Download Diabetes- 2010 - The Stephens Lab

Diabetes: 'dia' = through - 'betes' = to go
1500 B.C. Ancient Egyptians had a number of
remedies for combating the passing of too much urine
(polyuria).
Hindus in the Ayur Veda recorded that insects and
flies were attracted to the urine of some people, that
the urine tasted sweet, and that this was associated
with certain diseases.
1000 B.C. The father of medicine in India, Susruta
of the Hindus, diagnosed Diabetes Mellitus (DM).
Early Greeks had no treatment for DM, latter Greeks
like Aretaeus, Celsus and Galen described DM. Celsus
described the pathologic condition "diabetes"
Diabetes: 'dia' = through - 'betes' = to go
1798 A.D. John Rollo certifies excess sugar
in the blood.
1889 A.D. Mehring and Minkowski produce
DM in dogs by removing the pancreas.
1921 A.D. Banting and Best find insulin is
secreted from the islet cells of the
pancreas.
Diabetes is a
disease that is the
th
5 leading cause of
death in the USA
23.6 Million
Americans have
Diabetes (8% pop)
More have pre-diabetes
There are two (or 3)
different types of
diabetes and the
diseases are very
different
There are three categories of diabetes
mellitus:
Insulin-Dependent Diabetes Mellitus (IDDM)
[also called "Type 1" diabetes]
and
Non Insulin-Dependent Diabetes Mellitus
(NIDDM)
["Type 2"]
Inherited Forms of Diabetes Mellitus
(MODY)
There are three categories of diabetes mellitus:
IDDM (also called Type 1 diabetes)
is characterized by little (hypo) or no circulating insulin;
most commonly appears in childhood.
It results from destruction of the beta cells of the islets.
The destruction results from a cell-mediated
AUTOIMMUNE ATTACK of the beta cells.
What triggers this attack is still a mystery
IDDM is controlled by carefully-regulated injections of
insulin.
(Insulin cannot be taken by mouth)
Inhalable insulin was introduced in mid-2006
The first such product to be marketed was Exubera, a powdered form of
recombinant human insulin, delivered through an inhaler into the lungs
where it is absorbed. Once it has been absorbed, it begins working within
the body over the next few hours. Diabetics still need to take a longer
acting basal insulin by injection.
It has been concluded that inhaled insulin "appears to be as effective, but
no better than injected short-acting insulin.
The additional cost is so much more that it is unlikely to be costeffective."[\
In October 2007, Pfizer announced that it would be discontinuing the
production and sale of Exubera due to poor sales.
Several other companies are developing inhaled forms of the drug to
reduce the need for daily injections among diabetics.
PFIZER LOSS = 2.8 billion
For many years, insulin extracted from the glands
of cows and pigs was used. However, pig insulin
differs from human insulin by one amino acid;
beef insulin by three. Although both work in
humans to lower blood sugar, they are seen by
the immune system as "foreign" and induce an
antibody response in the patient that blunts their
effect and requires higher doses.
Two approaches were taken to solve this problem:
There are three categories of diabetes mellitus:
Two approaches have been taken to solve this problem:
Convert pig insulin into human insulin by removing the one amino
acid that distinguishes them and replacing it with the human
version.
This approach is expensive, so now the favored approach is to
Insert the human gene for insulin into E.coli and grow recombinant
human insulin in culture tanks.
Insulin is not a GLYCOPROTEIN so E. coli is able to manufacture a
fully-functional molecule (trade name = Humulin).
Yeast is also used (trade name = Novolin).
Recombinant DNA technology has also made it possible to
manufacture slightly-modified forms of human insulin that work
faster (Humalog® and NovoLog®) or slower (Lantus®) than
regular human insulin.
Each cell has
thousands of
proteins.
In many cases a
missing or defective
protein has no effect
Inherited Forms of Diabetes Mellitus
Some cases of diabetes result from mutant genes inherited from one
or both parents.
