Postgraduate Medicine

ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: https://www.tandfonline.com/loi/ipgm20

Basal Insulin: Physiology, Pharmacology, and

Clinical Implications

Kevin D. Niswender

To cite this article: Kevin D. Niswender (2011) Basal Insulin: Physiology, Pharmacology, and
Clinical Implications, Postgraduate Medicine, 123:4, 17-26, DOI: 10.3810/pgm.2011.07.2300

To link to this article: https://doi.org/10.3810/pgm.2011.07.2300

Published online: 13 Mar 2015.

Submit your article to this journal

Article views: 153

Citing articles: 9 View citing articles

Full Terms & Conditions of access and use can be found at

https://www.tandfonline.com/action/journalInformation?journalCode=ipgm20
 CLINICAL FOCUS: DIABETES

Basal Insulin: Physiology, Pharmacology,

and Clinical Implications

Kevin D. Niswender, MD, Abstract: Primary goals in the treatment of type 2 diabetes mellitus (T2DM) include lower-
PhD 1 ing blood glucose levels sufficiently to prevent micro- and macrovascular complications while
1
limiting side effects, such as hypoglycemia and excessive weight gain. Patients with T2DM are
Vanderbilt University School
of Medicine, Nashville, TN typically treated initially with oral antidiabetes agents; however, as the disease progresses, most
will require insulin to maintain glycemic control. Often insulin therapy is initiated with basal
insulin, and the objective of this article is to present the conceptual aspects of basal insulin therapy
and use these concepts to illustrate important clinical aspects. This will be accomplished within
a broader contextual discussion of the normal physiologic patterns of insulin secretion, which
consist of sustained levels of basal insulin production throughout the day, superimposed with
bursts of insulin secretion following a meal (termed bolus or prandial insulin secretion) that slowly
decay over 1 to 3 hours. Long-acting basal insulin analogs form a key component of basal-bolus
therapy and provide basal support for patients with T2DM. Insulin therapy is often initiated with
basal insulin, and newer long-acting analogs, such as insulin glargine and insulin detemir, pro-
vide steady, reliable basal insulin coverage in addition to significant advantages over traditional
long-acting insulins. This article will integrate conceptual aspects of basal insulin therapy in
the context of physiology, molecular pharmacology, and clinical implications of modern basal
insulin analogs to provide a foundational understanding of basal insulin biology and physiology.
Keywords: basal insulin; insulin analogs; insulin glargine; insulin detemir; physiology;
pharmacology

Introduction
In healthy individuals, endogenous insulin secretion occurs in 2 phases: 1) a rapid
increase in serum insulin that peaks 30 to 45 minutes after the onset of a meal (bolus/
prandial), returning to basal levels after 1 to 3 hours; and 2) the constant “flat-line”
secretion of insulin at a lower rate, also called basal insulin secretion. The basal com-
ponent of insulin action, together with glucagon, fine-tunes hepatic glucose production
while simultaneously modulating peripheral glucose utilization.
Physiologically, basal insulin is continuously released at low levels (concen-
trations of ∼5–15 μU/mL) in response to hepatic glucose output, and facilitates
the maintenance of normal plasma glucose concentration in individuals without
Correspondence: Kevin Niswender, MD,
PhD, diabetes, which is ∼80 to 90 mg/dL (∼4–5 mmol/L). Postprandially, glucose con-
Department of Medicine, centrations in individuals without diabetes can reach 135 mg/dL (7.5 mmol/L).1
Division of Diabetes, Endocrinology
and Metabolism, However, bolus (prandial) insulin is released in response to a meal (Figure 1),
Vanderbilt University School returning the glucose concentration to fasting levels. This regulatory mecha-
of Medicine,
7465 MRB IV, 2213 Garland Ave., nism maintains blood glucose levels within a narrow range (∼63–135 mg/dL
Nashville, TN 37232-0475. [∼3.5–7.5 mmol/L]). 1 In patients with type 2 diabetes mellitus (T2DM), both
Tel: 615-936-0500
Fax: 615-936-1667
aspects of insulin release can be markedly decreased or absent as the disease
E-mail: Kevin.niswender@vanderbilt.edu progresses. By definition, fasting hyperglycemia occurs when basal insulin secre-

© Postgraduate Medicine, Volume 123, Issue 4, July 2011, ISSN – 0032-5481, e-ISSN – 1941-9260 17
Kevin D. Niswender

Figure 1. Physiologic insulin secretion. of “metabolic memory”: that the effects of early insulin use
Breakfast Lunch Dinner resulted in less morbidity and mortality even after glycemic
control has decayed.9–11
Plasma Insulin, µU/mL

