Transcript PowerPoint Presentation - The Physiological Basis of the

The Physiological Basis of the Effects
of Cellular Activation Therapy:
It’s Not the Glucose –
It’s the Insulin and Glucose Signals
A Presentation
G Ford Gilbert, JD
Additional Slides Provided:
T. Steven Roosevelt, MD, PhD, FACE
Kevin J. Buckman, MD
Natural History of Type 2DM
Inability to handle glucose starts approx
5 to 7 years prior to failure (beta cell).
Obesity
IFG*
Uncontrolled
Hyperglycemia
Diabetes
Glucose (mg/dL)
350 –
Postmeal Glucose
300 –
250 –
Fasting Glucose
200 –
150 –
100 –
Relative Function (%)
50 –
250 –
Insulin Resistance
200 –
150 –
100 –
-Cell Function
-Cell Failure
50 –
0–
-10
-5
0
5
10
15
20
Years of Diabetes
*IFG = impaired fasting glucose.
©2000 International Diabetes Center, Minneapolis, USA. All rights reserved. Adapted with permission.
25
30
Cancer Rates
A Mayo Clinic study showed that for three years after their diagnosis with
diabetes, patients have eight times the risk of developing pancreatic cancer.
In a Swedish study of 125,162 patients pancreatic cancer was 4.25 times
the normal rate.
The risk of small intestine cancer among diabetic people is more than twice
as high as non-diabetic.
The risk of esophagus and thyroid cancer is more than twice the normal
rate.
The risk of kidney cancer is more than twice the normal rate.
The risk of nervous system cancer is more than twice the normal rate.
Traditional Therapies Do Not Maintain
Tight Control Over Time
United Kingdom Prospective Diabetes Study (UKPDS)
10
Median A1C (%)
9
8
7
6
0
ADA Goal
0
3
6
9
12
Conventional*
Insulin
Glibenclamide
Metformin
200
199
148
181
15
Time From Randomization (Years)
*Conventional therapy defined as dietary advice given at 3-month intervals where FPG was targeted at best levels feasible in clinical
practice. If FPG exceeded 270 mg/dL, then patients were re-randomized to receive non-intensive metformin, chlorpropamide,
glibenclamide, or insulin. If FPG exceeded 270 mg/dL again, then those on SU would have metformin added. If FPG exceeded
270 mg/dL after this, then insulin was substituted.
Adapted with permission from UK Prospective Diabetes Study (UKPDS 34) Group. Lancet. 1998;352:854-865.
“Control” is at Issue
Many patients have the misconception that “tight control”
will keep them from developing the complications of
diabetes. Often found in media and even assumed in
published clinical trials.
But, “tight control” is a relative term, with many patients
only able to maintain blood sugar levels significantly
above non-diabetic levels no matter how hard they try.
The point is, truly non-diabetic tight control cannot be
achieved with any current conventional therapy.
It is also well known that even excellent control does not
induce proper lipid and carbohydrate metabolism.
“while not controlling glucose worsens
complications, tight control does not prevent 25% to
40% of diabetic patients from developing overt
secondary complications within 10 years.”
Natural History of T2DM
UKPDS: -Cell Decline Over Time
In type 2 DM, patients slowly lose their -cell
functions, causing them to fail to produce sufficient
insulin and become insulin resistant.
100 –
-Cell Function (%)*
75 –
Patients Treated with
Metformin and/or
Sulfonylureas (SUs)‡
50 –
25 –
0 –l
IGT†
l
-12 -10
Postprandial
Hyperglycemia
l
-6
Type 2 Diabetes
l
-2
l
0
l
2
l
6
l
10
l
14
Years From Diagnosis
*Dashed line shows extrapolation backward from year 0 and forward from year 6 from diagnosis based on Homeostasis Model
Assessment (HOMA) data from UKPDS. † IGT = impaired glucose tolerance. ‡ The data points for the time of diagnosis (0) and the
subsequent 6 years are taken from the obese subset of the UKPDS population and were determined by the HOMA model.
Adapted with permission from Lebovitz HE. Diabetes Rev. 1999;7:139-153. ©1999 American Diabetes Association.
Insulin / Glucose
What are the potential mechanisms
and effects of insulin and glucose on
patient outcomes?
Link Between Improper Metabolism and
Poor Outcomes & Mechanisms
Metabolic stress response
↑ Stress hormones and peptides
Glucose
Insulin
Immune dysfunction
Infection dissemination
FFA
Ketones
Lactate
Cellular injury/apoptosis
Inflammation
Tissue damage
Altered tissue/wound repair
Acidosis
Infarction/ischemia
Reactive O2 species
Transcription factors
Secondary mediators
Prolonged hospital stay
Disability
Death
Copyright 2004 American Diabetes Association. From Clement S, et al. Diabetes Care.
2004;27:553–591. Reprinted with permission.
Candidate Mechanisms for Insulin
Protective Effects
Enhances Synthesis of Endothelial
Nitric Oxide
Suppresses Free Fatty Acids
Inhibits proinflammatory cytokines
Suppresses inflammatory repair
(growth) factors
Nitric Oxide
Inhibits
– Vascular smooth muscle cell growth
and migration
– Platelet aggregation and thrombosis
– Monocyte adhesion
– Inflammation
– Oxidation
Under physiologic conditions, production
from vascular endothelium contributes to
coronary blood flow.
Free Fatty Acids Cause
Endothelial Dysfunction
600
y = 1361.182x
-0.310
r = 0.497
p < 0.005
500
400
Maximum
∆% in
300
Leg Blood
Flow
200
100
0
0
1000
2000
3000
FFA
µmol
Change in Leg Blood Flow in response to the vasodilator methacholine
chloride. Steinberg HO, et al. J Clin Invest. 1997;100:1230–1239.
4000
5000
6000
Pro-inflammatory Cytokines
Tumor Necrosis Factor-α “TNF- α”,
Interleukin-6, IL-1, IL-2
Data strongly suggest a cause/effect
relationship as opposed to just a
marker of inflammation.
Thus, without proper insulin/glucose
ratios, inflammation is exacerbated.
(Hypoglycemic agents (Avandia)
TZDs
-
FFA
INSULIN
+
NOS
+
NO
IL-6
phosphorylation
-
-
TumorNF-α
Iκß (inhibitor κß)
+
-
-
+
Adhesion molecules
Trasnscription factor
Affect cellular
Translocation to the nucleus
Proinflammatory genes
transcription
ICAM-1
VCAM-1
Calcium dependent
Adhesion molecules,
How cells bind proteins
Iκß inhibits FOXO3
Which promotes tumor
growth
Chemokines
transcription
TNF-α
IL-6
Tumor Necrosis Factor
IL-1ß MCP-1 CRP
Thus
Improper insulin/glucose metabolism disrupts
the cellular functions of immunity, repair,
inflammatory response, and cellular damage.
