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372 Chapter 14 Diabetes mellitus and obesity
O/E:
1) Ulcer is warm and pus-filled
2) Pedal (foot) pulses are absent
3) Pinprick sensation is absent
4) Patient is extremely lethargic
5) Temperature: 38.9°C (reference 37°C)
6) BP = 140/80 mmHg (reference < 140/90 mmHg)
7) BMI = 31 kg/m
Andreas’s ulcer has resulted from peripheral neuropathy and ischaemia to his toes. This is confirmed
by the absence of a pedal pulse and the lack of sensation when his toes are pricked with a pin.
His temperature is elevated as a result of infection in the ulcerated area.
Biochemistry:
1) Random blood glucose level 38 mmol/l (reference 3.5–10.0 mmol/l)
2) Glycated haemoglobin = 9.7% (reference 4–6%)
3) White cell count = 16 × 109/l (reference = 4–9.5 × 109/l)
Urine testing:
1) Ketones: negative
2) Glucose: positive
1) Andreas’s blood glucose level taken at random is extremely elevated, indicative of diabetes.
2) HbA1C is haemoglobin that has been modified through an irreversible reaction with glucose. This
gives a convenient index of glucose control over the past 120 days (the lifespan of a red blood
cell), and is less variable than blood glucose levels. Andreas’s glycated haemoglobin (HbA1C) level is
elevated, indicating that his blood glucose levels are poorly controlled.
2
3) Diabetic foot ulcers are prone to infection, explaining Andreas’s raised white cell count.
4) Ketone bodies appear in the urine in severe diabetes because of the uncontrolled breakdown of
fats and proteins in the liver, which generates ketone bodies (acetoacetic acid and
-hydroxybutyric acid). This leads to muscle wasting. If levels of ketone bodies accumulate,
ketoacidosis occurs which can be life-threatening. This is more common in type I diabetes.
Andreas’s urine ketone level is not elevated.
5) When the concentration of glucose in the blood exceeds the kidneys’ capacity for reabsorption
(around 10 mmol/l), glucose will appear in the urine. The glucose is accompanied by water, leading
to an increased urinary frequency.
Diagnosis: Type II diabetes mellitus, infected ulcerated toe
Plan:
• Send swabs and blood cultures from ulcer site to microbiology department
• Intravenous antibiotics to treat infection
• Start oral antidiabetic drug
• Start soluble insulin infusion until blood glucose level <11 mmol/l
WORKBOOK 11 Diabetes mellitus and obesity 373
The doctor explains to Andreas that he has had undiagnosed diabetes for a while. This has
already led to long-term complications like the ulcer, as well as immediate complications.
1) What is diabetes mellitus?
2) Explain the meaning of the following:
Glycaemia
Glycosuria
Ketonuria
3) What happens to blood glucose levels in diabetes?
4a) Which hormone is principally responsible for decreasing the post-prandial levels of glucose?
4b) Which hormone is principally responsible for increasing levels of blood glucose between meals?
4c) Where specifically are these two hormones synthesized?
5a) Elaborate the steps by which glucose stimulates the release of insulin.
5b) List two other stimuli for insulin secretion besides glucose.
After 2 days on the insulin infusion, Andreas is fed up and asks the doctor when it will be
discontinued. The doctor explains that he has been put on insulin because his blood glucose
level was extremely high. The insulin infusion will help to control his blood glucose, and is being
adjusted according to the current level. The doctor promises that once his blood glucose has
stabilized,theinsulinwillbestopped.
6a) What are the main cell types that depend on insulin for their uptake of glucose?
6b) How does insulin affect uptake in these cells?
7) What type of receptor does insulin act at?
8) What is the effect of insulin on the following?
Carbohydrate metabolism
Fat metabolism
Protein metabolism
The doctor explains to Andreas that his increased thirst and urinary frequency are symptoms of
the diabetes.
374 Chapter 14 Diabetes mellitus and obesity
9) How do increased urinary frequency and thirst come about in diabetes?
