American Journal of Therapeutics 13, 349–361 (2006)

A Review of Types 1 and 2 Diabetes Mellitus and

Their Treatment with Insulin

Afshin Salsali* and Muriel Nathan

Diabetes is a chronic disease characterized by hyperglycemia, and the prevalence of type 2 diabetes
is growing to epidemic proportions in certain populations. Type 1 diabetes is primarily the result of
autoimmune destruction of beta cells. Type 2 diabetes is found in those with resistance to the action
of insulin, usually as a result of obesity, and deficient insulin secretion. Insulin use not only
prevents hyperglycemic emergencies, but also is the best safeguard to prevent the long-term
complications of diabetes by correcting fasting and postprandial hyperglycemia. Intensive glycemic
control can lead to a substantial decrease in the development of microvascular changes found in
patients with diabetes. Human insulin analogs, insulins manufactured by recombinant technology
which contain substituted or rearranged amino acids, allow more physiological patterns of insulin
replacement, termed the basal–bolus approach. Serious hypoglycemia is the biggest obstacle for
patients with diabetes treated with intensive insulin programs. Insulin is now available in prefilled
pens or can be delivered by a programmable pump to allow greater flexibility in use and to improve
glycemic control. Whereas hyperglycemic emergencies are usually treated with intravenous fluids
and an intravenous continuous insulin infusion, patients who are less critically ill can be treated
with fluid and subcutaneous insulin analogs.

Keywords: diabetes, type 1 diabetes, type 2 diabetes, insulin analogs, ketoacidosis

INTRODUCTION AND Diabetes can be divided into 2 major categories, one

CLASSIFICATION
Diabetes is a chronic medical disease characterized by
hyperglycemia. It is the leading cause of medically
related disabilities, including blindness, amputation,
and renal failure, in the United States. In this country
alone, the number of persons with diabetes has grown
2-fold since 1997 and estimated to be over 13 million.1
An additional 5 million persons have undiagnosed
disease. Worldwide, the number of people with
diabetes is projected to more than double to 366
million by 2030. 2
Department of Endocrinology, University of Vermont, Fletcher
Allen Health Care, Burlington, Vermont.
*Address for correspondence: Department of Endocrinology,
University of Vermont, Fletcher Allen Health Care, 1 South
Prospect Avenue, Burlington, VT 05401. E-mail: Afshin.
Salsali@vtmednet.org
associated with primarily insulin deficiency called
type 1 diabetes (T1DM) and the other with resistance
to the action of insulin as well as a relative insulin
deficiency called type 2 diabetes (T2DM).3,4 T1DM
comprises 5% to 10% of those with diabetes and
T2DM, 90% to 95%.
Different types of diabetes are summarized in Table 1.
PATHOGENESIS
One common denominator that both T1 and T2DM
share is insulin deficiency, which is more pronounced
in T1DM.5 Autoimmune T1DM (which we refer to as
T1DM in this article) is by far the most common type
of type1 diabetes seen in clinical practice.3 In T1DM,
a selective destruction of the b-cells of the pancreas
by the immune system is the main reason for the
decline in insulin secretion.
Triggering of the immune response targeting
destruction of the b-cells is the result of genetic and

1075-2765 r 2006 Lippincott Williams & Wilkins

350
Table 1. Classification of diabetes.
Classification
Type 1 diabetes Type 1A
Type 1B
Others
Type 2 diabetes
Genetic defects in beta cell function MODY 1–6 and others
Genetic defects in insulin action Type A, Lipoatrophy, and others
Associated with endocrine disorders Cushing’s syndrome, Acromegaly,
and others
Associated with Drugs New-generation antipsychotics and
others
*Summarized from reference 3.
environmental factors.6 Patients diagnosed with
T1DM were found to have accumulation of immune
cells in the pancreas (insulitis) on autopsy and
biopsy.7 In addition, autoantibodies against the b-cell
or insulin are found in the blood of most patients with
T1DM.8
These findings have led to the premise that people
with T1DM have a prodromal phase of islet cell
inflammation and decreased insulin production be-
fore the development of hyperglycemia. This pro-
drome can last days to weeks in the classic form of
T1DM, in which symptoms of diabetes, including
polyuria, polydipsia, and weight loss, may have an
abrupt onset. This presentation is found in most of the
newly diagnosed children and some adults with
T1DM. In other adults, T1DM has a more prolonged
onset with gradually evolving hyperglycemia as a
result of preserved b-cell mass after a less extensive
inflammatory period. This type of DM is called latent
autoimmune diabetes of adult (LADA). In LADA,
patients do not initially require insulin despite having
markers of autoimmune diabetes.9
One of the hallmarks of T1DM is a period of
recovery after an initial period of acute hyperglyce-
mia; this is the honeymoon phase of T1DM. It lasts
from several weeks to months, most commonly seen
in children, to years as is typical in LADA. Patients
with T1DM are prone to acute hyperglycemia as well
as ketoacidosis attributable to relatively low endo-
genous insulin production; therefore, treatment with
insulin is an essential part of the management of
T1DM.
American Journal of Therapeutics (2006) 13(4)
Salsali and Nathan
Subtypes Characteristics
Autoimmune
Antibody against islet cells, insulin,
or GAD (>90%)
Association with HLA DR3 and 4
Idiopathic
Pancreatitis, pancreatectomy, cystic
fibrosis
Insulin resistance and relative insulin
deficiency
Defect in the production of different
transcription factors in beta cells
Severe insulin resistance
Very similar to type 2 diabetes
mellitus in presentation
Most commonly presenting as type 2
diabetes mellitus
T2DM, on the other hand, is characterized by both
insulin resistance and deficient insulin secretion. The
inability of the pancreas to secrete insulin is un-
masked when there is increasing demand for insulin
as a result of resistance to insulin action. These
individuals usually have a metabolic syndrome of
obesity, hypertension, hyperlipidemia, and hypergly-
cemia.10–12 Some of the known insulin resistance
states are pregnancy, Cushing’s syndrome, acrome-
galy, and polycystic ovary syndrome. T2DM is the
most complex form of diabetes in terms of etiology
and genetic predisposition.
