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352 Chapter 14 Diabetes mellitus and obesity
insulin, as well as promoting -cell proliferation. GLP-1
also inhibits glucagon release by -cells. GIP also aects
adipocytes by stimulating lipoprotein lipase activity,
causing increased uptake of fatty acids and enhancing
lipogenesis.
14.2 Diabetes mellitus
Diabetes mellitus is the most common endocrine
disorder. It is a chronic incurable condition, which results
when the regulatory inuence of insulin on blood glucose
levels is either lost or compromised. It can be caused by
absolute or relative insulin deciency (reduced
production, or loss of cellular responsiveness to insulin,
termed insulin resistance). e characteristics of the
condition arise from the consequent disruptions to
metabolism. Glucose is overproduced by the liver through
gluconeogenesis and glycogenolysis, and underutilized
by insulin-dependent tissues (principally adipose tissue
and skeletal muscle); hyperglycaemia (raised blood
glucose levels) ensues. ere is a diversion of glucose
from insulin-dependent pathways to those not requiring
the hormone. e consequent rise in intracellular glucose
concentration in these insulin-independent tissues is
responsible for many of the symptoms and pathological
features associated with the disease (see below).
Glucose in the blood is ltered by the kidneys and then
actively reabsorbed in the proximal tubule by sodium–
glucose co-transporter proteins (SGLTs), principally
SGLT-2; in a healthy subject glucose is not present in the
urine. In a diabetic patient, however, the concentration of
glucose in the glomerular ltrate can reach a level where
it saturates the transporters, and glucose is excreted
(glycosuria). (e renal threshold for glucose absorption
from the blood is around 10 mmol/l.) e retained
glucose in turn leads to an increased volume of urine by
osmotic diuresis (polyuria),2 which promotes thirst.
If diabetes is not managed, the metabolic disturbances
arising from lack of blood glucose control lead to serious
complications (see Section 14.3); the condition is
associated with signicant morbidity and mortality.
2 e increased volume of sweet urine is the feature that gives the
condition its name: diabetes, meaning ‘to siphon’, refers to the large
quantities of urine, and mellitus means ‘sweet/honeyed’. Diabetes
mellitus should not be confused with another endocrine condition,
diabetes insipidus. is results from an insuciency in secretion of the
posterior pituitary hormone antidiuretic hormone (see Section P4.2 of the
Introduction to Part 4). e condition is characterized by the passing of an
excessive volume of very dilute urine—hence insipidus, meaning ‘weak’.
e incretins have a very short duration of action in the
body (the half-life of GLP-1 is ~2 minutes), as it is rapidly
inactivated by dipeptidyl peptidase 4 (DPP-4). Incretinbased therapy for diabetes involves incretin mimetics and
DPP-4 inhibitors.
14.2.1 Classification of diabetes mellitus
Diabetes is classied based on aetiology. ere are two
main types as discussed below; key dierences between
them are summarized in Table 14.2.
Type I diabetes mellitus
In type I diabetes mellitus there is an absolute deciency
of insulin. is most commonly arises when the insulinsecreting -cells of the pancreas are destroyed through
autoimmune disease. is T-cell-mediated destruction
may be initiated in some, but not all, cases by an
inappropriate immune response to viral or bacterial
infection. Genetic factors also appear to play a role in the
development of type I diabetes. ere are wide variations
across dierent ethnic and geographical populations, with
northern European countries (including Scandinavian
countries and the UK) showing particularly high rates.
e condition usually manifests before the age of 20, and
symptoms are often severe and develop very rapidly.
Suerers of type I diabetes are dependent on exogenously
administered insulin (the condition was formerly known
as insulin-dependent diabetes). Without it, patients will
die either from complications of extreme hyperglycaemia,
or from diabetic ketoacidosis.
e incidence of type I diabetes is much lower than that
of type II, accounting for around 5–20% of all cases of
diabetes.
Type II diabetes
In type II diabetes mellitus there is a relative deciency of
insulin, caused either because the pancreas is unable to
produce sucient insulin to meet the body’s demands, or
through decreased responsiveness of tissues to the
hormone (insulin resistance). e condition is often, but
not exclusively, linked to obesity, where insulin resistance
is a feature. (Around 20% of patients with type II diabetes,
however, are not overweight.) Incidence rises with age,
and the inuence of genetic factors is stronger than in
type I diabetes.