50
To utilize insulin successfully—enhancing efficacy while
reducing side effects—mimicking the physiologic profile
of insulin secretion for both prandial and basal components
25
offers maximal effect. Basal insulin has a relatively narrow
therapeutic window; too little can lead to hyperglycemia
and potentially hyperlipidemia, while too much can lead
4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00
to hypoglycemia, which is a potent stimulus to eat—and as
Clock Time, h
recent studies suggest, a potential mediator of cardiovascular
Reprinted with permission from Curr Paediatr.1
risk in that acute hypoglycemia can cause profound hemato-
logic and cardiovascular changes through sympathoadrenal
tion is no longer sufficient to normalize fasting plasma activation and counter-regulatory hormone secretion.12,13 To
glucose concentrations.2,3 understand key aspects of insulin therapy in a clinical setting,
The management of T2DM has traditionally followed a basic understanding of molecular pharmacology and physi-
a stepwise approach beginning with lifestyle changes, moving ology with respect to insulin formulations most frequently
to oral antidiabetes (OAD) medications as monotherapy, to encountered in clinical settings is necessary.
combinations of oral agents, and finally to insulin. Typically,
metformin is the first OAD medication prescribed and has Insulin Action at the Cellular Level
clear efficacy on hepatic insulin sensitivity and hepatic glucose The actions of insulin at the cellular level are initiated by
production. The clinical experience with metformin provides a insulin binding to its receptor on the cell membrane.14 This
window of insight into T2DM pathogenesis and progression, action at the insulin receptor (IR) activates a cascade of
given the effects of the agent to delay or prevent the progression intracellular signaling events, which in turn regulate critical
of individuals at high risk for diabetes to frank T2DM (albeit biologic processes, such as glucose and lipid metabolism,
significantly less potently than intensive lifestyle modification), gene expression, protein synthesis, and cell growth, division,
as demonstrated in the Diabetes Prevention Program.4 That and survival.14,15
metformin is thought to act largely in the liver, and that treat-
ment with metformin can delay the development of T2DM,4 Insulin Signal Transduction
provides further proof-of-principle that the liver is an important Simplistically, insulin signaling consists of a series of
therapeutic target in T2DM. phosphorylation events beginning with insulin binding
Traditionally, insulin is initiated only when combinations to the IR itself. Information is then provided to the cell
of OAD medications have failed to provide adequate glyce- by activation of several intracellular protein substrates,
mic control—suggesting failure of β-cells to supply prandial including IR substrate 1 (IRS1), IR substrate 2 (IRS2), and
as well as basal needs. In a study looking at the changes Src-homology-2–containing (Shc) protein, in turn initiating
between the National Health and Nutrition Examination 1 of 2 major signaling cascades. The first is the phosphati-
Survey (NHANES) III (1988–1994) and the initial release of dylinositol 3-kinase (PI3K) pathway that includes activation
NHANES 1999–2000, researchers determined that only 11% of protein kinase B (PKB), also known as Akt, leading to
of patients with T2DM who are treated with OAD medications translocation of the glucose transporter 4 (GLUT4), and
are administered insulin therapy,5 supporting the concept that activation of glycogen synthase and other enzymes respon-
insulin therapies are typically used late in disease progression sible for the metabolic effects of insulin. The other pathway,
as a last resort. Conversely, mounting evidence indicates that the mitogen-activated protein kinase (MAPK) pathway,
early introduction of insulin has salutary effects: reducing includes activation of extracellular signal-regulated kinases
insulin resistance, reversing glucose toxicity,6 and preserv- 1 and 2 (ERK1 and ERK2), leading to gene expression,
ing β-cell function better than OAD medications alone.7,8 protein translation, and cell growth. Critical nodes identi-
Furthermore, the United Kingdom Prospective Diabetes fied within the insulin signaling cascade include IR/IRS1,
Study (UKPDS)9 and Epidemiology of Diabetes Interven- PI3K, and Akt/PKB. Each of these components is highly
tions and Complications (EDIC) trial10 illuminate the concept regulated, and crosstalk with other signaling cascades regu-

18 © Postgraduate Medicine, Volume 123, Issue 4, July 2011, ISSN – 0032-5481, e-ISSN – 1941-9260
 Basal Insulin

lates processes such as glucose uptake, glucose synthesis, of lipids or metabolites thereof, which leads to defects in
gluconeogenesis, protein synthesis, and cell growth and insulin signaling via specific biochemical mechanisms.20
differentiation.15 Insulin resistance, when coupled with impairment in
glucose-stimulated insulin secretion, ultimately leads to
Physiology of Glucose Homeostasis fasting hyperglycemia due to impaired suppression of hepatic
As clinicians refocus on insulin as a glycemic agent, an glucose production.
appreciation of the complexity of the hormonal system will
encourage further utilization of this life-saving medication. Insulin Action in Muscle
For example, while used clinically to manage carbohy- In the skeletal muscle, insulin stimulates glucose uptake, amino
drate metabolism, insulin is truly the prototypical anabolic acid uptake, and glycogen storage. The muscle can utilize and
hormone in peripheral tissues, influencing the stores of all store (as much as ∼2/3 of prandial carbohydrate may be stored
macronutrient classes: carbohydrate, lipid, and protein. in muscle) but not produce glucose. In T2DM, muscle becomes
It is basal insulin secretion that helps maintain normal insulin resistant and the stimulatory effects of hyperinsulinemia
fasting blood glucose, while prandial insulin is secreted in are markedly reduced.21 Mechanisms of muscle insulin
response to increases in glucose and nutrients at mealtimes. resistance appear to involve several “lipotoxicity” effects and
Another hormone secreted by the pancreas, glucagon, subsequent defects in glucose transport.20
is also involved in the control of blood glucose levels.
In fact, it is the opposing actions of insulin and glucagon Insulin Action in Adipose Tissue
that help fine-tune glucose homeostasis. In the presence of The role of adipose tissue in glucose homeostasis primarily
hyperglycemia, the pancreatic β-cells secrete more insulin, involves blood levels of FFAs. Release of FFAs from the
stimulating glucose transport into muscle and adipocytes, adipose tissue can alter insulin sensitivity in muscle and
and inhibiting glucose production in the liver. These actions the liver. Plasma insulin inhibits lipolysis by inhibiting
are counterbalanced by those of glucagon (secreted by the hormone-sensitive lipase, decreasing serum FFA levels, and
pancreatic α-cells), which is suppressed by hyperglycemia increasing muscle uptake, thus helping to inhibit hepatic glu-
but stimulated during hypoglycemia. Glucagon promotes cose production.22 Because glucose and lipid metabolism are
hepatic glycogenolysis and ultimately gluconeogenesis, interrelated, it is thought that the excessive increase in plasma
which raises blood glucose levels.16,17 FFA levels with and between meals in patients with T2DM
may contribute to fasting and postprandial hyperglycemia as
Insulin Action in the Liver well as hyperlipidemia.23
Insulin, secreted by the pancreatic β-cells, arrives in the liver
through the portal circulation. Insulin causes the uptake of Molecular Pharmacologic Effects
glucose, free fatty acids (FFAs), and amino acids into adi- of Insulin
pose tissue, muscle, and the liver, where they are assimilated Regular human insulin (RHI) binds and activates the IR with
and stored.17 Liver cells can respond to feeding or fasting very high affinity (in the subnanomolar range) and also binds
conditions by storing or producing glucose as necessary. In the structurally related insulin-like growth factor 1 (IGF-1)
the fasting state, glycogenolysis, then gluconeogenesis, is receptor (IGF-1R), but with a ∼1000-fold lower affinity.24
stimulated and glucose is released. Postprandially, insulin The IR affinities of the 2 basal insulin analogs discussed here
prevents hyperglycemia by suppressing hepatic glucose differ significantly; insulin glargine is similar to that of RHI,
production.18 The actions of insulin in this process include while insulin detemir has significantly lower affinity than
inhibiting glucagon secretion, reducing plasma FFA levels RHI in binding to the IR in cells in culture. Recalling that
(which increase glycolytic action), and effects on adipose insulin has multiple effects on cellular function, the concept
and muscle tissue that ultimately decrease the supply of of potency indicates the magnitude of effect (on a molar
gluconeogenic substrates to the liver.19 basis) that insulin has in inducing a particular response. For
In T2DM, the body develops resistance to the biologic example, “metabolic potency” is defined loosely as the abil-
actions of insulin, including at the level of the liver, leading ity to stimulate glucose uptake, and is the clinically relevant
to defective control of blood glucose levels and ultimately potency for efficacy in T2DM treatment.
to fasting hyperglycemia.17 Insulin resistance in the liver With respect to IGF-1R binding, insulin glargine has a
is thought to be related to the intracellular accumulation ∼ 6.5-fold higher affinity than RHI, whereas insulin detemir