The capacity of b-cells to secrete insulin declines
with age; therefore, it is not surprising that there is a
higher incidence of T2DM in older adults. Never-
theless, any insulin-resistant state such as obesity,
pregnancy, or puberty may expedite the emergence of
hyperglycemia, especially in certain ethnic groups at
high risk such as Hispanics, blacks, and Native
Americans. This is now reflected in an alarming
number of children with new-onset T2DM who are
overweight, whereas those with T2DM are outnum-
bering patients with T1DM as the leading cause of
diabetes in this age group. The UKPDS, one of the
largest prospective studies of T2DM, suggested that
nearly 50% of the insulin secretory capacity of the
pancreas has already diminished at the time of
diagnosis with the gradual loss of the rest within the
next 5 to 10 years.13 This loss in insulin secretory
capacity is the result of progressive loss of b-cell mass,
which has started months to years before the
diagnosis of T2DM.13 There was also a steady increase
DM and Treatment with Insulin
IV G luc os e
St im ulus
Insulin
Secretion ST
1st
1 phase
Phase
–10 –5 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90
Insulin
Secretion
–10 –5 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90
Time (minutes)
FIGURE 1. Phasic secretion of insulin in non-diabetic and diabetic patients.
in the requirement for diabetes medications from one
to 2 oral agents within 3 years from the onset of
diabetes and multiple drug therapy, including insulin,
after 9 years, in more than 75% of patients with
T2DM.14 This important finding stresses the role of
insulin therapy in T2DM when oral therapy is failing
as a result of diminished b-cell reserve.
As learned from the pathophysiology of diabetes,
treatment with insulin is essential and lifesaving in
T1DM. These patients can die of acute complications,
including hyperglycemia and ketoacidosis, if insulin
is not replaced. Additionally, intensive blood glucose
control, reflected in low hemoglobin A1C level, has
been proven in many studies to be the best safeguard
to prevent long-term complications of diabetes,
especially those related to microvasculature damage
such as retinopathy, nephropathy, and foot ulcers.15
This goal is only achievable with multiple injections
or continuous subcutaneous insulin in T1DM and
synergistic therapy for oral medication with insulin
or insulin alone in many patients with T2DM.
Physiological secretion of insulin is composed of
basal and postprandial components. Basal secretion
refers to the amount of insulin that is needed between
meals. It is composed of small and continuous pulses
of insulin around 30 to 35 units per day in an average
adult. Postprandial insulin secretion is triggered by
eating and is composed of a high amplitude pulse, as
compared with the basal secretion, leading to a sharp
increase and decrease in the insulin level. The amount
351
Non-Diabetic
ND
2
P phase
2nd hase
Diabetic
of postprandial insulin is mainly determined by the
type and amount of food ingested.
After intravenous infusion of glucose, 2 phases of
insulin secretion can be observed; the first phase is
a brisk but short-term release of insulin followed by
more prolonged and sustained secretion. The first
phase of the insulin response, which is lost in patients
with diabetes, is mostly related to the release of
presynthesized insulin, whereas the second phase is
associated with the secretion of newly formed insulin
(Fig. 1).
DIAGNOSIS
The diagnosis of diabetes is made either through the
routine measurement of blood glucose or after an oral
glucose tolerance test (OGTT). Polyuria and poly-
dipsia are among the most common symptoms of
diabetes, but patients may be asymptomatic until
blood glucose is above 180 mg/dL. Glucosuria is only
detected when the blood glucose level exceeds the
renal threshold of 180 to 200 mg/dL, above which the
extra glucose is filtered through the kidneys and can
be measured in the urine. Weight loss, vaginal
candidiasis, or occasional blurry vision is among
other common symptoms. Complete or relative loss of
insulin secretion may lead to diabetic ketoacidosis
(DKA). DKA is potentially a life-threatening situation,
and in many cases, the onset is associated with mild to
American Journal of Therapeutics (2006) 13(4)
352 Salsali and Nathan

Table 2. Diagnosis of diabetes and prediabetes. period varies in different forms of diabetes from
weeks to years. Thus, it is imperative for the medical
OGTTz community to diagnose patients in the prediabetes
w
FPG* Random (2 hr postchallenge) phase and to try to intervene to reverse or delay the
Normal < 100 < 140 < 140 progression to full-blown diabetes to decrease the
Prediabetes 100–125 (IFG) 140–200 (IGT) morbidity associated with diabetic complications.
Diabetes Z126 Z200 Z200 Diabetes is diagnosed when fasting plasma glucose
is equal or greater than 126 mg/dL or a postchallenge
*No food or drink except for water for 8 to 10 hours. plasma glucose exceeds 200 mg/dL. A random blood
w
Provisional diagnosis, need confirmation with FPG or OGTT.
Random test is diagnostic only if patients have proper
sugar >200, in an individual with symptoms of
symptoms of diabetes. diabetes, is also consistent with the diagnosis of
z
Ingest 75 g oral glucose after an overnight fasting. diabetes.
FPG, fasting plasma glucose; OGTT, oral glucose tolerance test; Impaired fasting glucose (IFG), or impaired glucose
IFG, impaired fasting glucose; IGT, impaired glucose tolerance. tolerance test (IGT), is referred to as ‘‘prediabetes.’’ It
is most commonly seen in overweight individuals
moderate symptoms such as nausea, vomiting, and with central obesity. People with prediabetes are more
abdominal pain in addition to high blood glucose. prone to diabetes or its vascular complications.