These mechanisms of action appear at all
cellular levels, causing generalized corporal
dysfunction.
Cellular ActivationTherapy addresses these
mechanisms by normalizing metabolism
Blood Monocytes, Tissue Monocytes
IL-1 family
Acute Phase Proteins
TNF family
Stromal cells: IL-6, IL-8, monocyte chemoattractant proteins
Neutrophil recruitment, further inflammatory cytokine release
With tissue damage, you have cytokine release allowing for capillary leakage
and release of white blood cells.
*Trauma, burns, tissue infarction, cancer, immunologic and crystal inflammation.
INSULIN
Liver
-
+
IL-1, TNF, IL-6
ACUTE-PHASE PROTEINS
Serum amyloid A, CRP, C3, C4, fibrinogen,
plasminogen, TPa, PAI-1, ferritin
These proteins act upon the above,
all of which are necessary for the repair of tissues.
Conclusions About Insulin
and Cytokines
Hyperinsulinemia in the hyperglycemic
environment leads to an increase in
inflammatory cytokines.
Insulin deficiency in the hyperglycemic
environment leads to a modest increase in
inflammatory cytokines.
Hyperinsulinemia in the euglycemic
environment suppresses inflammatory
Circ Res. 2000;87:746–752.
cytokines.
Circulation. 2002;106:2067.
Circulation. 2004;109:849.
Hyperglycemia Is Proinflammatory
Patients with “stress” hyperglycemia but
without diabetes mellitus at the time of
Acute Myocardial Infarction are at
increased risk for in-hospital mortality,
Congestive Heart Failure and cardiogenic
shock.
Hyperglycemia (indicating a decrease in
insulin action) increases circulating free
fatty acids.
Capes SE et al., Lancet 2000, 355:773-778
Oliver, MF and Opie, LH, Lancet 1994, 343: 155-158
Further Inflammatory Effects of
Hyperglycemia
Hyperglycemia increases the production of
reactive oxygen species within aortic
endothelial cells.
Superoxide anion inactivates both
endothelial NO and prostacyclin produced
by endothelial cells, both of which are
potent vasodilators and platelet antiaggregators.
Das, UN, Critical Care 2002 6:389-393
Effects of Reduction of
Reactive Oxygen Species
Normalization of mitochondrial reactive
oxygen species prevents glucose-induced
activation of:
– Protein kinase C
– Sorbitol accumulation
– Nuclear factor-κB (NF- κB)
Das, UN, Critical Care 2002 6:389-393
Effects of Glucose Challenges
Stimulation of Reactive O2 Species generation
Induction of inflammatory events as evidenced
by:
– Increased leukocyte rolling
– Leukocyte adherence
– Leukocyte transmigration through mesenteric venules
associated with attenuation of endothelial NO release
– Increased expression of P-selectin on endothelial
surfaces (rolls white cells to the point of expression)
Nishikawa, T, et al., Nature 2000, 404;787-790; Mohanty, P, et
al., J Clin Endocrinol Metab 2000, 85:2970-2973
Effects of Insulin Infusion
Insulin infusion acts to attenuate the
inflammatory effects of hyperglycemia, viz:
– Inhibition of ROS generation;
– Inhibition of NF-κB generation;
– Reduction of soluble intercellular adhesion molecule1 production;
– Reduction of Monocyte chemoattractant protein-1
production;
– And plasminogen activator inhibitor-1 (PAI-1).
All actions mediated by increasing NO synthesis
Das, UN, Nutrition 2001, 17:409-413; Das UN, Crit Care 2002 6:262-263; Dandona, P, et
al., J Clin Endocrinol Metab 2001, 86:3257-3265; Alijada, et al., J Clin Endocrinol Metab
2000, 85:2572-2575; Alijada, A, et al, J Clin Endocrinol Metab 2000, 86:450-453.
Putative Mechanism of Glucose
Stimulation of Inflammation
Indirect evidence suggests that the mediator is TNF-α ( a
pro-inflammatory cytokine)
– Diets with hyperglycemic loads induce production of acute phase
reactants;
As with hyperglycemic diets:
– TNF-α also enhances free radical generation by augmenting
PMN NADPH oxidase activity;
– TNF-α activates NF-κB
– TNF-α increases intercellular adhesion molecule-1 expression in
endothelial cells.
The similarity of TNF-α and glucose, implies that
glucose, by increasing TNF-α production, increases
inflammation.
Liu, S, et al., Am J Clin Nutr 2002, 75:492-498; Fan J., et al, J Biol Chem 2002,
277:3404-3411; Guzik, et al, Circulation 2002, 277:3404-3411
Cytokines, Growth Factors and Hormones
SIGMA-ALDRICH
Tumor Necrosis Factor - α
TNFα: Structure
TNFα is a member of a group of other
cytokines that all stimulate the acute
phase reaction. It is a 185 amino acid
glycoprotein hormone, cleaved from a 212
amino acid-long propeptide. Some cells
secrete shorter or longer isoforms.
Genetically it links to chromosome 7p21.
TNFα: Physiology
TNFα is released by white blood cells,
endothelium and several other tissues in
the course of damage, e.g. by infection. Its
release is stimulated by several other
mediators, such as interleukin 1 and
bacterial endotoxin. It has a number of
actions on various organ systems,
generally together with interleukins 1 and
6:
TNFα: Pathophysiology
On the hypothalamus:
– Stimulating of the hypothalamic-pituitaryadrenal axis by stimulating the release of
corticotropin releasing hormone (CRH).
– Suppressing appetite (hence its name
"cachexin"
– Fever. Affects the hypothalamus causing an
altered temperature control.
TNFα: Pathophysiology
On the liver: stimulating the acute phase
response, leading to an increase in Creactive protein and a number of other
mediators.
On insulin sensitive tissues: increasing
insulin resistance.
TNF Signaling Pathway
SIGMA-ALDRICH
IGF Regulation of Apoptosis
SIGMA-ALDRICH
Summary: TNFα
Tumor Necrosis Factor - α is a mediator of
cell apoptosis as well as inflammation.
The re-establishment of proper insulin
uptake by the cells, and more proper lipid
and carbohydrate metabolism leads to
proper mediation of inflammation. This is
uniformly seen in CAT patients.
Insulin Infusion in the Treatment
of Macrovascular Inflammatory
Conditions
Insulin Infusion to Reduce Cardiovascular
Inflammation IS
the Standard of Care
The American College of Cardiology and the
American Heart Association both recommend
glucose-insulin-potassium (GIK) infusions in
patients with MI (intense cardiovascular
inflammatory state).
Why? Because the GIK protocol improves the
integrity and function of myocardial cells.
In essence it reduces the inflammatory state
associated with dysglycemia.
