The Physiological Basis of the Effects The Physiological Basis of the Effects of Cellular Activation Therapy:of Cellular Activation Therapy:

It’s Not the Glucose – It’s Not the Glucose – It’s the Insulin and Glucose SignalsIt’s the Insulin and Glucose Signals

A Presentation A Presentation G Ford Gilbert, JDG Ford Gilbert, JD

Additional Slides Provided:Additional Slides Provided:T. Steven Roosevelt, MD, PhD, FACET. Steven Roosevelt, MD, PhD, FACE

Kevin J. Buckman, MDKevin J. Buckman, MD

*IFG = impaired fasting glucose.©2000 International Diabetes Center, Minneapolis, USA. All rights reserved. Adapted with permission.

Natural History of Type 2DMNatural History of Type 2DM

Years of Diabetes

Glu

cose

(mg/

dL)

50 –

100 –

150 –

200 –

250 –

300 –

350 –

0 –

50 –

100 –

150 –

200 –

250 –

-10 -5 0 5 10 15 20 25 30

Rel

ativ

e Fu

nctio

n (%

)

Fasting Glucose

Postmeal Glucose

Obesity IFG* DiabetesUncontrolledHyperglycemia

Insulin Resistance

-Cell Function-Cell Failure

Inability to handle glucose starts approx 5 to 7 years prior to failure (beta cell).

Cancer RatesCancer Rates

A Mayo Clinic study showed that for three years after their diagnosis with A Mayo Clinic study showed that for three years after their diagnosis with diabetes, patients have eight times the risk of developing pancreatic cancer. 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 In a Swedish study of 125,162 patients pancreatic cancer was 4.25 times the normal rate. the normal rate. The risk of small intestine cancer among diabetic people is more than twice The risk of small intestine cancer among diabetic people is more than twice as high as non-diabetic. as high as non-diabetic. The risk of esophagus and thyroid cancer is more than twice the normal The risk of esophagus and thyroid cancer is more than twice the normal rate. rate. The risk of kidney 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.The risk of nervous system cancer is more than twice the normal rate.

United Kingdom Prospective Diabetes Study (UKPDS)

*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 exceeded270 mg/dL after this, then insulin was substituted.Adapted with permission from UK Prospective Diabetes Study (UKPDS 34) Group. Lancet. 1998;352:854-865.

Traditional Therapies Do Not Maintain Traditional Therapies Do Not Maintain Tight Control Over TimeTight Control Over Time

Conventional* 200

Insulin 199

Glibenclamide 148

Metformin 181

Med

ian

A1C

(%)

0

6

7

8

10

Time From Randomization (Years)0 3 6

9

9 12 15

ADA Goal

““Control” is at IssueControl” is at IssueMany patients have the misconception that “tight control” will Many patients have the misconception that “tight control” will keep them from developing the complications of diabetes. Often keep them from developing the complications of diabetes. Often found in media and even assumed in published clinical trials. found in media and even assumed in published clinical trials. But, “tight control” is a relative term, with many patients only able But, “tight control” is a relative term, with many patients only able to maintain blood sugar levels to maintain blood sugar levels significantlysignificantly above non-diabetic above non-diabetic levels no matter how hard they try.levels no matter how hard they try.The point is, The point is, trulytruly non-diabetic tight control cannot be achieved non-diabetic tight control cannot be achieved with any current conventional therapy. with any current conventional therapy. It is also well known that even excellent control does It is also well known that even excellent control does notnot induce induce proper lipid and carbohydrate metabolism.proper lipid and carbohydrate metabolism.

““while not controlling glucose worsens complications, tight while not controlling glucose worsens complications, tight control does not prevent 25% to 40% of diabetic patients control does not prevent 25% to 40% of diabetic patients from developing overt secondary complications within 10 from developing overt secondary complications within 10 years.”years.”

*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.

