++
Insulins derived from animals (pork or beef) are no longer available
in the United States. Pharmaceutical human insulin is manufactured
by recombinant DNA technology. Because the native insulin molecule
has a half-life of only a few minutes in the circulation, many preparations
are formulated to release the hormone slowly into the circulation.
The available insulin formulations provide five rates of onset and
durations of effect: ultra-rapid onset, rapid onset with short action, intermediate
onset and action, slow onset with peak action, and ultra-slow onset
with no peak (i.e., plateau only) action (Table 24–3).
All insulin preparations contain zinc. The ratio of zinc and other
substances to insulin influences the rate of release of active hormone
from the site of administration and the duration of action (Figure
24-4).
++
++
++
Ultra-rapid action insulins are represented by insulin lispro, insulin aspart, and insulin glulisine. These preparations
are recombinant human insulins that contain transpositions of two
amino acids or replacement of one or more native amino acids. These
changes alter physical properties of the peptides so that they dissolve
more rapidly at the site of administration and enter the circulation
approximately twice as fast as regular crystalline insulin. These
insulins are suitable for use immediately before meals. Unlike other
insulin preparations, increasing the dose only increases the maximum
effect, not the duration of effect.
++
Regular crystalline-zinc insulin is
a rapid-onset and short-action formulation. The insulin is used
intravenously in emergencies or administered subcutaneously in maintenance
regimens, alone or mixed with intermediate- or long-acting preparations.
Before the development of the ultra-rapid insulins, regular insulin
was the primary rapid-onset agent. However, regular insulin requires
administration 1 hour or more before each meal.
++
A special formulation of regular insulin was approved for inhalation
(Exubera) in 2007. This was the first insulin formulation that did
not require injection, but interest was too low to support continued
production and the drug was discontinued.
++
The major intermediate-onset and intermediate-action preparation
currently available is isophane insulin
suspension (NPH insulin). This preparation is given by subcutaneous
injection; it is not suitable for intravenous use. Intermediate-onset
NPH insulin can be mixed in the syringe or purchased premixed with
regular insulin for convenience of administration.
++
Insulins with very slow onset and prolonged action are represented
by ultralente insulin, insulin glargine,
and insulin detemir. Ultralente insulin has a very delayed
peak at 12 hours after injection and has fallen out of favor. Insulins
glargine and detemir achieve a plateau within 3 to 6 hours and maintain
a relatively constant blood level for up to 24 hours. These formulations
are usually given in the morning only or in the morning and evening
to provide maintenance or basal levels for 12 to 24 hours. This
basal insulin level may be supplemented (especially in the case
of insulins glargine and detemir) with injections of insulin lispro
or regular insulin during the day to meet the requirements of carbohydrate
intake.
+++
Insulin Delivery
Systems
++
The standard mode of insulin therapy is subcutaneous injection
with conventional disposable needles and syringes. More convenient
means of administration are also available. Portable pen-sized injectors
are used to facilitate subcutaneous injection. Some contain replaceable
cartridges, whereas others are disposable. Continuous subcutaneous
insulin infusion pumps avoid the need for multiple daily injections
and provide flexibility in the scheduling of patients’ daily
activities. These programmable pumps deliver a constant 24-hour
basal rate, and manual adjustments in the rate of delivery can be
made to accommodate changes in insulin requirements. Dosage changes may
be required prior to meals or exercise. While insulin pumps have
many advantages over subcutaneous injections, the pump and its disposable
accessories (e.g., tubing) are expensive. The inhaled formulation
of insulin had pharmacokinetic properties that made it useful for
covering mealtime insulin requirements. This insulin formulation
was administered within 10 minutes prior to a meal.
++
Diabetic patients who use insulin are subject to two types of
complications: hypoglycemia, from excessive insulin effect, and
immunologic toxic effects, from the development of antibodies. Hypoglycemia
is very dangerous because brain damage may result. Rapid development
of hypoglycemia in individuals with intact hypoglycemic awareness
causes autonomic hyperactivity, with both sympathetic and parasympathetic
manifestations. The sympathetic manifestations include tachycardia,
palpitations, sweating, and tremulousness. The parasympathetic manifestations
include nausea and hunger. Hypoglycemia may progress to convulsions
and coma if untreated. In diabetic patients who experience frequent
hypoglycemic episodes, autonomic warning signs can be less frequent
or even absent. These patients can develop severe manifestations
of hypoglycemia, including confusion, weakness, bizarre behavior,
coma, or seizures without warning. Every patient with DM who is
receiving hypoglycemic drug therapy should have an identification
bracelet, necklace, or card in the wallet or purse, as well as some
form of rapidly absorbed glucose. In patients with hypoglycemia,
prompt administration of glucose or simple sugars is essential.