Andreas asks to see the doctor because he is worried about a severe diabetic complication he
has heard about called diabetic ketoacidosis. The doctor explains that this is unlikely with type
II diabetes, but that it is a possible complication in type I diabetes.
10a) What is type I diabetes? How does it differ from type II?
10b) Which drug is essential for treating type I diabetes?
10c) What is ketoacidosis?
10d) Why is ketoacidosis much less likely in type II than in type I diabetes?
The doctor talks to Andreas about the plans for his treatment. The insulin has been stopped as
his blood glucose levels are within the normal range. The antibiotic has been switched to oral.
The doctor tells Andreas that he will have to take medication for his diabetes. Initially it will be
tablets, but eventually he might need insulin. Andreas seems worried and tells the doctor that
he hates injections.
11) Why does insulin need to be injected?
12a) Insulin preparations are divided into three main groups according to speed of onset and duration of
action. What are the three main groups?
12b) Some insulin preparations are injected immediately before meals. Which class do they belong to,
and why are they used?
The doctor reassures Andreas that his type II diabetes can for now be controlled with tablets.
The pharmacist and doctor discuss Andreas’s therapy. Two drugs are discussed: metformin and
thesulfonylureagliclazide.Thepharmacistsaysthatgliclazidemaynotbethebestchoice
because of one of its side effects.
13) Which side effect of sulfonylureas means that gliclazide may not be the best choice for Andreas?
Hint: What is Andreas’s BMI?
14) What is the mechanism of action of gliclazide?
The doctor agrees with the pharmacist that metformin is a better choice, and it is prescribed for
Andreas.
WORKBOOK 11 Diabetes mellitus and obesity 375
15a) What are the beneficial effects of metformin?
15b) List the advantages of biguanides over some of the other classes of antidiabetic drugs.
Andreas complains to the pharmacist that he feels very bloated, and wonders if it could be the
metformin.
16) How might you advise Andreas to take the drug so as to reduce the bloating effect?
Andreas is discharged from hospital because his blood glucose level has been within the
desiredrangefor3days,andhisulcerismuchimproved.Hisantihypertensivemedicationhas
beenchanged.Heisnowtakingacalciumchannelblockerinplaceofthethiazide-likediuretic
(indapamide) because these can worsen hyperglycaemia.
He is discharged on the following medication:
• amlodipine
• losartan
• metformin
• dicloxacillin,for4moredays.
He is urged to make regular appointments with the diabetes nurse at his surgery for advice and
monitoring.
MANAGING DIABETES
Andreas attends his local surgery for appointments with the specialist diabetes nurse. His
blood pressure and weight are routinely measured. He also has blood samples taken to
measure cholesterol and glycated haemoglobin levels.
The nurse speaks to Andreas about the need for controlling his blood glucose levels and that,
for now at least, this can be achieved through the use of oral diabetic medication. But she tells
him that he needs to help himself by trying to lose weight, by modifying his diet and exercising
more.
17a) Is Andreas obese? Explain the criteria for making this diagnosis.
17b) Explain the relationship between obesity and the development of diabetes
18) What is meant by the term insulin resistance?
376 Chapter 14 Diabetes mellitus and obesity
19) What is metabolic syndrome?
The nurse also informs Andreas about the long-term complications of diabetes and how it is
important that he manages his condition in order to decrease his risk. This will also help reduce
the rate of progression of the disease.
20a) Name some of the complications the diabetes nurse may have mentioned to Andreas.
20b) What is macrovascular disease?
20c) What is microvascular disease? Which organs/tissues are particularly affected?
Andreas has his blood pressure measurements taken every time he sees the diabetes nurse at
thesurgery.Histargetbloodpressureis130/80mmHg.
21a) Why is regulation of blood pressure important in diabetic patients?
21b) Why is target blood pressure for a diabetic patient lower than that for a non-diabetic patient?