Diaz, R, Circulation 1998, 98:2227-2234; Rogers, WJ et al, Am Heart J 1976 92:441-454, Marano, L,
Acta Cardkol 2000, 55:9-15; Lazar, HL, et al., Ann Thorac Surg 1995, 60:411-416; Malmberg, K et al,
J Am Coll Cardiol 1995, 26:57-65; Machtey, I et al., J Am Geriatr Soc 1976, 24:534-537; Malmbery, K
et al, BMJ 1997, 314:1512-1515.
GIK
But, there are conflicting data on the use
of GIK, with some studies showing a
beneficial effect and others not showing
such an effect.
Lell, WA, et al, Ann Thorac Surg 2002, 73:1246-1251; Bruemmer-Smith, A et al,
Br J Anaesth 2002, 88:489-495; Rao, V, et al, J Thorac Cardiovasc Surg 2002,
129:928-935; Diaz-Arya, G, et al, Crit Care Med 2002, 30:417-421.
The Difference in Outcomes with
GIK is the Insulin Concentration
Studies in which higher concentrations of
insulin were used showed better results
than did those studies that employed a
lesser does.
– Studies in which 33% glucose was infused
with 120 I.U. of insulin or 30% glucose with
300 I.U. of insulin yielded positive results.
– Studies in which lower doses (e.g., 500 ml of
D5W with 100 I.U. of insulin or 10 U of insulin
per 1000 ml of D5W were less favorable.
Lell, WA, et al, Ann Thorac Surg 2002, 73:1246-1251; Bruemmer-Smith, A et al, Br J Anaesth
2002, 88:489-495; Rao, V, et al, J Thorac Cardiovasc Surg 2002, 129:928-935; Diaz-Arya,
G, et al, Crit Care Med 2002, 30:417-421.
Is the Glucose Insulin Potassium
Effect Independent of Glucose?
The benefits of GIK infusion may extend
beyond the control of hyperglycemia
alone.
There is evidence that infusions of insulin
reverse cardiac failure and maintain
normal cardiac function in spite of wide
ranges of glucose concentrations.
Jonassen, AK, etl al, Circ Res 2001, 89:1191-1198; Rao et al., J
Thorac Cardiovasc Surg 1998, 116:485-494; Girard, C, et al, Ann
Thorac Surg 1992, 54:259-263
Summary: Insulin Effects
Insulin has the following actions:
– It lowers blood glucose by stimulating glucose uptake
and glycolysis;
– Stimulates pyruvate dehydrogenase and ATP
production;
– Inhibits the production of proinflammatory cytokines
(TNF-α, MIF, and superoxide anions);
– Inhibits apoptosis and improves repair of damaged
tissues;
– Promotes ischemic preconditioning;
– Lessens ischemia/reperfusion damage;
– Exhibits anti-inflammatory actions
Groeneveld, ABJ, et al., Insulin: a wonder drug in the critically ill?
Crit Care 2002 6:102-105
Complications of Diabetes

Heart Disease: Heart disease is the leading cause of diabetes related death.
 Stroke:





The risk of stroke is 4 times greater among people with diabetes.
High Blood Pressure:
Blindness:
73% of adults with diabetes have high blood pressure.
Diabetic retinopathy causes 12,000 to 22,000 cases of new blindness cases each year.
Kidney Disease:
Amputations:
Diabetes is the leading cause of renal disease, accounting for 43% cases.
60%+ of non-traumatic amputations happen among diabetes patients.
Nervous System Disease:
60% to 70% of diabetes patients have mild to severe forms of
nervous system damage.
Data on Depression: An unknown number of people will have depression
and senility from diabetes. It is estimated to be 80% of all diabetics.
In addition, many people experience dental problems, blackouts, a lack of energy, sexual
functions, loss of metal acuity, sleep disorders, and a host of other problems.
With prolonged insulin use, many diabetics lose the ability to sense when their glucose
levels are dropping.
In 2002, the same percentages remain as in 1992.
CAT patients are almost
never hospitalized.
Outpatient Hospital
$16.2 Bil (12%)
Office Visits
$13.5 Bil (10%)
Drugs & DME
$12.0 Bil (9%)
Home Healthcare
$5.4 Bil (4%)
Emergency Room
$1.75 Bil (1%)
Dental
$1.75 Bil (1%)
$132 Billion
Inpatient Hospital
$84 Billion (63%)
62% Of Diabetes Costs Related To
Hospitalization And Long-Term Care
50
Cost
($ billions)
40
2002 US Total Healthcare Costs Attributable To Diabetes
$132 Billion Total
Oral Antidiabetics
Insulin and Supplies
Outpatient Medication*
Outpatient Services†
Physician Office Visits
Nursing Home Care (11%)
Inpatient Care (41%)
30
20
10
0
Direct Costs
Indirect Costs‡
*All outpatient medications, excluding insulin, insulin supplies, and oral antidiabetics.
†Includes emergency department, hospital outpatient, and free-standing ambulatory surgical center encounters, home health visits,
hospice care days, and ambulance services.
‡Indirect Costs include work days, restricted activity days, mortality, and permanent disability.
American Diabetes Association. Diabetes Care. 2003;26:917-932.
High pulses of
insulin found
here, 200 to
1,000 m U / ml.
In processing food into
energy, the body needs
certain enzyme
pathways activated, and
normal people with
these can efficiently use
glucose to produce
energy (ATP).
If you feed 100 grams of
glucose to a normal
man, high pulses of
insulin will be found in
the portal vein within a
few minutes. One half of
all insulin stops in the
liver on first pass.
Note: The remaining
levels of insulin in the
body, all are very low
and blunted by the liver.
Maximum levels outside
portal vein are 75 m U/ml.
No normal pulses of
insulin (200 to 1,000 m U /
ml.) are found in the
diabetic portal vein
Thus, without the two
signals to the liver,
High insulin / Glucose
the functions associated
with liver are blunted,and
insulin cannot be given
in periphery without
overinsulinization of
other tissues and damage
to the brain.
If you feed 100 grams of
glucose to a diabetic
patient, Type 1 or Type
2, no high pulses of
insulin are found in the
portal vein.
Maximum levels outside
portal vein are 40 m U/ml
(from shots or CIIT).
Enzymes Induced or Repressed by Insulin
The following enzymes are affected by insulin ratios to the liver:
Enzymes induced by a high insulin to glucagon ratio:
– Glucokinase
– 6-phosphofructo 1-kinase
– 6-phosphofructo 2-kinase
– Citrate cleavage enzyme
– Acetyl-coa carboxylase
– Hmg-coa reductase
– Pyruvate kinase
Enzymes repressed by a high insulin to glucagon ratio:
– Glucose 6-phosphatase
– Fructose 1,6-biaphosphatase
– Phosphoenolpyruvate carboxykinase
FROM BASIC AND CLINICAL ENDOCRINOLOGY, THIRD EDITION
Enzymes Activated Or Inactivated by Insulin
Enzymes activated by a high insulin:glucagon ratios
– 6- phosphofructo 2-kinase
– Pyruvate kinase (l-isoenzyme)
– Pyruvate dehydrogenase complex
– Acetyl - coa carboxylase
– Glycerol phosphate acyltransferase
α
α
– Hmg - coa reductase
Enzymes inactivated by a high insulin:glucagon ratios
– Glycogen phosphorylase
– Fructose 2,6 biphosphatase
FROM BASIC AND CLINICAL ENDOCRINOLOGY, THIRD EDITION
Enzymes are Part of the Problem
The inability of the Type1 and Type 2
diabetic patient to to produce and activate
enzymes causes the cascade of metabolic
dysfunction, and sets in motion all of the
other insulin/glucose related disease
pathways. This is a result of the lack of
first phase insulin release (response) and
is directly treated by Cellular Activation
Therapy.