Examples:
mutant genes for one or another of the transcription factors needed
for transcription of the insulin gene .
mutations in one or both copies of the gene encoding the insulin
receptor.
These patients usually have extra-high levels of circulating insulin
but defective receptors.
The mutant receptors
may fail to be expressed properly at the cell surface or
may fail to transmit an effective signal to the interior of the cell.
Diagnostic Diabetes:
diagnosing maturity-onset
diabetes of the young
(MODY)
Diagnosing MODY
• What is MODY?
• Different types of MODY
- Glucokinase MODY
- Transcription factor MODY
• Separate from Type 1, Type 2 and
genetic syndromes
MODY (inherited)
MODY is caused by a change in a single gene.
6 genes have been identified that account for 87% of
MODY:
HNF1-a
Glucokinase
HNF1-b
HNF4-a
IPF1
Neuro D1
MOST ARE TF’s that modulate insulin transcription
Important to diagnose MODY
Diabetes in Young Adults (15-30 years)
Type 2
Type 1
MODY
MIDD
5
10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90
Age of diagnosis
Diagnostic criteria for MODY
•Early-onset diabetes
•Not insulin-dependent
diabetes
•Autosomal dominant
Diagnosis of diabetes before 25
years in at least 1 & ideally 2
family members
Off insulin treatment or
measurable C-peptide at least 3
(ideally 5) years after diagnosis
inheritance
•Caused by a single gene
defect altering beta-cell
function, obesity unusual
Tattersall (QJM 1974)
Must be diabetes in one parent
(2 generations) and ideally a
grandparent or child ( 3
generations)
The Genetic Causes of MODY
MODY
75%
11%
14%
Transcription factors
MODY x
Glucokinase
(MODY2) 69%
3%
3% <1% <1%
HNF1 HNF4 HNF1 IPF1 NeuroD1
(MODY3)
Frayling, et al Diabetes 2001
Two subtypes of MODY
Glucokinase and Transcription factor
Transcription
factor
(HNF-1)
20
16
Glucose
(mmol/l)
12
Glucokinase
8
.
Normal
4
0
0
20
40
60
80
100
Age (yr..)
Pearson, et al Diabetes 2001
Glucokinase and Transcription factor diabetes
MODY
Glucokinase
mutations
Transcription factor
mutations
(HNF-1, HNF-1, HNF-4)
Onset at birth
Stable hyperglycemia
Diet treatment
Complications rare
Adolescence/young adult onset
Progressive hyperglycemia
1/3 diet, 1/3 other, 1/3 Insulin
Complications frequent
MODY
Diagnostic Genetic Testing: why do
it?
• Makes diagnosis : defines monogenic and
defines subtype
• Differentiates from type 1
• Helps define prognosis
• Helps family counselling
• Helps treatment decisions
Inherited Forms of Diabetes Mellitus
a mutant version of the gene encoding glucokinase, the enzyme that
phosphorylates glucose in the first step of glycolysis.
Mutant version of insulin gene TFs
mutations in the gene encoding part of K+channel in the plasma
membrane of the  cell. The channels fail to close properly
causing the cell to become hyperpolarized and blocking insulin
secretion.
mutations in several mitochondrial genes which reduce insulin
secretion by  cells. These diseases are inherited from the mother
as only her mitochondria survive in the fertilized egg.
While symptoms usually appear in childhood or adolescence,
patients with inherited diabetes differ from most children with
NIDDM in having a history of diabetes in the family and not
being obese.
Inherited Forms of Diabetes Mellitus
MODY GENES
like Mutant glucokinase
insulin gene TFs
K+channel of the  cell.
IR
some mitochondria genes
Of 20+ million
Americans with
Diabetes, only 10%
have type I
diabetes
Most diabetics
Have Type II
diabetes
T2DM or NIDDM
90% of diabetics in
industrialized
nations have Type
II diabetes
Type II diabetes
Defined by insulin
resistance
insulin resistanceinability to respond
to insulin
Hyperglycemia
causes retinopathy,
neuropathy, and
nephropathy
Type II diabetespatients are insulin
resistance so can’t
get glucose into
cells
How do you get high blood glucose?