Natural History of T2DMNatural History of T2DMUKPDS: UKPDS: -Cell Decline Over Time-Cell Decline Over Time

Patients Treated with Metformin and/or Sulfonylureas (SUs)‡

-C

ell F

unct

ion

(%)*

PostprandialPostprandialHyperglycemiaHyperglycemia

IGTIGT††

Type 2 DiabetesType 2 Diabetes

Years From Diagnosis

25 –

100 –

75 –

0 –

50 –

l-12

l-10

l-6

l-2

l0

l2

l6

l10

l14

In type 2 DM, patients slowly lose their -cell-cell functions, causing them to fail to produce sufficient insulin and become insulin resistant.

Insulin / GlucoseInsulin / Glucose

What are the potential mechanisms What are the potential mechanisms and effects of insulin and glucose on and effects of insulin and glucose on

patient outcomes?patient outcomes?

Link Between Improper Metabolism and Link Between Improper Metabolism and

Poor Outcomes & MechanismsPoor Outcomes & Mechanisms

Copyright 2004 American Diabetes Association. From Clement S, et al. Diabetes Care. 2004;27:553–591. Reprinted with permission.

Immune dysfunction

Infection dissemination

Reactive O2 species

Secondary mediators

Transcription factors

Metabolic stress response

↑ Stress hormones and peptides

GlucoseInsulin

FFAKetonesLactate

Cellular injury/apoptosisInflammation

Tissue damageAltered tissue/wound repair

AcidosisInfarction/ischemia

Prolonged hospital stayDisability

Death

Candidate Mechanisms for Insulin Candidate Mechanisms for Insulin Protective EffectsProtective Effects

Enhances Synthesis of Endothelial Enhances Synthesis of Endothelial Nitric Oxide Nitric Oxide

Suppresses Free Fatty AcidsSuppresses Free Fatty Acids

Inhibits proinflammatory cytokinesInhibits proinflammatory cytokines

Suppresses inflammatory repair Suppresses inflammatory repair (growth) factors(growth) factors

Under physiologic conditions, production from vascular endothelium contributes to

coronary blood flow.

Nitric OxideNitric Oxide

Inhibits Inhibits – Vascular smooth muscle cell growth Vascular smooth muscle cell growth

and migrationand migration

– Platelet aggregation and thrombosisPlatelet aggregation and thrombosis

– Monocyte adhesionMonocyte adhesion

– InflammationInflammation

– OxidationOxidation

Change in Leg Blood Flow in response to the vasodilator methacholine chloride. Steinberg HO, et al. J Clin Invest. 1997;100:1230–1239.

Free Fatty Acids CauseFree Fatty Acids Cause Endothelial Dysfunction Endothelial Dysfunction

FFAµmol

3000 4000 500020001000 600000

600

500

400

300

200

100

y = 1361.182x r = 0.497 p < 0.005

Maximum ∆% in

Leg Blood Flow

-0.310

Pro-inflammatory CytokinesPro-inflammatory Cytokines

Tumor Necrosis Factor-Tumor Necrosis Factor-αα “TNF- “TNF- αα””, ,

Interleukin-6, IL-1, IL-2Interleukin-6, IL-1, IL-2

Data strongly suggest a cause/effect Data strongly suggest a cause/effect relationship as opposed to just a relationship as opposed to just a marker of inflammation.marker of inflammation.

Thus, without proper insulin/glucose Thus, without proper insulin/glucose ratios, inflammation is exacerbated.ratios, inflammation is exacerbated.

TumorNF-α IL-6

Iκß (inhibitor κß)

phosphorylation

Translocation to the nucleus

Proinflammatory genes

TNF-α IL-6 IL-1ß

Adhesion molecules

ICAM-1 VCAM-1

Chemokines

MCP-1 CRP

transcription transcription

-INSULIN-

NOS

NO

+

+

-

TZDs -FFA

-

+

-

+

Calcium dependent Adhesion molecules,

How cells bind proteins

Tumor Necrosis Factor

(Hypoglycemic agents (Avandia)

Iκß inhibits FOXO3 Which promotes tumor growth

Trasnscription factorAffect cellular

ThusThus

Improper insulin/glucose metabolism disrupts Improper insulin/glucose metabolism disrupts the cellular functions of immunity, repair, the cellular functions of immunity, repair, inflammatory response, and cellular damage. inflammatory response, and cellular damage.