Notice that the Type 2 diabetic does not have early (first phase) insulin
release, as does normal man. This failure to stimulate the liver (and
other tissue) is reversed by the CAT therapy.
This is why CAT works on Type 1 where there is no insulin release, and
Type 2 where the insulin is not in pulses as it is found in normal man.
Does this slide show that first phase insulin secretion is necessary to
prevent hyperglycemia or is this slide a demonstration that first phase
insulin is also an adaptive mechanism to effect the suppression of TNFα
and/or other proinflammatory cytokines?
This is the way that metabolism is measured:
This chamber directly measured calories produced and also measured the
oxygen consumed and the carbon dioxide produced. This ratio, the R.Q.
(respiratory quotient) shows actual body-wide carbohydrate & lipid metabolism.
Patient lies in this
chamber.
Equals the sitting patient
Oxygen consumed
CO2 Produced is
measured here.
High fat metabolism
respiratory quotient
(at rest).
“Fats burn in the
flame of
carbohydrates.”
-Banting
Insulin not only
addresses the uptake
of glucose by insulin
sensitive tissues but
also its oxidation by
these same tissues.
Low fat, high carb.
Respiratory quotient
Usual
diabetic
range
Usual
normal
range
With newer equipment, the Patient watches his or her own
resting metabolism change using insulin and glucose signals
to produce cellular energy (ATP) in a more normal way.
These carts prove that Cellular Activation
Theapy patients normalize their
carbohydrate and lipid metabolism as
they are treated. Patients view their own
metabolism as they are treated.
A non-Cellular Activation
Therapy treated diabetic, no
matter how well controlled,
cannot metabolize like a nondiabetic patient. They thus all
develop some metabolic
complications and shorten their
lives.
CAT changes diabetics from being unable to metabolize glucose, to being able to
burn, store and release glucose, thereby reducing the high levels of lipid oxidation.
1. When given glucose, normal people metabolize it
3. Diabetics don’t
4. Lipids stay up,
a bad condition.
2. And
lipid use
goes
down
5. These are the same
people, now activated,
and thus lower lipids
6. This happens every time as activation re-establishes
much more normal lipid and carbohydrate metabolism
This also applies to mixed meals, not just glucose. Diabetic patients of all ages, no matter how ill
or severely impacted, have been able to have their metabolism normalized, (an inducible event).
This shows activation being induced for the first time, as it takes a few treatments
to re-awaken the liver to produce the enzymes it produces for non-diabetics.
Diabetics before
treatment all look
the same.
Non-diabetic compared to activated people, by 4th day
Exercise Study, CAT
The next generation of muscle energy management
The study of energy from muscle
shows that CAT has the ability to
“pack” muscle with energy-ready
glucose. The use of muscle
glucose in exercise after CAT
shows that even a metabolism
impaired person (a diabetic) can
achieve better than normal
muscle uptake and metabolism.
This suggests that the treatment
can be used for training and
sports.
The patient’s 100-percent-exercise-rate (vmax) was determined, and for the tests a
sustained rate of 60% of vmax was used to track the differences.
These same diabetic patients can out-perform “normal” man in their carbohydrate
processing and are reestablishing muscle glycogen storage .
Diabetics, even
well controlled,
before CAT do
not oxidize fuel
as do nondiabetics.
After treatment
for 4 days, these
subjects became
able to outperform their
non-diabetic
counterparts.
Note the reduced levels of free fatty acids, and reduced glucose in sugar with treatment.
Free Fatty Acid levels before activation
Normal, non-diabetic
levels of FFA
Free Fatty Acid levels after activation
Carbohydrates Burn Fat
Diabetes mellitus is fundamentally a disordered metabolism,
primarily of carbohydrates and secondarily of protein and fat.
It is indisputably proven that for normal metabolism of
carbohydrate in the body, adequate amounts of Insulin are
essential. It follows, therefore, that the treatment consists in
giving sufficient Insulin to make up for the deficiency in the
patient’s pancreas.
Fats burn in the fire of carbohydrate. The ability of the severe
diabetic to burn glucose is markedly impaired, therefore the
excess of fat incompletely oxidized, giving rise to ketone
bodies. These appear in the blood and urine as acetone,
diacetic and betaoxybutyric acids. Insulin causes increased
carbohydrate metabolism, and consequently fats are
completely burned.
Diabetes and Insulin. Nobel Lecture delivered at Stockholm on
September 15th, 1925 By: Frederick G. Banting
Insulin Growth Factor (IGF) Regulation of Apoptosis
Model of Insulin Growth Factor-Insulin Receptor regulation of apoptosis:
Ligand binding to IGF-IR activates the tyrosine kinase domain
which initiates a set of signaling cascades. This leads to a higher
concentration of the anti-apoptotic proteins bcl-2 and bcl-xL a lower level
of the apoptotic proteins bax and bcl-xs.
IGF-IR signaling also activates phosphatidylinositol 3-kinase
(P13-K), which in turn activates protein kinase B (PKB/Akt) that also
prevents apoptosis. These pathways converge on the inhibition of
caspases, especially caspase-3, which is then blocked from performing
an apoptosis-initiating cleavage of poly (adenosine diphosphate ribose)
polymerase (PARP) and blocked from degrading -catenin, part of the
cadherin cell-adhesion system.
Thus, IGF stimulates IGF-IR to lower the probability of apoptosis
initiation and to retain cell-to-cell junctions.
Cytokines, Growth Factors and Hormones
Cytokines, growth factors (GF), and hormones are all chemical messengers that mediate
intercellular communication. The regulation of cellular and nuclear functions by cytokines,
growth factors, and peptide or protein hormones is initiated through the activation of cell
surface receptors (Rc). All receptors have two main components: 1) a ligand-binding domain
that ensures ligand specificity and 2) an effector domain that initiates the generation of the
biological response upon ligand binding. The activated receptor may then interact with other
cellular components to complete the signal transduction process. Many growth factors bind
to receptors that are linked through G-proteins to membrane-bound phospholipase C (PLC).
