Clarifying the Role of Insulin in Type 2

Diabetes Management
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John R. White, Jr., PA-C, PharmD,

Stephen N. Davis, MD, FRCP,
Ramachandiran Cooppan, MD,
Mayer B. Davidson, MD,
Kathryn Mulcahy, RN, MSN, CDE,
Gary A. Manko, MD,
Donald Nelinson, PhD and
the Diabetes Consortium Medical Advisory Board
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Abstract
In Brief
The prevalence of type 2 diabetes has been increasing rapidly and with it has been resultant
morbidity and mortality. Strict glycemic control reduces the progression of diabetic microvascular
disease; however, most patients treated with sulfonylureas require additional insulin therapy. This
article addresses common clinician concerns about prescribing insulin early in type 2 diabetes. It
presents strategies for incorporating basal insulin therapy with glargine (Lantus) into a regimen that
promotes compliance.
Diabetes is a highly prevalent chronic disease. The Third National Health and Nutrition Examination
Survey, conducted between 1988 and 1994, estimated the prevalence of diagnosed and
undiagnosed diabetes in people aged 20 years and older at 15.6 million.1 Of these people, 90
95% have type 2 diabetes, with a higher prevalence seen among Native Americans and Americans
of African, Mexican, and Japanese descent.2 The prevalence of diabetes rose from 4.9% in 1990 to
6.9% in 1999, primarily because of an increase in the prevalence of obesity. It has been postulated
that, with the growing obesity problem, diabetes will become an even more pervasive threat.3
Type 2 diabetes produces or is a contributor to considerable morbidity in the form of metabolic
complications, vision disorders, neuropathy, kidney disease, peripheral vascular disease, ulcerations
and amputations, heart disease, stroke, digestive diseases, infection, oral complications, and
depression. The associated mortality rate has been estimated at 5.5% annually. Moreover, the
disease reduces life expectancy by 510 years.1
Although there is no cure for diabetes, two large controlled studies, the Diabetes Control and
Complications Trial (DCCT)4 and the U.K. Prospective Diabetes Study (UKPDS)5 have pointed to
the importance of intensive blood glucose control in reducing its associated morbidity. In fact, the
UKPDS, the largest and longest trial ever conducted in patients with type 2 diabetes, found that for
each 1% reduction in hemoglobin A1c (A1C), there was a 21% decrease in any endpoint related to
diabetes and in diabetes-related death, a 14% decrease in all-cause mortality and myocardial
infarction, a 43% decrease in amputation or death from peripheral vascular disease, and a 37%
decreased risk for microvascular complications, each of which was statistically significant.5 The
Japanese Kumamoto study6 also found that intensive glycemic control reduced the risk for
retinopathy, nephropathy, and neuropathy in patients with type 2 diabetes.
Although sulfonylurea therapy has been the mainstay of treatment for type 2 diabetes for >40 years,
the UKPDS reported that over a 6-year period, 53% of patients who were randomized to receive
treatment with sulfonylureas needed additional insulin therapy, reinforcing the concept that

hyperglycemia in type 2 diabetes is progressive.7Clinicians should consider this when establishing a

therapeutic regimen for patients with type 2 diabetes.
This article addresses the pathophysiology of type 2 diabetes, goals of therapy, misconceptions
about insulin, restoration of natural insulin patterns, and ways to incorporate basal insulin into a
strategy that promotes compliance.
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Pathophysiology of Type 2 Diabetes