These mechanisms of action appear at all These mechanisms of action appear at all cellular levels, causing generalized corporal cellular levels, causing generalized corporal dysfunction. dysfunction.

Cellular ActivationTherapy addresses these Cellular ActivationTherapy addresses these mechanisms by normalizing metabolismmechanisms by normalizing metabolism

Blood Monocytes, Tissue Monocytes

IL-1 family TNF family

Stromal cells: IL-6, IL-8, monocyte chemoattractant proteins

Neutrophil recruitment, further inflammatory cytokine release

Acute Phase Proteins

*Trauma, burns, tissue infarction, cancer, immunologic and crystal inflammation.

With tissue damage, you have cytokine release allowing for capillary leakage and release of white blood cells.

ACUTE-PHASE PROTEINS

Liver

IL-1, TNF, IL-6+

INSULIN

-

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 Conclusions About Insulin and Cytokinesand Cytokines

Hyperinsulinemia in the hyperglycemic Hyperinsulinemia in the hyperglycemic environment leads to an increase in environment leads to an increase in inflammatory cytokines.inflammatory cytokines.

Insulin deficiency in the hyperglycemic Insulin deficiency in the hyperglycemic environment leads to a modest increase in environment leads to a modest increase in inflammatory cytokines.inflammatory cytokines.

Hyperinsulinemia in the euglycemic Hyperinsulinemia in the euglycemic environment suppresses inflammatory environment suppresses inflammatory cytokines.cytokines.

Circ Res. 2000;87:746–752.Circulation. 2002;106:2067. Circulation. 2004;109:849.

Hyperglycemia Is ProinflammatoryHyperglycemia Is Proinflammatory

Patients with “stress” hyperglycemia but Patients with “stress” hyperglycemia but without diabetes mellitus at the time of without diabetes mellitus at the time of Acute Myocardial Infarction are at Acute Myocardial Infarction are at increased risk for in-hospital mortality, increased risk for in-hospital mortality, Congestive Heart Failure and cardiogenic Congestive Heart Failure and cardiogenic shock.shock.Hyperglycemia (indicating a decrease in Hyperglycemia (indicating a decrease in insulin action) increases circulating free insulin action) increases circulating free fatty acids.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 Further Inflammatory Effects of Hyperglycemia Hyperglycemia

Hyperglycemia increases the production of Hyperglycemia increases the production of reactive oxygen species within aortic reactive oxygen species within aortic endothelial cells.endothelial cells.

Superoxide anion inactivates both Superoxide anion inactivates both endothelial NO and prostacyclin produced endothelial NO and prostacyclin produced by endothelial cells, both of which are by endothelial cells, both of which are potent vasodilators and platelet anti-potent vasodilators and platelet anti-aggregators.aggregators.

Das, UN, Critical Care 2002 6:389-393

Effects of Reduction of Effects of Reduction of Reactive Oxygen SpeciesReactive Oxygen Species

Normalization of mitochondrial reactive Normalization of mitochondrial reactive oxygen species prevents glucose-induced oxygen species prevents glucose-induced activation of:activation of:– Protein kinase CProtein kinase C– Sorbitol accumulationSorbitol accumulation– Nuclear factor-Nuclear factor-κκB (NF- B (NF- κκB)B)

Das, UN, Critical Care 2002 6:389-393

Effects of Glucose ChallengesEffects of Glucose Challenges

Stimulation of Reactive OStimulation of Reactive O22 Species generation Species generation

Induction of inflammatory events as evidenced Induction of inflammatory events as evidenced by:by:– Increased leukocyte rollingIncreased leukocyte rolling– Leukocyte adherenceLeukocyte adherence– Leukocyte transmigration through mesenteric venules Leukocyte transmigration through mesenteric venules

associated with attenuation of endothelial NO releaseassociated with attenuation of endothelial NO release– Increased expression of P-selectin on endothelial Increased expression of P-selectin on endothelial

surfaces (rolls white cells to the point of expression)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 InfusionEffects of Insulin Infusion