Whereas it might be a common presentation in T1DM, Occasionally, autoantibodies against insulin or
DKA is rarely seen in T2DM. Blacks and Latino other islet cell antigens as well as serum C-peptide
Americans are especially prone to DKA as compared or insulin levels are measured to confirm the
with other patients with T2DM.16 diagnosis of T1DM.
The criteria for the diagnosis of diabetes and As pointed out in the following section, there are
impaired fasting glucose has changed over the last different types of insulin, many of them made
several years as our understanding has improved available to us in the last several years. The advent
about the normal level of blood glucose and the level of newer insulin analogs allow us to provide to
that is associated with diabetic complications. One of patients a more efficient regimen and type of insulin
the changes proposed by the American Diabetes replacement, similar to the natural physiological
Association was for the diagnosis of prediabetes.3 secretion of insulin.
The diagnosis of diabetes can be established by
checking either a random or fasting blood glucose
(Table 2). INSULIN THERAPY
Whereas a standard OGTT may also be used for the
diagnosis, it is mostly used in clinical studies or to
Introduction
identify patients with a tendency toward diabetes
known as prediabetes. Insulin, an 86-amino acid 6000 molecular-weight
Many patients with diabetes go through a phase of protein, is the only medication for glucose control in
impaired fasting glucose or impaired glucose toler- people with T1DM. Most of people with diabetes, and
ance, collectively referred to as prediabetes, before the fastest growing segment of the population with
full-blown diabetes develops (Fig. 2). The transitional diabetes, are those with T2DM. Standard glycemic
goals are often not met with oral medications, dietary
Obesity IGT/IFG Diabetes
interventions, and physical exercise in those with
Plasma
T2DM.17,18 Insulin for these people is often viewed as
Glucose a treatment of last resort, and many doctors and
120 (mg/dL)
nurses ‘‘threaten’’ patients with the use of insulin if
100 (mg/dl) they do not stick to their diet and exercise regimens.
Insulin is viewed as the medication to use to avoid
Insulin Level diabetic emergencies such as ketoacidosis, but is not
(β-cell Function)
seen as the tool to correct or reverse dyslipidemia and
100 (%) diabetic complications. Further studies of people with
T2DM show that there is a slow progressive loss of
–10 –5 0 5 10 20 beta cell function such that 35% of them will need to
Time (Years)
use insulin.13 There is a shift in paradigm now in
FIGURE 2. Evolution of diabetes and impairement of which insulin is viewed not only as a hypoglycemic
insulin secretion. agent for all patients with diabetes, but also as a
American Journal of Therapeutics (2006) 13(4)
DM and Treatment with Insulin 353

Table 3. Goals of insulin therapy.
Elimination of glucosuric symptoms.
Prevention of diabetic ketoacidosis and hyperosmolar
state.
Delay, arrest, or prevent microvascular and
macrosvascular complications of diabetes.
Decrease in fetal malformations and fetal and maternal
morbidity in pregnancy.
Restoration of lost lean body mass.
Improvement in exercise capability and work
performance.
Improvement in sense of well-being.
Reduction in frequent infections.
Reprinted from reference 22.
medication that slows the progression of diabetic
complications13,15 and decreases the risk of adverse
cardiovascular events19,20 (Table 3).
History
Banting and Best first used insulin extracted from
bovine pancreata to treat a boy with T1DM in Toronto
in 1922.21 Before the use of insulin, T1DM was treated
by diet alone, leading to slow marasmus and
inevitable death. At first, soluble insulin extracted
from animal sources was available for injection at
each meal and bedtime. Regular insulin, the standard
insulin preparation, is crystalline zinc-insulin in a
clear neutral pH buffer. In 1936, Hagedorn discovered
that the onset and duration of insulin activity after
injection could be altered by adding basic proteins to
it. Scott and Fisher showed that same year that zinc
could also prolong the duration of injected insulin.
This led to the manufacture of neutral protamine
Hagedorn (NPH) insulin and Lente insulins, and
patients often took these once or twice a day.22 Their
actions and durations are comparable (see Table 4),
although NPH has a slightly shorter onset of activity
and peak.
Before 1970, injected insulins were not pure and
contained contaminants, particularly proinsulin and
other proteins from the islet cells such as glucagon,
somatostatin, and pancreatic polypeptide.22 Purifica-
tion methods have now improved from using
recrystallization (impurities were up to 20,000 ppm)
to using ion-exchange chromatography and molecular
sieving techniques (impurities are up to 20 ppm
or less).22
Until the 1990 s, the most commonly prescribed
insulins were extracted from bovine or porcine
pancreata. There was a concern then that beef or pork
insulin would lead to the production of antibodies,
increasing insulin resistance. Eli Lilly Company then
manufactured human insulin (Humulin line) in 1981
using recombinant DNA technology to synthesize the
alpha and beta chains of insulin within Escherichia coli.
Novo Novodisk followed with human insulins
(Novolin line) made by DNA technology using yeast.
These human insulins have a quicker onset of activity
compared with animal insulins and a shorter duration
of action.23 There are few well-designed comparative
blind studies in the literature, but 18 studies recently
reviewed to look at ‘‘evidence-based medical prac-
tices’’ concludes that human insulins do not differ
significantly from animal insulins in efficacy (based
on HgbA1cs, fasting glucoses) or in creating less
hypoglycemia.24 Antibodies to insulin were decreased
when human insulin use was compared with bovine
insulin use, but there was no difference when human
insulin use was compared with porcine insulin. The
authors concluded that there was little evidence to
support the use of human rather than animal insulins,
particularly because patient preferences were not
considered. Nonetheless, to use animal or human
insulin became a moot point after 1998, when the
Eli Lilly Company stopped manufacturing beef and
beef–pork insulins. The shift to human insulins was a
fait accompli after that.

