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.
Are thiazolidines safe?
Rosiglitazone has become one of most commonly utilized
drugs in treatment of type 2 diabetes. Recently,
several large studies have suggested that rosiglitazone may be cardiotoxic and
may be involved in hundreds of instances of cardiac failure. In contrast to this, pioglitizone has not
been reported to affect the heart and may be a better choice for treatment of
type 2 diabetes. As of February 2010 the
FDA has not withdrawn rosiglitazone from the market. Check Medscape.com or the FDA for more and
current information.
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 one of the following links:
http://www.drugwatch.com
is comprehensive a Web
site featuring extensive information about thousands medications and drug side
effects.
http://www.medscape.com is an
excellent source for up-to-date information concerning diabetes and many other
medical areas.
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.