Insulin infusion acts to attenuate the Insulin infusion acts to attenuate the inflammatory effects of hyperglycemia, viz:inflammatory effects of hyperglycemia, viz:– Inhibition of ROS generation;Inhibition of ROS generation;– Inhibition of NF-Inhibition of NF-κκB generation;B generation;– Reduction of soluble intercellular adhesion molecule-1 Reduction of soluble intercellular adhesion molecule-1

production;production;– Reduction of Monocyte chemoattractant protein-1 Reduction of Monocyte chemoattractant protein-1

production;production;– And plasminogen activator inhibitor-1 (PAI-1).And plasminogen activator inhibitor-1 (PAI-1).

All actions mediated by increasing NO synthesisAll 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 Putative Mechanism of Glucose Stimulation of InflammationStimulation of Inflammation

Indirect evidence suggests that the mediator is TNF-Indirect evidence suggests that the mediator is TNF-αα ( a ( a pro-inflammatory cytokine)pro-inflammatory cytokine)– Diets with hyperglycemic loads induce production of acute Diets with hyperglycemic loads induce production of acute

phase reactants;phase reactants;

As with hyperglycemic diets:As with hyperglycemic diets:– TNF-TNF-αα also enhances free radical generation by augmenting also enhances free radical generation by augmenting

PMN NADPH oxidase activity;PMN NADPH oxidase activity;– TNF-TNF-αα activates NF- activates NF-κκBB– TNF-TNF-αα increases intercellular adhesion molecule-1 expression in increases intercellular adhesion molecule-1 expression in

endothelial cells.endothelial cells.

The similarity of TNF-The similarity of TNF-αα and glucose, implies that and glucose, implies that glucose, by increasing TNF-glucose, by increasing TNF-αα production, increases production, increases inflammation.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 - Tumor Necrosis Factor - αα

TNFTNFαα: : StructureStructure

TNFα is a member of a group of other TNFα is a member of a group of other cytokines that all stimulate the that all stimulate the acute phase reaction. It is a 185 . It is a 185 amino acid glycoprotein hormone, cleaved , cleaved from a 212 amino acid-long propeptide. from a 212 amino acid-long propeptide. Some cells secrete shorter or longer Some cells secrete shorter or longer isoforms. Genetically it links to isoforms. Genetically it links to chromosome 7p21. 7p21.

TNFTNFαα: Physiology: Physiology

TNFα is released by TNFα is released by white blood cells, , endothelium and several other and several other tissues in in the course of damage, e.g. by the course of damage, e.g. by infection. Its . Its release is stimulated by several other release is stimulated by several other mediators, such as mediators, such as interleukin 1 and 1 and bacterial endotoxin. It has a number of endotoxin. It has a number of actions on various organ systems, actions on various organ systems, generally together with interleukins 1 and generally together with interleukins 1 and 6:6:

TNFTNFαα: Pathophysiology: Pathophysiology

On the hypothalamus: On the hypothalamus: – Stimulating of the hypothalamic-pituitary-Stimulating of the hypothalamic-pituitary-

adrenal axis by stimulating the release of adrenal axis by stimulating the release of corticotropin releasing hormone (CRH). corticotropin releasing hormone (CRH).

– Suppressing appetite (hence its name Suppressing appetite (hence its name "cachexin" "cachexin"

– Fever. Affects the hypothalamus causing an Fever. Affects the hypothalamus causing an altered temperature control.altered temperature control.

TNFTNFαα: Pathophysiology: Pathophysiology

On the liver: stimulating the acute phase On the liver: stimulating the acute phase response, leading to an increase in C-response, leading to an increase in C-reactive protein and a number of other reactive protein and a number of other mediators. mediators.

On insulin sensitive tissues: increasing On insulin sensitive tissues: increasing insulin resistance. insulin resistance.

TNF Signaling Pathway SIGMA-ALDRICH

IGF Regulation of Apoptosis SIGMA-ALDRICH

Summary: TNFSummary: TNFαα

Tumor Necrosis Factor - Tumor Necrosis Factor - αα is a mediator of is a mediator of cell apoptosis as well as inflammation.cell apoptosis as well as inflammation.