Table 4. Pharmacokinetics of subcutaneous insulin

preparations. ANALOG INSULINS
Peak Duration
Insulin Onset (hours) (hours) The newest insulins are insulin analogs25 or designer
insulins, which appeared on the market for use after
Lispro or Aspart 15–30 mins 1–2 3–5 1995. These insulins are no longer classified as ‘‘long-
Regular 30–60 mins 2–4 6–8 acting’’ or ‘‘short-acting,’’ but rather are made to
Neutral protamine 1–3 hrs 5–7 13–18 mimic the action of endogenous insulin and are
Hagedorn classified as basal (fasting) or bolus (mealtime)
Lente 1–3 hrs 4–8 13–20 insulins.
Ultralente 2–4 hrs 8–14 18–30
The newest rapid-acting bolus insulins include Eli
Glargine None None 24
Lilly’s Humalog (lispro), Novo Novodisk’s Novolog
American Journal of Therapeutics (2006) 13(4)
354
(aspart), and Sanofi-Aventis’ Apidra (glulisine), which
is expected to be released April 2005. These designer
insulins differ from the human insulins in that certain
amino acids in the insulin molecule itself are
rearranged or substituted to allow a faster onset of
activity and shorter duration. When Humulin or
Novolin regular insulin is injected, insulin monomers
tend to self-associate from hexamers or tightly packed
insulin crystals in the concentrated solution.22 The
crystal formation is dependent on the presence of
preservatives metacresol and phenol within the
solution. The formation of these crystals is a critical
factor in the absorption and onset of action for insulin,
and regular insulin resulting from its slower absorp-
tion compared with analogs shows a greater varia-
bility in absorption and insulin action between users
and even within the same person, leading to day-to-
day variability in glycemic control. Lispro differs from
regular insulin in that the 28th and 29th amino acids
of the beta-chain of insulin are reversed to form lys-
pro instead of pro-lys.25,26 This results in weaker self-
association of the insulin monomers, preventing the
formation of hexamers. In addition, the preservative is
rapidly lost from the concentrated solution after
injection, so that the insulin monomers are more
rapidly absorbed. Aspart is a recombinant human
insulin in which aspartic acid is substituted for
proline at B28.25
Glulisine has a lysine substituted for arginine at
B3 and glutamic acid replaces lysine at B29.
Of designer basal insulins, Glargine (Lantus by
Sanofi-Aventis) was the first to be released in 2001.25 It
has no onset of action or peak as a result of the
addition of 2 arginines at the carboxyterminal end of
the beta chain (B31 and B32) and the substitution of
glycine for asparaginase at A21, which delays its
solubility at physiological pH. Because Glargine
precipitates at physiological pH, the solution is
acidic (pH 4), thus other insulins cannot be mixed in
the same syringe as the Glargine. Once a vial of
Glargine is opened, it should be discarded after 28
days.
Another basal analog insulin to be released in 2005
is Detemir (Novo Nordisk). This analog created by
fatty acid acylation within the insulin molecule is like
NPH and is used twice a day, but has less of a peak. In
preliminary testing among type 1 and 2 patients with
diabetes, Detemir led to improved glycemic control
without weight gain, which could prove to be a
substantial advantage over other insulins and insulin
secretagogues.
Most studies comparing human and analog insulin
use found that postprandial glucoses were lower
and hypoglycemic episodes were lower, particularly
American Journal of Therapeutics (2006) 13(4)
Salsali and Nathan
overnight, with the newer analogs.25–28 This was true
whether an analog was used at dinnertime or at
bedtime. Not all studies showed a benefit in lowering
the HgbA1c.25
KINETICS OF THE COMMON
INSULINS
Insulin injected intravenously has a circulating half-
life of 5 to 10 minutes unless insulin antibodies are
present. Insulin distribution is estimated to be the
extracellular space or approximately 16% of body
weight. The liver clears most of the insulin (50%),
whereas the kidney and skeletal muscle account for
the rest of the clearance. The clearance rate is 700 to
800 mL/meter-squared/min. As supraphysiological
doses of insulin are given, the liver clearance becomes
saturated but the kidney does not. To prepare insulin
infusions, usually regular insulin is added to a saline
solution at a concentration of 1 U/mL. It is stable at
room temperature or at 41C for 24 hours. All lines
must be flushed to prevent absorption of insulin by
the tubing.29 This is usually done initially, and then a
second flush is done 30 minutes later before the
infusion is initiated.
Bioavailability of injected insulin is 55% to 77%,
and it is either excreted unchanged by the kidney
or metabolized by the kidney and liver.29 Insulin
does not cross the placenta and has until recently been
the sole option for treatment of hyperglycemia
in pregnant women. Subcutaneous insulin absorption
is variable between sites, and the presence of
insulin antibodies can prolong this activity. Insulin
absorption is increased if low doses are given or sites
are chosen that have increased subcutaneous blood
flow such as limbs after exercise, massage, or
heat exposure. Abdominal injection of insulin is often
more rapidly absorbed than insulin given in the thigh
or arm at rest.29 Decreased insulin absorption
could occur from injecting high doses or a more
concentrated solution of insulin. For example, most
insulin in the United States is U100 (concentration
of 100 U/mL), but there is U500 Regular that is often
used to treat people with high insulin requirements,
usually more than 200 units per day. If a large dose of
U500 Regular is injected subcutaneously, its duration
of action may be similar to smaller volumes of
intermediate-acting insulins. Finally, the onset
of action of insulin can be delayed by injecting into
a subcutaneous area with poor blood flow from shock,
cold exposure, or lipohypertrophy. To prevent the
latter, it is suggested that the sites of insulin injections
are rotated to prevent repetitive use of the same site.