14.2 Diabetes mellitus 353
Table 14.2 Features of diabetes mellitus
Type I diabetes Type II diabetes
Prevalence 5–20% of all diabetes 80–95% of all diabetes
Alternative name Juvenile onset diabetes Adult onset diabetes
Insulin production Absent Variable
Initial treatment Insulin Diet followed by oral medication
Insulin treatment Necessary for survival Only needed if oral medication fails
Age of onset Usually under 30 Usually over 40
Body mass index at diagnosis Not overweight Often (but not always) overweight
Type II diabetes is by far the most prevalent type of
diabetes, accounting for around 80–95% of all cases. It
again shows distinct patterns of increased incidence in
certain ethnic groups and geographical regions; those of
South Asian, African, and African Caribbean origin are at
particular risk. Worldwide, the prevalence is increasing.
In countries with fast-developing economies, such as
China and India, the pace of this increase is alarming,
reaching over 10% of the population of some areas in just
a few decades.
e link between type II diabetes and obesity is clear cut;
the prevalence in non-obese populations is estimated to
be 1–3%, rising steeply in more obese societies, e.g. over
9% in the USA. (Highly unusually for a non-infective
disease, diabetes has been designated an epidemic by the
Centres for Disease Control and Prevention (CDC) in the
USA.) As obesity rates continue to increase, the numbers
of people aected by the condition are set to rise, and the
already considerable healthcare burden on society will
increase still further.
In the rst stages of the development of type II diabetes,
tissues which normally respond to insulin lose their
sensitivity to the hormone. Obesity is a contributing
factor to the development of this insulin resistance. (A
cluster of features known as metabolic syndrome—
insulin resistance, obesity, hyperglycaemia, and
dyslipidaemia (high circulating triglycerides, cholesterol,
and low density lipoproteins)—is thought to be a
predecessor of type II diabetes.) In the obese state the
amount of triglyceride consumed exceeds the storage
capacity of the adipose tissue, and fat begins to
accumulate in other tissues, notably the liver and skeletal
muscle. e deranged metabolism of fats interferes with
the signal transduction pathways activated by insulin,
ultimately reducing the ability of the insulin receptor
substrates to propagate the insulin signal; the tissues
become resistant to the presence of insulin. In an attempt
to regain insulin action, the pancreas responds by
synthesizing and releasing greater amounts of insulin
(hyperinsulinaemia). During this pre-diabetic stage, the
high concentration of insulin, and more importantly the
co-secreted amylin, form aggregates in the vicinity of the
cells, causing long-term damage and reducing their
ability to release hormone. Eventually the -cells
succumb and die. e impairment in insulin secretion
develops progressively over a sustained period of time,
and if it is allowed to continue, type II diabetes will ensue.
(Type II diabetes mellitus was formerly known as
non-insulin-dependent diabetes—given that a signicant
number of patients with type II diabetes require insulin as
the disease progresses, this terminology is misleading
and is no longer favoured.)
Gestational diabetes
A third type of diabetes mellitus, gestational diabetes
mellitus, is associated with pregnancy. It aects up to 10%
of pregnant women who have not previously been
diagnosed as diabetic. Onset is typically between the 24th
and 28th weeks of pregnancy, and the condition usually
resolves after the birth, although there is an increased risk
of subsequently developing type II diabetes. e exact
cause remains uncertain, although it is thought that
placental hormones may lead to insulin resistance.
Babies born to mothers who have suered gestational
diabetes have additional fat due to the abundance of
circulating glucose, which crosses the placenta. e blood
glucose level at birth may be low, because of increased
levels of insulin produced by the newborn’s pancreas.
Such babies are possibly at increased risk of later
becoming obese and of developing type II diabetes.
354 Chapter 14 Diabetes mellitus and obesity
14.3 Complications of diabetes
Untreated or under-managed diabetes results in a range
of complications, which are the main cause of mortality
and morbidity associated with the disease. Management
of these diabetic complications also accounts for most of
the high healthcare costs associated with the condition.
e most common complications can be grouped into
acute complications and long-term complications.
14.3.1 Acute complications of diabetes
Acute complications are more common in type I diabetes,
and are often metabolic emergencies that can be lifethreatening. Diabetic ketoacidosis can result from severe
type I diabetes, as a result of the uncontrolled breakdown
of fats and proteins. is generates a ketogenic state,
where large amounts of acetyl CoA are channelled into
the production of ketone bodies (acetoacetic acid and
-hydroxybutyric acid) in the liver. ese molecules,
which are moderately strong acids, can be used as sources
of energy, but in the diabetic state they are produced far in
excess of the body’s ability to utilize them. ey cause
nausea and vomiting, and seriously disturb the acid–base
balance, leading to acidosis. e patient hyperventilates
in an attempt to correct the acidosis, and the breath may
smell of acetone (like pear drops/nail-varnish remover)
owing to the excreted ketones. Coupled with dehydration,
the decreased plasma pH can result in the patient going
into a coma; diabetic ketoacidosis is a medical emergency
with a high mortality rate.
Diabetic ketoacidosis is rarely seen in type II diabetes, as
insulin is usually suciently active to prevent excessive
lipolysis in the liver and adipose tissue.