The glucose may be given either as sugar or candy by mouth or as
intravenous glucose. Alternatively, an intramuscular injection of
glucagon can be used to raise serum glucose concentrations. Patients
with advanced renal disease, the elderly, and children younger than
7 years are most susceptible to hypoglycemia and its detrimental
effects.
++
The most common form of insulin-induced immunologic complication
is the formation of antibodies to insulin or noninsulin protein
contaminants, which results in resistance to insulin’s
action or allergic reactions. With the current use of highly purified
human insulins, immunologic complications are very uncommon. Insulin
may also cause weight gain, which is particularly undesirable in
patients with type 2 DM, who are frequently overweight.
++
Amylin, a 37–amino acid protein that activates G protein–coupled
receptors, is co-secreted with insulin from the B cells. Pramlintide is a synthetic analog
of amylin. Administration of pramlintide has multiple effects on
glucose regulation. The drug reduces postprandial glucose elevation
by prolonging gastric emptying and reducing glucagon secretion following
a meal. Through centrally mediated appetite suppression, it reduces
caloric intake and causes weight loss, an important benefit for
overweight patients. Administration is by subcutaneous injection,
with a time to peak plasma concentration of 20 minutes and a half-life
of 48 minutes (Table 24–4). Pramlintide is used in both
types 1 and 2 DM.
++
++
Headaches, nausea, vomiting, and loss of appetite occur. Severe
hypoglycemia also occurs and is more common in patients with type
1 DM compared to patients with type 2 DM. Arthralgia has been reported
in some patients, and allergic reactions are possible.
++
Exenatide, a newer drug for treating
type 2 diabetes, is a long-acting peptide with a high degree of
homology to a hormone called glucagon-like
peptide-1 (GLP-1). A finding that long puzzled endocrinologists
was the ability of oral glucose to induce more insulin release than
an equivalent amount of intravenous glucose. This finding suggested
the existence of a gastrointestinal tract–derived substance
that stimulates insulin release. Further research led to discovery
of two hormones, called incretins,
that are released from endocrine cells in the bowel epithelium in
response to food. One of these is GLP-1. GLP-1 and exenatide have
multiple effects. In addition to augmentation of glucose-stimulated
insulin release from pancreatic B cells, they retard gastric emptying,
inhibit glucagon secretion, and produce a sense of satiety. Exenatide
must be injected subcutaneously twice daily, has a time to peak
plasma concentration of approximately 2 hours, and has an elimination
half-life of 2.5 hours; the duration is given in Table 24–4.
Exenatide has modest therapeutic utility, and is always used in
combination with metformin or a secretagogue.
++
Nausea, especially early in the course of treatment, is a problem
and can be accompanied by vomiting and diarrhea. Hypoglycemia has
occurred when exenatide is combined with an insulin secretagogue
but has not been seen when exenatide is combined with metformin.
+++
Oral Antidiabetic
Drugs
++
Five groups of drugs are used for the oral treatment of type
2 DM: insulin secretagogues, biguanides, thiazolidinediones, gliptins,
and α-glucosidase inhibitors. Important members
of these groups are listed in Table 24–4.
++
The primary action of the insulin secretagogues is to stimulate
the release of endogenous insulin. Most of the insulin secretagogues
are in the chemical class known as sulfonylureas. The sulfonylureas close the ATP-regulated
potassium channels in the pancreatic B cell membranes; channel closure
depolarizes the cells, which triggers insulin release (Figure 24–2).
Insulin secretagogues are not effective in patients who lack functional
B cells. These drugs may also reduce glucagon release and increase
the number of functional insulin receptors in peripheral tissues.
The second-generation sulfonylureas such as glyburide,
glipizide, or glimepiride are
considerably more potent and much more commonly used than the older
agents such as tolbutamide or chlorpropamide.
++
Repaglinide and nateglinide are
newer insulinsecretagogues. Repaglinide is from a chemical class
called meglitinides, whereas nateglinide is a D-phenylalanine derivative.
Both of these drugs also promote insulin release by closing ATP-regulated
potassium channels in pancreatic B cell membranes. The most notable
difference between the newer drugs and sulfonylureas is the rapid
onset and short duration of action of the newer agents (Table 24–4).
They can be taken just before meals to control postprandial glucose
concentrations.
++
Hypoglycemia is the most common adverse effect of the secretagogues.