DM and Treatment with Insulin
Table 5. Brand names of insulin.
Rapid-acting Intermediate-acting
Human Humulin R, Novolin R, Humulin L, Humulin N,
Novolin R penfilled, Novolin L, Novolin N,
Velosulin Human Novolin N penfilled
Analog Humalog, Humalog pen,
Novalog, Novalog
penfilled, Novalog
flexpen Apidra*
*To be released in 2005.
It is also important to note that the upright posture
will decrease blood flow to the legs and to a
lesser extent the abdominal wall, decreasing insulin
absorption.29
Whereas intradermal injections are painful and are
not well absorbed, intramuscular injections can result
in a more rapid absorption of insulin and can be used
for a quicker response to hyperglycemia. Intramus-
cular injections should not be used repetitively
because this can cause scar tissue to form.
Certain intermediate-acting and short-acting insu-
lins can be mixed in the same syringe without
degrading the activity of the component insulins.
Regular insulin and insulin analogs can be mixed
with NPH, thus insulin mixtures are also available
(see Table 5). Lente and Ultralente insulins can be
mixed with short-acting insulins if the injection
is given immediately after. Thus, these types of
longer-acting insulins are not available as premixed
solutions.
Insulin should be kept refrigerated until the time
of use; on opening a vial, the insulin is kept at room
temperature and discarded after a month of
use. Insulin is discarded sooner if the solution
contains particulate matter or is frozen or in direct
sunlight. Insulin with the exception of Glargine can be
stored as prefilled syringes in the refrigerator for up to
3 weeks.
BASAL–BOLUS REGIMEN
Providing continuous basal insulin throughout the
day and night with boluses of insulin at mealtimes
can be used for those with either type 1 or type 2
diabetes (Table 6). If regular insulin is used, injections
are given approximately 30 to 45 minutes before
meals. Injecting regular insulin just before the meal
355
Long-acting Mixtures
Humulin U Humulin 50/50, Humlin 70/30,
Novolin 70/30, Novolin 70/
30 penfilled, Novolin 70/30
prefilled
Lantus Detemir* Humalog 75/25, Humalog
75/25 pens, Novalog 70/30,
Novalog 70/30 penfilled,
Novalog 70/30 flexpen
often results in a mismatch of food and insulin,
because the postprandial glucose will rise before the
insulin peaks. In addition, when the insulin peaks
much later, hypoglycemia can ensue. To avoid this,
shorter-acting analogs, Aspart and lispro, are pre-
ferred premeal and are more convenient for people
who often ‘‘eat on the run’’ and have variable
mealtimes.25,27,29
Basal insulins Ultralente and NPH are often given
multiple times a day, often prebreakfast and pre-
dinner. The advantage of using these basal insulins is
that these can be mixed with short-acting insulins,
decreasing the number of insulin injections. The
disadvantages of using Ultralente and NPH as basal
insulin include their intrapatient variability in effect
and that both insulins have peak action in 5 to 7 hours,
which can create unpredictable nocturnal hypoglyce-
mia. For this reason, some practitioners move the
second NPH injection from predinner time to bed-
time.
At this time, there is one insulin (Glargine) that is
peakless and thus can be given once a day, providing
effective basal insulin coverage. It is often given at
bedtime because it cannot be mixed in the same
syringe with the premeal analogs. Basal coverage is
approximately 50% of the total calculated insulin
dose per day. Recent papers suggest that not only can
Glargine be given prebreakfast, but it may be more
effective given at that time.25
Patients using a basal–bolus multiple shot regimen,
are taught to count carbohydrates to estimate meal-
time insulin coverage, and correct any premeal
hyperglycemia using a predetermined correction
factor for each premeal insulin bolus. For most
patients with T1DM, 1 unit of insulin is used for
every 15 g of carbohydrates (1:1 carbohydrate
exchange) ingested and 1 unit of insulin is added to
correct every 50 mg/dL above premeal goals, usually
American Journal of Therapeutics (2006) 13(4)
356
Table 6. Estimation of insulin boluses in a basal–bolus
regimen.
For less intensive control or those not on insulin
analogs:
Sensitivity factor for correction factor = 1500/total
insulin dose.
Correction factor = blood sugar (mg/dL)–120/sensitivity
factor.
500/insulin dose = sensitivity factor for carbohydrate
coverage.
Meal coverage = carbohydrates (g)/sensitivity factor.
For more intensive coverage or those on analogs or
those on insulin pump:
1800/total insulin dose = sensitivity factor for
correction factor.
Correction factor = blood sugar (mg/dL)–100/sensitivity
factor.
450/insulin dose = sensitivity factor for carbohydrate
coverage.
100 to 120 mg/dL. In those who are more insulin-
resistant, using a ratio of 1:7 and a correction factor of
1:25 may be more effective.
REGIMENS FOR OUTPATIENTS
Insulin needs depend on the amount of insulin
deficiency and resistance and can be gauged by the
body weight and exercise regimen of the patient.
Dietary practices such as eating the largest meal at
noon or 6 PM can also dictate which insulin program is
more likely to be successful. Nonobese patients
(usually type 1) start at 0.4 to 0.6 U/kg, whereas
obese patients may need 0.7 to 1.0 U/kg with 50% of
the dose as the basal insulin. Medications can increase
or decrease the need for insulin (see Table 7). Patients
with renal or hepatic failure require less insulin,
usually 0.3 U/kg. Insulin needs will increase precipi-
tously in pregnant women and teenagers in their
growth spurt so that taking 2 U/kg is not unusual.