Glucose comes from the food you eat and is also made in
your liver and muscles.
Your blood carries the glucose to all the cells in your body.
Insulin controls glucose disposal into fat and skeletal
muscle
The pancreas releases insulin into the blood.
Insulin helps the glucose from food get into your cells.
If your body doesn't make enough insulin or if the insulin
doesn't work the way it should, glucose can't get into
your cells. It stays in your blood instead. Your blood
glucose level then gets too high, causing pre-diabetes or
diabetes.
Type II diabetes
research related to
adipocytes
Adipocytes
accumulate
lipid
accumulate
lipid
insulin
insulinsensitive
sensitive
Endocrine
Endocrine
functions
function
Most patients with
Type II diabetes
are obese
> 85%
Strong link
between T2DM and
Obesity
Many diseases due
to loss or defect of
one protein
Sickle Cell Anemia
Huntington’s Disease
Type I Diabetes
MODY
Many diseases due
to loss or defects in
many proteins
Heart Disease
Cancer
Type II Diabetes
Very hard to cure
diseases that have
multiple proteins
defective
What is pre-diabetes?
Pre-diabetes is a condition in which blood glucose
levels are higher than normal but are not high
enough for a diagnosis of diabetes.
People with pre-diabetes are at increased risk for
developing type 2 diabetes and for heart disease
and stroke.
The good news is if you have pre-diabetes, you can
reduce your risk of getting diabetes. With
modest weight loss and moderate physical
activity, you can delay or prevent type 2 diabetes
and even return to normal glucose levels.
How does Exercise work
Exercise results in an increase in
GLUT4 vesicles moving to the PM
The effect is independent of insulin
The effects of insulin and exercise are additive.
Exercise, even in the absense of WEIGHT LOSS
can reduce blood glucose levels and increase insulin
sensitivity
What are the signs of diabetes?
being very thirsty
urinating often
feeling very hungry or tired
losing weight without trying
having sores that heal slowly
having dry, itchy skin
losing the feeling in your feet or having tingling in
your feet
having blurry eyesight
may have had one or more of these signs before you found
out you have diabetes. Or may have had no signs at all.
A blood test to check your glucose levels will show if you
have pre-diabetes or diabetes.
A1C, also known as glycated hemoglobin or
glycosylated hemoglobin, indicates a patient's blood
sugar control over the last 2-3 months.
A1C is formed when glucose in the blood binds
irreversibly to hemoglobin to form a stable glycated
hemoglobin complex.
Since the normal life span of red blood cells is 90-120
days, the A1C will only be eliminated when the red
cells are replaced; A1C values are directly
proportional to the concentration of glucose in the
blood over the full life span of the red blood cells.
A1C values are not subject to the fluctuations that are seen
with daily blood glucose monitoring.
The A1C value is an index of mean blood glucose over the
past 2-3 months but is weighted to the most recent
glucose values.
Values show the past 30 days as ~50% of the A1C, the
preceding 60 days giving ~25% of the value and the
preceding 90 days giving ~25% of the value. This bias is
due to the body's natural destruction and replacement of
RBC. Because RBCs are constantly being destroyed and
replaced, it does not take 120 days to detect a clinically
meaningful change in A1C following a significant change
in mean blood glucose.
WHY IS IT SO HARD
TO TREAT NIDDM
Medications for NIDDM
Many types of diabetes pills can help people with T2DM
lower their blood glucose.
Each type of pill helps lower blood glucose in a different
way.
Sulfonylureas- stimulate your pancreas to make
more insulin.
Biguanides decrease the amount of glucose made
by your liver.
 glucosidase inhibitors slow the absorption of
the starches you eat.
Medications for NIDDM
Thiazolidinediones TZDs-make you more sensitive
to insulin.
Meglitinides -stimulate your pancreas to make
more insulin.
D-phenylalanine derivatives -help your pancreas
make more insulin quickly.