Activation of PLC cleaves phosphatidylinositol 4,5-bisphosphate (PIP2) to form
diacylglycerols (DAG) and D-myo-inositol-1, 4, 5-trisphosphate (IP3). IP3 regulates
intracellular Ca2+ by binding to the IP3 receptor on the endoplasmic reticulum (ER) and
stimulating Ca2+ release from the ER. Free intracellular Ca2+ can bind to calmodulin, and this
Ca2+-calmodulin complex, in the presence of cyclic-AMP (cAMP), activates protein kinase A
(PKA) by binding to the regulatory subunit of the enzyme. DAG binds to and activates protein
kinase C (PKC). Other hormone receptors may be linked through G-proteins to adenyl
cyclase (AC) instead of PLC. Activation of AC increases the cellular levels of cAMP and, in
the presence of the Ca2+-calmodulin complex, will activate PKA. Additionally, some growth
factor and cytokine receptors are protein tyrosine kinases (PTK) that are directly activated by
ligand-receptor interaction. Activation of any of the protein kinases, PKA, PKC, or PTK,
catalyzes the phosphorylation of other proteins within the cell. Enzymes that are activated or
inhibited by phosphorylation may mediate functional processes within the cell, while others
may be one step in a protein kinase cascade that regulates nuclear events.
Steroid hormones (i.e. estrogen, glucocorticoids), thyroid hormone, vitamin D3, and retinoids
are all small lipophilic molecules that easily penetrate both the cellular and nuclear
membranes to enter the nucleus where they bind to their respective receptors that are
ligand-dependent transcription factors. These ligand-receptor complexes bind to specific
DNA response elements in the promoter region and regulate gene expression.
References
Luttrell, L.M., et al., G-protein-coupled receptors and their regulation: activation of the MAP kinase signaling pathway by G-protein-coupled receptors.
Adv. Second Messenger Phosphoprotein Res., 31, 263-277 (1997).
Marshall, C.J., Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell.,
80,179-185 (1995).
Kumar, R., Thompson, E.B., The structure of the nuclear hormone receptors. Steroids, 64, 310-319 (1999).
Tumor Necrosis Factor Signaling Pathway:
When bound to tumor necrosis factor (TNF), the TNFreceptor (TNFR)
(55 kDa) transduces growth regulatory signals into the cell. TNF is
mitogenic in normal cells; however, TNF initiates programmed cell
death (PCD) or apoptosis in transformed cells causing DNA
fragmentation and cytolysis. Functional studies have identified a
conserved region within the receptor, termed the death domain (DD), a
protein-protein interaction motif that is necessary to transmit the
apoptotic signal. The TNF-induced survival pathway is mediated by the
transcription factor NF-B. Activation of NF- B occurs via
phosphorylation of I B at Ser32 and Ser36, resulting in the dissociation
and subsequent nuclear localization of active NF- B. Recent studies
have demonstrated that cells in which the NF- B signaling pathway is
blocked are more likely to undergo apoptosis in response to TNF.
Therefore, the availability of NF- B may play a critical role in the ability
of TNF to act as an apoptosis-inducer and anti-tumor agent.
References
Plumpe, J., et al., NF- B determines between apoptosis and proliferation in hepatocytes
during liver regeneration. Am. J. Physiol. Gastrointest. Liver Physiol., 278, G173-G183
(2000).
Pimentel-Muinos, F.X., and Seed, B., Regulated commitment of TNF receptor signaling: a
molecular switch for death or activation. Immunity, 11, 783-793 (1999).
Schwandner, R., et al., TNF receptor death domain-associated proteins TRADD and
FADD signal activation of acid sphingomyelinase. J. Biol. Chem., 273, 5916-5922 (1998).
Pulsatile Insulin Therapy: Review
Articles
The novel approach to insulin therapy know as chronic
intermittent intravenous insulin, (CAT), delivers insulin in
a specific pulsatile fashion and achieves physiologic
concentrations of insulin in the portal vein. Done as a
weekly outpatient procedure combined with daily
intensive subcutaneous insulin therapy, this procedure
has been shown to 1) significantly improve glycemic
control while decreasing the incidence of hypoglycemic
events 2) improve hypertension control, 3) slow the
progression of overt diabetic nephropathy, and 4)
reverse some manifestations of diabetic autonomic
neuropathy.
Chronic intermittent intravenous insulin therapy: A new frontier in
diabetes therapy. Diabetes Technology and Therapeutics 2001; 3(1): 111123.
Cellular Activation Therapy:
Nephropathy
A multi-center randomized controlled trial in patients with Type 1
diabetes and diabetic nephropathy compared outcomes in 23
patients treated with pulsatile intravenous insulin therapy (CIIIT) plus
intensive insulin therapy compared to 26 patients treated with
intensive insulin therapy alone. Blood pressure was controlled in
both groups and patients were seen weekly. Hemoglobin A1c levels
declined significantly in both groups. However, the rate of decline of
the creatinine clearance level was significantly less (2.2 mL/min/yr)
in the treatment group(CAT plus intensive insulin therapy) as
compared to 7.7 mL/min/yr in the control group( intensive insulin
therapy alone.) Projected average-time-until-dialysis/transplant is
5.2 years for the control group and 18.2 years for the CAT treatment
group.
Conclusion: Pulsatile intravenous insulin therapy (CAT) appears to
markedly reduce the progression of diabetic nephropathy.
Effects of pulsatile intravenous insulin therapy on the progression of diabetic
nephropathy. Dailey GE, Boden GH, Creech RH, Johnson DG, Gleason RE,
Kennedy FP, Weinrauch LA, Weir M, D'Elia JA. Metabolism 2000; 49: 1491-1495.
Cellular Activation Therapy:
Nephropathy
In patients with advanced diabetic kidney disease, the
gradual deterioration of kidney function (decrease of
creatinine clearance [CrCl] by 8-10 ml/min/year) cannot
be arrested with "routine" insulin therapy. This study
reports the treatment outcome of an average of 37
months (range 1-7 years) of CIIIT in 31 patients with
Type I diabetes and advanced diabetic renal disease.
The CrCl at the end of the treatment period was
essentially unchanged, suggesting that adding weekly
CIIIT to daily intensive insulin therapy could arrest or
markedly delay progression to the end stage renal
disease, when kidney dialysis or transplantation is
required.
Effect of intensive insulin therapy on progression of overt nephropathy in patients with
Type I diabetes mellitus. Aoki TT, Grecu EO, Gollapudi GM, Barber RA, Arcangeli MA,
Benbarka MM, Prescott P, Meisenheimer R. Endocrine Practice 1999; 5: 174-8.
Cellular ActivationTherapy:
Glycemic Awareness
A study of 20 diabetic patients over 42 months showed
that hepatic activation (CAT) resulted in a 98 percent
decrease in major hypoglycemic reactions. On treatment
with CAT, patients with "brittle" diabetes and
"hypoglycemia unawareness" gradually regained the
ability to detect falling blood glucose levels.
