CHAPTER

60

Glucagon Like Peptide 1

Related Analogs
V. Seshiah, V. Balaji

Insulin release from the beta cells is influenced

by nutrients (both carbohydrates and noncarbohydrates), hormonal factors including gut
hormones and neural factors. Of all these insulin
secretagogues, glucose availability is the major
physiological determinant of insulin secretion.
The insulin secretory response is greater after oral
administration of glucose than after intravenous
glucose administration (Fig 1), an indication that
absorption of glucose by way of gastro-intestinal
tract stimulates the release of hormones and other
mechanism that ultimately enhance the sensitivity
of the beta cell to glucose. This phenomenon is
known as Incretin effect and is facilitated by gut
hormones.
Glucagon is secreted from a cells and functions
predominantly during the fasting state to maintain
Figure 1 : Incretin Effect

Adapted from Joslins Textbook of Diabetes Mellitus (14 th

edition).

blood glucose levels by the mobilization of glucose

from glycogen stores in peripheral tissues such as
muscle and liver. Excessive production of glucagon
contributes to hyperglycemia and thus approaches
that antagonize glucagon action in subjects with
diabetes are being actively investigated. Two
aspects of the gut have interested the diabetologists
over the past 30 years. They are the incretin effect
and the occurrence of glucagon-producing L-cells
in the gut. The incretin effect is the amplification
of nutrient-induced insulin secretion by hormones
from the gut particularly GIP (gastric inhibitory
peptide) and GLP 1 (glucagon like peptide 1)1 [Fig
2]. Of these two peptides, GLP 1 is the most potent
and efficacious insulinotrophic hormone 1. The
Figure 2 : Nutrients and Gut Hormones

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Medicine Update 2008 Vol. 18

Figure 3 : Nor GLP 1 Action (Short Life) Enzyme

resistant GLP 1 Analog

adenylate cyclase, thereby stimulating cyclic AMP

production and calcium influx. Secondly they may
influence the mobilization of intracellular calcium
stores notably the endoplasmic reticulum and thus
cytosolic calcium concentration. Thirdly they may
modify the calcium sensitivity of the contractile
protein interactions that lead to the release of
insulin secretory granules. Cyclic AMP and calcium
stimulate rapid release of insulin from the cells and
induce transcription of the insulin gene, thereby
replenishing insulin stores. GLP-1 also activates
receptors in neurons located in the hypothalamus,
resulting in a reduction in food intake; thus, GLP-1
has an important role in controlling energy balance.
GLP-1 receptors are also located on neurons in brain
regions, such as the hippocampus, that are involved
in learning and memory.

insulinotrophic actions of GLP 1 appear to be due

to an increase in the insulinogenic index, such that
the same degree of insulin secretion is produced at
lower glucose levels. The incretin effect is markedly
impaired or absent in patients with type 2 diabetes
because of decreased secretion of GLP 1.

GLP 1 and diabetes treatment

The glucagon like peptides are secreted in

response to feeding. Glucagon like peptide 1 (GLP
1) and gastric inhibitory polypeptide (GIP) comprise
the intestinal incretin hormones released from the
intestine in response to feeding and augment glucose
stimulated insulin secretion from the b cells2, 3. GLP
1 also enhances insulin stimulated glucose uptake
in peripheral tissues (muscle, fat, liver), suppresses
glucagon secretion, induces satiety, and promotes
the growth and differentiation of new b cells in
the pancreas. These antidiabetic properties of
GLP 1 have prompted considerable interest in the
therapeutic potential of GLP 1 for the treatment
of diabetes.
The regulation of secretion of GLP-1 from the
L-cells in the gut is complex and appears to involve
combination of nutrient, hormonal and neural
stimuli. There are atleast three potential sites where
insulin secretion can be modulated by peptides.
Firstly GLP-1 binds to receptors on pancreatic
b-cells and thus affects the ion channels that
regulate the membrane potential by activation of

GLP-1 powerfully inhibited glucagon secretion4.