The re-establishment of proper insulin The re-establishment of proper insulin uptake by the cells, and more proper lipid uptake by the cells, and more proper lipid and carbohydrate metabolism leads to and carbohydrate metabolism leads to proper mediation of inflammation. This is proper mediation of inflammation. This is uniformly seen in CAT patients.uniformly seen in CAT patients.

Insulin Infusion in the Treatment Insulin Infusion in the Treatment of Macrovascular Inflammatory of Macrovascular Inflammatory

ConditionsConditions

Insulin Infusion to Reduce Cardiovascular Insulin Infusion to Reduce Cardiovascular Inflammation Inflammation ISIS

the Standard of Carethe Standard of CareThe American College of Cardiology and the The American College of Cardiology and the American Heart Association both recommend American Heart Association both recommend glucose-insulin-potassium (GIK) infusions in glucose-insulin-potassium (GIK) infusions in patients with MI (intense cardiovascular patients with MI (intense cardiovascular inflammatory state).inflammatory state).

Why? Because the GIK protocol improves the Why? Because the GIK protocol improves the integrity and function of myocardial cells.integrity and function of myocardial cells.

In essence it reduces the inflammatory state In essence it reduces the inflammatory state associated with dysglycemia.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.

GIKGIK

But, there are conflicting data on the use But, there are conflicting data on the use of GIK, with some studies showing a of GIK, with some studies showing a beneficial effect and others not showing beneficial effect and others not showing such an effect.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 The Difference in Outcomes with GIK is the Insulin ConcentrationGIK is the Insulin Concentration

Studies in which higher concentrations of Studies in which higher concentrations of insulin were used showed better results insulin were used showed better results than did those studies that employed a than did those studies that employed a lesser does.lesser does.– Studies in which 33% glucose was infused Studies in which 33% glucose was infused

with 120 I.U. of insulin or 30% glucose with with 120 I.U. of insulin or 30% glucose with 300 I.U. of insulin yielded positive results.300 I.U. of insulin yielded positive results.

– Studies in which lower doses (e.g., 500 ml of Studies in which lower doses (e.g., 500 ml of D5W with 100 I.U. of insulin or 10 U of insulin D5W with 100 I.U. of insulin or 10 U of insulin per 1000 ml of D5W were less favorable.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 Is the Glucose Insulin Potassium Effect Independent of Glucose?Effect Independent of Glucose?

The benefits of GIK infusion may extend The benefits of GIK infusion may extend beyond the control of hyperglycemia beyond the control of hyperglycemia alone.alone.

There is evidence that infusions of insulin There is evidence that infusions of insulin reverse cardiac failure and maintain reverse cardiac failure and maintain normal cardiac function in spite of wide normal cardiac function in spite of wide ranges of glucose concentrations.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 EffectsSummary: Insulin Effects

Insulin has the following actions:Insulin has the following actions:– It lowers blood glucose by stimulating glucose uptake It lowers blood glucose by stimulating glucose uptake

and glycolysis;and glycolysis;– Stimulates pyruvate dehydrogenase and ATP Stimulates pyruvate dehydrogenase and ATP

production;production;– Inhibits the production of proinflammatory cytokines Inhibits the production of proinflammatory cytokines

(TNF-(TNF-αα, MIF, and superoxide anions);, MIF, and superoxide anions);– Inhibits apoptosis and improves repair of damaged Inhibits apoptosis and improves repair of damaged

tissues;tissues;– Promotes ischemic preconditioning;Promotes ischemic preconditioning;– Lessens ischemia/reperfusion damage;Lessens ischemia/reperfusion damage;– Exhibits anti-inflammatory actionsExhibits 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: 73% of adults with diabetes have high blood pressure.

Blindness: Diabetic retinopathy causes 12,000 to 22,000 cases of new blindness cases

each year.

Kidney Disease: Diabetes is the leading cause of renal disease, accounting for

43% cases.

Amputations: 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.