Occasionally, rash and allergy are reported. The older sulfonylureas,
which include tolbutamide and chlorpropamide, are extensively bound
to serum proteins, and drugs that compete for protein binding may
enhance their hypoglycemic effects. Chlorpropamide has a long duration
of action, and liver and kidney disease may greatly increase blood
levels of the drug. Like insulin, insulin secretagogues cause weight
gain, which is undesirable in the large number of patients with
type 2 DM who are overweight.
++
The biguanides act by a poorly understood mechanism to reduce
postprandial and fasting glucose levels in patients with type 2
DM. Their effects do not depend on functional B islet cells. Proposed
mechanisms for their action include reduced hepatic gluconeogenesis,
stimulation of glycolysis in peripheral tissues, reduction of glucose
absorption from the gastrointestinal tract, and reduction of plasma
glucagon levels. Several biguanides are in use overseas. Metformin is the only member of this
group available in the United States. Unlike the sulfonylureas,
the biguanides do not cause hypoglycemia. Unlike all other oral
antidiabetic drugs and insulin, metformin does not cause weight
gain. The duration of action of metformin is intermediate when compared
to most other oral antidiabetic drugs (Table 24–4).
++
The most common toxicity associated with metformin is nausea
and diarrhea, and the most serious toxicity is lactic acidosis.
The increased risk of lactic acidosis presumably arises because
of impaired conversion of lactic acid to glucose, an important reaction
normally performed in the liver. Patients with renal or liver disease,
alcoholism, or conditions that predispose them to tissue anoxia
and excess lactic acid production, such as chronic cardiopulmonary
dysfunction, are at greatest risk. Metformin also inhibits vitamin
B12 absorption.
++
Thiazolidinediones increase target tissue sensitivity to insulin. Troglitazone was the first thiazolidinedione
introduced, but it was removed from the market in several countries
because of hepatotoxicity. Rosiglitazone and pioglitazone appear
to carry less risk of serious liver dysfunction. The mechanism of
action of the thiazolidinediones is not fully understood, but they
stimulate the peroxisome proliferator-activated receptor-gamma nuclear
receptor (PPAR-γ receptor). This nuclear receptor
regulates the transcription of genes encoding proteins involved
in carbohydrate and lipid metabolism.
++
The thiazolidinediones increase glucose uptake in muscle and
adipose tissue, inhibit hepatic gluconeogenesis, and have effects
on lipid metabolism and the distribution of body fat. Thiazolidinediones
reduce both fasting and postprandial hyperglycemia. They are used
as monotherapy or in combination with insulin or other oral antidiabetic
drugs. Durations of action of thiazolidinediones are presented in
Table 24–4.
++
When these drugs are used alone, hypoglycemia is extremely rare.
Liver function should be monitored. Thiazolidinediones can cause
volume expansion, which presents as edema and mild anemia, especially
when combined with exogenous insulin. Heart failure and other cardiovascular complications
may occur. Some evidence suggests an increased risk of fractures.
Because pioglitazone and troglitazone appear to induce cytochrome
P450 enzymes, these drugs can reduce serum concentrations of drugs
such as oral contraceptives or cyclosporine that are also metabolized
by these enzymes.
++
The gliptins are orally active inhibitors of dipeptidyl peptidase-4,
the enzyme that metabolizes endogenous incretins and similar GLP-1–like
molecules. Their effects on glucose metabolism thus resemble those
of exenatide, which mimics GLP-1. Elimination is via the kidney,
so dosage must be reduced in patients with renal impairment. Sitagliptin is the first of this class
to be approved. The adverse effects of the drug include headache, nasopharyngitis,
and upper respiratory tract infections.
+++
α-Glucosidase
Inhibitors
++
Acarbose and miglitol are
carbohydrate analogs that act within the intestine to inhibit α-glucosidase,
an enzyme necessary for the conversion of complex starches, oligosaccharides,
and disaccharides to monosaccharides that can be transported out
of the intestinal lumen and into the bloodstream. As a result of
impaired absorption, postprandial hyperglycemia is reduced. These drugs
have no effect on fasting blood sugar. Both drugs can be used as
monotherapy, or in combination with other anti-diabetic drugs.
This drug class has one of the shorter durations of action of the
oral antidiabetic drugs (Table 24–4).
++
The primary adverse effects of α-glucosidase
inhibitors include flatulence, diarrhea, and abdominal pain resulting
from increased fermentation of unabsorbed carbohydrate by bacteria
in the colon. Patients taking an α-glucosidase
inhibitor who experience hypoglycemia should be treated with oral
glucose (dextrose) and not sucrose because the absorption of sucrose
will be delayed.