Type 2 diabetes is characterized by hyperglycemia caused by defects in insulin secretion (impaired
-cell function) and insulin action (insulin resistance by the liver and muscle tissue).810 These
defects occur early in the course of the disease and are often present before diagnosis.
In a prospective study11 of Pima Indians, a group at high risk for developing diabetes, body
composition, insulin action, insulin secretion, and endogenous glucose output were measured over
several years in subjects whose glucose tolerance went from normal to impaired to diabetic. A twostep hyperinsulinemic, euglycemic glucose clamp test assessed insulin action. During the transition
from normal to impaired glucose tolerance, there was a 27% decrease in the acute insulin secretory
response (AIR), the average incremental plasma insulin concentration from the third to the fifth
minute after the glucose bolus. Furthermore, during the transition from impaired glucose tolerance to
diabetes, there was an additional 57% decrease in AIR.
Another controlled study in patients with type 2 diabetes who were either untreated or attempting to
achieve control using diet or oral hypoglycemic agents9 found that basal and mean 24-hour glucose
concentrations were significantly higher in the diabetic patients, pointing to potentially impaired
insulin secretion. During the hyperglycemic clamp portion of this study, patients secreted 70% less
insulin than control subjects (Table 1). In nondiabetic individuals, a biphasic insulin response begins
upon glucose stimulation, starting with a rapid rise in insulin 13 minutes after the glucose level is
raised (first phase), returning toward baseline 610 minutes after glucose stimulation, and rising
gradually once again (second phase).12 Among patients in this study, however, the first-phase
response after meals (glycemic load) was either absent or greatly diminished.9 As a result of bolus
(mealtime) and basal (between-meal) defects in insulin activity in type 2 diabetes, bolus and basal
glucose levels are increased, producing hyperglycemia.
In the early stages of type 2 diabetes, blood glucose levels can often be controlled with changes in
diet and physical activity along with sulfonylureas. Unfortunately, the -cell dysfunction that leads to
impaired insulin secretion is progressive, and eventually patients will require a treatment strategy
that includes insulin, either alone or with oral agents.7 It should be noted that some patients who
develop diabetes in adulthood have immune-mediated -cell destruction that is characteristic of type
1 diabetes. This disease, latent autoimmune diabetes of adulthood, is often treated in the same way
as type 2 diabetes because it does not require insulin initially.13
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Therapeutic Objective
The American Diabetes Association (ADA) recommends that patients with diabetes receive care
from a medical team. Working with patients and their families, these teams develop selfmanagement and problem-solving plans that consider each patients cultural, social, physical, and
medical needs. ADA supports the findings of the DCCT and the UKPDS for intensive glycemic
control; Table 2 lists its recommendations for nonpregnant people with diabetes.14
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Insulin: Misconceptions and Reality