Results: patients went from an average of 3 severe
hypoglycemic reactions (requiring outside intervention)
per month to an average of 0.1 episodes per month. The
average frequency of hypoglycemic reactions returned to
three per month when CAT was stopped.
Long-term intermittent intravenous insulin therapy and type I diabetes
mellitus. Aoki TT, Benbarka MM, Okimura MC, Arcangeli MA, Walter RM Jr.,
Wilson LD, Truong MP, Barber AR, Kumagai, L. Lancet 1993; 342: 515-8.
Cellular Activation Therapy:
Hypertension
Chronic intermittent intravenous insulin
therapy for patients with high blood
pressure led to a 46% decrease in the
amount of medication required to control
the patients' blood pressure in 3 months.
Effect of Cellular Activation Therapy on anti-hypertensive medication
requirements in IDDM subjects with hypertension and
nephropathy. Diabetes Care 1995; 18: 1260-5.
Cellular Activation Therapy:
Hypertension
Patients with severe diabetes often have increased night
time blood pressure, a condition that may worsen the
complications of diabetes. Patients in randomized,
controlled clinical trials comparing two treatments 1) four
subcutaneous insulin injections daily, vs 2) weekly CAT
added to the four subcutaneous injections daily had
monthly measures of 24 hour ambulatory blood
pressure.
Results: Patients treated with CAT showed a 3% decline
in the night/day blood pressure ratio. In contrast, those
on only four subcutaneous injections daily had a 3%
increase in night/day blood pressure ratio. In addition,
the group on CAT had an significant improvement in the
average HbA1c levels.
Effect of intensive insulin therapy on abnormal circadian blood pressure pattern in patients with Type
1 diabetes mellitus. The Online Journal of Current Clinical Trials, 1995; Dec. 13: Doc. No.199.
Cellular Activation Therapy:
Hypotension
On CAT therapy, patients reported
complete relief from dizziness and fainting
when they stood up and blood pressure no
longer dropped precipitously with upright
posture.
Chronic intermittent intravenous insulin therapy CAT corrects
orthostatic hypotension of diabetes. Amer. J. Med. 1995; 99: 683-4.
Effects on Biochemistry of Diabetes
Acute insulin effects on plasma homocysteine levels in patients with
diabetes mellitus. Aoki TT, Grecu EO, Medina M, Goodman M. J
Invest Med (in Press).
IGF-1 and IGFBP-1 blood levels in type 1 diabetes mellitus on
intensive intravenous insulin therapy. Aoki TT, Grecu EO. J Invest
Med, 1999; 47(2) 78 A.(abstract).
Restoration of glucose homeostasis in insulin-dependent diabetic
subjects. An inducible process. Foss MC, Vlachokosta FV,
Cunningham LN, Aoki TT. Diabetes 1982; 31: 46-52.
Role of muscle in CO2 production after oral glucose administration
in man. Meistas MT, Vlachokosta FV, Gleason RE, Arcangeli M,
Aoki TT. Diabetes 1985; 34: 960-63.
Evidence for restoration of hepatic glucose processing in type I
diabetes mellitus. Aoki TT, Vlachokosta FV, Foss MC, Meistas
MI. Journal of Clinical Investigation 1983; 71:837-839.
The Final Validation: Pulses of Insulin
happen to be the normal mode of pancreatic
insulin delivery to the liver.
Peter Butler, professor of medicine and chair of the division of endocrinology
and diabetes, and research fellow Soon Song, received the Endocrine
Society's first prize for best clinical paper published in The Journal of Clinical
Endocrinology and Metabolism in the year 2002. The paper, "Direct
Measurement of Pulsatile Insulin Secretion from the Portal Vein in Human
Subjects," reported that insulin is secreted from beta cells in the
pancreas almost exclusively in secretory bursts every four to six
minutes. The results of the study show that very large amplitude oscillations
of insulin (pulses) concentration in the portal vein directly perfuse the liver.
Prior to this study, no one had shown this effect in human beings. The
subject was entrained to show the agreement between frequency and portal
vein insulin oscillations. “We conclude that insulin release in the human
portal vein occurs at a mean periodicity of 4.4 [plus minus] 0.2 min with
a high signal-to-noise ratio (pulse amplitude 660% of basal).”
Am J Physiol Endocrinol Metab 2002 Mar;282(3):E695-E702
Diabetic People can now get their lives back
• Cellular Activation Therapy makes huge quality of life differences in the
lives of extremely ill people with advanced complications.
• CAT has been uniformly effective, as it provides the proper insulin/glucose
signals to the liver and tissue, addressing the core of the disease.
• The metabolic measurement cart provides immediate proof of metabolic
adjustment, which the patient can see as well as feel.
• Patients on this treatment are not hospitalized for out of control diabetes.
They do not have chronic diabetes symptoms, and their entire lives are
normalized in important ways. This saves significant amounts of costs in
addition to avoiding the progression of complications.
• With the Bionica pump, the treatment is delivered in the only way that is
effective to stimulate the liver.
• This treatment is the ONLY current way to STOP THE SUFFERING of
diabetes for patients who have failed on conventional therapy.
• This treatment is shown by anecdotal evidence to stop the onset of complications
as a result of treating brittle patients who do not develop other diabetic diseases.
From young to pregnant, to old, Cellular Activation
Therapy works uniformly to normalize metabolism,
and provides constant benefits.
This 7 year old girl was
diagnosed at age 2, and was
chronically ill with
hypoglycemic reactions
hypoglycemic unawareness,
and many hospitalizations.
She has now been on the
treatment for 20 years.
The pump in the foreground
is the Bionica infusion device
with the treatment
programmed into its
memory.
The same girl diagnosed at age 2, who was chronically ill, started CAT at age 6,
now at age 28 is a mother of three healthy children, and is again pregnant. She is no
longer ill, and her only hospitalization since activating was for giving birth. She has
no complications, none of the signs of being a diabetic for 26 years, and has no
hypoglycemic reactions.
Thus, people with diabetes are trapped with
insufficient enzyme action, not “cheaters” with no
self control.
The liver is the target organ of insulin. When it is not stimulated correctly, it does
not produce the enzymes needed for proper metabolism.
When a non-diabetic person eats, that person activates all the associated enzymes
needed for continued proper resting metabolism. But people with Type 1 and
Type 2 have blunted, late, or no insulin release, causing them to be very hungry
after they have eaten.
This condition is NOT just a RESULT of overeating, it also CAUSES
overeating. Pulse Activation stops this cycle of hunger and depression causing
overeating.
This is the NIH 10 year study of intensive insulin therapy “tight control”
This study shows that tight control does not stop complications.
The inverse number of patients, 37%, 46% and 40% develop one or more
diabetic complication without CAT, AFTER JUST 10 YEARS.
Prior to CAT there was nothing other than tight control, and even with
Cellular Activation Therapy, tight control is helpful.
Just as in the US DCCT, the Japanese Ohkubo study of Type 2 patients
shows tight control therapy does not stop their complications either.