14.3.2 Long-term complications of
diabetes
Sustained hyperglycaemia can cause damage to a wide
range of organs and cells through a variety of mechanisms.
e cells most aected are those which are not dependent
on insulin for glucose transport. eir rate of uptake is
largely governed by the concentration gradient for glucose
across the cell membrane, which is much greater in the
hyperglycaemic state. ese cells include the kidney, red
blood cells, nerves, liver, blood vessels, and the lens of the
eye. In such tissues the elevated glucose levels inside the
cells can cause non-enzymatic bonding of glucose with
other molecules (e.g. fats, proteins, and nucleic acids) to
produce advanced glycation end-products. Important
examples include haemoglobin in red blood cells, and
structural proteins such as collagen and elastin. ese
advanced glycation end-products show altered function,
and underlie many of the pathological changes that are
characteristic of long-term diabetes. For instance,
collagen proteins become crosslinked by the transformed
sugar groups, aecting turnover and function. Glycated
molecules thicken basement membranes, and lead to
alterations in permeability and transport mechanisms of
cells. e cells of the kidney are particularly susceptible,
leading to defective ltration and kidney damage
(nephropathy). Accumulation of the advanced glycation
end-products can also give rise to an inammatory state.
Glycation of the -crystallin protein in the lens of the eye
can lead to cataract formation.
Glycated haemoglobin (HbA1C) has an altered anity for
oxygen, and this may compromise the function of tissues
through reduced oxygen supply (hypoxia). (HbA1C is a
convenient marker used in diabetes management; see
Section 14.5).
A high concentration of glucose inside cells promotes the
sorbitol pathway, which diverts glucose into fructose. e
rst step in this pathway is catalysed by aldose reductase and
generates sorbitol. As this enzyme is easily saturated, sorbitol
accumulates inside cells. Metabolism of glucose via this
pathway is favoured by the high NADPH/NADP+ ratio in
aected cells, due to the decrease in reductive synthetic
reactions such as fatty acid synthesis. e accumulation of
sorbitol causes disturbances to the phospholipid bilayer, and
osmotic disturbance. In the eye this compounds the damage
to the lens, and further promotes cataract formation.
e vascular endothelium is aected at an early stage by
these processes. An increase in vascular permeability and
loss of the vasodilatory inuence of nitric oxide are key
features, and are involved in the pathogenesis of both
microvascular and macrovascular complications
associated with diabetes.
Macrovascular disease
e increased mortality associated with diabetes largely
results from complications associated with damage to
large blood vessels caused by the high levels of circulating
glucose. e blood vessels aected include the coronary
arteries; the risk of cardiovascular disease, itself the
leading cause of death in developed countries, is two to
four times higher in diabetic patients.
14.4 Diagnosis of diabetes 355
As describedin Section 14.1.3, under post-prandial
conditions (after a meal) insulin induces the adipose
tissue enzyme, lipoprotein lipase. is enzyme is
responsible for hydrolysing the triglyceride component of
circulating chylomicrons and very low density lipoprotein
(VLDL), the fat particles that appear in the circulation
soon after a meal (see Chapter 6). e released fatty acids
are rapidly absorbed into the fat cells, where they
recombine into triglycerides to be stored. In the absence of
insulin, the circulating fats persist in the blood and an
imbalance is created in the levels of circulating
lipoproteins. Hyperlipidaemia ensues, and encourages the
abnormal deposition of fat into arterial walls, facilitated by
the compromised endothelial lining, and promoting the
atherosclerotic process (see Chapter 6, Box 6.1).
Microvascular disease
Damage to smaller blood vessels (microvascular disease)
caused by hyperglycaemia results in complications
involving the eyes, kidneys, and nerves.
Diabetic retinopathy is the leading cause of blindness in
people aged under 60 in developed countries, and aects
over 80% of patients who have had diabetes for more than
20 years. Changes to the retinal capillaries occur
progressively, with swelling and leakage of uid. New blood
vessels develop and scar tissue forms, which can lead to
retinal detachment with loss of vision. e changes can be
symptomless until the deterioration is well advanced; eye
screening is therefore a key part of diabetic care.
Diabetes mellitus is the commonest cause of chronic renal
failure (nephropathy). e exact mechanism whereby high
blood glucose levels lead to kidney damage has not been
claried, but the outcome is compromised ltration and
the appearance of protein in the urine. is is in turn
associated with an increased risk of cardiovascular disease.
e damage is exacerbated by high blood pressure.