DAYTIME ORALS WITH BEDTIME
INSULIN
Studies have shown that patients with T2DM can
attain better glycemic control with less weight gain by
taking one insulin shot at bedtime rather than multi-
ple shots (Table 8). Glargine often leads to lower
morning glucoses without hypoglycemia compared
with NPH, and a recent study shows that patients can
American Journal of Therapeutics (2006) 13(4)
Salsali and Nathan
be instructed to increase the dose of Glargine by 1 U
per night until morning glucoses are at goal.28,30
Often, once the fasting glucose has been lowered,
other glucoses during the day are lower, and
concomitant use of an oral sulfonylurea can be
reduced in dosage or discontinued. Metformin is
continued at 1000 to 2000 mg per day, because of its
ability to decrease exogenous insulin requirements
without causing significant weight gain. If glucoses
are high postdinner and fasting, Novolin or Humulin
70/30 or an analog mixture (Humalog 75/25 or
Novolog 70/30) can be given predinner. If glucoses
remain high prelunch and predinner, despite normal
glucoses in the morning, the patient is advanced to 2
injections of mixed insulin. Premixed insulin, 75/25
Humalog or 70/30 Novalog, can be used for conve-
nience. If glucoses are still above goals, short-acting
insulin at each meal with bedtime Glargine is
recommended.
COMPLICATIONS OF INSULIN
THERAPY
The most dreaded complication of using insulin,
particularly for those on intensive regimens, is
hypoglycemia. At the extreme, repeated episodes of
hypoglycemia (glucoses < 65 mg/dL) can lead to
permanent brain damage (hypoglycemic encephalo-
pathy) or death. Patients with insulin-dependent
diabetes have one to 2 episodes of hypoglycemia per
week and up to 25% experience severe hypoglycemia
with seizure or coma each year. Hypoglycemia causes
death in 4%.31 In a study of up to 5000 patients on
intensive subcutaneous continuous insulin infusions,
there were 12 unexpected deaths from 1972 to 1982
attributed to hypoglycemia.32 It was recommended
that patients with renal failure, panhypopituitarism,
adrenal failure, or autonomic neuropathy and those
on beta-blockers be excluded from meticulous control
of diabetes. This opinion was written before insulin
analogs were used. Analogs have significantly
Table 7. Drug interactions.
Decrease insulin effectiveness:
Corticosteroids, oral contraceptives, diltiazem,
epinephrine, niacin, thiazides, smoking.
Increase insulin effectiveness:
Alcohol, alpha-adrenergic blockers, nonselective beta-
blockers, clofibrate, fenfluramine, MAO inhibitors,
pentamidine, salicylate, tetracycline, anabolic steroids,
and guanethidine.
DM and Treatment with Insulin
Table 8. Estimation of insulin use for those on oral
medications and bedtime insulin.
Start with a basal insulin dose of 0.3 U/kg or, for
Ultralente, can estimate basal insulin by average
morning glucose-50/10.
For Glargine, can start at 10 U and increase by one
unit each day until morning glucose is at goal of
70–110 mg/dL.
decreased by 25%, but not eliminated, severe hypo-
glycemia for those on intensive insulin programs. 25
Hypoglycemia in insulin-treated patients is more
common, because exogenous insulin interferes with
endogenous hormone pathways that act to correct
hypoglycemia. Glucagon release, which normally
occurs as glucose levels falls to promote release of
glucose from tissue stores through gluconeogenesis
and glycogenolysis, is suppressed by insulin. Insulin
decreases the availability of other substrates by
promoting organ storage. Furthermore, those patients
with autonomic neuropathy have the additional
inability to respond to falling glucose levels by
increasing catecholamine release, which promotes
glucagon release and inhibits insulin release. Epi-
nephrine becomes a critical part of the defense against
hypoglycemia when glucagon is deficient.31
Higher than ideal (>110 mg/dL) glucoses in the
morning in patients with diabetes have been attrib-
uted to several processes. First, a patient could have
low levels of insulin as a result of the viable
absorption and peaks of intermediate-acting insulins
given at dinnertime or bedtime. Second, the patient
may be responding to higher levels of counter-
regulatory hormones for insulin such as growth
hormone and cortisol that peak in the morning, the
so-called dawn effect. Finally, a patient with a slightly
higher glucose in the morning may have had
undetected hypoglycemia overnight, called the So-
mogyi effect, in which blood glucoses increase after
hypoglycemia as a result of increased cortisol, growth
hormone, and catecholamine secretion at the time of
hypoglycemia. The Somogyi effect has been called
into question, particularly for most adults with
diabetes, and it is now thought that hypoglycemia
usually leads to lower and not higher glucose read-
ings.31,33,34
Besides increasing the risk for hypoglycemia, there
are some more common and uncommon side effects
of using insulin. Insulin use is associated with weight
gain. In the Diabetes Control and Complications Trial
(DCCT) trial, the patients on intensive insulin regi-
357
mens gained 5.1 kg versus those on conventional
therapy who gained 2.4 kg.15 In the UKPDS study,
those on insulin or insulin secretagogues gained
weight (10.4 kg for insulin users and 3.7 kg for those
using sulfonylureas), whereas those on metformin
had no significant weight gain.13 Some of this is the
result of sodium and fluid retention, which can lead to
frank edema, particularly if there was a period of
uncontrolled blood glucoses. The edema may be the
result of increased capillary permeability associated
with poor control, whereas the sodium retention is the
result of the effect of insulin on the kidney and the
lowering of glucagon levels, because glucagon is
natriuretic.35 Most of the weight gain resulting from
insulin use is attributed to the decreasing glucosuria
with absorption of calories that were previously lost
in the urine.
