor blockers
(see Index)
Adrenaline (epinephrine) raises the blood sugar
by mobilising liver and muscle glycogen; it does
not antagonise the peripheral actions of insulin
Glycosuria and diabetic symptoms may occur in
patients with phaeochromocytoma
Adrenal steroids, either endogenous or exogenous,
antagonise the actions of insulin, although this effect
is only slight with the primarily mineralocorticoid
group; the glucocorticoid hormones increase
gluco-neogenesis and reduce glucose uptake and
util-isation by the tissues Patients with Cushing's
syndrome thus develop diabetes very readily and
O R A L A N T I D I A B E T E S D R U G S
may be resistant to insulin Patients with Addison's disease, hypothyroidism and hypopituitarism are abnormally sensitive to insulin action
Oral contraceptives can impair carbohydrate tolerance
Growth hormone antagonises the actions of insulin
in the tissues Acromegalic patients may develop insulin-resistant diabetes
Thyroid hormone increases the requirements for insulin
Oral antidiabetes drugs
Oral antidiabetes drugs are of two kinds:
sulphon-amide derivatives (sulphonylureas) and guanidine
derivatives (biguanides) They are used by 30% of all diabetics Unlike insulin they are not essential for life
Following the observation in 1918 that guanidine had hypoglycaemic effect, guanides were tried in diabetes in 1926, but were abandoned a few years later for fear of hepatic toxicity
In 1930 it was noted that sulphonamides could cause hypoglycaemia, and in 1942 severe hypo-glycaemia was found in patients with typhoid fever during a therapeutic trial of sulphonamide In the 1950s a similar observation was made during a chemotherapeutic trial in urinary infections This was followed up and effective drugs soon resulted The first sulphonylureas were introduced into clinical practice in 1954
MODE OF ACTION
Sulphonylureas block the ATP-sensitive potassium channels on the p-islet cell plasma membrane This results in the release of stored insulin in response to glucose They do not increase insulin formation Sulphonylureas appear to enhance insulin action on liver, muscle and adipose tissue by increasing in-sulin receptor number and by enhancing the post-receptor complex enzyme reactions mediated by insulin The principal result is decreased hepatic
687
Trang 10glucose output and increased glucose uptake in
muscle They are ineffective in totally
insulin-deficient patients and for successful therapy
prob-ably require about 30% of normal [3-cell function to
be present Their main adverse effects are
hypo-glycaemia and weight gain
Secondary failure (after months or years) occurs
due to declining f}-cell function and to insulin
resistance
Biguanides These agents have been in use since
1957 Metformin is the only biguanide in current use,
and is a major agent in the management of Type 2
diabetes Its cellular mode of action is uncertain but
the most important effect is reduction of hepatic
glucose production Other effects include
enhance-ment of peripheral insulin sensitivity increaseing
glucose uptake in peripheral tissues; biguanides are
ineffective in the absence of insulin Rare
com-plications are hypoglycaemia and lactic acidosis
Secondary failure is not a problem Metformin can
be used in combination with either insulin or other
oral hypoglycaemic agents
Thiazolidinediones Pioglitazone and rosiglitazone
reduce peripheral insulin resistance, leading to a
reduction of blood glucose concentration These
drugs stimulate the nuclear hormone receptor,
per-oxisome proliferator-activated receptor (PPARy),
which causes differentation of adipocytes.8 They
should be initiated only by a physician experienced
in treating Type 2 diabetes and should always be
used in combination with metformin or with a
sulphonylurea (if metformin is inappropriate) The
drugs can cause 3-4 kg weight gain in the first year
of use, with peripheral oedema in 3-4% of patients
Other adverse effects of the class have included
abnormal liver function, and relevant tests should
be monitored during the first year
8 The importance of PPARyin insulin sensitivity was
confirmed with the finding, in Cambridge, of two families
presenting with severe insulin resistance in whom rare
mutations of the PPARy gene caused loss of PPARy activity
(Barroso I, Gurnell M, Crowley VE, et al 1989 Dominant
negative mutations in human PPARy associated with severe
insulin resistance, diabetes mellitus and hypertension.
Nature 402: 880-882.)
INDIVIDUAL DRUGS
Absorption from the alimentary tract is good for all the oral agents It is advisable to take drugs -30 min before a meal These three groups of drugs are effective only in the presence of insulin If a patient fails to respond to one drug, response to another as single treatment is unlikely Proceeding to a com-bination of drugs from different classes may then be effective
Sulphonylureas (see also Table 35.1)
Several sulphonylureas are available Choice is determined by the duration of action as well as the patient's age and renal function, and unwanted effects The long-acting sulphonylureas, e.g gliben-clamide, are associated with a greater risk of hypoglycaemia; for this reason they should be avoided in the elderly for whom the shorter-acting alternatives, such as gliclazide or tolbutamide, should be used As chlorpropamide is both long-acting and has more unwanted effects than the other sulphonylureas (see below) it is no longer recommended In patients with impaired renal function, gliclazide, glipizide or tolbutamide are preferred since they are not excreted by the kidney Generally, it is prudent to start at the lowest recommended dose in order to minimise risk of hypoglycaemia
TABLE 35.1 Principal oral antidiabetes drugs Drug
Sulphonylureas glibeclamide gliclazide glipizide glimepiride Biguanide metformin Thiazolidinedione rosiglitazone pioglitazone Meglitinide repaglinide nateglinide a-glucosidase inhibitor acarbose
Total daily dose (mg)
2.5-20 40-320 2.5^tO
1-6
500-3000
2-8
15-30 0.5-16 60-180
50-300
Dosing schedule (doses/day)
1-2 1-2 1-2 1 2-3 1-2 1 3 3 3
Duration
of action
(h)
12-24 12-24 12-24 16-24
8-12
12-24 16-24
3^t 2-3 3-4
Other sulphonylureas include tolbutamide,gliquidone, glibornuride, tolazamide.