Furthermore, GLP-1 not only stimulated glucoseinduced insulin secretion, but also all steps of
insulin biosynthesis and insulin gene expression 5.
GLP- 1 also turned out to have powerful effects
on gastrointestinal secretion and motility6,7, and it
was shown that inhibition of gastric emptying had
strong effects on postprandial glucose excursions 8 in
healthy subjects and patients with type 2 diabetes9.
In addition, GLP-1 was shown to inhibit appetite
and food intake, both in healthy individuals 10,
and in patients with type 2 diabetes 11. These
gastrointestinal ileal brake effects of GLP-1 may in
fact be the most important actions of the hormone
under physiological conditions12.
GLP-1 had dramatic effects on insulin secretion
and blood glucose in patients with type 2 diabetes
and was capable of completely normalizing fasting
blood glucose levels, even in patients with longstanding type 2 diabetes and HbA1c levels of
11% 13-16.

GLP 1 Preparation
Metabolic control in Type 2 DM can be restored or
greatly improved by administration of exogenous
GLP 1. Initial preparation of GLP 1 was ineffective

Glucagon Like Peptide 1 Related Analogs

Figure 4 : Analog-Toprolong GLP 1 Action

when injected subcutaneously or intravenously as

its effect on insulin and blood glucose was both
transient and weak 17,18. The explanation for this
was that the molecule is broken down extremely
rapidly after both subcutaneous and intravenous
administration 19-21. Mechanism involved in the
degradation of GLP 1 is the ubiquitous enzyme,
dipeptidyl peptidase IV (DPP-IV) 19.
The degradation is truly extensive, which means
that the peptide has a plasma half-life of 1 to 2
min and a clearance of 5 to 10 l/min. (Fig 3). For
practical diabetes treatment, there were now three
possibilities: (a) to provide GLP-1 continuously; (b)
to develop stable analogs of GLP-1 or agonists of
the GLP-1 receptors; and (c) to try to inhibit the
enzyme, DPP-IV.

Enzyme resistant GLP 1 Analog

Exenatide (Byetta)
GLP-1 peptide is almost immediately degraded by
dipeptidyl peptidase IV (DPP IV) and therefore
has little clinical value. DPP IV resistant analogs
(incretin mimetics) have been identified. Exendin-4 is
a GLP-1 receptor agonist originally isolated from the
venom of the Gila monster and is resistant to DPPIV degradation and survives longer in circulation
(Fig 4).
Exenatide (Synthetic Exendin-4, Byetta) is a
39 amino acid peptide incretin mimetic agent that
exhibits its glucoregulatory activities similar to
the mammalian incretin hormone GLP 1. These

461

actions include glucose dependent enhancement of

insulin secretion, restoration of first phase insulin
response, suppression of inappropriately high
glucagon secretion, slowing of gastric emptying,
and reduction of food intake. Exenatide has acute
effects on pancreatic cell responsiveness to glucose
and leads to insulin release only in the presence
of elevated glucose concentrations. This insulin
secretion subsides as blood glucose concentrations
decrease and approach euglycemia.22 Exenatides
glucose dependent enhancement of insulin secretion
may be mediated by exenatide binding to the
pancreatic GLP 1 receptor.23
The collective glucoregulatory effects of
Exenatide (Byetta) complement the actions
of existing therapies, making it an excellent
treatment option for combination therapy. The
effects of Exenatide (Byetta) on the cell to
enhance glucose dependent insulin secretion and
restore first phase insulin secretion are unique. It
is also apparently cleared in the kidneys only by
glomerular filtration 24.
Exenatide (Byetta) is found to be more stable
and when given twice daily subcutaneously in
type 2 diabetic patients reduces blood glucose.
Exenatide is initiated as 5 mcg twice a day and
up-titrated to 10 mcg twice a day. Following
subcutaneous administration to patients with type
2 DM, exenatide reaches median peak plasma
concentration in 2.1 hours.
Long term use of Exenatide (Byetta) in
combination with metformin, sulfonylurea, or
both, reduced both fasting and postprandial plasma
glucose concentrations in a statistically significant,
dose dependent manner through week 30. 25,26,27
Patients with type 2 diabetes receiving Exenatide
(Byetta) 10 mcg BID experienced placebo
corrected A1c changes of 0.9 to -1.0%, with 34% to
46% of patients achieving A1c target levels of d7% by
significantly reducing both fasting and postprandial
plasma glucose concentrations25,26,27. Improvements
in glycemic control with Exenatide (Byetta) were
achieved with the added benefit of reduction in

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Medicine Update 2008 Vol. 18

body weight in most patients25,26,27. Adverse effects

were mild and generally gastrointestinal.

effect of gender or age has been seen with respect

to the pharmacokinetics of liraglutide 31.