Occasionally, people on insulin report lightheaded-
ness after insulin use. Patients with a history of
autonomic neuropathy may experience cerebral hypo-
perfusion after insulin injection as a result of its direct
vasodilation of vascular beds.
Local and systemic reactions to insulins are now
rarer as the purity of the product has improved and
now there is less antigenicity with the use of human
insulins. There seems to be a genetic predisposition to
insulin allergy. Studies have shown that insulin
antibodies are more likely to form if a patient is
HLA-BW44 and DR7 or B15 or DR4 than those with
B8 and DR3.36 Most reactions (>75%) are now local,
including pruritus, erythema, and induration at the
site of injection. These reactions usually sponta-
neously resolve after 2 to 3 weeks of therapy. Insulin
users can also have local or systemic reactions to
insulin additives such as zinc and protamine. Using
analog insulins may solve this problem. Whereas
lipohypertrophy from repeated insulin injection into
one site is a nonimmune phenomenon, lipoatrophy is
thought to be an immunologic response to insulin.
In this situation, subcutaneous fat is lost from an
injection site, which can cause frank disfigurement as
a result of impurities in the insulin. It is thought
that the immune reaction causes a lipolytic cytokine to
be released, because biopsies of affected areas contain
immunoglobulins and C3.37 This condition is treated
by injecting the sites with purified insulin,
which leads to restoration of normal subcutaneous
fat in a few months. Serious insulin reactions,
including anaphylaxis, generalized urticaria, or an-
gioedema, are mediated through IgE antibodies.
Desensitization techniques are then used to allow
use of insulin.
Several studies have shown that retinopathy wor-
sens during the first year of improved glycemic
American Journal of Therapeutics (2006) 13(4)
358
control in persons with underlying retinopathy pre-
viously suboptimally controlled in terms of blood
sugars.15,38 After 5 to 7 years of improved blood sugars,
the degree of retinopathy is less severe than those with
continued uncontrolled glucoses. Yet, during the first
year of improved control, proliferative retinopathy can
occur leading to blindness in patients with either type 1
or T2DM. The risk of worsening retinopathy appears to
be dependent on the degree of poor control before
intensification of control and the amount of decline in
the HgbA1c during the first year. The retinal damage is
likely the result of retinal ischemia and elevated IGF-1
levels during that time. This has led to a mixed message
to patients with retinopathy. Thus, it is recommended
that patients with known retinopathy see an ophthal-
mologist more frequently during the start of a more
intensive insulin regimen.
Glargine is the first clear rather than cloudy long-
acting insulin, which has led to many errors among
patients mistakenly using it premeal or using analogs
at bedtime leading to serious hypoglycemia. This
error can be reduced by using Glargine with orals in
type 2 patients with diabetes or using a syringe or
pen-filled Glargine at bedtime with insulin pens filled
with human regular insulin or analogs at meals in
type 1 or type 2 patients with diabetes.
INTENSE GLYCEMIC CONTROL
AND COMPLICATIONS OF
DIABETES
Only a minority of patients with diabetes die during
hyperglycemic emergencies. Most of the morbidity
and mortality is from complications of diabetes, either
microvascular or macrovascular disease. Although it
was always postulated that uncontrolled hyperglyce-
mia was the cause of diabetic complications, it was
not proven until 1993 that intensive control of blood
sugars could delay or slow the progression of
retinopathy and nephropathy. In a large multicenter
center, the DCCT studied the effect of intensive insulin
use (3–4 injections of insulin per day or use of an
insulin pump) versus conventional 1 to 2 injections
per day.15 The study included 1441 type 1 patients
with diabetes who were followed for 3 to 9 years
(mean 6.5 years or a total of 9300 patient-years). The
study had an astounding 99% completion rate and
a treatment compliance rate of 95%. The risks of
developing retinopathy or microalbuminuria de-
creased 76% and 34%, respectively. The risk of
progression of retinopathy and microalbuminuria
decreased 54% and 56%, respectively. The risk of
neuropathy was reduced 57% and its progression
American Journal of Therapeutics (2006) 13(4)
Salsali and Nathan
reduced 69%. It is to be noted that at the time of this
study, the analog insulins were not available and most
patients were on NPH and Regular. Furthermore,
although there was a tendency to see fewer
macrovascular complications, the study enrolled young
adults (mean age 26–27 years), in which cardiac events
were exceedingly rare. The take-home message of this
important trial was that any improvement in glycemic
control would be expected to be beneficial.
Nonetheless, the DCCT trial highlighted several
adverse effects of intensive insulin use. First of all, the
patients on intensive treatment experienced a 4.6-kg
weight gain compared with controls. There was also a
3-fold increase in the number of hypoglycemic events
in which the person needed assistance to recover.
Finally, intensive insulin therapy appeared to increase
retinopathy.15
The positive message of the DCCT was repeated at
the end of the U.K. Prospective Diabetes Study
(UKPDS), which looked at more intensive control of
blood glucoses in persons with T2DM.13 This study
was also ambitious in studying 5102 patients for 10
years. Insulin was not used in all patients, but results
showed that lowering the HgbA1c reduced micro-
vascular complications. Whereas insulin use was
again associated with more hypoglycemia and weight
gain, there was no evidence that the higher endogen-
ous insulin levels led to macrovascular disease. In
fact, there was a 16% reduction in myocardial
infarctions and sudden death.
The results of the DIGAMI study showed that good
glycemic control and the use of insulin decreased
mortality and morbidity in this patient group.19 Far
from the predicted outcome, those patients perceived to
be at the lowest risk for complications benefited the
most, leading some researchers to hypothesize that the
benefit was not related to blood sugar reduction alone.
