Chapter 34

Insulin and oral

hypoglycemic agents
OVERVIEW OF DIABETES MELLITUS

*Approximately 150 million people have diabetes mellitus worldwide,

and this number may well double by the year 2025 (WHO report).
* Adult blindness, amputation, renal failure, heart attacks and strokes.
* Diabetes is heterogeneous group of syndromes characterized by an
elevation of fasting blood glucose due to relative or absolute lack of
insulin.
* Metabolic alterations due to insulin deficiency are exacerbated by the
excess of glucagon.

Two types of Diabetes Mellitus :

Insulin-dependent diabetes mellitus (IDDM) or Type I
Non-insulin-dependent diabetes mellitus (NIDDM) or Type II
 Diabetes Mellitus

Virtually all forms of diabetes mellitus are caused by

a decrease in the circulating concentration of insulin
(insulin deficiency) and a decrease in the response of
peripheral tissues to insulin (insulin resistance). These
abnormalities lead to alterations in the metabolism of
carbohydrates, lipids, ketones, and amino acids; the
central feature of the syndrome is hyperglycemia.
Treatment of diabetes mellitus

1. Attention to diet

2. Physical exercise

3. Medication
Drug classification

1. Insulin

2. Oral hypoglycemic Agents:

Sulfonylureas

Biguanides

α-Glucosidase Inhibitor
 Discovery of insulin
In 1921, Frederick G. Banting, a young Canadian
surgeon, convinced a professor of physiology in Toronto, J.
J. R. Macleod, to allow him access to a laboratory to search
for the antidiabetic principle of the pancreas. Banting
assumed that the islet tissues secreted insulin but that the
hormone was destroyed by proteolytic digestion prior to or
during extraction. Then he attempted to overcome the
problem by tying the pancreatic ducts. The acinar tissue
Frederick G. Banting
degenerated, leaving the islets undisturbed; the remaining
tissue was then extracted with ethanol and acid. Banting and
Macleod thus obtained a pancreatic extract that was
effective in decreasing the concentration of blood glucose in
diabetic dogs.
In 1923, the Nobel Prize in Medicine and Physiology was
awarded to Banting and Macleod with remarkable rapidity. J. J. R. Machleod
 β(B) cells produce insulin
A cells produce glucagons
D cells produce somatostatin

Insulin These hormones play an important role

in regulating the metabolic activities of the
body, and in doing so, help maintain the
homeostasis of blood glucose.

Insulin is secreted from B cells located in the islets of

Langerhans, and it is an acidic protein.
Insulin is a small protein consisting of two polypeptide
chains that are connected by disulfide bonds.
Insulin is isolated from beef and pork pancreas.
However, human insulin is replacing the animal hormone
for therapy. Pork insulin is closest in structure to human
insulin, differing by only one amino acid.
【 Pharmacokinetics 】