Treatment with Exenatide (Byetta) for 1

year resulted in sustained reductions in A1c and
progressive reductions in body weight. Patients in
the 5 mcg BID Exenatide (Byetta) treatment arm
showed changes from baseline to week 30 of -0.8%
in A1c and -1.6kg in body weight. Upon shifting
to 10 mcg BID during the extension, changes from
baseline to week 52 were -1.0% in A1c and -3.1 kg in
body weight. Patients in the 10mcg BID Exenatide
(Byetta) treatment arm showed changes from
baseline to week 30 of -0.9% in A1c and -2.1 kg in
body weight, and changes from baseline to week 52
of -1.1% in A1c and -3.2 kg in body weight 28.

Other analogs currently in clinical development

include slightly modified versions of the GLP 1
molecule that attach to albumin, thereby acquiring
the pharmacokinetic profile of albumin.

The glucoregulatory mode of action of liraglutide

in patients with Type 2 diabetes mellitus includes
a glucose-dependent enhancement of insulin
secretion and suppression of glucagons secretion
together with a slowing of gastric emptying after
both single and multiple injections. In addition,
liraglutide has been shown to promote increased
b-cell mass in animal models of Type 2 diabetes
mellitus. 32,33 In Phase II studies in patients with
Type 2 diabetes mellitus on diet or oral antidiabetic
treatment as monotherapy, liraglutide injected once
daily significantly lowered fasting plasma glucose
(FPG) concentrations, improved b-cell function
and reduced body weight with a very low risk of
hypoglycemia.34,35 The risk of hypoglycemia during
GLP-1 treatment is very low. Liraglutide induced
hypoglycemia do not impair the glucagon response
or the general hypoglycemic counter-regulatory
responses and liraglutide has not been proven to
be insulinotropic at hypoglycemic plasma glucose
concentrations. 36 Preclinical studies have shown
that liraglutide lowers blood glucose, body weight
and food intake in a broad selection of animal
models.32, 37-39

Liraglutide is a potent, long-acting G LP-1

analog. The peptide is based on the structure
of native GLP-1. The modifications include an
amino acid substitution (replacement of lysine
with arginine at position 34) and an attachment
of a C16 acyl chain via a glutamoyl spacer to
lysine at position 26. Liraglutide is administered
as an isotonic solution for injection by the
subcutaneous route; it is slowly absorbed with
a time to maximum concentration (Tmax) of ~
10 14 h and half-life (t) of ~ 11 13 h 29,
making it suitable for once-daily injection. The
long half-life of liraglutide is believed to be
based on albumin binding and an ability to form
micellar-like aggregates in the subcutis, resulting
in prolonged absorption and elimination as well
as DDP IV stability. It has been proven that
liraglutide provides 24-h glycemic control 30. No

Recent data from a randomised, double-blind,

parallel- group trial including 165 patients with
Type 2 diabetes mellitus administered higher
doses of liraglutide (0.65, 1.25 or 1.9 mg) for 14
weeks and demonstrated that liraglutide is capable
of decreasing FPG levels between 2.7 mM (0.65
mg) and 3.4 mM (1.25 and 1.9 mg) on average
when compared with placebo. 35 All three doses of
liraglutide lowered both pre and postprandial selfmonitored blood glucose levels. Interestingly, in
the same study, a decrease in levels of HbA1c of
d1.7 percentage points was noted and ~ 50% of
the patients with Type 2 diabetes mellitus managed
to reach the goal level of < 7% in HbA1c set by
the American Diabetes Association (ADA) 40 when
receiving the 2 highest doses of liraglutide (1.25
and 1.9 mg) compared with only 5% in the placebo
group.35 In the highest liraglutide dose group (1.9

Exenatide thus represents an efficacious

supplement to failing conventional oral
antihyperglycemic agents, and the sustained effect
observed in the extension studies and its continued
weight-lowering effects must be considered.
Liraglutide

