INSULIN
What is the structure of insulin ?
It is a 51 amino acid protein consisting of two polypeptide chains connected by disulfide
bonds
Where does insulin work?
Insulin binds to proteins in the circulation and cell membrane receptors. Insulin does not
enter the cell nucleus.
What type of receptor does insulin bind to?
Tyrosine kinase
What are the effects of insulin?
Insulin affects almost every tissue in the body, but the most important target organs are:
Liver-promotes glucose storage as glycogen; increases triglyceride synthesis
Muscle-facilitates protein and glycogen synthesis
Adipose tissue improves triglyceride storage by activating plasma lipoprotein lipase; reduces
circulating free fatty acids
What are the types of insulin preparations used clinically?
There are three main classes of insulin: .1 Short-acting insulin lispro
(Humalog) and regular (Humulin)
2 Intermediate-acting-isophane
insulin suspension (neutral protamine Hagedorn [NPH] insulin) and insulin zine suspension
(lente)
3. Long-acting-insulin zine suspension extended (ultralente)
Protamine and Semilente insulin are no longer used in the United States.
Which types of insulin are used for management of hyperglycaemic emergencies?
Lispro and regular, because they can be given intravenously and work rapidly
What are the sources of insulin?
Animal insulin preparations are made from beef and pork. Human insulin can be made
through bacterial DNA recombinant technology.
What is the standard route for the administration of insulin?
Subcutaneous injection
What are adverse effects of insulin use?
Symptoms of hypoglycemia diaphoresis, vertigo, tachycardia
Insulin allergy— an immunoglobulin E-mediated reaction
Insulin antibodies-immunoglobulin G-mediated
Lipodystrophy—a change in the fatty tissue surrounding the injection site
1. Biguanides
Metformin
▪ Its action is unclear, but may involve activation of adenosine monophosphate
(AMP)-activated protein kinase.
▪ Actions may include:
▪ ● increased glucose uptake into muscle
▪ ● reduced absorption of glucose from the gastrointestinal tract
▪ ● reduced output of glucose from the liver.
▪ It is the drug of choice for most (especially obese) patients.
▪ Metformin does not cause hypoglycaemia.
▪ It should not be used in renal impairment.
Sulphonylureas
e.g. glibenclamide, gliclazide, tolbutamide
Mechanism of action
▪ Sulphonyulureas increase insulin secretion.
▪ They inhibit adenosine triphosphate (ATP)-sensitive potassium (KATP)
channels (see Chapter 4).
▪ Glucose leads to ATP production, which inhibits these channels, leading to
cellular depolarisation, which results in calcium influx and insulin
secretion.
▪ When glucose is low, ATP levels fall and adenosine diphosphate (ADP)
rises, channels open, with membrane hyperpolarisation, and this decreases
insulin release.
▪ Sulphonylureas bind to a receptor associated with these channels, resulting
in channel closure, which leads to insulin release.
Adverse effects
■ Insulin secretion is associated with weight gain and hypoglycaemia. Meglitinide
analogues
e.g. nateglinide, repaglinide
▪ These also act on b-cells but interact with the sulphonylurea receptor in
a slightly different manner than sulphonylureas to cause closure of the
KATP-channels, leading to depolarisation and insulin release.
▪ They have a rapid rate of onset and are given at meal times to stimulate
postprandial insulin secretion, which is relatively short-lived.
■ Their effects may be enhanced by the patient having a meal and they are referred to as
prandial glucose regulators (PGRs).
Thiazolidinediones (‘glitazones’)
e.g. pioglitazone, rosiglitazone
▪ Thiazolidinediones activate nuclear peroxisome proliferator-activated
receptor-c (PPAR-c), which alters gene expression and results in insulin-like
effects (see Chapter 2).
▪ They are ‘insulin sensitisers’ which work by enhancing glucose utilisation
in tissues, and so reduce insulin resistance.
▪ Effects include:
▪ ● reduced hepatic glucose output
▪ ● increased glucose transporters (GLUT) in skeletal muscle with increased
peripheral glucose utilisation
▪ ● increased fatty acid uptake into adipose cells
▪ ● anti-inflammatory.
Glucosidase inhibitors
Acarbose
▪ Acarbose competitively inhibits the a-glucosidases which metabolise oligosaccharides
to monosaccharides in the small intestine brush border epithelium.
▪ It reduces the production of glucose in the gastrointestinal tract, thereby preventing
sharp rises in blood glucose after a meal.
▪ The subsequent increased presence of carbohydrates in the gastrointestinal tract may
lead to flatulence and osmotic diarrhoea as side-effects.
Modulation of incretins
Exenatide, sitagliptin
▪ Incretins are endogenous hormones which regulate the endocrine pancreas.
▪ Exenatide is an incretin mimetic which acts on b-cells of the islets of
Langerhans to stimulate the release of insulin and also reduces glucagon
release.
▪ Sitagliptin is a dipeptidyl peptidase-4 inhibitor which inhibits the
breakdown of incretins and so enhances their action, promoting insulin secretion and
suppressing glucagon release.
Key points
▪ Type 1 diabetes requires insulin.
▪ Insulin receptors have tyrosine kinase activity.
▪ Type 2 diabetes is managed by diet and antidiabetic drugs.
▪ Metformin may activate AMP-activated protein kinase.
▪ Sulphonylureas inhibit ATP-sensitive potassium channels and stimulate insulin
secretion.
▪ Thiazolidinediones activate nuclear PPAR-c and sensitise towards insulin.
CHELATORS AND HEAVY METALS
What is a chelator
A chelator is a molecule with two or more electronegative groups that is used to bind toxic
metals in stable complexes. These complexes have relatively low toxicity and enhanced fecal
and renal excretion. Chelators are used in the treatment of heavy metal toxicities.
Name the five most commonly used chelators.
1. Ethylenediamine tetra-acetic acid (EDTA)
.2 Dimercaprol (also known as BAL)
3. Penicillamine
.4 Deferoxamine
.5 Succimer