Prolonged hyperglycaemia predisposes to nerve damage,
and can lead to the progressive loss of peripheral nerve
bres, including sensory, autonomic, and motor nerves
(diabetic neuropathy). e accumulation of sorbitol is
implicated in the degenerative process, and high blood
pressure and elevated levels of triglycerides compound
the damage. Dysfunction of sensory neurons is
commonly experienced in the feet, and can progress to a
complete loss of sensation. Dysfunction in the autonomic
nervous system can lead to loss of bladder function and to
impotence. Patients with diabetic neuropathy can
sometimes experience profound pain which can cause
considerable morbidity; this pain often does not respond
to conventional analgesia (see Chapter 20, Section 20.3.3,
for information on treating neuropathic pain).
e combined eects of neuropathy and macrovascular
damage can lead to diabetic foot problems, with the
development of foot ulcers which can easily become
infected, and can even necessitate amputation. e loss
of sensation in the region is compounded by the reduced
blood supply because of the macrovascular damage to
local blood vessels. e ischaemia that results limits the
supply of oxygen and nutrients required for the healing
process. Andreas, the ctional patient in Workbook 11,
presents with this complication of diabetes—a
neuroischaemic ulcer on a toe.
14.4 Diagnosis of diabetes
Many countries, including the UK, follow the World
Health Organization’s criteria for the diagnosis of
diabetes mellitus.
1. Symptoms of diabetes (polyuria, abnormal thirst,
unexplained weight loss) plus:
• serumglucoselevel11.1 mmol/l taken randomly, or
• serumglucoselevel>7.0 mmol/l for fasting patients, or
• serumglucoselevel11.1 mmol/l 2 hours after a
glucose tolerance test (see below).
2. Where no symptoms are present, at least two serum
glucose measurements made on dierent days must be
within the diabetic range for diagnosis to be conrmed.
Lower levels (e.g. random levels between 5.6 and 11
mmol/l) may indicate the pre-diabetic state of reduced
glucose tolerance. In these cases a patient may be
requested to undergo a glucose tolerance test; overnight
fasting is followed in the morning by measurement of
plasma glucose levels before and after ingestion of 75 g of
glucose, usually in the form of a drink.
When the plasma level of glucose exceeds its renal
threshold (around 10 mmol/l), glucose appears in the
urine (glycosuria). is can be measured using a simple
dipstick that changes colour in response to the presence
of glucose; this should not, however, be used for
diagnostic purposes.
356 Chapter 14 Diabetes mellitus and obesity
14.5 Drug treatment of diabetes mellitus
e two main groups of pharmacological agent used are
insulin and antidiabetic drugs. Exogenous insulin is
necessary for survival in type I diabetes patients, given in
a pattern that most closely mimics the release of insulin in
the patient.
Oral antidiabetic drugs are the drugs of choice in the
initial stages of type II diabetes. As the disease progresses,
the function of the pancreatic -cells declines, and insulin
therapy often becomes necessary.
Persistent high blood glucose leads to increased glycation
of proteins including haemoglobin (see above). e
glycated haemoglobin level (HbAC1) is the key
parameter used to clinically monitor long-term glycaemic
control in patients diagnosed with diabetes. It gives a
picture of how much glucose has been in the blood for the
last 2–3 months (the lifespan of a red blood cell), and is an
extremely useful tool for checking compliance and the
long-term response to treatment. Target levels for HbA1C
set in the UK by the National Institute for Health and
Care Excellence (2015) are <7% for type II diabetic
patients and <6.5% for those with type I diabetes.
At home, control of blood glucose levels is monitored in
all patients with type I diabetes and some with type II,
using a simple handheld meter which takes
measurements from a drop of blood.
14.5.1 Insulin treatment
Nowadays nearly all insulin for clinical use is
manufactured using genetic engineering and
recombinant DNA technologies, all but replacing the
animal-derived products previously used.
Insulin cannot be taken orally as its peptide structure
would be destroyed in the gut. e most common method
of administration is by subcutaneous injection
administered by the patient; intravenous and
intramuscular routes are used in an emergency. Insulin
preparations are grouped according to speed of onset or
duration of action.
Short-acting insulin preparations
Short-acting insulin preparations contain soluble insulin
mixed with zinc (e.g. Actrapid). is form of insulin is
usually administered subcutaneously, approximately
30–45 minutes before meal times, or intravenously for
urgent lowering of blood glucose (e.g. in ketoacidosis). A
pump that delivers the insulin through a subcutaneous
needle can be used for patients who have poor glycaemic
control; the rate of delivery can be increased just before a
meal, and is an eective means of delivery in motivated
patients.
Rapid-acting insulin preparations
ree rapid-acting insulins have been developed, which
are recombinant human insulin analogues in which one
or two amino acids are switched through genetic
engineering.
1. Insulin aspart, which has a substitution of the amino
acid proline by aspartic acid at position 28 on the
B-chain.
2. Insulin lispro, in which the amino acids proline and
lysine at positions 28 and 29 on the B-chain are
inverted.