Andreas’s cholesterol levels are also monitored closely during his visits. His levels of high
density lipoprotein (HDL) and low density lipoprotein (LDL) are measured, along with total
cholesterol. He is already taking simvastatin.
22) Why is it important to control blood cholesterol levels in diabetic patients?
23) Which lipoprotein is centrally involved in atherosclerosis?
24) How does simvastatin help to reduced cholesterol levels? (See Chapter 6, Section 6.2.2.)
After a few visits to the surgery, it is apparent that Andreas’s glycaemic control is not optimal.
His HbA1C level is routinely higher than his target 7%. Further drug treatment is necessary.
25) What is HbA1C and how is it used to monitor glycaemic control?
26) List some of the other classes of drugs that the nurse might consider adding to metformin.
27) Which class of antidiabetic drug has a beneficial blood pressure lowering effect? How is this brought
about?
Andreasisprescribedpioglitazonetotakealongsidemetformin.
WORKBOOK 11 Diabetes mellitus and obesity 377
28a) At what type of receptor does pioglitazone act?
28b) What are the effects of pioglitazone?
During this time Andreas has been trying hard to lose weight. He has modified his diet and
exercises more, but over the months his weight fluctuates and is not consistently reduced.
The diabetes nurse suggests that he takes orlistat.
29a) Describe the mechanism of action of orlistat.
29b) What are its common adverse effects?
After 12 weeks of taking orlistat, Andreas’ weight loss is found to be minimal. The nurse
discusses bariatric surgery with Andreas.
Andreas decides to have surgery; the outcome is very good. His control of blood glucose levels
is soon improved and is controlled through use of metformin alone. Andreas avoids having to
inject insulin as he had so feared.
Chapter 15
Thyroid disorders and
pharmacological methods
of contraception
Useful terms for this topic
Goitre: A swelling in the neck resulting from
enlargement of the thyroid gland.
Tetraiodothyronine (T4 or thyroxine): Thyroid
hormone with reduced biological activity compared
with T3; may be regarded as a pro-hormone
for T3.
Thyroglobulin: The large glycoprotein within the
structure of which thyroid hormones are
synthesized.
Thyroid-stimulating hormone (TSH; also called
thyrotrophin): Hormone released from the anterior
pituitary. Acts on the thyroid gland to stimulate growth
and synthesis of thyroid hormones.
Thyrotrophin-releasing hormone (TRH): Hormone
released from the hypothalamus. Acts on the anterior
pituitary to stimulate secretion of thyroid-stimulating
hormone.
Triiodothyronine (T3): The thyroid hormone with
greatest biological activity.
e thyroid gland is responsible for controlling the body’s
basal metabolic rate, as well as having essential roles in
growth and development. Virtually all cells are aected by
the thyroid hormones it secretes, and this underlies the
broad spectrum of symptoms experienced in thyroid
dysfunction. In this chapter we consider the
consequences of both decient and excessive secretion of
thyroid hormones. In order to do so, we must rst
consider the anatomy of the thyroid gland, and how
thyroid hormones are synthesized. e regulation of the
thyroid gland involves both the pituitary and
hypothalamus, an understanding of which is necessary in
order to appreciate the treatment of common thyroid
diseases. In Workbook 12 at the end of this chapter Sunita
is diagnosed with a hyperactive thyroid. She has Graves’
disease, the most common cause of hyperthyroidism.
Whilst undergoing treatment for thyroid disease, Sunita is
prescribed medication to prevent pregnancy. e second
half of this chapter looks at the hormonal changes that
occur during the female reproductive cycle, and how they
can be controlled using pharmacological agents in order
to prevent conception.
15.1 The thyroid gland
e thyroid weighs about 16–20 g, and is one of the largest
endocrine glands. It consists of two lobes situated on
either side of the trachea, and joined together by a narrow
portion of tissue (the isthmus). It lies over the trachea in
the lower neck area, the region commonly referred to as
the Adam’s apple in men. e functional unit in the thyroid
gland is the follicle—a single layer of cuboidal epithelial
(follicular) cells arranged spherically around a central
lumen lled with homogenous colloid (Figure 15.1). e
main constituent of this colloid is thyroglobulin, a large
globular glycoprotein produced by the follicular cells and
secreted into the follicle lumen. e thyroid hormones are
synthesized by modication of tyrosine residues within the
thyroglobulin structure (see below).