Because insulin is a protein, it is degraded in the gastro-

intestinal tract if taken orally. Therefore, it is generally
administered by subcutaneous injection.
The half-life of insulin in plasma is about 9~10 minutes.
Insulin is inactivated by the reducing enzyme, insulinase,
found mainly in the liver and kidney.
Insulin preparations vary primarily in their times of onset of activity
and duration of the insulin crystals in the preparations. Dose, site of
injection, blood supply, temperatures and physical activity can affect the
duration of action of the various preparations.
【 Pharmacologic effects 】
1. Insulin reduces blood glucose by promoting glucogen
synthesis and storage, converting glucose into fat, and
inhibiting glycogenolysis and gluconeogenesis.
2. Insulin promotes fatty acid and glucose transport, and
increases adipose synthesis and inhibits it breakdown,
and reduces circulating free fatty acids.
3. Insulin promotes protein synthesis by increasing amino
acid transport and depresses protein breakdown.
4. Insulin increases heart rate, and enhances myocardial
contraction, and reduces renal blood flow.
5. Insulin enables glucose to pass across cell membranes,
and the transit of potassium into the cell is enhanced.
 【 Insulin receptor 】
Once insulin has entered the circulation, it is bound by
specialized receptors that are found on the membranes of most
tissues. The insulin receptor consists of two heterodimers, each
containing an alpha subunit, which is entirely extracellular and
constitutes the recognition site, and a beta subunit that spans the
membrane. The beta subunit contains a tyrosine kinase.
When insulin binds to the alpha subunit at the outside surface of
the cell, tyrosine kinase activity is stimulated in the beta portion.
Then the network of phosphorylations within the cell is stimulated,
which results in some actions such as hypoglycemia, and so on.
Insulin receptor
【 Preparations 】
1. Short-acting insulins:
Regular Insulin: soluble; peak 2-4 hours, duration 5-7 hours, used in
subcutaneous or intravenously, is a good agent for controlling ketoacidosis.
2. Intermediate-acting insulins
Neutral Protamine Hagedorn ( NPH ): peak 8-12 hours, duration 18-24
hours.
3. Long-acting insulins
Protamine Zinc Insulin: less soluble; injected as a tissue depot-slow
absorption; peak 16-18 hours, lasting up to 36 hours; Fine control of
hyperglycemia is difficult with such a long-acting preparation.
4. Human insulins
Useful for individual with an allergy to insulin from animal sources.
【 Therapeutic uses 】
1. Treatment of Type 1 diabetes: all patients with type 1 DM
2. Treatment of Type 2 diabetes: not adequately controlled by
diet and/or oral hypoglycemic agents, and for patients with
postpancreatectomy diabetes or gestational diabetes.
3. Insulin is critical for the management of diabetic
ketoacidosis, and it has an important role in the treatment of
hyperglycemic, nonketotic coma and in the preoperative
management of both type 1 DM and type 2 DM patients.
In all case, the goal is the normalization not only of blood glucose
but also of all aspects of metabolism; the latter is difficult to achieve.
Optimal treatment requires a coordinated approach to diet, exercise,
and the administration of insulin.
【 Adverse
effects 】
1. Hypoglycemia: the most common adverse reaction
This may result from an inappropriately large dose, from a mismatch
between the time of peak delivery of insulin and food intake. Hypoglycemia
may lead to hunger, palpitations, sweating, tremulousness, coma and even
death(<2.77mmol/L).
All insulin-treated diabetic patients and family members should be
instructed in the recognition of hypoglycemia, and the sue of sugar water for
normal patients and injection 50% glucose solution for severe patients.

2. Insulin allergy
Allergic reactions are very rare, but may occur to any insulin and to any
constituent of the formulation.
 【 Adverse
3. Insulin】
effects resistance
Most insulin-treated patients develop a low titer of circulating IgG anti-
insulin antibodies that neutralize the action of insulin to a small extent. In some
diabetic patients, principally those with some degree of tissue insensitivity to
insulin (such as occurs in obese diabetics) and a history of interrupted insulin
therapy with preparations of less-than-pure beef insulin, a high titer of
circulating IgG anti-insulin antibodies develops. This results in extremely high
insulin requirements.

4. Lipoatrophy and lipohypertrophy

Atrophy of subcutaneous fat at the site of insulin injection (lipoatrophy) is
probably a variant of an immune response to insulin, whereas lipohypertrophy
(enlargement of subcutaneous fat depots) has been ascribed to the lipogenic

action of high local concentrations of insulin.