Contrary to some beliefs, there is no evidence that doses of insulin used in clinical practice
exacerbate insulin resistance. It has long been recognized that the chronic hyperglycemia
associated with type 2 diabetes (glucose toxicity) leads to impairment in insulin secretion and a
possible defect in glycogen synthesis.15 In a study of intensive insulin therapy in patients with type 2
diabetes,16 the use of insulin partially reversed the postbinding defect in peripheral insulin action,
produced near-normal basal hepatic glucose output, and enhanced insulin secretion, thereby
maintaining lower glucose values. In addition, the mean daily insulin requirement fell by 23% after
2 weeks of therapy, leveling off thereafter.
The use of insulin has been associated with weight gain, which in turn has been considered a major
factor in insulin resistance. In the UKPDS, patients in intensive therapy gained more weight than
those in conventional therapy groups; patients taking insulin gained 4 kg compared to 2.6 kg for
those on chlorpropamide (Diabinese) and 1.7 kg for those on glibenclamide (glyburide
[Micronase]).17 Yet patients in the intensive therapy groups also had fewer microvascular
complications, suggesting that tight glycemic control may be more important in therapeutic decisionmaking. The use of metformin (Glucophage) as an adjunct to insulin therapy provides effective
glycemic control without significant weight gain.18,19
The incidence of heart disease and ischemic heart mortality is up to four times higher in people with
diabetes. Ischemic heart disease, other heart disease, and cerebrovascular disease account for 40,
15, and 10% of all deaths in this population, respectively (Figure 1).20 A population-based survey of
almost 3,000 people21 identified high prevalence rates for a constellation of disorders known as
syndrome X, metabolic syndrome, and insulin resistance syndrome interchangeablyabdominal
obesity, type 2 diabetes, glucose intolerance, hypertension, hypertriglyceridemia, and
hypercholesterolemiathat far exceeded the rates for each disorder alone or in pairs. For each of
these conditions, fasting and post-glucose hyperinsulinemia was a common thread that suggested
the presence of insulin resistance. When insulin-resistant subjects were compared to control
subjects, significantly lower HDL cholesterol levels were also seen.
Because of the connection among hyperinsulinemia, insulin resistance, and cardiovascular risk
factors, the UKPDS17 compared cardiovascular events among patients randomized to conventional
lifestyle and dietary management and those on a tight glycemic control regimen with sulfonylureas,
metformin (in overweight patients), or insulin. No adverse effects on cardiovascular outcomes were
seen with any of the treatments, including insulin.
The Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction study22,23 assessed
the effect of acute insulin-glucose infusion followed by long-term intensive (multidose) insulin
treatment in diabetic patients who have had an acute myocardial infarction. Among patients who had
received an acute infusion, there was a significant decrease in glucose. After 1 year, there was a
significant reduction in mortality in the group who received intensive insulin treatment, particularly in
patients who had a low cardiovascular risk profile and were insulin naive.22 These effects persisted
after a mean follow-up of 3.4 years; the absolute reduction in mortality was 11%.23
Other studies2426 have reported improvement or neutral effects on other cardiovascular risk
factorstotal cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, or hypertensionwith
insulin, even among obese patients.
Considering the comorbidity of diabetes and several cardiovascular risk factors, ADA14recommends
the following in addition to lifestyle alterations: blood pressure measurement at routine medical visits;
the use of antihypertensive agents in patients with hypertension; testing for lipid disorders at least
annually; lowering LDL and triglycerides; increasing HDL and using statins as first-line lipid therapy;
using fibrates in patients with low HDL; and using aspirin therapy to prevent cardiovascular events.
Clinicians often cite hypoglycemia as an adverse effect that might preclude the use of insulin.
Indeed, in the DCCT study of type 1 diabetes,4 tighter control produced a risk of severe
hypoglycemia three times higher than that of conventional therapy (Figure 2). This must be viewed,
however, in the context of substantially reduced microvascular and neurological complications.
Furthermore, the rates of severe hypoglycemia are quite low in type 2 diabetes. In the Kumamoto
study of type 2 diabetes,6 average A1C results were 7.1 and 9.4% for tight and conventional groups,

respectively. However, only mild hypoglycemic reactions occurred and at similar rates in both
groups.
The UKPDS17 found that the rate of major hypoglycemic episodes (defined as an episode in which
help from another person or medical intervention was necessary) was higher for patients taking
insulin (2.3%) than for patients undergoing any other intensive therapy or conventional treatment
(<1%). The rate of any hypoglycemic episode (including episodes that the patient was able to treat
unaided) was 36.5% with insulin treatment, compared to 11, 17.7, and 1.2% for chlorpropamide,
glibenclamide, and diet, respectively. In a secondary analysis of obese patients on intensive
glycemic control, the rate of major hypoglycemic events per year for intensive insulin treatment was
2.5% versus <1% for other treatments.
Despite the increased risk of mild hypoglycemia, aggressive therapy that combines patient education
and self-management with a form of exogenous insulin that closely mimics normal insulin secretion
can help to reduce the morbidity and mortality associated with type 2 diabetes.
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Restoring Natural Insulin Patterns