Combination oral medicines put together
different kinds of pills.
Gila monsters are one of only
two venomous lizards in the
world, the other being the
closely related beaded lizards
A fairly new diabetes treatment from Eli Lilly and
Amylin that is extracted from the saliva of the
Gila monster received approval from the Food
and Drug Administration in April 2005
Byetta, which was co-developed by both companies,
improves blood sugar control in patients with type
2 diabetes. The drug, developed from a compound
in the toxic saliva of a rare lizard found only in the
Southwest U.S. and Mexico.
Came on Market in June of 2005
Used in patients who aren't getting enough insulin
through oral medication
DRAWBACK:
Has to be injected twice a day
Some History
• 1980s an endocrinologist named Dr. John Eng
worked of the VA Medical Center in the Bronx
His mentor - Dr. Rosalyn S. Yalow, won the
1977 Nobel Prize in Physiology or Medicine for
the development of RIAs of peptide hormones.
• Dr. Eng wanted to discover new hormones.
RIA are insensitive and not a good way to
discover new hormones. But chemical assays
are sensitive. So he developed a new type of
chemical assay and looked for hormones that no
one had discovered.
Some History
• Dr. Eng first discovered a new hormone in the
venom of the Mexican beaded lizard, which in
1990 he named exendin-3. But this hormone was
vasoactive, which means that it contracts or
dilates blood vessels.
• Prompted Dr. Eng to look at the venom of the
Gila monster, which is not vasoactive. There he
discovered a hormone, which he named
exendin-4, that was similar in structure to
glucagon-like peptide 1 (GLP-1).
Some History
• GLP-1 regulates blood glucose and satiety, as a
potential drug it has a short half-life requiring
multiple daily injections. He published his key
paper on exendin-4 in a 1992 issue of The Journal
of Biological Chemistry.
• But exendin-4 works for 12 or more hours.
"That's how it is better," Dr. Eng says. So,
Amylin Pharmaceuticals invested millions of
dollars to develop it.
Some History
• When Dr. Eng began to realize exendin-4's
potential to control diabetes, he told the
Department of Veterans Affairs that the agency
should patent it. " VA declined, because at that
time inventions must be veteran specific," he
recalls. The VA did retain a royalty-free license.
• "That put me in a difficult position," he says,
"because it meant I had to essentially make a bet.
Patenting it came out of my pocket with no
guarantee that anything would come of it. I
ended up with this patent, and I couldn't develop
it. So I went around to drug companies."
Some History
• Finally, in 1996, Dr. Eng licensed the patent to
Amylin, which calls it AC2993. The company
completed the Phase 1 study in 1998 and filed an
investigational new drug application with the
FDA in 1999. Phase 2 studies, announced at the
ADA's 2001 Annual Meeting, showed an
approximate 1% reduction in A1c after 28 days.
Since A1c measures average blood glucose of the
past 2-3 months, this is a lot.
• Amylin had success in Phase 3 trials.
Some History
• Used by 2 injections a day. "The initial target
population is for people with NIDDM who have
not progressed to taking insulin," "It stimulates
insulin production when it is needed and is only
active when glucose is high." It also reduces
appetite, causing some weight loss.
• Amylin is also working on alternatives to shots
and a long-acting formulation of one shot a
month, AC2993 LAR.
Some History
• Who would have imagined that a Gila monster
could be so valuable to people with diabetes? But
Dr. Eng did. Ironically, the venom he worked
with came from a lab in Utah, and he says he has
never seen a Gila monster.
Not as many proteins as we thought.
Not surprising we have some "super-genes“like one
that encodes glucagon (increases glucose).
As it turns out, the gene for glucagon also codes
for at least 2 other hormones, called glucagonlike peptides 1 and 2 (GLP-1, GLP-2). Not only
do the GLPs come from the same gene as
glucagon, but have a very similar aa sequence as
well.
Despite these parallels, the GLPs have very
different functions than glucagon, and there is a
lot of excitement about using these hormones to
treat problems ranging from diabetes and obesity
to chemotherapy-induced intestinal damage.
