Endocrinology Associates,
with type 2 diabetes mellitus for the past 90 years. This trend
Flushing, NY 11365-1414.
E-mail: jtibaldi@aol.com
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Pathophysiologic
Profile of T2DM Drives
Treatment Choices
S30
420
360
Glucose, mg/dL
90
30
60
90
120
150
180
Time, min
500
Insulin, pmol/L
400
300
200
100
low-dose insulin therapy (given as premixed insulin in one study) for patients
with newly diagnosed T2DM led to evi-
30
60
90
120
150
180
Time, min
dence of -cell recovery, as documented by plasma insulin and C-peptide levels.17 It appears that reversing glucose
toxicity may result in a rapid improvement in -cell function, which then allows the cell to start to function and
to secrete adequate amounts of insulin
for clinically significant periods of up to
1 year.14-16 This series of events is also
known as a second-wind phenomenon
for the cell.13 After symptom relief oc-
Figure 1.
Glucose and insulin levels before insulin therapy, immediately
after insulin therapy, and 1 year after insulin therapy,
demonstrating the effects of short-term intensive insulin therapy
in patients with newly diagnosed type 2 diabetes mellitus.14
Reprinted with permission from the American Diabetes
Association, from Ryan EA, Imes S, Wallace C. Short-term
intensive insulin therapy in newly diagnosed type 2 diabetes
mellitus. Diabetes Care. 2004;27(5):1028-1032; permission
conveyed through Copyright Clearance Center, Inc.
S31
initial treatment.
tor agonists.
Harry
much glucagon.
18
Case Study
S32
Chronic
hyperglycemia
Glucose
Pancreatic cell
Glucokinase activity
PDX-1 activity
Insulin biosynthesis
Insulin secretion
Figure 2.
The mechanism of insulin secretion reduction caused by glucose toxic effects.
The binding capacity of PDX-1 decreases as a result of oxidative stress caused
by hyperglycemia, while insulin biosynthesis and secretion also decrease.
Reprinted from Kawahito et al.6 Abbreviations: PDX-1, pancreatic duodenal
homeobox-1; ROS, reactive oxidative species.
insulin doses.23
receptor agonists).
initiating insulin.36,37
S33
Table 1.
Outcomes of Select Studies of Dipeptidyl Peptidase-4 Inhibitors
in Combination With Insulin Over 24 Weeks Duration
Source Agent Comparison
Patients
Outcome
Hong et al,
Sitagliptin
Add-on to insulin vs
Patients with T2DM (n=140);
201228
an insulin dose increase
baseline HbA1c level, 9.2%
Add-on to basal or
premixed insulin vs
placebo
Table 2.
Comparison of Onset, Peak, and Duration of Longer-Acting Basal Insulins
Basal Insulin
Onset
Peak
Duration
1-2 h
4-8 h
8-12 h
Glargine
30-60 min
Relatively peakless
16-24 h
Detemir
30-60 min
Relatively peakless
16-24 h
Degludec
30-90 min
Peakless
>24 h
Neutral protamine
Hagedorn
Source: Reprinted from Nasrallah SN, Reynolds LR. Insulin degludec, the new generation basal insulin
or just another basal insulin? Clin Med Insights Endocrinol Diabetes. 2012;5:31-37.38 Copyright 2012,
with permission from Libertas Academica Ltd.
injections at mealtimes.
S34
Brain
Muscle
Glucose
Liver
Adipose tissue
I
ce
ns
lls
uli
Native GLP-1
Glucagon
In
Pancreas
( cells)
su
(
lin
ce
lls
Amylin
( cells)
Figure 3.
Different approaches to enhancing the effects of the naturally
occurring incretin hormonepharmacologic replacement or minimizing
degradation.9 Abbreviation: GLP-1, glucagon-like peptide 1.
Ultra-Long-Acting Basal
Insulin in Development
neously daily.
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Table 3.
Published Trials of Ultra-Long-Acting Insulins
Source
Insulin
Agent
Patient
Insulin
Characteristics Comparator
Design
Outcomes
Rosenstock LY2605541
T1DM; basal-bolus
Glargine
8-wk randomized,
et al, 201356 (pegylated
therapy
phase 2, open-label,
insulin lispro)
22 crossover study
Bergenstal LY2605541
et al, 201257 (pegylated
insulin lispro)
Birkeland
Degludec
T1DM; mean HbA1c Glargine
16-wk randomized,
et al, 201143
level 8.4%
phase 2 controlled trial
T2DM; background
Glargine
therapy for OAD;
baseline HbA1c level
7% to 10%
1-year treat-to-target,
open-label, randomized
trial
T1DM; basal-bolus
Glargine
insulin therapy;
HbA1c level 10%
1-year treat-to-target,
open-label, randomized
trial
T2DM; basal-bolus
Glargine
insulin; HbA1c level,
7% to 10%
1-year treat-to-target,
open-label, randomized
trial
Niskanen
et al, 201258
Degludec/
T2DM; HbA1c level
aspart (twice 7% to 11%
daily) and an
alternative
formulation
Biphasic
16-wk, open-label,
insulin aspart randomized,
twice daily
treat-to-target trial
Abbreviations: HbA1c, glycated hemoglobin; NPH, neutral protamine Hagedorn; OAD, oral antidiabetic drugs; T1DM, type 1 diabetes mellitus;
T2DM, type 2 diabetes mellitus.
S36
pharmacodynamics of longer-acting
49
lowering effect,
and it is associated
41
approval process.
Oral Insulin
insulin therapy.
42-47
The
Inhaled Insulin
regimens.2
Conclusion
52
S37
References
1. Best JD, Drury PL, Davis TM, et al. Glycemic
control over 5 years in 4,900 people with
type 2 diabetes: real-world diabetes therapy
in a clinical trial cohort. Diabetes Care.
2012;35(5):1165-1170.
2. Tibaldi JM. Evolution of insulin development:
focus on key parameters. Adv Ther.
2012;29(7):590-619.
3. Defronzo RA. From the triumvirate to the
ominous octet: a new paradigm for the treatment
of type 2 diabetes mellitus [Banting Lecture].
Diabetes. 2009;58(4):773-795.
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