© Postgraduate Medicine, Volume 123, Issue 4, July 2011, ISSN – 0032-5481, e-ISSN – 1941-9260 19
Kevin D. Niswender

has a  5-fold lower affinity.24 As a relevant aside, acanthosis regimen. A basal-bolus regimen with a long- and rapid-acting
nigricans, in the setting of profound insulin resistance, is the insulin analog currently mimics physiologic insulin secretion
result of insulin activation of IGF-1R in skin. At physiologic as closely as possible while providing both glycemic control
circulating levels of insulin, interaction with IGF-1R seldom and safety (primarily in regard to hypoglycemia).3,26
occurs. Differences in receptor interaction, phosphorylation Thus, an important consideration in selecting the appropriate
pattern of the IR, subsequent internal signaling, and finally, insulin therapy for a patient is understanding the basics
rates of receptor internalization, all affect the final biologic (ie, whether the patient is experiencing basal or prandial
outcome observed in response to insulin. insufficiency). The timing of hyperglycemia is helpful:
Other “potencies” of interest, besides metabolic (primary morning fasting hyperglycemia, particularly when evening
effects on glucose uptake) and mitogenic (cell division), blood glucose levels are not elevated, reflects basal insulin
include effects on lipogenesis and any number of other insufficiency. Conversely, if the hyperglycemia is predomi-
insulin effects in target tissues. Interestingly, glargine and nantly postprandial, a prandial insulin may be indicated.
detemir appear to have very different molecular pharma- Of course, as T2DM progresses, patients will usually require
cology (eg, insulin and IGF-1R affinity, receptor on/off both types of insulin to achieve and maintain glycemic targets.
rates, and various potencies) while having similar effects
in vivo on glucose metabolism at marketed concentrations. What Is the Ideal Basal Insulin?
It is, however, currently difficult to understand how these Successful initiation of exogenous insulin therapy with
differences in molecular pharmacology translate to in vivo the ideal basal insulin depends on an understanding of
efficacy in humans. the physiologic characteristics of endogenous insulin
secretion. Similarly, it is necessary to understand the
Role for Basal Insulin Analog physicochemical properties of commercial insulin for-
Therapy in T2DM mulations that are employed to achieve prolonged time-
Given the importance of fasting glucose levels in overall action profiles following subcutaneous administration.
glycemic control, basal insulin therapy attempts to recreate Prior to injection, molecules of RHI typically self-
the constant low levels of insulin seen overnight and between aggregate to form dimers, which in turn stabilize around
meals, thereby sustaining fasting plasma glucose control. Its zinc ions to form hexamers. 28 Following injection, the
flat time-action profile allows for maintenance of euglycemia subcutaneous insulin depot is diluted by the interstitial
within the narrow therapeutic window. Long duration of fluid, causing the hexamers to break down into dimers
action allows maintenance of the flat profile without multiple and biologically active monomers. Insulin hexamers
injections over short periods of time. Indeed, a relatively are too bulky to be transported across the vascular
flat, consistent time-action profile constitutes the critical endothelium, and the rate of absorption into circulation
pharmacodynamic and pharmacokinetic component of basal is limited by their dissociation and eventual formation
insulin therapy. Of course, a pronounced “dawn phenom- of monomers. This results in a pharmacokinetic profile
enon” may lead to early-morning hyperglycemia even in characterized by a slow increase to peak of 2 to 3 hours,
the setting of a reasonable physiologic dose of basal insulin, followed by slow decline over 10 hours, a pattern that
and overcompensation may lead to hypoglycemia; in this does not replicate the physiologic basal or bolus/prandial
clinical situation, additional management strategies may be phases.28
employed.25 Thus, an important step in developing the ideal basal
A typical regimen to initiate insulin in patients who have insulin has been modifying the self-associative properties
not achieved the recommended glycated hemoglobin (HbA1c) of insulin to achieve a kinetic profile that more closely
level of 6.5% (or individualized HbA1c goal for those with matches normal physiology. Considering that absorp-
cardiovascular disease or other higher-risk clinical situations) tion is dependent on local factors, which can lead to
combines OAD therapy with a long-acting basal insulin inter- and intrapatient variability, a key determinant of
either at bedtime or in the morning.3,26,27 If insulin is started the successful generation of useful basal insulin analogs
late in the disease process, patients with T2DM may have is a reproducible absorption profile.29 Further, having a
little β-cell function left, making once-daily injection of basal insulin with a long duration of action would help
basal insulin insufficient to achieve glycemic targets; in this minimize injection frequency and allow for a steady
instance, prandial insulin is added to generate a basal-bolus state of absorption.

20 © Postgraduate Medicine, Volume 123, Issue 4, July 2011, ISSN – 0032-5481, e-ISSN – 1941-9260
 Basal Insulin