15.1 The thyroid gland 379
A. Normal Follicle
Basal membrane
Apical membrane
Reduced volume
of colloid
Enlarged follicular cells,
reabsorbing colloid
Capillaries
Lumen containing
thyroglobulin colloid
B. Hyperthyroid C. Hypothyroid
Increased volume
of colloid
Flattened underactive
follicular cells
Figure 15.1 Structure of follicles within the thyroid gland.
(A) Follicles in the normal thyroid. Cuboidal epithelial cells are arranged spherically. The follicle lumen is filled with
thyroglobulin-containing colloid. A rich network of capillaries surrounds the follicles. (B) In the underactive thyroid
gland the follicles are distended with increased colloid, and the epithelial cells are thin and flattened. By contrast,
in the overactive thyroid (C) the follicular cells are increased in size, and the colloid content reduced, due to
increased reabsorption by the cells.
15.1.1 Synthesis and transport of thyroid
hormones
e thyroid gland produces two iodine-containing
hormones: tetraiodothyronine (T4, or thyroxine) and
triiodothyronine (T3).1 Synthesis of these hormones
requires iodide (I–), which is obtained from the diet and
delivered to the follicular cells in the blood, via the rich
network of capillaries surrounding the follicles. Two
separate transporters are involved in the movement of
I− from the blood into the follicle lumen:
1 A third unrelated hormone, calcitonin, is synthesized in C cells, located
between the follicles. is hormone is involved in Ca2+ metabolism, and is
not considered further here.
1. e Na+/I− symporter captures I− from the blood and
brings it into the follicular cells
2. e I−/Cl− transporter (pendrin) on the luminal
membrane carries I− into the lumen.
e iodide is activated by oxidation. is reaction is
catalysed by hydroperoxidase, an enzyme complex on the
luminal membrane of the follicular cells. In its active state
iodide participates in the iodination of tyrosine residues
in thyroglobulin (for more details see Box 15.1).
yroglobulin contains more than 120 tyrosine residues,
although only the few that are accessible from the surface
can be iodinated. e iodination reaction generates two
intermediates: monoiodotyrosine (MIT) and
diiodotyrosine (DIT), which remain attached to the
Box 15.1
Synthesis and release of thyroid hormones
Blood vessel
1
CH
2
OH
CH
2
OH
Tyrosine
residues on
thyroglobulin
CH
OH
CH
OH
2
–
I
HO
2
Follicular
cell
H
O
H
CCN
H
CH
2
II
O
HO
II
OH
T
4
H
O
CC
CH
H
N
H
2
II
O
I
OH
T
3
5
2
Lumen of follicle
–
I
CH
2
3
I
OH
CH
2
Coupling
II
4
OH
CH
2
II
O
MIT DIT
II
OH
T
4
CH
2
II
O
I
OH
T
3
Figure a
1. Iodide is actively transported from the blood by the iodide pump (Na+–I– symporter; NIS). The transport is driven by the
electrochemical gradient for Na+ established by the Na+K+-ATPase (not shown). The activity of this transporter is switched on
by activation of the receptors for thyroid-stimulating hormone (TSH) on the follicle cells, which also increases the synthesis of
the transporter proteins.
2. The iodide diffuses across the follicular cell, and is transported into the colloid in the follicular lumen by a second transporter:
pendrin, an I–/Cl– exchanger in the luminal membrane.
