Some newer approaches to the
treatment of type 2 diabetes
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The number of patients with
type 2 diabetes has increased greatly during the past years. It is
estimated that more than 220 million people will suffer from this disease
within 2020. Because insulin and glucagon control energy metabolism, disturbances
in lipid, carbohydrate and protein metabolism follow the development of
diabetes.
Several good review
articles have been published in Medscape this fall. A comprehensive review of the physiopathology
and treatment of diabetes type 2 as well as a discussion of incretin hormone
treatment of DT2 can be found here: (Diabetes and Intestinal Incretin Hormones: A
New Therapeutic Paradigm, Medscape October 2004). This is a presentation from the
A second very informative
article is: Getting to Goal in Type 2 Diabetes:
Role of Postprandial Glycemic Control.
Both articles discuss shortcomings of current
treatment and the possibilities offered by incretines. Among these are glucagon-like peptide-1 and exendin-4.
Let us take a look at these.
Glucagon-like
peptide 1 (GLP-1).
We have previously seen
that glucagon and insulin secretion are linked. Low blood levels of
glucose cause release of glucagon and inhibition of insulin secretion.
Never the less, glucagon (or perhaps glutamate from glucagon-producing alpha
cells) increases insulin release when a meal follows a fasting period.
This is nothing new. However, during the past few years it has become
evident many other hormones, known as incretins, regulate the functions of the
endocrine pancreas. Recently, much
attention has been given glucagon-like peptide 1 (GLP-1). This peptide is produced by and released from
intestinal L-cells. It is a 37 amino
acid peptide produced from proglucagon.
GLP-1 is released from intestinal L-cells in response to dietary fat and
carbohydrate. GLP-1 reduces food intake by inhibiting gastric emptying,
increasing satiety through central actions and by suppressing glucagon
release. GLP-1 lowers plasma glucose levels by increasing pancreas islet
cell proliferation and increases insulin production following food
consumption.
Note that the increased
insulin secretion caused by GLP-1 is glucose-dependent. GLP-1 and related materials seem to work in beta
cells by increasing K+ levels following increased blood glucose
levels. Therefore, GLP-1 appears to
augment insulin secretion only when blood glucose is increased following a
meal. Insulin levels fall in a normal
manner following a reduction of blood glucose by uptake to tissues. GLP-1 and related peptides normalize blood
glucose levels in diabetes type 2 patients without invoking hypoglycemia.
These are preliminary
findings. Please go to the review
articles listed above for more information.
Modification
of GLP-1; Liraglutide
As mentioned above, GLP-1
is rapidly metabolized by a peptidase (dipeptidylpeptidase IV or DPP-IV). This results in a very short half-live and
makes GLP-1 unsuitable as a therapeutic drug.
One way to counter the rapid degradation of the hormone is to couple it
to a fatty acid. Liraglutide is such a
preparation. Liraglutide binds to serum
albumin and is a poor substrate for the peptidase. Single injections of liraglutide give
therapeutically active blood levels for 8 to 15 hours.
A recent clinical trial
demonstrated that liraglutide reduced blood glucose levels postprandial and
fasting, increased insulin secretion and decreased serum levels of
glucagon. Thus, Liraglutide has the
expected actions of GLP-1 and a much longer half-life.
A recent (June 2004)
Medscape article presents data from another trial study of Liraglutide. The authors report a clear improvement in
glycemic control following single daily injections of Liraglutide. Click here to pick up this
article.
Inhibitors of
dipeptidyl peptidase IV (DPP-4)
Another approach to extending the effectiveness of GLP-1 is to inhibit
the hepatic dipeptidase responsible for its inactivation. Several compounds have been prepared and
tested clinically. A recent (December
04) report presented a year-long study of the effects of a combination of
metformin and LAF237 (a DPP-4 inhibitor) in 100 diabetes type
2 patients. The results were quite promising
with a marked lowering of HbA1c levels in patients who received the combined
therapy (figure to the left. Note that
LAF/MET denotes the combination, PBO/MET the placebo therapy). You can pick up the Medscape
article by clicking here.
NB: October
2004:
The latest article
concerning GLP-1 and Exenatide has men cited earlier. This gives the most up-to-date information
available today. Click on (Diabetes and Intestinal Incretin Hormones: A
New Therapeutic Paradigm, Medscape October 2004)
if you have not already done so.