3. Insulin glulisine where the amino acid asparagine at
position 3 on the B chain is replaced by lysine, and the
lysine in position 29 is replaced by glutamic acid.
Ordinary soluble insulin forms into hexamers which must
break apart into monomers in order to be absorbed into
the bloodstream. e modications in the side chains of
insulin aspart, lispro, and glulisine ensure they remain as
monomers, thus speeding up the rate of absorption
(Figure 14.1). e rapid onset of action of these insulin
preparations means that they can be given just before
eating. eir short duration of action reduces the risk of
the patient becoming hypoglycaemic.
Intermediate and long-acting insulins
ese formulations contain a mixture of insulin and other
ingredients (protamine, cationic proteins, or zinc ions)
that modify the pharmacokinetics of the hormone. is
gives rise to intermediate insulins with a gradual onset of
action (up to 2 hours) and long duration (up to 20 hours).
Long-acting insulins have an onset of action within
4 hours, and the duration of action is prolonged up to
36 hours.
Insulin glargine and insulin detemir are both long-
acting insulins with a duration of action around 24 hours.
ey have the most predictable and attest prole of
action without pronounced peaks. Insulin detemir has a
14-carbon fatty acid (myristic acid) bound to the B chain,
which promotes its binding to the plasma protein
14.5 Drug treatment of diabetes mellitus 357
Insulin aspart, insulin lispro, and insulin glulisine
Regular soluble insulin
Subcutaneous tissue
Blood vessel
Figure 14.1 Absorption of regular insulin compared with insulin aspart, insulin
lispro, and insulin glulisine.
albumin. Dissociation of the hormone from albumin is
slow, and gives rise to a prolonged eect; it is given once
or twice daily. e binding to albumin also means that it
has to be given at a higher dose.
Insulin glargine has two additional arginine residues at
the C terminus of the B chain, and a glycine replacing an
arginine in the A chain. ese structural changes to the
insulin molecule render it less soluble at physiological pH
than ordinary insulin. When injected it forms microprecipitates, which give rise to a slow rate of absorption. It
is given once daily, in the evening.
ese dierent formulations of insulin are combined in
regimes individualized to suit the patient. For instance,
those with type I diabetes may inject a soluble fast-acting
insulin at mealtimes, supplemented by a once- or
twice-daily injection of an intermediate or long-acting
insulin to give basal control of blood glucose levels. e
aim is to mimic the physiological release of insulin as
closely as possible, thereby avoiding deleterious
uctuations in blood glucose concentrations.
Adverse effects of insulin
e two most common adverse eects are local injection
site reactions and, much more seriously, hypoglycaemia.
Local eects are caused by repeated injections in the same
spot, and can lead to lipodystrophy (degeneration of
adipose tissue) and scarring. is can look unsightly, and
may also alter the absorption of insulin. To avoid this
occurring patients are advised to rotate the site of injection.
Hypoglycaemia is a potentially life-threatening side
eect of insulin treatment and of some of the longeracting oral diabetic drugs (see below). It may also result
from changes to eating or exercise patterns, or to
consumption of alcohol. e symptoms of hypoglycaemia
are caused by the physiological response to the lowered
blood glucose levels, and are principally mediated by
release of glucagon, noradrenaline, and adrenaline. Signs
include trembling, tachycardia, palpitations, drowsiness,
and confusion. Patients need to be able to recognize these
symptoms, which alert them to the need to consume
carbohydrates. is is particularly important at nighttime, as nocturnal hypoglycaemia can result in death,
especially in type I diabetes patients (dead in bed
syndrome). Alcohol intoxication is a common reason for
hypoglycaemic symptoms to go unnoticed. Many of these
symptoms result from autonomic nervous system
activation and are suppressed through use of -blockers;
these drugs should be used with caution in diabetic
patients.
Mild/moderate hypoglycaemia can be corrected with oral
administration of glucose (e.g. as a glucose-containing
drink, or glucose tablet). In severe hypoglycaemia the
patient may become unconscious, presenting a medical
emergency. In this case parenteral therapy with glucagon
or glucose is required. Whereas glucose is given as an
intravenous infusion, glucagon can be delivered by
intramuscular or subcutaneous injection, enabling its
administration by a carer or medical personnel to an
unconscious patient.
358 Chapter 14 Diabetes mellitus and obesity
OO
O
O
14.5.2 Antidiabetic drugs
e management of type II diabetes involves a variety of
drugs with wide-ranging mechanisms of action as
detailed below.