Box 15.1 Synthesis and release of thyroid hormones
3. The iodide interacts with the accessible tyrosine residues on thyroglobulin. (The glycoprotein thyroglobulin is produced by
follicular cells, and is the main constituent of the colloid filling the follicle lumen.) Iodide is first oxidized in the presence of
hydrogen peroxide (H2O2) to the highly reactive free radical I•. This is achieved by the thyroperoxidase enzyme complex
located on the luminal side of the follicular cell membrane. The reactive iodide interacts with the phenyl grouping of the
exposed tyrosine residues in thyroglobulin, forming two different products: monoiodotyrosine (MIT) and diiodotyrosine (DIT).
This process is referred to as the organification of iodide. This is the site of action of thioureylenes (e.g. carbimazole and
propylthiouracil).
4. Triiodothyronine (T3) and tetraiodothyronine (T4, thyroxine) are produced by coupling of MIT and DIT (one MIT combining with
a DIT to produce T3, and two DITs yielding T4).
5. The thyroglobulin–T3/T4 complex enters the follicular cell where it is proteolytically cleaved by lysosomal enzymes to release
T3/T4. These lipophilic molecules readily cross the plasma membrane to enter the blood.
DIT, diiodotyrosine; MIT, monoiodotyrosine; T3, triiodothyronine; T4, tetraiodothyronine (thyroxine).
thyroglobulin molecule. e nal stage of synthesis
involves the coupling of MIT and DIT molecules. ese
coupling reactions generate the completed thyroid
hormones T3 and thyroxine (T4). e thyroid hormones,
then, are synthesized within the structure of the
thyroglobulin molecule, which therefore provides a store
of hormones inside the follicles.
When stimulated to release thyroid hormones (see
below), follicular cells endocytose a portion of the
colloid containing the iodinated thyroglobulin. rough
the action of proteolytic enzymes within these cells, the
thyroid hormones are released from the thyroglobulin
structure and are actively transported into the blood.
e lipophilic properties of T3 and T4 ensure that they
rapidly bind to serum proteins in the blood, which
transport them around the body. e hormones bind
tightly to two proteins: thyroxine-binding globulin
and transthyretin (thyroxine-binding pre-albumin). ey
also bind to albumin, although less tightly. Very little of
the thyroid hormones remains free: around 0.03% of T4
and 0.3% of T3. It is this free hormone which is able to
enter target cells to cause an eect. As a consequence of
binding to serum proteins, the thyroid hormones have
long half-lives: around 1–3 days for T3, and 5–7 days for
thyroxine. e blood can therefore be considered as a
reservoir for both hormones, and in particular thyroxine,
which is more strongly bound to serum proteins, as
reected in its longer plasma half-life.
T3 is biologically more active than thyroxine, yet the thyroid
gland secretes more thyroxine than T3, in the approximate
ratio 9:1. yroxine is itself subject to deiodination in many
peripheral tissues, principally the kidneys and liver;
around 90% of circulating T3 is derived from thyroxine in
this way. e deiodinase enzymes that catalyse this
conversion contain selenium. yroid hormone function
is therefore dependent on two trace elements, iodine and
selenium; deciencies in either can lead to severe
hypothyroidism and endemic goitre (see below).
In a healthy individual, the levels of thyroid hormones in
the plasma settle to constant values around 3 days after
birth, and do not change signicantly throughout life.
15.1.2 Regulation of thyroid gland activity
e release of thyroxine and T3 from follicular cells
into the blood follows activation of the thyroid glands
by thyroid-stimulating hormone (TSH; also called
thyrotrophin). is hormone is released by the anterior
pituitary gland, and its secretion is in turn regulated by
thyrotrophin-releasing hormone (TRH) from the
hypothalamus (see Figure 15.2).
Production of the thyroid hormones only occurs when
TSH stimulates its receptors on follicular cells. ese are
G-protein-coupled receptors that show dual coupling to
Gs and Gq; their activation leads to increases in cyclic
AMP (through Gs) and increased inositol trisphosphate
levels (through Gq). TSH stimulates all aspects of thyroid
hormone synthesis and release, including the activity of
the iodide pump and the production and iodination of
thyroglobulin. TSH also maintains the structure and
vascularization of the thyroid gland.