Basal Insulin Is Usual Practice rainbow trout sperm) in a zinc suspension. Protamine pro-
Prior to the introduction of basal insulin analogs, exogenous longs the absorption time of insulin from the subcutaneous
basal insulin therapy traditionally involved zinc or protamine- tissue because of its dependence on proteolytic enzymes
retarded formulations of porcine or human insulin such as to cleave the protamine from insulin. Neutral protamine
the intermediate-acting neutral protamine Hagedorn (NPH) Hagedorn insulin has an intermediate duration of action
insulin, lente insulin, or the longer-acting ultralente.30 These (10–16 h), a significant peak in action (4–6 h), and a less
preparations are injected subcutaneously as precipitates, predictable profile of absorption and activity than the newer
which dissolve slowly to delay absorption into the circulation. long-acting analogs (Figure 2).3,29 Neutral protamine Hage-
dorn insulin provided the advantage of being compatible
Lente and Ultralente Insulins when combined with RHI, forming a stable mixture (70%
To eliminate foreign proteins and further slow the absorption NPH, 30% RHI) that enabled adequate management of both
of insulin, zinc was used in varying amounts to produce prandial and basal glycemia in preformulated mixtures.
the lente family (semilente, lente, ultralente) of insulin However, the duration of action of NPH necessitates twice-
zinc suspensions.31 However, surplus zinc ions lead to daily dosing to provide 24-hour glucose control.37 Because
incompatibility when insulin zinc suspensions are mixed its peak activity is from 4 to 6 hours, NPH is associated with
with soluble insulin.32 an increased risk of hypoglycemia, particularly nocturnal
Lente and ultralente insulins are crystalline suspensions hypoglycemia if injected at bedtime,38 making it less desir-
of human insulin with zinc that provide slower onset and a able as a basal insulin. Similar to the lente family, NPH has
longer duration of action than RHI.33 Both lente and ultralente a degree of variability in its absorption profile. Intrapatient
insulins have been discontinued in the United States due to variability in absorption may reach 35%34 due to the need for
excessive inter- and intrapatient variability, likely due to the resuspension prior to injection, which is another disadvantage
need rotate the vial numerous times to properly resuspend of NPH.39 Patients’ inability to accurately resuspend NPH
the solution, but presumably also due to local subcutaneous in cartridges prior to administration have resulted in NPH
tissue factors.34 content varying from 5% to 214%, and leading to hyper- and/
or hypoglycemia.40 It is of interest to note that this study used
U-500 NPH cartridges, rather than the vials that are more commonly
In the context of the parallel obesity and T2DM epidemics, used today. However, vials are not without resuspension
the number of patients with T2DM and extreme insulin problems that can lead to inter- and intrapatient variability; as
resistance is seemingly increasing. Insulin formulations mentioned, such problems were part of the reason that lente
sold in the United States are prepared in a concentration and ultralente insulin vials were removed from the market.
of 100 units per mL (U-100). U-500 is a 5-fold more The variable pharmacokinetic and pharmacodynamic
concentrated (500 units per mL) formulation of RHI. It peaks profiles of these older insulins do not precisely match physiologic
at approximately the same time as RHI (per prescribing insulin secretion, thus limiting their ability to achieve glycemic
information35), but has a prolonged duration of action. Indeed, control.28,41 Intrapatient variability can complicate daily dosing
U-500 may be considered a hybrid prandial-basal insulin and increase the risk of interprandial and nocturnal hypoglyce-
when administered as multiple injections over the course mia.28,42 This potentially explains much of the clinical challenge
of a day or when used in an insulin pump via continuous that patients experience with basal insulin.
infusion. Because 1) it is not typically used solely for basal Intrasubject variability in glucose-lowering effect is
coverage; 2) because of the potential for dosing errors given common in patients with T2DM, regardless of insulin for-
the more concentrated formulation; and 3) because of unique mulation. This variability may be due to a number of factors,
clinical considerations for the care of patients with extreme such as the absorption rate (pharmacokinetics) and metabolic
insulin resistance, U-500 will not be discussed further here, effects (pharmacodynamics) of the circulating hormone
but several excellent recent reviews of U-500 are available.36 in a particular patient, the blood flow at the injection site,
differences in injection site (ie, abdomen, thigh, or arm),
NPH Insulin and differences in insulin sensitivity. Differences in insulin
Since its introduction in 1946, NPH insulin has been the preparation characteristics, such as the physical nature of the
most commonly used intermediate-acting insulin. It consists preparation (ie, suspension or soluble), concentration, and
of insulin combined with protamine (a protein isolated from dose, also contribute to this variability.29

© Postgraduate Medicine, Volume 123, Issue 4, July 2011, ISSN – 0032-5481, e-ISSN – 1941-9260 21
Kevin D. Niswender

Figure 2. Pharmacokinetic profile of NPH insulin and long-acting basal analogs. subcutaneous tissue and is slowly released to provide
basal insulin supplementation over the once-daily dos-
age interval. The rate of absorption of insulin glargine
Relative Insulin Effects

Intermediate-acting insulin (eg, NPH)

Long-acting insulin (eg, glargine, detemir) provides a basal insulin level that remains relatively
constant for ∼24 hours (Figure 2). 3

Signal Transduction Characteristics of Glargine

Using in vitro models, the affinity of glargine for IR was
shown to be similar to that of RHI, whereas its dissocia-
tion from the IR was about 50% faster than that of RHI.24,47
Insulin glargine and RHI also showed similar rates of recep-
0 2 4 6 8 10 12 14 16 18 20
tor activation and phosphorylation of IRS1 and Shc.48 The
Time, h
metabolic potency of glargine was similar to that of RHI,
Adapted from J Am Osteopath Assoc.3 as measured by lipogenesis or glucose transport in several
Abbreviations: NPH, neutral protamine Hagedorn.
studies.24,49,50 The mitogenic potency of insulin glargine,
Long-Acting Insulin Analogs evaluated by its potential to stimulate DNA synthesis in
The limitations of the older intermediate- and long- human osteosarcoma cells, was determined to be ∼8-fold
acting insulin preparations prompted the development of higher than that of RHI.24 In another in vitro study, serum
new insulin analogs that can better simulate physiologic from patients injected with glargine had 11% more mito-
basal insulin secretion and provide less variability. genic activity than with RHI.51
There are 2 long-acting insulin analogs commercially
available in the United States, insulin glargine and Insulin Detemir
insulin detemir. Insulin detemir is a neutral, noncrystalline, clear, soluble
While glargine and detemir have remarkably insulin preparation in which residue B29 Lys has been
different molecular structures and molecular phar- covalently bound to a 14-carbon myristoyl fatty acid
macology, they have similarly improved pharma- (myristic acid) (Figure 3B).46,52 The detemir structure is
codynamic characteristics, lower levels of fasting composed of 4 molecules of insulin in an asymmetrical unit,
glucose, reduced risk of nocturnal hypoglycemia, in addition to zinc ions, chloride ions, phenol molecules,
and reduced intrapatient variability compared with and fatty acid side chains. The molecules form dimers, and
NPH. 43,44 zinc and phenol facilitate the formation of hexamers similar
to RHI. The addition of a fatty acid chain permits normal
Insulin Glargine hexamer formation and does not interfere with insulin
One of the initial hypotheses applied to the development action, permitting reversible insulin-albumin binding.53 This
of basal analogs included modification of the amino modification also allows detemir to be formulated as a solute
acid sequence of human insulin in an attempt to shift in a neutral liquid preparation that does not precipitate at
the isoelectric point of the molecule toward neutrality, any stage in the injection and absorption process, thereby
thereby reducing the solubility at physiologic pH. The avoiding a key source of variability.
primary structure of glargine is different from that of It has been suggested that 2 mechanisms contribute
human insulin because of 2 modifications: 1) 2 arginine to the protracted action of detemir: the reversible bind-
residues are added to the C-terminus of the B-chain, ing to albumin and the delayed absorption due to self-
which raises the isoelectric point from pH 5.4 to 6.7, association.54 Thus, 2 distinct “buffering” mechanisms
making the molecule less soluble at the physiologic pH likely contribute both to prolonged duration of action and
of subcutaneous tissue; and 2) the asparagine residue to less injection-to-injection variability.55,56 It was hypoth-
at position 21 in the A-chain is replaced with a neutral esized that the latter causes retention of the compound in
glycine residue, which stabilizes the molecule, limiting the subcutaneous tissue long enough to establish albumin
dimerization at the acidic pH (4.0) (Figure 3A).45,46 Fol- binding in the interstitial space. In circulation, detemir
lowing injection of a homogeneous solution, glargine is  98% bound to albumin,57 which reduces the rate of
forms amorphous microprecipitates at the neutral pH of transport from blood to interstitial fluid, relative to RHI.