Biguanides
Metformin, the only biguanide drug used clinically to
treat diabetes, is found in the French lilac plant, and has
been used for centuries in traditional medicines. It is
classied as an insulin receptor sensitizer, potentiating the
eects of insulin at its cellular targets (i.e. it reduces insulin
resistance). e identity of the molecular target conferring
benet in diabetes is unclear, but it achieves a decrease in
blood glucose levels through a variety of eects:
• reduced hepatic glucose production through inhibition
of gluconeogenesis, and decreased hepatic
glycogenolysis
• increased uptake of glucose into insulin-dependent
tissues (particularly muscle)
• reduced glucose absorption from the gastrointestinal tract
• reduced fatty acid oxidation.
Metformin has the additional benecial eect of lowering
circulating LDL and VLDL levels.
Some of the eects are thought to be due to metformin
stimulating AMP-activated protein kinase (AMPK), an
enzyme involved in insulin signalling and hepatic
glucose production. Activation of AMPK also increases
translocation of insulin-sensitive glucose transporters
(GLUT-4), resulting in glucose uptake by skeletal muscles.
Metformin is an eective antidiabetic drug. It does not
cause hypoglycaemia, and it is not associated with weight
gain; it may, in fact, have a benecial eect in
encouraging weight loss in some patients. It is the
rst-line choice of drug for many patients with type II
diabetes, and the drug of choice for overweight patients.
e most common side eects of metformin are
gastrointestinal disturbances, such as distension and
pain, nausea, and diarrhoea. Adverse gastric eects can
be lessened by taking the tablets with food, and by slowly
increasing the dose.
e most serious side eect of metformin is lactic acidosis;
fatal episodes with earlier biguanide drugs resulted in
their withdrawal from the market. Under aerobic
conditions, pyruvate, the end-product of glycolysis, is
metabolized to acetyl CoA. is then enters the citric acid
cycle for oxidative decarboxylation to generate ATP. In
anaerobic conditions, when tissues are poorly perfused,
pyruvate is instead shunted into synthesis of lactate (lactic
acid). is accumulates and causes a drop in plasma pH
(acidosis). Metformin is eliminated unchanged in the
urine, and lactic acidosis is therefore more likely in renal
impairment where drug elimination is reduced. It is also a
risk where liver function is impaired, and in conditions
associated with hypoxia (e.g. pulmonary disease,
myocardial infarction). Lactic acidosis can rapidly become
fatal, and patients should be aware of the signs
(tachycardia, lethargy, cramps, abdominal pain, etc.).
Long-term use of metformin is associated with the
malabsorption of vitamin B12.
Sulfonylureas
Sulfonylureas are insulin secretagogues (agents that
cause insulin secretion), and require there to be some
functioning -cells in order to be eective; they are
therefore not used in the later stages of the disease where
-cell function is lost. ey are structurally related to
sulphonamide antibiotics (e.g. sulfamethoxazole; see
Figure 14.2).
e main sulphonylureas used are the rst-generation
agents chlorpropamide and tolbutamide, and the
second-generation agents glibenclamide, glimepiride,
gliclazide, and glipizide which have improved side-eect
proles. ese drugs bind to specic high-anity binding
sites on the ATP-dependent K+ channels in the pancreatic
-cells (see Box 14.1). e channels are blocked, leading to
depolarization of the cells and the continuous release of
insulin. is secretagogue eect is independent of the
presence of glucose (in contrast with the incretin mimetics;
O
N
S
N
H
N
H
2
Sulfamethoxazole
Figure 14.2 Comparison of a sulfonamide antibiotic and a
sulfonylurea.
O
S
NHN
H
Tolbutamide
14.5 Drug treatment of diabetes mellitus 359
Table 14.3 Hypoglycaemic risk with sulfonylureas
Highest risk Intermediate
Chlorpropamide
Glibenclamide
a
Immediate-release formulation presents low risk; sustained-release
formulation presents intermediate risk.
risk
Glimepiride Glipizide
Lowest risk
Gliclazide
a
see below). ey may also increase the sensitivity of tissues
to insulin. Sulfonylureas are cheap and eective
antidiabetic agents, proved to confer cardiovascular benet
in the long term to diabetic patients, which explains their
widespread use in diabetes (second only to metformin,
with which they can be combined). A disadvantage of their
use arises from their slow onset of action (around 3–4
hours), which makes them ineective at tackling the most
damaging post-prandial peak of glucose.
As sulfonylureas stimulate a continuous release of
insulin irrespective of glucose level, the most common
adverse eect associated with their use is hypoglycaemia.
e relative risk increases with duration of action, and is
greatest for the rst-generation agents (see Table 14.3).
eir hypoglycaemic eects lead to increased appetite,
and patients on sulfonylureas have a tendency to gain
weight; drugs of this class are therefore not rst choice for
those who are already overweight. ey are also not
recommended for elderly patients who are more sensitive
to hypoglycaemia. Chlorpropamide is associated with the
most adverse eects, including a disulram-type reaction
when taken with alcohol (see metronidazole in
Chapter 22), and is now rarely used.