$132 Billion

Inpatient Hospital$84 Billion (63%)

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%)

CAT patients are almost never hospitalized.

In 2002, the same percentages remain as in 1992.

Cos

t ($

bill

ions

)

*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.

62% Of Diabetes Costs Related To 62% Of Diabetes Costs Related To Hospitalization And Long-Term CareHospitalization And Long-Term Care

$132 Billion Total$132 Billion Total

2002 US Total Healthcare Costs Attributable To Diabetes5050

4040

3030

2020

1010

00Direct CostsDirect Costs Indirect CostsIndirect Costs‡‡

Oral AntidiabeticsInsulin and SuppliesOutpatient Medication*Outpatient Services†

Physician Office VisitsNursing Home Care (11%)Inpatient Care (41%)

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.

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).

High pulses of insulin found here, 200 to 1,000 U / ml.

Maximum levels outside portal vein are 75 U/ml.

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.

No normal pulses of insulin (200 to 1,000 U / ml.) are found in the diabetic portal vein

Maximum levels outside portal vein are 40 U/ml (from shots or CIIT).

Thus, without the twosignals to the liver, High insulin / Glucosethe functions associatedwith liver are blunted,and insulin cannot be givenin periphery without overinsulinization of other tissues and damageto the brain.

Enzymes Induced or Repressed by InsulinEnzymes Induced or Repressed by InsulinThe following enzymes are affected by insulin ratios to the liver:The following enzymes are affected by insulin ratios to the liver:

Enzymes Enzymes inducedinduced by a high insulin to glucagon ratio: by a high insulin to glucagon ratio:– GlucokinaseGlucokinase– 6-phosphofructo 1-kinase6-phosphofructo 1-kinase– 6-phosphofructo 2-kinase6-phosphofructo 2-kinase– Citrate cleavage enzymeCitrate cleavage enzyme– Acetyl-coa carboxylaseAcetyl-coa carboxylase– Hmg-coa reductase Hmg-coa reductase – Pyruvate kinase Pyruvate kinase

Enzymes Enzymes repressedrepressed by a high insulin to glucagon ratio: by a high insulin to glucagon ratio:– Glucose 6-phosphataseGlucose 6-phosphatase– Fructose 1,6-biaphosphataseFructose 1,6-biaphosphatase– Phosphoenolpyruvate carboxykinasePhosphoenolpyruvate carboxykinase

FROM BASIC AND CLINICAL ENDOCRINOLOGY, THIRD EDITION

Enzymes Activated Or Inactivated by InsulinEnzymes Activated Or Inactivated by Insulin

Enzymes Enzymes activatedactivated by a high insulin:glucagon ratios by a high insulin:glucagon ratios– 6- phosphofructo 2-kinase6- phosphofructo 2-kinase– Pyruvate kinase (l-isoenzyme)Pyruvate kinase (l-isoenzyme)– Pyruvate dehydrogenase complexPyruvate dehydrogenase complex– Acetyl - coa carboxylaseAcetyl - coa carboxylase– Glycerol phosphate acyltransferaseGlycerol phosphate acyltransferase– Hmg - coa reductaseHmg - coa reductase

Enzymes Enzymes inactivatedinactivated by a high insulin:glucagon ratios by a high insulin:glucagon ratios– Glycogen phosphorylaseGlycogen phosphorylase– Fructose 2,6 biphosphataseFructose 2,6 biphosphatase

FROM BASIC AND CLINICAL ENDOCRINOLOGY, THIRD EDITION

αααα

Enzymes are Part of the ProblemEnzymes are Part of the Problem

The inability of the Type1 and Type 2 The inability of the Type1 and Type 2 diabetic patient to to produce and activate diabetic patient to to produce and activate enzymes causes the cascade of metabolic enzymes causes the cascade of metabolic dysfunction, and sets in motion all of the dysfunction, and sets in motion all of the other insulin/glucose related disease other insulin/glucose related disease pathways. This is a result of the lack of pathways. This is a result of the lack of first phase insulin release (response) and first phase insulin release (response) and is directly treated by Cellular Activation is directly treated by Cellular Activation Therapy.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 thischamber.