22 © Postgraduate Medicine, Volume 123, Issue 4, July 2011, ISSN – 0032-5481, e-ISSN – 1941-9260
 Basal Insulin

Figure 3. Structure of A) insulin glargine and B) insulin detemir.

A
Asn Deletion
S S
A chain
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
Addition
Gly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser Leu Tyr Gin Leu Glu Asn Tyr Cys Gly

S
B chain Addition
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32
Phe Val Asn Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Pro Lys Thr Arg Arg

A chain S S

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
Gly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser Leu Tyr Gin Leu Glu Asn Tyr Cys Asn

S S

S S
B chain Addition
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29
Phe Val Gln Val Glu Leu Gly Arg Gly Phe Phe Tyr Thr Lys NH
Asn His Leu Cys Gly Ser His Leu Ala Leu Tyr Val Cys Glu Pro

Thr Deletion

Reprinted with permission from Acta Diabetol.46

Importantly, plasma albumin binding of detemir acts as a In keeping with this reduced affinity at the IR, the
buffering mechanism against any rapid or irregular changes metabolic potency of detemir is ∼50-fold lower than that of
in absorption.58 Because detemir is immediately and almost RHI. Considering that detemir is 93.7% albumin-bound in
completely bound to albumin, the concentration of free this particular assay, and that only free detemir is biologically
insulin in the capillary is limited. Because the distribution active, the metabolic potency was corrected to be ∼27%.24,59
of detemir from plasma to target tissues is slower than that Similar to metabolic potency, the measured mitogenic potency
of RHI, changes in detemir concentration in the plasma will was  250-fold lower than that of RHI. Mitogenic potency,
be slow to affect interstitial concentrations. These buffering when corrected for album binding, was calculated to be
mechanisms appear to underlie the low intrapatient vari- ∼11%.24 In another in vitro study, serum containing detemir
ability observed with detemir.55,56 did not exhibit increased mitogenicity compared with serum
containing RHI.51
Signal Transduction Characteristics of Detemir In the in vitro studies described above, detemir—with a
It has been shown that amino acid modifications in the molar potency 10% of that of RHI, adjusted for potency—
insulin B-chain beyond position B25 are not essential for evoked 100% maximal responses equivalent to that of RHI.
binding to IR.24 Nonetheless, insulin detemir has reduced In vivo, detemir demonstrated a reduced molar potency, about
affinity at the IR and IGF-1R (18% and 16%, respectively) 25% of RHI.60 As a result, insulin detemir is formulated at
compared with RHI. Receptor affinities were determined 4 times the molar strength of RHI to maintain parity in unit
using solubilized receptors, to which RHI bound with an doses and injection volumes. However, despite the lower
affinity of ∼0.01 nmol/L. The IR affinities correlated well molar potency, the ability of insulin detemir to evoke a full
with metabolic potencies.24 The lower affinities are hypoth- and complete insulin-driven metabolic response indicates that
esized to be attributed to the fatty acid side chain attached to the numbers of cellular IRs necessary to evoke a clinically
B29 Lys, possibly making contacts with aromatic amino acids relevant biologic response can be triggered.
in positions B24–25 and shielding them from recognizing the
IR.24 Furthermore, detemir dissociated twice as fast as RHI Clinical Implications
from the IR, contributing to the reduced residence time of Both basal insulin analogs are characterized by a relatively
detemir, and theoretically reducing any mitogenic signaling flat time-action profile (Figure 2)—ie, they reach peak and
through the receptor. remain at that level, mirroring the physiologic action of basal

© Postgraduate Medicine, Volume 123, Issue 4, July 2011, ISSN – 0032-5481, e-ISSN – 1941-9260 23
Kevin D. Niswender