Meglitinides
ere are two drugs in this class: nateglinide and
repaglinide. Like sulfonylureas, they are insulin
secretagogues, acting in a similar fashion to block the
ATP-sensitive K+ channels but binding at a distinct site (see
Box 14.1). ey too sensitize the glucose-stimulated release
of insulin. ese drugs have a more rapid onset, and shorter
duration of action than sulfonylureas, with an elimination
half-life of around 1 hour. eir pharmacokinetic properties
mean that they can be taken immediately before a meal,
aording the patient greater exibility in terms of
mealtimes. Meglitinides appear to have a reduced risk of
hypoglycaemia, and are less likely to cause weight gain than
sulfonylureas. ey have been shown to have a similar
ecacy to metformin and sulfonylureas. ey can be used
in combination with metformin, and repaglinide can be
give as monotherapy for patients who are not overweight, or
where metformin is not suitable or not tolerated.
Thiazolidinediones(glitazones)
e only glitazone used in the treatment of diabetes in the
UK is pioglitazone; earlier drugs (troglitazone and
rosiglitazone) have been withdrawn due to serious
cardiovascular and liver toxicity.
Pioglitazone shows close structural resemblance to
brates (see Chapter 6, Section 6.2.4), and has a similar
mechanism of action. It is a selective agonist at the
peroxisome proliferator activator receptor (PPAR), a
class of intracellular (nuclear) receptors which, when
activated, serve as transcription factors. (Fibrates act at the
related PPAR receptor.) e PPAR receptors are
activated by endogenous unsaturated fatty acids and some
inammatory mediators, and are mainly found in adipose
tissue. eir stimulation increases the transcription of a
large number of genes encoding proteins involved in fat
metabolism in adipocytes. ese include genes involved
in insulin signalling, including lipoprotein lipase, fatty
acid transporter protein, and the insulin-sensitive glucose
transporter GLUT-4, amongst others.
e overall eects of pioglitazone are:
• decreased glucose release by the liver
• a net increase in storage of fatty acids and a reduction
in circulating fatty acids
• reduced insulin resistance in adipose tissue, skeletal
muscle, and liver with promotion of glucose uptake and
utilization
• reduced levels of triglycerides are also seen in the liver
and skeletal muscle.
Pioglitazone also aects the levels of adipokines—
signalling molecules released from adipose tissue,
including hormones and cytokines with a wide range of
eects. Release of resistin and the inammatory mediator
tumour necrosis factor- are decreased by pioglitazone,
whereas the level of the benecial adiponectin is raised.
(Adipokines are described in more detail in Section 14.7.3.)
e ecacy of pioglitazone is less than that of metformin
or sulfonylureas. Its eects, though, are additive with
either when used in dual therapy; all three can be
combined in triple therapy. Importantly, because
pioglitazone does not lead to insulin secretion, it does not
cause hypoglycaemia.
Pioglitazone has a number of important adverse
reactions. e inuence on fat cell proliferation and
dierentiation leads to weight gain. e fat distribution
does, however, favour peripheral subcutaneous fat over
360 Chapter 14 Diabetes mellitus and obesity
the more harmful visceral fat (see Section 14.7.2). It also
aects Na+ channels in the distal collecting ducts of the
kidney, leading to sodium reabsorption and uid
retention. As a result, it is contraindicated in patients with
heart failure or those with a history of the condition.
Some earlier glitazones were withdrawn because of
hepatic toxicity, and liver function should be monitored
periodically while taking pioglitazone which has itself
been associated with changes to liver enzymes.
-Glucosidase inhibitors
e nal step in the conversion of ingested carbohydrates
to monosaccharides in the small intestine is catalysed by
the enzyme -glucosidase in the brush border of the
ileum. is enzyme is competitively and reversibly
inhibited by acarbose, which delays absorption of
glucose and results in a small but signicant reduction in
blood glucose levels. e drug is particularly useful in
reducing the post-prandial peak in glucose levels. (It
could theoretically be used for this purpose in type I
diabetes, although in practice it rarely is.) It also
signicantly improves dyslipidaemia, presumably by
interfering with the absorption of fats.
Acarbose is associated with gastrointestinal disturbance
to an extent that has limited its use. e adverse eects
result from the enhanced activity of gut ora as a
consequence of the increased availability of sugar
nutrients. is leads to bloating and atulence. e sugars
exert an osmotic pressure, retaining water in the gut and
leading to diarrhoea (see Chapter 13). ese eects can
be lessened or avoided by initiating the drug at a low
dose, and titrating up slowly.
Acarbose is an option for treatment of patients with type
II diabetes, most usually in combination with other oral
antidiabetic medications.