Glucagon Like Peptide 1 Related Analogs

Figure 5 : GLP 1 Action Protected by DPP IV
Inhibitors

mg), change from baseline in body weight was

-2.99 and -1.21 kg compared with placebo 35. The
most frequently reported side effects involve the
gastrointestinal system during liraglutide treatment.
Gradual dose escalation of liraglutide successfully
reduced the proportion of subjects experiencing
dose-limiting nausea.
Liraglutide as an add-on therapy to metformin
was evaluated by Nauck et al. Following 5 weeks
of treatment, HbA1c was significantly reduced
relative to baseline in all of the groups except the
group receiving metformin as a monotherapy.
Furthermore, combination therapy with liraglutide
plus metformin resulted in significantly greater
reductions in HbA1c than liraglutide or metformin
monotherapy 41. Liraglutide in combination with
metformin induced a clinically and statistically
significant weight loss (2.9 kg) compared with
metformin plus glimepiride.

DPP IV Inhibitors
Inhibitors of DPP IV have also proved effective in
protecting endogenous GLP 1 from degradation.
The therapeutic use of inhibitors of DPP-IV,
the enzyme responsible for inactivation of GLP-1
(Fig 5), as an antihyperglycemic agent was first
proposed based on the finding that GLP-1 seems
uniquely sensitive to cleavage by DPP-IV. 42 DPPIV inhibitors improve beta cell function and
peripheral tissue sensitivity. This reduces both

463

fasting and postprandial glucose concentration

and thus A1c. Another important consideration
is that insulin levels are not elevated during
inhibitor treatment. 43,44 The DPP-IV inhibitors
are given orally.
GLP 1 invariably inhibits gastric emptying
whereas DPP IV inhibitors have little effect on
gastric emptying. It has been established that nausea
will be elicited when circulating concentrations
of active GLP 1 exceeds 60 pmol/l which can be
initially reached after subcutaneous injections of
GLP 1 or GLP 1 mimetics. However this effect has
never been seen when DPP IV inhibitors are used.
In contrast to the results obtained with the GLP-1
analogs, no change in body weight was seen with
DPP-IV inhibition.
The main effects of DPP IV inhibitors are
mediated by GLP 1. One of the more important
therapeutic effects of GLP 1 may be the inhibition
of glucagon secretion, which also seems to be the
case for DPP IV inhibitors a striking similarity.
Protection of GLP 1 is a major contributor to the
effects of DPP IV inhibition.
The binding kinetics, type of inhibition and
selectivity with respect to other peptidases for
the inhibitor (now called vildagliptin) has been
reported. 45 Januvia (Sitagliptin) is one of the
marketed preparations under this category.
When comparing liraglutide with the orally
administered DPP IV inhibitors (sitagliptin or
vildagliptin), the effect of liraglutide seems to be
more pronounced with the DPP IV inhibitors
being weight neutral with an effect on HbA1c
levels in the range of ~ 0.6 1%.46-48 The reason
for this difference is most likely to be due to the
substantially greater concentrations obtained when
using a GLP-1 analog.

Protective effects of GLP 1

The GLP-1-based therapies possess a unique
potential: GLP-1 has trophic effects on beta cells49.
Not only does it stimulate beta cell proliferation 50,51,
it also enhances the differentiation of new beta
cells from progenitor cells in the pancreatic
duct epithelium 52 and, most importantly, GLP-1

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is capable of inhibiting apoptosis of beta cells

including human beta cells.53
G LP-1 improves postprandial lipidemia,
presumably as a result of delayed gastric emptying
and insulin-mediated inhibition of lipolysis. Thus,
by lowering both glucose and lipid concentrations,
GLP-1 administration may reduce the cardiovascular
risk in patients with type 2 diabetes. 54
GLP 1 based therapy should be started as early
in the clinical course as possible, before beta cell
function has deteriorated to unacceptable levels.

References

potential. Trends Endocrinol Metab 1999; 10:229234.