insulin. The current gold standard is a duration of action of up hypoglycemia was higher in the detemir group versus the
to 24 hours, and both glargine and detemir have durations of NPH group (26% vs 16%; P = 0.008).70 In addition, treat-
action in this range37,55,61,62 (with detemir, on average, perhaps ment with detemir reduced the risk for overall hypoglycemia
being slightly shorter), indicating that they are well suited by 47% (P  0.001) and for nocturnal hypoglycemia by
as basal insulins. At the same time, rates of absorption of 55% (P  0.001) compared with NPH. In another study,
glargine do not differ between injection sites and no evidence detemir in combination with OAD medications reduced
of accumulation was observed after multiple injections.63,64 24-hour and nocturnal hypoglycemic events by 65%
Similarly, detemir demonstrated a dose-dependent duration (P = 0.031) and 53% (P = 0.019), compared with NPH plus
of action of from 5.7 hours at the lowest dose (0.1 U/kg) to OAD medications, respectively.71
23.2 hours at the highest dose (1.6 U/kg), with an onset of Thus, the insulin analogs glargine and detemir demon-
action within 1 to 2 hours. Although the duration of action strate improved pharmacokinetic and pharmacodynamic
of glargine and detemir are similar in the clinically relevant profiles compared with NPH, offering advantages in safety,
dose range of 0.4 to 0.8 U/kg, within-subject variability in efficacy, and variability. The 24-hour profiles of these insu-
metabolic effect—determined as the area under the curve lins therefore offer reliability, predictability, fewer injec-
for glucose infusion rate (AUC-GIRtotal)—was significantly tions, and a lower risk of hypoglycemia relative to NPH.
lower with detemir than with glargine (47% vs 215%, respec- These factors may also contribute to less weight gain in the
tively; P  0.001).55 context of improved glycemic control,72 and some studies
suggest a unique property of detemir to affect appetite.73
Pharmacokinetic and Pharmacodynamic These factors ultimately help to overcome some of the
Profiles of Glargine and Detemir barriers associated with insulin therapy, such as multiple
The absence of clear peaks in the time-action profiles daily injections, hypoglycemia, and variability. Of course,
of glargine and detemir contributes to the lower risk of glargine and detemir typically have a higher cost than NPH.
nocturnal hypoglycemia with both of these analogs versus These long-acting insulin analogs represent significant
NPH insulin, and therefore the ability to achieve lower progress toward the ideal insulin from the historical use
fasting blood glucose levels concomitantly with reduced of lente and ultralente insulin. However, there are still
hypoglycemia risk when administered before the evening opportunities for research in designing insulin with more
meal or at bedtime.55,65 ideal characteristics. Although both glargine and detemir
Results from the glargine vs NPH Treat-to-Target possess flat, long durations of action allowing for once-daily
trial66 demonstrated that nearly 25% more patients treated administration, future research may make it possible to
with insulin glargine achieved an HbA1c value of  7.0% develop an insulin that could be used even less frequently
without nocturnal hypoglycemia versus those treated with (ie, once every 3 days or even once per week). Similarly,
NPH insulin. A meta-analysis of 4 open-label, random- it may be possible to develop “tissue-selective” insulins
ized, parallel-group studies comparing glargine with NPH with enhanced or biased activity in a given tissue, such as
demonstrated a significant risk reduction associated with liver, muscle, or brain.
glargine for severe hypoglycemia (46%; P = 0.0442) and
severe nocturnal hypoglycemia (59%; P = 0.0231).67 In Summary
patients achieving the target HbA1c level of  7.0%, those The majority of patients with T2DM eventually require
treated with glargine demonstrated a lower incidence of the addition of insulin to achieve glycemic control. With
nocturnal hypoglycemia than those taking NPH (39% vs this in mind, the addition of basal insulin to existing OAD
49%; P  0.01). therapy is an effective means for achieving the goal. The 2
Consistent with its time-action profile, similar effects on long-acting insulin analogs, glargine and detemir, represent
overall and nocturnal hypoglycemia have been reported for significant advances in providing basal insulin supplementa-
detemir.68 In long-term basal-bolus therapy, insulin detemir tion, specifically regarding their reduction of hypoglycemia
administered at mealtime with insulin aspart demonstrated and allowing improved glycemic control. Structural
reduced nocturnal hypoglycemia (32% lower; P = 0.02) modifications to the insulin molecule can result in altered
and weight gain compared with NPH.69 Seventy percent of self-association characteristics toward a more physiologic
patients receiving either detemir or NPH achieved HbA1c pharmacokinetic profile. Structural alterations can also
levels of  7.0%, but the proportion of patients without affect binding to and signaling via the insulin and IGF-1Rs,

24 © Postgraduate Medicine, Volume 123, Issue 4, July 2011, ISSN – 0032-5481, e-ISSN – 1941-9260
 Basal Insulin