In fact, the United Kingdom study shows the trend of all conventional
therapies over ten years, and after 10 years, the results are similar.
In a brief fast, energy comes from glucose stored in the liver, and muscle. When
glucose is present, gluconeogenesis causes the liver and muscle to store glycogen,
thereby automatically “buffering” blood glucose levels.
(not a diabetic)
When a “normal” fasts for a prolonged time, the glycogen is depleted, and free fatty
acids are converted to glucose to provide the energy (the use of fat for energy since
there is no available carbohydrates or glycogen.)
Diabetic patients
have the
metabolism of a
person on a
Prolonged Fast
all the time,
and don’t burn
glucose like a
normal person.
They are
constantly
“butter burners”
and this is very
unhealthy.
Cellular Activation Therapy Treatment Results:
Brittle Diabetic: People who cannot seem to “control” their “blood
glucose”, are often thought to be “cheating” by their physicians.
Activation solves the brittle patient problem.
Brittle patients do not process carbohydrates correctly so that both
liver and muscle do store and releasing glycogen (sugar) to buffer
glucose causing brittle patients to have wide swings in blood glucose
and often pass out or hospitalized.
Patients on Pulsatile Therapy do not have wide swings and
excursions as their bodies store and release glycogen. This is seen by the
uptake of glucose from their blood.
More proper carbohydrate and lipid metabolism results in more control, not as
the “goal” but as a “by-product” of treatment.
Hypoglycemia Unawareness: Many diabetic
people cannot “feel” the onset of a low blood
sugar reaction (hypoglycemia).
Patients who have had diabetes for years can lose their ability to sense
the onset of low blood sugar, and "pass out“ without warning.
This becomes a severe life-controlling and confidence deflating problem.
Driving cars is no longer possible, nor are many types of jobs.
Clinical trials show patents on CAT regain their ability to sense blood
sugars, and decrease the episodes of hypoglycemia by 98%.
Patients who re-acquire their ability to sense low and high blood sugars are
significantly changed. Being able to sense a pending reaction is a great gift.
Patients sleep better knowing that they will be able to awake if they over
medicate themselves, something that was always a worry.
.
One striking result of CAT is the elimination of
hypoglycemic reactions. This 41 month study showed that
CAT almost totally eliminated major “low blood sugar”
reactions, and dramatically reduced even minor reactions.
Severe Kidney Disease (a leading killer)
Patients without any kidney disease have Creatinin Clearance ("CCL") of about 80
to 120. The following is a published study:
Patients who have progressed to a CCL of 60 should expect to
continue to lose 9 to 12 CCL points per year on average, with
kidney failure and dialysis at around 20 CCL. Life expectancy is greatly
shortened, a matter of a few years.
Patients on Pulsatile expect not to lose any of their CCL points
levels if caught in time, as supported studies showing on 31 patients
with CCL of 46, after 37 months, they remained at 46. These patients
should have progressed to renal dialysis by this time.
It is assumed that patients should never develop kidney disease if they
don’t have it when they start CAT treatment.
At the end of the three year study the patients had maintained an average
of 46 (instead of losing their ability to filter), and had slightly reduced the
protein in their urine. This is unlike and superior to any other therapy.
SECOND STUDY: A multi-center study showed the power of pulse insulin
therapy in even a shorter study (18 months) conducted at several centers. 74
patients were randomly placed, one-half treated, while one half continued on tight
control (intensive insulin therapy). The results were showed the importance of
CAT.
This study showed patients on Cellular Activation Therapy (CIIIT) lost only
0.89 creatinine clearance (ml/min/yr) where the tightly controlled patients
without CAT lost an expected 9.08 to 8.07 creatinine clearance per year.
This multiple center study was completed at some of the best diabetes centers
in the world.
A Graphing of patents shows the importance of earlier treatment.
Wound Healing, and the role of insulin.
Because of poor circulation, the lack of oxygenated blood and other factors,
including TNF alpha, diabetic patients do not heal well, and are prone
to infection. Diabetes is the leading cause of amputations.
Patients on Cellular Activation Therapy can expect to heal more quickly,
avoid pending amputations, and heal more quickly from surgery or
infections of all types.
A pre-surgery treatment will “spiff up” the patient’s metabolism and in
diabetic patients shown to limit hospital stays.
This diabetic patient has pressure wounds due to loss of sensation,
(Neuropathy) and then was unable to heal after trying every possible
conventional therapy. This is the Left foot.
This diabetic patient has pressure wounds due to loss of sensation, (Neuropathy)
and then was unable to heal after every conventional therapy including skin
grafting and hyperbaric chamber . This is the right foot.
This is the same diabetic patient 5.5 months later.
And this is the left foot. Notice that the skin is more pink and healthy
appearing. This result is uniformly seen with all patients on CAT to date.
HYPERTENSION
(Is hypertension, a metabolic disease? Just another
form of diabetes?)
Hypertension is a major problem. The diabetic blood pressure often stays
elevated while asleep. The loss of circadian rhythm is associated
with kidney disease.
Patients on Pulsatile Therapy experience a reduction in high blood
pressure, but also eliminate orthostatic hypotension (low blood
pressure), also regaining healthy lowering of their blood pressures at night.
(see publications)
This is a study of the use of anti-hypertensive medicines by patients who maintained the
same blood pressures measured by 24 hour blood pressure monitors. The patients were
placed randomly, one half treated while the others remained in intensive insulin control
therapy, then they were crossed, and the untreated became the treated. Note that the
use of medicines were consistently 46% less after just three months of treatment.
We Can Stop the Progression of Blindness
Diabetic Retinopathy is the leading cause of
non-injury blindness.
Diabetic Patients often require laser treatments.
Diabetes is a major cause of blindness. “Tight Control” under DCCT showed
worsening of retinopathy, as you would expect with underfed eyes.
Patients on Pulsatile Therapy experience a remarkable stabilization
of eye disease, and expect not to require laser treatments after being on
the treatment for one year or more. While there have been no large
clinical studies showing that this will always take place, it has been highly
successful to date. This includes yellowing and proliferative retinopathy.
After 5 months, patients will no longer require laser therapy.
Heart Metabolism, not only diabetic but
other types of cardiac dysfunction
Many heart failures are really due to diabetes, and the failure of the heart
to be properly "fed" due to improper heart metabolism and resulting
athrosclerosis.
Patients on Pulsatile Therapy can expect to have their Heart Muscle fed
with reduced oxygen requirements, and recover a more normal life,
as their hearts are no longer starving in a “sea” of glucose.
Making the energy available to the heart muscle in a more anaerobic form,
reduces the oxygen requirements for work and repair, and avoids syndromes
associated with reduced vascular flows to the injured heart muscle tissues.
The result is that patients with severe cardiac disease can experience the
beginning of heart repair and lifestyle changes within a few weeks.