Exendin-4
Strangely enough, we find a
peptide resembling GLP-1 (exendin-4) in the saliva of the Gila monster, a
poisonous lizard that lives in the 
few as four times each year,
storing large amounts of fat in their tails and living off that in longer
periods of time. When the lizard eats, the exendin-4 in the spit of the
animal "wakes" pancreatic islet activity, giving rise to beta-cell
activity, insulin release and control of glucose and fat metabolism.
Exendin-4 has a longer half-life than GLP-1 and has very recently been shown to
have a hypoglycemic effect in humans when given twice a day for one
month. Like glucagon and glucagon-like-peptide 1, exendin-4 increases
insulin release only following meals. Exendin-4 is presently being tested
by several pharmaceutical firms and may possibly be used in treatment of type 2
diabetes.
Gut hormones and diabetes
were a subject of interest at the recent
Exenatide, a
synthetic version of Exendin-4
Exenatide
is a 39-amino acid peptide which closely resembles exendin-4. It is DPP-4 resistant and has many of the
actions of GLP-1. That is, it slows
stomach emptying, increases satiety and decreases food intake and leads to
increased release and synthesis of insulin.
Exenatide is now (May 2005) approved by the FDA for treatment of type 2
diabetes. If you click
here you will go to Medscape and find the details.
Fat tissue and thiazolidinediones
(TZDs), a new class of medicaments in the fight against diabetes type 2
Insulin's mechanism of action in our organs has been studied
since Banting's work in 1922. In spite of this, the hormone's way of
working is still somewhat of a mystery. We know that adipose tissue,
especially central fat depots, is related to glucose intolerance and
development of diabetes type 2. Furthermore, the production of so many
peptide hormones in fat tissue suggested that control of protein production
might help in regulation of metabolism and counteract insulin resistance.
About ten years ago, one found a new class of controlling elements in the
nuclei of liver and fat cells, the so-called PPAR's or peroxisome
proliferator-activated receptors. The alpha form is most common in the
liver, while the gamma form is found in fat depots. The
thiazolidinediones troglitazone, rosiglitazone and pioglitazone activate
PPAR-gamma and were tried out as hypoglycemic agents in diabetes type 2.
All of these improve the diabetic picture, reducing blood glucose and lowering
blood lipid levels. Troglitazone was found to adversely affect hepatic
metabolism and has been withdrawn from the market. The others are used in
clinical practice today.
The mechanism of action of the TZDs is not
clear. While they do combine with the PPARs, this may not be their sole
working mechanism. Fat cells are rich in PPAR-gamma. Originally, it
was hypothesized that these drugs acted in fat cells, changing the secretion of
one or more of the many peptide hormones produced there, and that these in some
way altered muscle metabolism and insulin sensitivity. That is, an altered
adipocyte protein synthesis controlled muscle glucose uptake.
It has as been recently shown that muscle cells also
have PPAR-gamma, although at quite a bit lower level than that found in fat
cells. Muscle cells have been shown to respond directly to TZDs. While
PPAR independent mechanisms have been demonstrated in muscle, specific blocking
of PPAR-gamma in skeletal muscle has now been shown to duplicate "insulin
resistance" in mice. These data indicate that skeletal muscle
PPAR-gamma may underlie development of glucose intolerance and diabetes type
2. The link between obesity and increased blood lipids and skeletal
muscle PPAR is not known. See A. I. Hevener et al, Nature
Medicine, 9, 1491-1497 (2003) or click here to go to the original article.
Which medicine should I choose?
There is an increasing number of new approaches and
drugs for treatment of type 2 diabetes during the past few years. It is expected that this tendency will
continue.
Which drugs shall a doctor suggest for patients? How can diabetic patients follow
developments? One possibility can be
found at clicking the following link: Drugwatch.com is comprehensive a Web
site featuring extensive information about thousands medications and drug side
effects.
Central
(brain) control and integration of metabolism.
The involvement of
central neural mechanisms in homeostasis has become increasingly evident during
the past few years. Even insulin
resistance has been suggested to be controlled in the brain. This offers new approaches to treatment of
type 2 diabetes. You
can click here to go to a discussion of this topic.