Follow-up studies using insulin during and after
cardiac events led to the hypothesis that insulin exerts
an antiinflammatory effect. During myocardial infarc-
tion, plasma markers of inflammation rise.20 Insulin
infusion can reduce increases in C-reactive protein
and serum amyloid A. Furthermore, increase in PAI-1
was suppressed, as well as p47 phox-subunit
of NADPH oxidase, which generates superoxide
radicals, causing oxidative stress. More patients in
the insulin-treated group had >50% ST-segment
resolution.20
NEWER INSULIN DELIVERY DEVICES
Insulin pens allow delivery of insulin without the
need to fill syringes, avoiding errors in drawing up
DM and Treatment with Insulin
the insulin. Pens are available for all the human
insulins and analogs except Ultralente and Lente
(Table 5). Insulin mixtures, both human and analogs,
are also available in pen-delivery systems. The pens
are either disposable with prefilled insulin or take
cartridges containing 300 units (3 mL). They are ideal
for patients on intensive regimens who like the
portability of the product and need to take injections
away from home prelunch or predinner. The pen can
deliver 1- or 2-unit increments of insulin, and there is
a Novolog junior pen that allows half-unit dosing for
the youngsters with diabetes or those adults with low
insulin requirements and high insulin sensitivity as a
result of low weight, increased exercise, or renal
insufficiency.
Several manufacturers sell insulin pumps, devices
that contain a small syringe that can be filled with
insulin and can be programmed using a touchscreen
to deliver through a catheter placed in a subcutaneous
site small hourly doses of insulin (basal needs) and
insulin boluses before meals. The site is changed
every 48 to 72 hours, and the insulin syringe often
holds 220 to 350 mL of an insulin analog.
These devices are now very sophisticated, about the
size of a common pager. Users can program the pump
to calculate mealtime coverage (based on carbohy-
drate counting and insulin ratios) and to calculate
insulin use to cover episodes of unexpected hyper-
glycemia.
INHALED INSULIN
Cefalu reported that after a 3-month study in 26
patients with T2DM, there was no significant change
in pulmonary function, whereas blood sugar control
improved when patient were switched from orals or
insulin injections to inhaled insulin use at mealtimes
and bedtime.39 The inhaler delivered consistent doses
of insulin, similar to injected insulin in bioavailability
and potency. Intrapulmonary insulin delivery has
been preferred to intranasal delivery, because the
latter would require the use of surfactants to allow
insulin to cross the nasal mucosa, and the bioavail-
ability of the dose is low at no more than 10%.
TREATMENT OF HYPERGLYCEMIC
EMERGENCIES
Treatment of hyperglycemic emergencies is now
undergoing a change in practice, mainly as a result
of the economic impact of treating uncontrolled
hyperglycemia. Since 1973, low-dose intravenous
359
Table 9. Insulin therapy for uncomplicated diabetic
ketoacidosis (DKA).
Initially give 1 L 0.9% NS, then 1/2 NS at 200–1000 L/hr.
K is replaced before insulin if K < 5.5 mEq/L and K is
checked every 1–2 hrs until resolution of DKA.
Confirm ketoacidosis and give 0.4 U Regular insulin/kg
body wt, 1/2 given subcutaneously and 1/2 given
intravenous push; use 7–10 U/hr (0.1 U/kg) as a
continuous infusion if ketoacidosis is severe or patient
is comatose.
When the blood glucose reaches 250 mg/dL, change to
100–300 mL/hr D5-1/2NS if the Na >140 mEq/L; use
D5NS if the Na is less than 140 mEq/L.
Decrease intravenous infusion to 0.05 U/kg/hr and adjust
every 2 hrs to keep glucose between 100–160 mg/dL in
alert patients and 160–220 mg/dL in obtunded patients.
When glucose is under 200 mg/dL, HCO3 >15 mEq/L and
pH >7.3, if patient is ready to eat change to
subcutaneous insulin.
Reprinted from references 40 and 41.
insulin infusion using Regular insulin during diabetic
ketoacidosis was shown to result in the same
improvements in glycemia and ketonemia as high-
dose insulin (50 U) given subcutaneously without the
same risk of hypoglycemia or hypokalemia. During
DKA and nonketotic hyperosmolar coma (NKHC),
use of Regular insulin intravenous infusions have
become the standard the care40,41 (see Table 9). It is
noted whereas Humalog can be given intravenously,
it offers no advantage over intravenous Regular
insulin. In addition, whereas fluids can initially
decrease blood sugar by dilution and increasing
glucosuria, only the use of insulin can lead to near-
normal glucoses and facilitate ketoanion metabolism
leading to hydrogen ion consumption and regenera-
tion of bicarbonate in DKA. In NKHC, it is often not
necessary to use an insulin infusion, because the
Table 10. Therapy for uncomplicated diabetic
ketoacidosis (DKA).
Patients in DKA are given 1 L NS, then 500–1000 cc/hr NS.
Give 0.3 U/kg subcutaneous Lispro after initial 1 L NS,
then 0.1 U/kg/hr subcutaneous Lispro.
Once glucose is 250 mg/dL, decrease to 0.05 U/kg/hr
subcutaneous Lispro and change fluid to D5-1/2NS.
Continue regimen keeping glucose approximately
200 mg/dL until resolution of ketoacidosis (bicarbonate
>18 and venous pH >7.3).
Reprinted from reference 43.
American Journal of Therapeutics (2006) 13(4)
360
literature supports that correction of the profound
dehydration may be sufficient.42 More recently,
published articles have shown that repeated use of
subcutaneous Humalog can be used to safely reverse
DKA in patients with less severe acidosis who have
no comorbidities43 (see Table 10).
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