 Oral hypoglycemic Agents

These agents are useful in the treatment of patients who have

non-insulin-dependent diabetes (NIDDM) but cannot be managed
by diet alone. The patient most likely to respond well to oral
hypoglycemic agents is one who develops diabetes after ages 40
and has had diabetes less than 5 years.
Patients with long-standing disease may require a combination
of a hypoglycemic drug and insulin to control their
hyperglycemia. And oral hyperglycemic agents should not be
given to patients with Type 1 diabetes.
Oral hypoglycemic Agents:

Sulfonylureas

Biguanides

α-Glucosidase Inhibitor
 Sulfonylureas

The first generation agents:

tolbutamide, acetohexamide, tolazamide,
chlorpropamide
The second generation agents:
glibenclamide, glipizide, gliclazide,
glimepiride
【 Pharmacokinetics
】 The different sulfonylureas all are effectively absorbed from the
gastro-intestinal tract. Sulfonylureas in plasma are largely (90% to 99%)
bound to serum proteins, and are metabolized by the liver, and the
metabolites are excreted in the urine.
The half-life of acetohexamide is short, but the drug is reduced to an
active compound with a half-life that is similar to those of tolbutamide
and tolazamide (4 to 7 hours). Chlorpropamide has a long half-life (24 to
48 hours).
The second generation agents are approximately 100 times more
potent than those first generation agents. Although their half-lives are
short (3 to 5 hours), their hypoglycemic effects are evident from 12 to 24
hours, and it is often possible to administer them once daily.
These drugs are contraindicated in patients with hepatic or renal
insufficiency because they may cause hypoglycemia.
【 Pharmacologic
effects 】
The mechanisms of the action of the
sulfonylureas include:
(1) to stimulate insulin release from the β-cells
of the pancreas;
(2) to reduce serum glucagons levels;
(3) to potentiate insulin action on target tissues.
【 Therapeutic uses 】

Treatment of diabetes mellitus

Sulfonylureas are used to control hyperglycemia in type 2
DM patients who cannot achieve appropriate control with
changes in diet alone.

In all patients, however, continued dietary restrictions are essential to

maximize the efficacy of the sulfonylureas. Patients with type 2 DM whose
disease is controlled with relatively low doses of insulin are more likely to
respond to sulfonylureas, as those who are obese and/or older than 40
years of age.
【 Adverse
effects 】
Adverse effects of the second-generation sulfonylureas
are slightly less than those of the first-generation agents in
patients.
1. Hypoglycemic reactions, including coma.
2. Other side effects: nausea and vomiting, cholestatic
jaundice, agranulocytosis, aplastic and hemolytic anemias,
generalized hypersensitivity reactions and dermatological
reactions.

Contraindications: type 1 DM, pregnancy, lactation, and

significant hepatic or renal insufficiency.
 Biguanides

The biguanides includes metformin, phenformin and buformin.

Metformin is well absorbed mainly from the small intestine. The drug does
not bind to plasma proteins, and is excreted unchanged in the urine. Its half-life
is about 1.5 hours.
Metformin acts primarily by decreasing hepatic glucose output and by
increasing insulin action in muscle and fat, largely by inhibiting gluconeogenesis.
Metformin given alone or in combination with a sulfonylurea improves glycemic
control and lipid concentrations in patients who respond poorly to diet or to a
sulfonylurea alone.
Adverse effects are largely gastrointestinal, include diarrhea, abdominal
discomfort, nausea, metallic taste, and anorexia. Rarely, potentially fatal lactic
acidosis has occurred.
 α-Glucosidase Inhibitor
α-Glucosidase inhibitors (for example, acarbose) reduce intestinal
absorption of starch, dextrin, and disaccharides by inhibiting the action of
intestinal brush border α-glucosidase. Inhibition of this enzyme slows the
absorption of carbohydrates; The postprandial rise in plasma glucose is
blunted in both normal and diabetic subjects treated with these agents.
These agents may be considered as monotherapy in elderly patients or in
patients with predominantly postprandial hyperglycemia. α-Glucosidase
inhibitors typically are used in combination with other oral antidiabetic
agents and/or insulin.
Adverse effects: These agents cause dose-related malabsorption,
flatulence, diarrhea, and abdominal bloating. Titrating the dose of drug
slowly will reduce gastrointestinal side effects.