13. Gutniak M, Orskov C, Holst JJ, et al. Antidiabetogenic effect
of glucagon-like peptide-1 (7-36) amide in normal subjects and
patients with diabetes mellitus. N Engl J Med 1992; 326:13161322.
14. Nathan DM, Schreiber E, Fogel H, et al. Insulinotropic action
of glucagon like peptide-I-(7-37) in diabetic and nondiabetic
subjects. Diabetes Care 1992; 15:270-276.
15) Nauck MA, Kleine N, Orskov C, et al. Normalization of fasting
hyperglycaemia by exogenous glucagon-like peptide 1 (7-36
amide) in type 2 (non-insulindependent) diabetic patients.
Diabetologia 1993; 36:741744.
16. Nauck MA, Heimesaat MM, Orskov C, et al. Preserved incretin
activity of glucagon-like peptide 1 [7-36 amide] but not of
synthetic human gastric inhibitory polypeptide in patients with
type-2 diabetes mellitus. J Clin Invest 1993; 91:301307.
17.

Nauck MA, Wollschlager D, Werner J et al. Effects of

subcutaneous glucagon-like peptide 1(GLP-1 [7-36 amide]) in
patients with NIDDM. Diabetologia 1996; 39:15461553.

1.

Vilsboll T, Holst JJ. Incretins, insulin secretion and Type 2

diabetes mellitus. Diabetologia 2004; 47: 357366.

2.

Brown JC. Gastric inhibitory polypeptide. Monogr Endocrinol

1982; 24:188.

3.

Dupre J, Ross SA, Watson D, et al. Stimulation of insulin secretion

by gastric inhibitory polypeptide in man. J Clin Endocrinol Metab.
1973; 37:826828.

4.

Orskov C, Holst JJ, Nielsen OV. Effect of truncated glucagon-like

peptide-1 [proglucagon-(78-107) amide] on endocrine secretion
from pig pancreas, antrum, and nonantral stomach. Endocrinology
1988; 123:20092013.

5.

Fehmann HC, Habener JF. Insulinotropic hormone glucagonlike peptide-I(7-37) stimulation of proinsulin gene expression
and proinsulin biosynthesis in insulinoma beta TC-1 cells.
Endocrinology 1992; 130:159166.

6.

Schjoldager BT, Mortensen PE, Christiansen J, et al. GLP-1

(glucagon-like peptide 1) and truncated GLP-1, fragments of
human proglucagon, inhibit gastric acid secretion in humans.
Dig Dis Sci 1989; 34:703708.

7.

Wettergren A, Schjoldager B, Mortensen PE, et al. Truncated

GLP-1 (proglucagon 78-107-amide) inhibits gastric and pancreatic
functions in man. Dig Dis Sci 1993; 38:665673.

8.

Nauck MA, Niedereichholz U, Ettler R et al. Glucagonlike peptide 1 inhibition of gastric emptying outweighs its
insulinotropic effects in healthy humans. Am J Physiol 1997;
273:E981E988.

9.

Willms B, Werner J, Holst JJ, et al. Gastric emptying, glucose

responses and insulin secretion after a liquid test meal: effects
of exogenous glucagon-like peptide-1 (GLP-1)-(7-36) amide in
type 2 (non insulin-dependent) diabetic patients. J Clin Endocrinol
Metab 1996; 81:327332

24. Edwards CM, Stanley SA, Davis R et al. Exendin-4 reduces

fasting and postprandial glucose and decreases energy intake
in healthy volunteers. Am J Physiol Endocrinol Metab 2001;
281:E155E161.

10. Flint A, Raben A, Astrup A, et al. Glucagon-like peptide 1

promotes satiety and suppresses energy intake in humans. J Clin
Invest 1998; 101:515520.

25. DeFronzo RA, Ratner RE, Han J et al. Effects of exenatide

(exendin 4) on glycemic control and weight over 30 weeks in
Metformin treated patients with type 2 DM. Diabetes Care 2005;
28: 1092 1100.

11. Gutzwiller JP, Drewe J, Goke B et al. Glucagon-like peptide-1

promotes satiety and reduces food intake in patients with diabetes
mellitus type 2. Am J Physiol 1999; 276:R1541-R1544.
12. Holst JJ. Glucagon-like peptide 1(GLP-1): an intestinal hormone
signaling nutritional abundance, with an unusual therapeutic