Nondiabetic pancreases self-regulate the amount of insulin secreted, acting in response to changes
in blood glucose concentration that result from the ingestion of food. In people with diabetes,
however, bolus and basal glucose levels are increased; thus, strategies for insulin replacement must
focus on mimicking the phases of insulin secretion. Figure 3 shows available insulins by onset, peak,
and usual effective duration.27
Prandial (Bolus) Insulin
Prandial forms of insulin mimic the normal first-phase response. These regular insulin or rapid-acting
insulin analogs are administered 3060 minutes (regular) or 1015 minutes (lispro [Humalog] or
aspart [Novalog]) before food consumption. They must also mimic the second-phase response,
requiring a more prolonged duration of action to control prolonged glucose elevation after the
meal.28 Although prandial forms offer flexibility in that they can be injected just before a meal, most
patients also require daily basal insulin injections.29
Basal Insulin
Both intermediate (NPH and lente) and long-acting (ultralente and glargine [Lantus]) insulins have
been used to mimic physiological basal insulin secretion, with varying results. An insulin that mimics
basal secretion should be slowly and evenly absorbed with no peak, have consistent bioavailability,
and have a long half-life that permits once-daily administration.30,31 This has not been the case
with most basal insulin products. NPH and lente have early peaks with rapid waning of action; this
may contribute to both nighttime hypoglycemia and the dawn phenomenon, a pre-breakfast rise in
plasma glucose. There is also variability in the absorption of NPH and lente. 29,32 Data on ultralente
vary; in one study of type 1 diabetes,30 the onset of action of human ultralente was 24 hours, and
there was a broad, variable peak 612 hours after injection. The authors concluded that this product
did not provide a constant basal insulin concentration.
Basal insulin in type 1 diabetes. The pharmacokinetics and pharmacodynamics of the insulin
analog glargine were compared to those of NPH, ultralente, and continuous subcutaneous insulin
infusion (CSII) of lispro in 20 type 1 diabetic patients using an isoglycemic 24-hour
clamp.33 Glargine was absorbed slowly and produced no pronounced peaks over a 24-hour period.
Its onset of action was 1.5 hours, compared with 0.8 hours for NPH, 1 hour for ultralente, and 0.5
hours for CSII. Its concentration/action profile was similar to CSII, with lower intersubject variability
than with NPH and ultralente. These factors make glargine an excellent choice for basal insulin
replacement.
In another study of type 1 diabetes,34 256 patients were randomized to receive NPH (once daily at
bedtime or twice daily before breakfast and at bedtime) or glargine once daily at bedtime. After 1
week and sustained throughout the 4-week study, fasting plasma glucose was significantly lower in