Incretin mimetics (glucagon-like peptide-1 receptor
agonists)
Drugs have been developed that mimic the endogenous
incretin glucagon-like peptide-1 incretins. Exenatide was
the rst to be marketed, and has been followed by
liraglutide and lixisenatide.
Exenatide is a synthetic form of exendin-4, a naturally
occurring analogue of GLP-1, found in the saliva of the
Gila monster lizard. It is resistant to degradation by
DPP-4, and therefore has a much longer half-life than
GLP (4 hours). It mimics all the eects of GLP-1 as set out
in Table 14.4, notably to increase the secretion of insulin.
It is important to note that GLP-1 potentiates insulin
secretion only when glucose is present. e mimetic
drugs are therefore very eective at controlling the
damaging post-prandial peak in glucose levels. GLP-1
also promotes proliferation of the insulin-secreting
-cells, an eect which is benecial in type II diabetes
where these cells become damaged as the disease
progresses (see Section 14.2.1). A further benet to
overweight patients is delayed gastric emptying, which
can lead to decreased food intake by promoting a feeling
of satiety, which is reinforced by the direct action of
GLP-1 on the appetite centres in the hypothalamus of the
brain (see Section 14.7.4).
Incretin mimetics are given by subcutaneous injection.
Exenatide is given by subcutaneous injection twice a day,
Table 14.4 Effects of the endogenous incretins
Tissue/organ Glucagon-like peptide-1 (GLP-1) Glucose-dependent insulinotropic peptide (GIP)
Pancreas
Adipocytes
Gastrointestinal tract
Skeletal muscle
Liver
Brain
Glucose-stimulated release of insulin
Synthesis of insulin
Proliferation of -cells
Secretion of glucagon from -cells
Lipogenesis Lipogenesis
Gastric emptying
Intestinal motility
Insulin resistance
Utilization of glucose
Glucose output
Deposition of fats
Food intake
Satiety
Glucose-stimulated release of insulin
Synthesis of insulin
Adipokine secretion
14.5 Drug treatment of diabetes mellitus 361
Bowman's capsule
Proximal
Distal
or as a modied-release preparation once a week.
Liraglutide and lixisenatide are given once daily.
GLP-1 receptor agonists are used in combination with
metformin and/or a sulfonylurea, often for patients
who are overweight. As they cause glucose-dependent
insulin release, hypoglycaemia is uncommon (unless
combined with a sulfonylurea). ey are associated
with a high incidence (up to 50% of patients) of
gastrointestinal upset, particularly nausea, although this
resolves with time. is adverse reaction is less
commonly encountered with the once-weekly exenatide
preparation. Because they slow gastric emptying, incretin
mimetics may aect the absorption of certain drugs (e.g.
some antibiotics).
Dipeptidyl peptidase 4 inhibitors (gliptins)
Gliptins, e.g. sitagliptin, vildagliptin, alogliptin,
linagliptin, and saxagliptin, are competitive inhibitors of
DPP-4 and thereby prolong the action of the endogenous
incretins. All are given orally once a day, except
vildagliptin, which is given twice daily. Although there are
some data supporting the use of gliptins as monotherapy,
the best evidence has come from trials combining them
with other oral hypoglycaemic drugs. ey are generally
well tolerated, with the major side eects being nausea
and hypoglycaemia (mainly when used with a
sulfonylurea). is class of drug is, however, relatively
new and long-term safety data are not yet available. One
advantage is that there is no apparent weight gain, unlike
glitazones and sulfonylureas.
Sodium–glucoseco-transporter2inhibitors(gliflozins)
As described earlier (Section 14.2) glucose is actively
reabsorbed in the proximal tubule of the kidney,
principally by the sodium–glucose co-transporter-2
(SGLT-2). is protein is targeted by a new class of
diabetic drugs: the gliozins (dapagliflozin,
canagliflozin, and empagliflozin). ese drugs are
reversible inhibitors of SGLT-2, reducing reabsorption of
glucose and favouring its excretion in the urine; the
amount excreted is in direct proportion to the level of
glucose in the plasma (Figure 14.3).
Glomerulus
+
K
+
Na
ATPase
Gliozins
Blood
Glucose
Na+Glucose
Na+Glucose
Lumen
GLUT2
SGLT2
tubule
SGLT2
Lumen
Loop of
Henle
tubule
Collecting
duct
Blood
Figure 14.3 Siteofactionforgliozins.
The reabsorption of glucose from the glomerular filtrate is mainly achieved by sodium–glucose co-transporter-2
(SGLT-2), located in the proximal convoluted tubule. Gliflozin drugs are reversible inhibitors of SGL-2, and so
reduce uptake of glucose from the filtrate. ATPase: Na+/K + exchanger.