18. Juntti-Berggren L, Pigon J, Karpe F et al. The antidiabetogenic

effect of GLP-1 is maintained during a 7-day treatment period
and improves diabetic dyslipoproteinemia in NIDDM patients.
Diabetes Care 1996; 19:12001206.
19. Deacon CF, Johnsen AH, Holst JJ. Degradation of glucagonlike peptide-1 by human plasma in vitro yields an N-terminally
truncated peptide that is a major endogenous metabolite in vivo.
J Clin Endocrinol Metab 1995; 80:952957.
20. Deacon CF, Nauck MA, Toft-Nielsen M, et al. Both subcutaneously
and intravenously administered glucagon-like peptide I are rapidly
degraded from the NH2-terminus in type II diabetic patients and
in healthy subjects. Diabetes 1995; 44:11261131.
21. Kieffer TJ, McIntosh CH, Pederson RA. Degradation of glucosedependent insulinotropic polypeptide and truncated glucagonlike peptide 1 in vitro and in vivo by dipeptidyl peptidase IV.
Endocrinology 1995; 136:35853596.
22. Kolterman OG, Buse JB, Fineman MS et al. Synthetic exendin 4
(AC2993) significantly reduces postprandial and fasting plasma
glucose in subjects with type 2 diabetes. J Clin Endrinol Metab
2003; 88: 3082 3089.
23. Egan JM, Clocquet AR, Elahi D. The insulinotrophic effect
of acute exendin 4 administered to humans: comparison of
nondiabetic state to type 2 diabetes. J Clin Endocrinol Metab.
2002; 87: 1282-1290.

26. Buse JB, Henry RR, Han J et al. Effects of exenatide (exendin
4) on glycemic control over 30 weeks in sulfonylurea treated
patients with type 2 diabetes. Diabetes Care 2004; 27: 2628
-2635.

Glucagon Like Peptide 1 Related Analogs

465

27. Kendall DM, Riddle MC, Rosenstock J et al. Effects of exenatide

(exendin 4) on glycemic control over 30 weeks in patients with
type 2 DM treated with Metformin and a sulfonylurea. Diabetes
Care 2005; 28: 1083 1091.

41. Nauck MA, Hompesch M, Filipczak R, et al. Five weeks

of treatment with the GLP-1 analogue liraglutide improves
glycaemic control and lowers body weight in subjects with Type 2
diabetes. Exp. Clin. Endocrinol. Diabetes 2006; 114(8):417-423.

28. Data on file. Amylin Pharmaceuticals, Inc.

42. Deacon CF, Nauck MA, Toft-Nielsen M, et al. Both subcutaneously

and intravenously administered glucagon-like peptide I are
rapidly degraded from the NH2-terminus in type II diabetic
patients and in healthy subjects. Diabetes 1995; 44:11261131.

29. Agerso H, Jensen LB, Elbrond B, et al. The pharmacokinetics,

pharmacodynamics, safety and tolerability of NN2211, a new
long-acting GLP-1 derivative, in healthy men. Diabetologia 2002;
45(2):195-202.
30. Degn KB, Juhl CB, Sturis J et al. One weeks treatment with
the long-acting glucagon-like peptide 1 derivative liraglutide
(NN2211) markedly improves 24-h glycemia and - and -cell
function and reduces endogenous glucose release in patients with
Type 2 diabetes. Diabetes 2004; 53(5):1187-1194.
31. Damholt B, Golor G, Wierich W, et al. An open-label, parallel
group study investigating the effects of age and gender on the
pharmacokinetics of the once-daily glucagon-like peptide-1
analogue liraglutide. J Clin Pharmacol 2006; 46(6):635-641.
32. Rolin B, Larsen MO, Gotfredsen CF, et al. The long-acting
GLP-1 derivative NN2211 ameliorates glycemia and increases
-cell mass in diabetic mice. Am. J. Physiol. Endocrinol. Metab. 2002;
283(4):E745-E752.
33. Sturis J, Gotfredsen CF, Romer J, et al. GLP-1 derivative
liraglutide in rats with -cell deficiencies: influence of metabolic
state on -cell mass dynamics. Br. J. Pharmacol. 2003; 140(1):123132.
34. Madsbad S, Schmitz O, Ranstam J, et al. Improved glycemic
control with no weight increase in patients with Type 2 diabetes
after once-daily treatment with the long-acting glucagon-like
peptide 1 analog liraglutide (NN2211): a 12-week, double-blind,
randomized, controlled trial. Diabetes Care 2004; 27(6):13351342.
35. Vilsboll T, Zdravkovic M, Le-Thi T et al. Liraglutide significantly
improves glycemic control, and lowers body weight without risk
of either major or minor hypoglycemic episodes in subjects with
Type 2 diabetes. Diabetes 2006; A115.
36. Nauck MA, El-Ouaghlidi A, Hompesch M, et al. No impairment
of hypoglycemia counterregulation via glucagon with the
long-acting GLP-1 derivative, NN2211, in subjects with Type 2
diabetes. Diabetologia 2003; A285.
37. Bock T, Pakkenberg B, Buschard K: The endocrine pancreas
in non-diabetic rats after short-term and long-term treatment
with the long-acting GLP-1 derivative NN2211. APMIS 2003;
111(12):1117-1124.
38. Larsen PJ, Fledelius C, Knudsen LB, et al. Systemic administration
of the long-acting GLP-1 derivative NN2211 induces lasting and
reversible weight loss in both normal and obese rats. Diabetes
2001; 50(11): 2530-2539.
39. Ribel U, Larsen MO, Rolin B et al. NN2211: a long-acting
glucagon-like peptide-1 derivative with anti-diabetic effects in
glucose-intolerant pigs. Eur. J. Pharmacol. 2002; 451(2):217-225.
40. American Diabetes Association: Standards of medical care in
diabetes. Diabetes Care 2005; 28 (Suppl 1):S4-S36.