the pooled glargine groups than in the NPH group (165.6 vs. 203.4 mg/dl, respectively; P = 0.0001).
Patients who had been taking NPH twice daily before the study were more likely to demonstrate
greater improvement if randomized to a glargine group than were patients previously on once-daily
NPH. The longer duration of glargine also provided a statistically significant advantage in reducing
the likelihood of the dawn phenomenon.
Basal insulin in type 2 diabetes. The management of type 2 diabetes has traditionally followed a
stepped approach of lifestyle changes, to oral agents, to combinations of oral agents, to insulin.
Along the way, however, complications resulting from poor glycemic control may occur, some of
which might have been reduced or possibly avoided with the early introduction of insulin.35
Many studies have evaluated how to use insulin effectively for the treatment of type 2 diabetes. Twoand four-dose regimens of NPH improved glycemic control but caused basal
hyperinsulinemia.36 The addition of 70/30 insulin (a premixed formulation with 30% fast-acting
insulin and 70% intermediate-acting insulin) before supper to glimepiride (Amaryl) restored glycemic
control more quickly than did 70/30 insulin alone, without producing severe hypoglycemia.25 The
addition of NPH to glipizide (Glucotrol) was superior to high- and low-dose NPH alone in restoring
glycemic control.37 Combination therapy with an intermediate-acting insulin at bedtime plus
metformin was superior to bedtime insulin plus glyburide and metformin, bedtime insulin plus
glyburide, and insulin twice daily and produced no weight gain.18 The addition of evening NPH to
existing oral agents was similar in efficacy to morning NPH plus an existing antidiabetic agent, a twoinjection regimen of 70/30 insulin, multiple injections, and oral hypoglycemic agents alone; however,
this regimen did not induce as much weight gain and hyperinsulinemia.38
Recent clinical trials suggest that glargine provides basal insulin glycemic control equal to that of
NPH with less risk of hypoglycemia. Glargine has been evaluated in patients with type 2 diabetes in
a trial comprising 518 patients who had been receiving NPH with or without regular insulin for
postprandial control.39 This 28-week, multicenter, open-label comparison of NPH once or twice daily
and glargine once daily at bedtime reported similar decreases in A1C but a lower risk of nocturnal
hypoglycemia with glargine compared with NPH (26.5 vs. 35.5%; P = 0.016). There was significantly
less weight gain with glargine than with NPH (0.4 vs. 1.4 kg; P = 0.0007).
A 6-month, multicenter, randomized, open-label trial40 compared the addition of glargine or NPH to
an oral therapy regimen to restore glycemic control to a target A1C 7% in 756 insulin-nave patients
with type 2 diabetes. A1C results were lower in both treatment groups and 7% in 58% of patients.
At the end of the study, the mean glargine dose was higher than that of NPH; however, symptomatic
hypoglycemia rates, particularly nocturnal hypoglycemia, were significantly lower in the glargine
group. Risk was reduced by 21% for any incidence of hypoglycemia and by 42% for nocturnal
hypoglycemia (Table 3).
Other studies comparing glargine to NPH at bedtime reported that similar control was achieved with
each agent; however, there were significantly less hypoglycemia41 and significantly lower postdinner
glucose concentrations42 with glargine than with NPH. Among insulin-naive patients and overweight
patients who had been taking oral agents with or without insulin, significantly fewer receiving
glargine experienced nocturnal hypoglycemia.43
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An Algorithm for Using Insulin

There is no single best way to initiate insulin therapy in patients with type 2 diabetes in whom oral
treatments no longer maintain adequate control. Clinicians should consider 10 units of basal insulin
at bedtime, supper, or in the morning a safe, effective recommendation for beginning insulin therapy.
This dose can then be titrated based on how well a patient has met individual glycemic goals as
measured by fasting blood glucose, postmeal glucose levels, and self-monitoring of blood glucose.
In obese, insulin-resistant patients, a higher starting dose may be safely used.
Figure 444 provides an algorithm that includes recommendations for the use of insulin therapy in
type 2 diabetes.

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Compliance
Patients with diabetes play an integral role in any treatment strategy. Lifestyle modification; goal
setting; self monitoring; preventing, detecting, and treating acute complications; and using
medications correctly are all important components in achieving glycemic control.45 This makes
patient education crucial, particularly when it comes to dispelling myths about insulin therapy. The
content areas that must be clearly established for patients are listed in Table 4.
The relationship between health care provider and patient is crucial to compliance. In the
management of diabetes, this is more than a relationship between the patient and a single provider
it includes an entire health care team.
Other factors also influence compliance. On the patients side, the belief that the benefits of therapy
are worth the consequences, a readiness to change, memory, communication skills, literacy level,
knowledge, competence, confidence, skills, and a good support system work together to influence
the patients acceptance of therapy. On the teams side, communication skills, the quality of
information and instructions, and a willingness to identify and address barriers affect compliance.
The regimen itself is also a factor; if it is difficult, costly, or has many side effects, compliance may
diminish.4649
In the treatment of type 2 diabetes with insulin, reluctance to inject oneself and fear of weight gain or
hypoglycemia may hinder compliance.35 Clinicians need to explain to their patients that type 2
diabetes is progressive and that insulin will probably have to be used at some point; therefore,
clinicians may need to dispel myths associated with insulin use, allay patient fears, and assure
patients that insulin will likely improve symptoms, enhance quality of life, and provide a sense of
well-being.
Resistance to insulin on the part of clinicians may also be a significant provider-driven factor in
compliance.50 Concerns regarding hypoglycemia, patients fear of needles, cultural health beliefs,
and the time necessary to teach self-injection can all emerge as barriers to insulin use.
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Conclusions
With the prevalence of type 2 diabetes on the rise and with the recognized need for strict glycemic
control in the prevention of complications, strategies for aggressive treatment must be put into effect.
Such strategies might include the early use of insulin, alone or in combination with other antidiabetic
agents. Clinicians must weigh the risks associated with the use of insulin against the benefits.
Several studies have clearly shown that basal insulin therapy, particularly using the insulin analog
glargine, closely mimics the bodys physiological secretion of basal insulin and may be added to an
existing oral regimen, used alone, or used with preprandial insulin.
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Figure 1.
Cardiovascular and cerebrovascular diseases account for 65% of all deaths in patients with
diabetes. Adapted from Ref. 20.