From a diabetes perspective, the interesting GLP is
GLP-1.
GLP-1 is secreted from cells in the gut in response to a
meal, and helps to integrate many of the normal
physiological responses that occur after eating.
For one, GLP-1 induces insulin secretion from the
pancreas, and simultaneously reduces glucagon
release. This release of insulin actually seems to
occur only when the ambient glucose concentration
is high, thus reducing the chance that hypoglycemia
will develop (an especially attractive feature in a
diabetes therapy).
Over a longer period, GLP-1 actually
increases the number of insulinproducing  cells.
GLP-1 also acts directly on the GI tract,
reducing the rate at which food spills
out of the stomach and into the SI,
making the absorption and storage of
energy more efficient.
Finally, and perhaps most intriguingly, GLP-1
acts on the CNS to signal a sense of fullness so
that we don't overeat.
So isn’t GLP-1 prescribed to everyone with
T2DM? Well, there are a few problems, The
most daunting has been that our bodies destroy
GLP-1 within a few minutes. This means that
it needs to be continuously infused (Because it
is a protein, GLP-1 cannot be given orally),
which is clearly not going to work for most
people. The enzyme that destroys GLP-1 is
called dipeptidyl-peptidase IV (DPP IV), and
intense focus has been placed on figuring out
ways to disable the enzyme so that GLP-1 can
do it's thing for longer periods of time.
One way to get around the problem of DPP IV is to administer
a form of GLP-1 that is resistant to destruction. Such forms
of GLP-1 have already been found, and the source is
delightfully unexpected--the poisonous saliva of the Gila
monster lizard. GLP-1 (called exendin-4) from these reptiles
has a few key differences from the form found in humans,
one consequence of which is immunity to DPP IV.
pharmaceutical companies made synthetic forms of exendin-4
(one imagines that it's easier to make the chemical from
scratch than it is to harvest toxic lizard spit).
Phase 2 clinical trials of exendin-4 in patients with T2DM
showed improvements in hemoglobin A1c levels
comparable to those seen with currently available ant
diabetic drugs. Other studies show reductions of caloric
intake after exendin-4 administration.
Another strategy that is being pursued is the use of drugs that will
inhibit DPP IV directly.
Studies have shown that 24 hours after taking such a drug, patients with
mild T2DM have reduced fasting, post-meal, and average blood sugar
levels.
The primary advantage of this approach (vs. exendin-4) is that DPP
IV inhibitors can be given orally. On the other hand, DPP IV affects
other hormones besides GLP-1, and there is concern that blocking the
enzyme could cause other problems.
One reassuring piece of data is that mice that are genetically engineered
to lack DPP IV are viable and appear to do well, and this provides
some reassurance that the strategy is sound. Still, longer term studies
with both DPP IV inhibitors need to be performed to assess possible
toxicity. It is also unclear if the beneficial effects of GLP-1 will be
sustained over time, and this too will have to be tested. Nonetheless, a
drug that that causes weight loss as well as improved insulin secretion
in type 2 diabetes is a potential blockbuster.
GLP-1
extendin-4
DDP1V
Diabetes Myths
Myth #1 You can catch diabetes from someone else.
Myth #2 People with diabetes can't eat sweets or chocolate.
Myth #3 Eating too much sugar causes diabetes.
Myth #4 People with diabetes should eat special diabetic foods.
Myth #5 If you have diabetes, you should only eat small amounts of
starchy foods, such as bread, potatoes and pasta.
Myth #6 People with diabetes are more likely to get colds and other
illnesses.
.
Myth #7 Insulin causes atherosclerosis (hardening of the arteries)
and high blood pressure.
Diabetes Myths
Myth #8 Insulin causes weight gain, and because obesity is bad for
you, insulin should not be taken.
Myth #9 Fruit is a healthy food. Therefore, it is ok to eat as
much of it as you wish.
Myth #10 You don’t need to change your diabetes regimen
unless your A1C is greater than 8 %