which in turn regulate the metabolic and mitogenic effects of 11. Ceriello A. Hypothesis: the “metabolic memory,” the new challenge of
diabetes. Diabetes Res Clin Pract. 2009;86(suppl 1):S2–S6.
insulin. Taken together, the advantageous pharmacokinetic 12. Taubes G. Diabetes: paradoxical effects of tightly controlled blood sugar.
profile facilitates a continuous basal supply of insulin over Science. 2008;322(5900):365–367.
a 24-hour period, with not only reduced variability but also 13. Wright RJ, Frier BM. Vascular disease and diabetes: is hypoglycaemia
an aggravating factor? Diabetes Metab Res Rev. 2008;24(5):353–363.
reduced risk of nocturnal and overall hypoglycemia. These 14. Jensen M, De Meyts P. Molecular mechanisms of differential intracellular
factors are clinically beneficial in allowing more aggressive signaling from the insulin receptor. Vitam Horm. 2009;80:51–75.
15. Taniguchi CM, Emanuelli B, Kahn CR. Critical nodes in signalling
titration toward desired glycemic targets. pathways: insights into insulin action. Nat Rev Mol Cell Biol.
2006;7(2):85–96.
Acknowledgments 16. Bansal P, Wang Q. Insulin as a physiological modulator of glucagon
secretion. Am J Physiol Endocrinol Metab. 2008;295(4):E751–E761.
The author would like to thank Anu Santhanagopal, PhD, 17. Lomberk G, Urrutia R. Primers on molecular pathways—the insulin
and Barbara Saldinger, of MedVal Scientific Information pathway. Pancreatology. 2009;9(3):203–205.
18. Klover PJ, Mooney RA. Hepatocytes: critical for glucose homeostasis.
Services, LLC, for providing writing and editorial assis- Int J Biochem Cell Biol. 2004;36(5):753–758.
tance. Funding to support the preparation of this manuscript 19. Cherrington AD. The role of hepatic insulin receptors in the regulation
was provided by Novo Nordisk, Inc. This article was pre- of glucose production. J Clin Invest. 2005;115(5):1136–1139.
20. Samuel VT, Petersen KF, Shulman GI. Lipid-induced insulin resistance:
pared according to the International Society for Medical unravelling the mechanism. Lancet. 2010;375(9733):2267–2277.
Publication Professionals’ “Good Publication Practice for 21. Bays H, Mandarino L, DeFronzo RA. Role of the adipocyte, free
fatty acids, and ectopic fat in pathogenesis of type 2 diabetes mellitus:
Communicating Company-Sponsored Medical Research: peroxisomal proliferator-activated receptor agonists provide a rational
the GPP2 Guidelines.” therapeutic approach. J Clin Endocrinol Metab. 2004;89(2):463–478.
22. Galic S, Oakhill JS, Steinberg GR. Adipose tissue as an endocrine organ.
Mol Cell Endocrinol. 2010;316(2):129–139.
Conflict of Interest Statement 23. Groop LC, Bonadonna RC, DelPrato S, et al. Glucose and free fatty acid
Kevin D. Niswender, MD, PhD discloses a conflict of interest metabolism in non-insulin-dependent diabetes mellitus. Evidence for
multiple sites of insulin resistance. J Clin Invest. 1989;84:205–213.
with Novo Nordisk. 24. Kurtzhals P, Schäffer L, Sorensen A, et al. Correlations of receptor
binding and metabolic and mitogenic potencies of insulin analogs
designed for clinical use. Diabetes. 2000;49(6):999–1005.
References 25. Sheehan JP. Fasting hyperglycemia: etiology, diagnosis, and treatment.
1. Thompson R, Christie D, Hindmarsh PC. The role for insulin analogues Diabetes Technol Ther. 2004;6(4):525–533.
in diabetes care. Curr Paediatr. 2006;16:117–122. 26. Nathan DM, Buse JB, Davidson MB, et al. Medical management of
2. Bonadonna RC, Stumvoll M, Fritsche A, et al. Altered homeostatic hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation
adaptation of first- and second-phase β-cell secretion in the offspring and adjustment of therapy. A consensus statement of the American
of patients with type 2 diabetes: studies with a minimal model to assess Diabetes Association and the European Association for the Study of
β-cell function. Diabetes. 2003;52(2):470–480. Diabetes. Diabetes Care. 2009;32(1):193–203.
3. Freeman JS. Insulin analog therapy: improving the match with physiologic 27. Rodbard HW, Jellinger PS, Davidson JA, et al. Statement by an
insulin secretion. J Am Osteopath Assoc. 2009;109(1):26–36. American Association of Clinical Endocrinologists/American College
4. Diabetes Prevention Program Research Group. 10-year follow-up of of Endocrinology consensus panel on type 2 diabetes mellitus: an
diabetes incidence and weight loss in the Diabetes Prevention Program algorithm for glycemic control. Endocr Pract. 2009;15(6):540–559.
Outcomes Study. Lancet. 2009;374(9702):1677–1686. 28. Brange J, Volund A. Insulin analogs with improved pharmacokinetic
5. Koro CE, Bowlin SJ, Bourgeois N, Fedder DO. Glycemic control profiles. Adv Drug Deliv Rev. 1999;35(2–3):307–335.
from 1988 to 2000 among U.S. adults diagnosed with type 2 diabetes: 29. Heinemann L. Variability of insulin absorption and insulin action.
a preliminary report. Diabetes Care. 2004;27(1):17–20. Diabetes Technol Ther. 2002;4(5):673–682.
6. Chen HS, Wu TE, Jap TS, Hsiao LC, Lee SH, Lin HD. Beneficial 30. Hirsch IB. Insulin analogues. N Engl J Med. 2005;352(2):174–183.
effects of insulin on glycemic control and beta-cell function in newly 31. Owens DR, Zinman B, Bolli GB. Insulins today and beyond. Lancet.
diagnosed type 2 diabetes with severe hyperglycemia after short-term 2001;358(9283):739–746.
intensive insulin therapy. Diabetes Care. 2008;31(10):1927–1932. 32. Owens DR, Vora JP, Jones IR, et al. Soluble and Lente human insulin
7. Dailey G. Optimum management of type 2 diabetes—timely mixtures in normal man. Diabetes Res. 1988;7(1):35–40.
introduction, optimization and intensification of basal insulin. Diabetes 33. Humulin L Lente human insulin (rDNA origin) zinc suspension
Obes Metab. 2008;10(suppl 2):5–13. [prescribing information]. Indianapolis, IN: Eli Lilly & Co; 2004.
8. Gavin JR 3rd, Peragallo-Dittko V, Rodgers PT. A new look at estab- 34. Binder C, Lauritzen T, Faber O, Pramming S. Insulin pharmacokinetics.
lished therapies: practical tools for optimizing insulin use. Diabetes Diabetes Care. 1984;7(2):188–199.
Educ. 2010;36(suppl 2):26S–38S. 35. Humulin R (regular U-500 [concentrated] insulin human injection [rDNA
9. Colagiuri S, Cull CA, Holman RR; UKPDS Group. Are lower fasting origin]) [prescribing information]. Indianapolis, IN: Eli Lilly & Co; 2011.
plasma glucose levels at diagnosis of type 2 diabetes associated with 36. Dailey AM, Tannock LR. Extreme insulin resistance: indications and
improved outcomes? U.K. Prospective Diabetes Study 61. Diabetes approaches to the use of U-500 insulin in type 2 diabetes mellitus. Curr
Care. 2002;25(8):1410–1417. Diab Rep. 2011;11(2):77–82.
10. Nathan DM, Cleary PA, Backlund JY, et al; Diabetes Control and 37. Lepore M, Pampanelli S, Fanelli C, et al. Pharmacokinetics and
Complications Trial/Epidemiology of Diabetes Interventions and pharmacodynamics of subcutaneous injection of long-acting human
Complications (DCCT/EDIC) Study Research Group. Intensive diabetes insulin analog glargine, NPH insulin, and ultralente human insulin
treatment and cardiovascular disease in patients with type 1 diabetes. and continuous subcutaneous infusion of insulin lispro. Diabetes.
N Engl J Med. 2005;353(25):2643–2653. 2000;49(12):2142–2148.

© Postgraduate Medicine, Volume 123, Issue 4, July 2011, ISSN – 0032-5481, e-ISSN – 1941-9260 25
Kevin D. Niswender