Metabolic Syndrome Studies Suggest that
Non-diabetic Dysfunction Responds to CAT
Current studies are focusing on “Metabolic Syndrome” patients who are
much like average people with age related heart disease. Impaired Glucose
Tolerant people and non-diabetic conditions is the frontier for this therapy.
Patients with age related heart disease may be treated on a less
frequent basis. The timing is expected to be once every three
weeks +/- a weeks. This timing between treatments is based upon the
treatment of non-diabetic people in other countries where the treatment can
be legally given without a diagnosis of any metabolic syndrome.
Non-diabetic people become unable to process glucose as efficiently, and at
75 years have 60% of their normal glucose metabolism efficiency. Patients
of this age and greater have uniformly been able to reestablish cellular
glucose oxidation, giving evidence of the ability to regain normal cellular
metabolism for non-diabetic heart disease patients.
Nerve Damage (Neuropathy)
an extremely common complication.
Diabetic neuropathy is common, and causes pain even while at rest. The
problem is severe, and pain can be great. Diabetic feet often lose
sensation, leading to undiscovered damage in areas with poor
circulation. The damage then often leads to infection and
amputations.
Patients on Pulsatile Therapy enjoy the first ever elimination of
neuropathy progression, and some recovery or reversal, depending
upon the duration of that nerve’s damage. Every patient with
neuropathy treated to date has responded. It is logical that all neuropathic
processes are helped with normalization of carbohydrate metabolism as the
brain only uses glucose and converted glucose.
Brain tissues are so glucose dependent that they will die without glucose
faster than without oxygen.
Cellular Activation Therapy Improves
Nerve Conduction Velocities (Neuropathy)
Multiple metabolic pathways can contribute to Diabetic Neuropathy.
Hyperglycemia is an abnormality causing activation of the PKCβ enzyme,
increased oxidative stress, protein glycosilation (AGE) and abnormal polyol
metabolism resulting in direct neurotoxicity and ischemic changes at the nerve
cell membrane and vasa nervorum.
In the last few years anecdotal and objective studies have confirmed the
paramount role of chronic pulsatile intravenous insulin therapy (CAT) in the
amelioration and improvement of the microvascular and macrovascular
complications of diabetes.
In a prospective study of 26 patients at the University of Puerto Rico, 8 having
been unable to participate, of the 18 who could, Above findings revealed a
sixty five (65%) percent improvement in nerve conduction velocity.
Basic Quality of Life, Peace of Mind, and
energy levels, as well as the ability to sleep.
Diabetic patients have very slowly progressed to a state of malaise,
depression and lost energy. They feel badly and forgot how to feel
“well.” The treatment of diabetes is a 24 hour, 7 days a week constant battle
to maintain some sense of normality.
Patients on Pulsatile Therapy realize how it is to feel well. CAT treated
patients regain their former energy levels, feel better, and realize
just how ill they had become. CAT addresses the core of their
disease, makes their lives very different and gives them justified
hope.
Sleeping, eating, exercise, emotional stability and sexual function
are all greatly improved with CAT.
The Final Validation: Pulses of Insulin
happen to be the normal mode of pancreatic
insulin delivery to the liver.
Peter Butler, professor of medicine and chair of the division of endocrinology
and diabetes, and research fellow Soon Song, received the Endocrine
Society's first prize for best clinical paper published in The Journal of Clinical
Endocrinology and Metabolism in the year 2000. The paper, "Direct
Measurement of Pulsatile Insulin Secretion from the Portal Vein in Human
Subjects," reported that insulin is secreted from beta cells in the
pancreas almost exclusively in secretory bursts every four to six
minutes. The results of the study show that very large amplitude oscillations
of insulin (pulses) concentration in the portal vein directly perfuse the liver.
Prior to this study, no one had shown this effect in human beings. The
subject was entrained to show the agreement between frequency and portal
vein insulin oscillations. “We conclude that insulin release in the human
portal vein occurs at a mean periodicity of 4.4 [plus minus] 0.2 min with
a high signal-to-noise ratio (pulse amplitude 660% of basal).”
Am J Physiol Endocrinol Metab 2002 Mar;282(3):E695-E702
A Miles Biostator was modified to
allow the initial experiments.
This Biostator was modified to
review the “control theory” method
of balancing blood levels, and then
the unit was used to develop CAT.
The treatment reawakens the
sleeping liver, and now we know
that not only the liver, but the
whole body’s metabolism is
improved.
This was original work, with no
prior work on which to build,
making the entire approach subject
to initial skepticism. Now there is
no question as to the validity of the
treatment.
This pump is the size of a video cassette,
is FDA certified for CAT insulin treatment,
and unique in its pressures.
This Bionica infusion device has the
treatment built into the software. The
treatment requires that the weight of the
patient be programmed into the pump,
the concentration is then determined by
the pump, and the patient’s dosing (as
determined by prior tests) is programmed
into the pump.
The patient is treated for one hour, with
the pump counting down between pulses.
Three one hour treatments are given,
with one hour wait between treatments.
Patients know when their treatment
“wears off” as their blood sugars and
energy levels change back to diabetic.
As can be seen, the CAT pump delivers the very accurate
pulses of insulin, at all levels of infusion. This is required
as one of the signals needed to reawaken dormant
carbohydrate metabolism, and produce the many effects.
Home Medical Device
Current Bionica Device is extremely accurate
and has a unique safety record.
It is also “ambulatory” and therefore is FDA
cleared for home use.
Only patients who have been treated for 6
months will be sufficiently stabilized where their
treatment is routine enough for them to be
trained, (along with a friend) to treat at home
and return for verification every one to three
months.
Facilities and Reimbursement
A clinic can be started in almost any type of facility, a
doctor’s office, a shopping mall or even just a large
room.
Only restrooms and a sink are required.
The Doctor prescribes the treatment, and only a trained
Med Tech is needed.
Billings under Medicare codes in the USA equate to
$950 to $1,200 per treatment day, insurance companies
may be billed more than the Medicare (CMS) codes.
New law provides an incentive to employers who engage
in cost limiting practices.
Patients will pay for 6 months and then be graduated to
home therapy, thereby making reimbursement attractive
to insurance providers.
Conclusion: Giving their lives back:
• CAT makes significant quality of life differences in the lives of people with
advanced complications.
• CAT has been effective on every patient treated to date, as it provides the
proper signals to the liver and tissue, addressing the core of the disease.
• The metabolic measurement cart provides immediate proof of metabolic
normalization, which the patient can see (as well as feel).
• Patients on this treatment are not hospitalized for out of control diabetes,
have energy and feel normal again. They do not have chronic diabetes
symptoms, and their entire lives are improved.
• The Bionica pump is “ambulatory” which means that it can be taken home
for treatment by non-practitioners.
• When patients are treated for only 6 months before they are eligible to treat at
home, the resistance to the therapy is eliminated. Even the most conservative
reimbursement entity will respond to proven savings which also provide better
health…..and they get their lives back from diabetes.