43. Ahren B, Simonsson E, Larsson H et al. Inhibition of dipeptidyl

peptidase IV improves metabolic control over a 4- week study
period in type 2 diabetes. Diabetes Care 2002; 25:869875.
44. Ahren B, Landin-Olsson M, Jansson PA, et al. Inhibition of
dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels,
and reduces glucagon levels in type 2 diabetes. J Clin Endocrinol
Metab 2004; 89:20782084.
45. Brandt I, Joossens J, Chen X et al. Inhibition of dipeptidylpeptidase IV catalyzed peptide truncation by Vildagliptin
((2S)-{[(3-hydroxyadamantan-1-yl)amino]acetyl}-pyrrolidine-2carbonitrile). Biochem Pharmacol 2005; 70 :134143.
46. Aschner P, Kipnes M, Lunceford J et al.: Sitagliptin monotherapy
improved glycaemic control in patients with Type 2 diabetes.
Diabetologia (2006):0005 (Abstract).
47. Deacon CF, Holst JJ: Dipeptidyl peptidase IV inhibitors: a
promising new therapeutic approach for the management of Type
2 diabetes. Int. J. Biochem. Cell Biol. 2006; 38(5-6):831-844.
48. Pratley RE, Jauffret-Kamel S, Galbreath E, et al. Twelve-week
monotherapy with the DPP-4 inhibitor vildagliptin improves
glycemic control in subjects with Type 2 diabetes. Horm. Metab.
Res. 2006; 38(6):423-428.
49. Egan JM, Bulotta A, Hui H, et al. GLP-1 receptor agonists are
growth and differentiation factors for pancreatic islet beta cells.
Diabetes Metab Res Rev 2003; 19:115123.
50. Xu G, Stoffers DA, Habener JF et al. Exendin-4 stimulates both
beta-cell replication and neogenesis, resulting in increased betacell mass and improved glucose tolerance in diabetic rats. Diabetes
1999; 48:22702276.
51. Stoffers DA, Kieffer TJ, Hussain MA et al. Insulinotropic
glucagon-like peptide 1 agonists stimulate expression of
homeodomain protein IDX-1 and increase islet size in mouse
pancreas. Diabetes 2000; 49:741748.
52. Zhou J, Wang X, Pineyro MA, et al. Glucagon-like peptide 1 and
exendin-4 convert pancreatic AR42J cells into glucagon- and
insulin-producing cells. Diabetes 1999; 48:23582366.
53. Buteau J, El-Assaad W, Rhodes CJ, et al. Glucagon-like peptide-1
prevents beta cell glucolipotoxicity. Diabetologia 2004; 47:806
815.
54. Meier J. J, Gethmann A, Gtze O et al. Glucagon-like peptide 1
abolishes the postprandial rise in triglyceride concentrations and
lowers levels of non-esterified fatty acids in humans. Diabetologia
2006; 49: 452458.