A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition
A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition
A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition
Create successful ePaper yourself
Turn your PDF publications into a flip-book with our unique Google optimized e-Paper software.
CHAPTER 37<br />
DIABETES MELLITUS<br />
● Introduction 285<br />
● Pathophysiology 285<br />
● Principles <strong>of</strong> management 286<br />
● Diet in diabetes mellitus 286<br />
● Drugs used to treat diabetes mellitus 286<br />
INTRODUCTION<br />
Before the discovery <strong>of</strong> insulin, type 1 diabetes – where insulin<br />
deficiency can lead to ketoacidosis – was invariably fatal. Since<br />
the introduction <strong>of</strong> insulin, the therapeutic focus has broadened<br />
from treating <strong>and</strong> preventing diabetic ketoacidosis to preventing<br />
long-term vascular complications. Type 2 diabetes – where<br />
insulin resistance <strong>and</strong> a relative lack <strong>of</strong> insulin lead to hyperglycaemia<br />
– not only causes symptoms related directly to hyperglycaemia<br />
(polyuria, polydipsia <strong>and</strong> blurred vision – see below),<br />
but is also a very powerful risk factor for atheromatous disease.<br />
Glucose intolerance <strong>and</strong> diabetes mellitus are increasingly<br />
prevalent in affluent <strong>and</strong> developing countries, <strong>and</strong> represent a<br />
major public health challenge. Addressing risk factors distinct<br />
from blood glucose, especially hypertension, is <strong>of</strong> paramount<br />
importance <strong>and</strong> is covered elsewhere (Chapters 27 <strong>and</strong> 28). In<br />
this chapter, we focus mainly on the types <strong>of</strong> insulin <strong>and</strong> oral<br />
hypoglycaemic agents.<br />
PATHOPHYSIOLOGY<br />
Insulin is secreted by β-cells (also called B-cells) <strong>of</strong> the islets <strong>of</strong><br />
Langerhans. It lowers blood glucose, but also modulates the<br />
metabolic disposition <strong>of</strong> fats <strong>and</strong> amino acids, as well as carbohydrate.<br />
It is secreted together with inactive C-peptide, which<br />
provides a useful index <strong>of</strong> insulin secretion: its plasma concentration<br />
is low or absent in patients with type 1 diabetes, but<br />
very high in patients with insulinoma (an uncommon tumour<br />
which causes hypoglycaemia by secreting insulin). This should<br />
not be confused with ‘C-reactive peptide’ (CRP) which is an<br />
acute phase protein synthesized by the liver <strong>and</strong> used as a nonspecific<br />
index <strong>of</strong> inflammation. C-peptide concentration is not<br />
elevated in patients with hypoglycaemia caused by injection <strong>of</strong><br />
insulin.<br />
Diabetes mellitus (fasting blood glucose concentration<br />
<strong>of</strong> 7 mmol/L) is caused by an absolute or relative lack <strong>of</strong><br />
insulin. In type 1 diabetes there is an absolute deficiency <strong>of</strong><br />
insulin. Such patients are usually young <strong>and</strong> non-obese at<br />
presentation. There is an inherited predisposition. However,<br />
concordance in identical twins is somewhat less than 50%, so<br />
it is believed that genetically predisposed individuals must<br />
also be exposed to an environmental factor. Viruses (including<br />
Coxsackie <strong>and</strong> Echo viruses) are one such factor <strong>and</strong> may initiate<br />
an autoimmune process that then destroys the islet cells.<br />
In type 2 diabetes there is a relative lack <strong>of</strong> insulin secretion,<br />
coupled with marked resistance to its action. The circulating<br />
concentration <strong>of</strong> immunoreactive insulin measured by st<strong>and</strong>ard<br />
assays (which do not discriminate well between insulin<br />
<strong>and</strong> pro-insulin) may be normal or even increased, but more<br />
discriminating assays indicate that there is an increase in proinsulin,<br />
<strong>and</strong> that the true insulin concentration is reduced.<br />
Such patients are usually middle-aged or older at presentation,<br />
<strong>and</strong> obese. Concordance <strong>of</strong> this form <strong>of</strong> diabetes in identical<br />
twins is nearly 100%. Type 2 diabetes is rarely if ever associated<br />
with diabetic ketoacidosis, although it can be complicated by<br />
non-ketotic hyperosmolar coma or, rarely (in association with<br />
treatment with a biguanide drug such as metformin, see<br />
below), with lactic acidosis.<br />
An increased concentration <strong>of</strong> glucose in the circulating<br />
blood gives rise to osmotic effects:<br />
1. diuresis (polyuria) with consequent circulating volume<br />
reduction, causing thirst <strong>and</strong> polydipsia;<br />
2. the refractive index <strong>of</strong> a high glucose concentration<br />
solution in the eye differs from healthy aqueous humour,<br />
causing blurred vision.<br />
In addition, glycosuria predisposes to C<strong>and</strong>ida infection, especially<br />
in women. The loss <strong>of</strong> calories in the urine is coupled<br />
with inability to store energy as glycogen or fat, or to lay down<br />
protein in muscle, <strong>and</strong> weight loss with loss <strong>of</strong> fat <strong>and</strong> muscle<br />
(‘amyotrophy’) is common in uncontrolled diabetics.<br />
Both types <strong>of</strong> diabetes mellitus are complicated by vascular<br />
complications. Microvascular complications include retinopathy,<br />
which consists <strong>of</strong> background retinopathy (dot <strong>and</strong><br />
blot haemorrhages <strong>and</strong> hard exudates which do not <strong>of</strong> themselves<br />
threaten vision), <strong>and</strong> proliferative retinopathy which