38. Fanelli CG, Pampanelli S, Porcellati F, Rossetti P, Brunetti P, Bolli GB. 57. Kurtzhals P. Pharmacology of insulin detemir. Endocrinol Metab
Administration of neutral protamine Hagedorn insulin at bedtime versus Clin North Am. 2007;36(suppl 1):14–20.
with dinner in type 1 diabetes mellitus to avoid nocturnal hypoglycemia 58. Kurtzhals P, Colding-Jorgensen M. Albumin binding of insulin
and improve control. A randomized, controlled trial. Ann Intern Med. detemir reduces the risk for hypoglycemic events. Diabetes.
2002;136(7):504–514. 2004;53(suppl 2):A477 (abstract).
39. Owens DR, Bolli GB. Beyond the era of NPH insulin-long-acting insulin 59. Kurtzhals P, Havelund S, Jonassen I, et al. Albumin binding of
analogs: chemistry, comparative pharmacology, and clinical application. insulins acylated with fatty acids: characterization of the ligand-protein
Diabetes Technol Ther. 2008;10(5):333–349. interaction and correlation between binding affinity and timing of the
40. Jehle PM, Micheler C, Jehle DR, Breitig D, Boehm BO. Inadequate insulin effect in vivo. Biochem J. 1995;312(part 3):725–731.
suspension of neutral protamine Hagedorn (NPH) insulin in pens. 60. Kurtzhals P. Engineering predictability and protraction in a basal
Lancet. 1999;354(9190):1604–1607. insulin analogue: the pharmacology of insulin detemir. Int J Obes.
41. Gerich JE. Novel insulins: expanding options in diabetes management. 2004;28(suppl 2):S23–S28.
Am J Med. 2002;113(4):308–316. 61. Plank J, Bodenlenz M, Sinner F, et al. A double-blind, randomized, dose-
42. Barnett AH. A review of basal insulins. Diabet Med. 2003;20(11):873–885. response study investigating the pharmacodynamic and pharmacokinetic
43. Rosenstock J, Davies M, Home PD, Larsen J, Koenen C, Schernthaner G. properties of the long-acting insulin analog detemir. Diabetes Care.
A randomised, 52-week, treat-to-target trial comparing insulin detemir 2005;28(5):1107–1112.
with insulin glargine when administered as add-on to glucose-lowering 62. Heise T, Pieber TR. Towards peakless, reproducible and long-acting
drugs in insulin-naive people with type 2 diabetes. Diabetologia. insulins. An assessment of the basal analogues based on isoglycaemic
2008;51(3):408–416. clamp studies. Diabetes Obes Metab. 2007;9(5):648–659.
44. King AB. Once-daily insulin detemir is comparable to once-daily insulin 63. Owens DR, Coates PA, Luzio SD, Tinbergen JP, Kurzhals R.
glargine in providing glycaemic control over 24 h in patients with type Pharmacokinetics of 125I-labeled insulin glargine (HOE 901) in healthy
2 diabetes: a double-blind, randomized, crossover study. Diabetes Obes men: comparison with NPH insulin and the influence of different
Metab. 2009;11(1):69–71. subcutaneous injection sites. Diabetes Care. 2000;23(6):813–819.
45. Barnett AH. Insulin glargine in the treatment of type 1 and type 2 64. Heise T, Bott S, Rave K, Dressler A, Rosskamp R, Heinemann L. No
diabetes. Vasc Health Risk Manag. 2006;2:59–67. evidence for accumulation of insulin glargine (LANTUS): a multiple
46. Baxter MA. The role of new basal insulin analogues in the initiation injection study in patients with type 1 diabetes. Diabet Med.
and optimisation of insulin therapy in type 2 diabetes. Acta Diabetol. 2002;19(6):490–495.
2008;45(4):253–268. 65. Dailey G, Strange P. Lower severe hypoglycemia risk: insulin
47. Le Roith D. Insulin glargine and receptor-mediated signalling: clinical glargine versus NPH insulin in type 2 diabetes. Am J Manag Care.
implications in treating type 2 diabetes. Diabetes Metab Res Rev. 2008;14(1):25–30.
2007;23(8):593–599. 66. Riddle MC, Rosenstock J, Gerich J. The treat-to-target trial: randomized
48. Berti L, Kellerer M, Bossenmaier B, Seffer E, Seipke G, Häring HU. The addition of glargine or human NPH insulin to oral therapy of type 2
long acting human insulin analog HOE 901: characteristics of insulin diabetic patients. Diabetes Care. 2003;26(11):3080–3086.
signalling in comparison to Asp(B10) and regular insulin. Horm Metab 67. Rosenstock J, Dailey G, Massi-Benedetti M, Fritsche A, Lin Z, Salzman
Res. 1998;30(3):123–129. A. Reduced hypoglycemia risk with insulin glargine: a meta-analysis
49. Ciaraldi TP, Carter L, Seipke G, Mudaliar S, Henry RR. Effects of the comparing insulin glargine with human NPH insulin in type 2 diabetes.
long-acting insulin analog insulin glargine on cultured human skeletal Diabetes Care. 2005;28(4):950–955.
muscle cells: comparisons to insulin and IGF-I. J Clin Endocrinol 68. Home P, Kurtzhals P. Insulin detemir: from concept to clinical
Metab. 2001;86(12):5838–5847. experience. Expert Opin Pharmacother. 2006;7(3):325–343.
50. Bahr M, Kolter T, Seipke G, Eckel J. Growth promoting and metabolic 69. De Leeuw I, Vague P, Selam JL, et al. Insulin detemir used in basal-
activity of the human insulin analogue [GlyA21, ArgB31, ArgB32] bolus therapy in people with type 1 diabetes is associated with a lower
insulin (HOE 901) in muscle cells. Eur J Pharmacol. 1997;320(2–3): risk of nocturnal hypoglycaemia and less weight gain over 12 months
259–265. in comparison to NPH insulin. Diabetes Obes Metab. 2005;7:73–82.
51. Mayer D, Chantelau E. Treatment with insulin glargine (Lantus) 70. Hermansen K, Davies M, Derezinski T, Ravn GM, Clauson P, Home P.
increases the proliferative potency of the serum of patients with type-1 A 26-week, randomized, parallel, treat-to-target trial comparing insulin
diabetes: a pilot study on MCF-7 breast cancer cells. Arch Physiol detemir with NPH insulin as add-on therapy to oral glucose-lowering
Biochem. 2010;116(2):73–78. drugs in insulin-naive people with type 2 diabetes. Diabetes Care.
52. Chaykin LB. Insulin detemir and its unique mechanism of action. 2006;29(6):1269–1274.
Int J Endocrinol. 2007;4(1):e1. 71. Philis-Tsimikas A, Charpentier G, Clauson P, Martinez Ravn G, Roberts
53. Kurtzhals P. How to achieve a predictable basal insulin? Diabetes Metab. VL, Thorsteinsson B. Comparison of once-daily insulin detemir with
2005;31(4 pt 2):4S25–4S33. NPH insulin added to a regimen of oral antidiabetic drugs in poorly
54. Havelund S, Plum A, Ribel U, et al. The mechanism of protraction controlled type 2 diabetes. Clin Ther. 2006;28(10):1569–1581.
of insulin detemir, a long-acting, acylated analog of human insulin. 72. Pollock RF, Erny-Albrecht KM, Kalsekar A, Bruhnand D, Valentine
Pharm Res. 2004;21(8):1498–1504. WJ. Long-acting insulin analogs: a review of “real-world” effectiveness
55. Klein O, Lynge J, Endahl L, Damholt B, Nosek L, Heise T. Albumin- in patients with type 2 diabetes. Curr Diabetes Rev. 2011;7(1):61–74.
bound basal insulin analogues (insulin detemir and NN344): comparable 73. Hallschmid M, Jauch-Chara K, Korn O, et al. Euglycemic infusion of
time-action profiles but less variability than insulin glargine in type 2 insulin detemir compared to human insulin appears to increase direct
diabetes. Diabetes Obes Metab. 2007;9(3):290–299. current brain potential response and reduces food intake while inducing
56. Heise T, Nosek L, Ronn BB, et al. Lower within-subject variability of similar systemic effects. Diabetes. 2010;59(4):1101–1107.
insulin detemir in comparison to NPH insulin and insulin glargine in
people with type 1 diabetes. Diabetes. 2004;53(6):1614–1620.

26 © Postgraduate Medicine, Volume 123, Issue 4, July 2011, ISSN – 0032-5481, e-ISSN – 1941-9260