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Figure 2.
Rate of severe hypoglycemia in patients receiving intensive therapy. As tighter glycemic
control is attained, the risk of severe hypoglycemia increases. Points, which correspond to
more than 400 patient-years, indicate crude rates within deciles of the mean glycosylated
hemoglobin (A1C) values during the trial. Copyright 1988 Massachusetts Medical Society.
All rights reserved. Adapted with permission, 2002.

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Figure 3.
The action of human insulins. Onset, peak, and usual effective durations vary among
available insulins. In some reports, ultralente has demonstrated a peak concentration after
several hours, followed by waning. Values shown are the mean in each range. Adapted with
permission from Ref. 27.

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Figure 4.
An algorithm of treatment for patients with type 2 diabetes. Reprinted with permission from
Ref. 44.

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Table 1.
Glucose Concentrations and Insulin Secretion in Control and Diabetic Subjects Under Three
Conditions

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Table 2.
ADA Guidelines for Glycemic Control for Patients With Diabetes

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Table 3.
Relative Risk of Hypoglycemic Episodes per Patient-Year

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Table 4.
Content Areas for Diabetes Self-Management Education
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Acknowledgments
The research for this article was supported by an unrestricted grant from Aventis.

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Footnotes

John R. White, Jr., PA-C, PharmD, is a professor at Washington State University College of
Pharmacy in Spokane. Stephen N. Davis, MD, FRCP, is chief of the Division of Diabetes,
Endocrinology, and Metabolism at Vanderbilt University Medical School in Nashville, Tenn.
Ramachandiran Cooppan, MD, is an assistant clinical professor at Harvard Medical School in
Boston, Mass. Mayer B. Davidson, MD, is director of the Clinical Trials Unit at Charles R. Drew
University in Los Angeles, Calif. Kathryn Mulcahy, RN, MSN, CDE, is program director of the INOVA
Diabetes Center in Fairfax, Va. Gary A. Manko, MD, is president of Clinical Associates, PA, in
Reisterstown, Md. Donald Nelinson, PhD, is executive director of the Diabetes Consortium. The
Diabetes Consortium, Inc., is a nonprofit, multidisciplinary collaboration dedicated to the
development and dissemination of professional and patient initiatives implementing optimal diabetes
care. For more information, write to: P.O. Box 8262, Parsippany, NJ, 07054-8262, or call 877-4624356.
Note of disclosure: Dr. White has served on an advisory board for Aventis; has received honoraria
for speaking engagements from Aventis, Takeda, Omron, Pfizer, and TheraSense; and has received
research support from Aventis. Dr. Cooppan has received honoraria from Bristol-Myers Squibb,
Pfizer, Aventis, Novartis, Takeda, Eli Lilly, GlaxoSmithKline, and Wyeth-Ayerst. Ms. Mulcahy has
served on advisory boards and received honoraria from Aventis and Novo Nordisk. Dr. Manko has
received honoraria from Pharmacia, Wyeth-Ayerst, and Bristol-Myers Squibb. All of these
companies manufacture or market insulin or other pharmaceutical products for the treatment of type
2 diabetes or its complications.
American Diabetes Association
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