Oxygen consumedCO2 Produced is measured here.

Equals the sitting patient

“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.

High fat metabolism respiratory quotient (at rest).

Low fat, high carb.Respiratory quotient

Usualdiabeticrange

Usualnormalrange

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 non-diabetic patient. They thus all develop some metabolic complications and shorten their lives.

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.

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.

6. This happens every time as activation re-establishes much more normal lipid and carbohydrate metabolism

1. When given glucose, normal people metabolize it

2. And lipid use goes down

3. Diabetics don’t

4. Lipids stay up, a bad condition.

5. These are the same people, now activated, and thus lower lipids

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 treatmentsto re-awaken the liver to produce the enzymes it produces for non-diabetics.

Non-diabetic compared to activated people, by 4th dayDiabetics beforetreatment all lookthe same.

Exercise Study, CATThe 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.

Diabetics, even well controlled, before CAT do not oxidize fuel as do non-diabetics. After treatment for 4 days, these subjects became able to out-perform their non-diabetic counterparts.

These same diabetic patients can out-perform “normal” man in their carbohydrate processing and are reestablishing muscle glycogen storage .

Note the reduced levels of free fatty acids, and reduced glucose in sugar with treatment.

Free Fatty Acid levels before activation

Free Fatty Acid levels after activationNormal, non-diabeticlevels of FFA

Carbohydrates Burn FatCarbohydrates Burn Fat

Diabetes mellitus is fundamentally a disordered metabolism, Diabetes mellitus is fundamentally a disordered metabolism, primarily of carbohydrates and secondarily of protein and fat. primarily of carbohydrates and secondarily of protein and fat. It is indisputably proven that for normal metabolism of It is indisputably proven that for normal metabolism of carbohydrate in the body, adequate amounts of Insulin are carbohydrate in the body, adequate amounts of Insulin are essential. It follows, therefore, that the treatment consists in essential. It follows, therefore, that the treatment consists in giving sufficient Insulin to make up for the deficiency in the giving sufficient Insulin to make up for the deficiency in the patient’s pancreas. patient’s pancreas.

Fats burn in the fire of carbohydrate.Fats burn in the fire of carbohydrate. The ability of the severe The ability of the severe diabetic to burn glucose is markedly impaired, therefore the diabetic to burn glucose is markedly impaired, therefore the excess of fat incompletely oxidized, giving rise to ketone excess of fat incompletely oxidized, giving rise to ketone bodies. These appear in the blood and urine as acetone, bodies. These appear in the blood and urine as acetone, diacetic and betaoxybutyric acids. Insulin causes increased diacetic and betaoxybutyric acids. Insulin causes increased carbohydrate metabolism, and consequently fats are carbohydrate metabolism, and consequently fats are completely burned.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 HormonesCytokines, 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.ReferencesLuttrell, 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.

ReferencesPlumpe, 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 Pulsatile Insulin Therapy: Review ArticlesArticles

The novel approach to insulin therapy know as chronic The novel approach to insulin therapy know as chronic intermittent intravenous insulin, (CAT), delivers insulin in intermittent intravenous insulin, (CAT), delivers insulin in a specific pulsatile fashion and achieves physiologic a specific pulsatile fashion and achieves physiologic concentrations of insulin in the portal vein. Done as a concentrations of insulin in the portal vein. Done as a weekly outpatient procedure combined with daily weekly outpatient procedure combined with daily intensive subcutaneous insulin therapy, this procedure intensive subcutaneous insulin therapy, this procedure has been shown to 1) significantly improve glycemic has been shown to 1) significantly improve glycemic control while decreasing the incidence of hypoglycemic control while decreasing the incidence of hypoglycemic events 2) improve hypertension control, 3) slow the events 2) improve hypertension control, 3) slow the progression of overt diabetic nephropathy, and 4) progression of overt diabetic nephropathy, and 4) reverse some manifestations of diabetic autonomic reverse some manifestations of diabetic autonomic neuropathy.neuropathy.

Chronic intermittent intravenous insulin therapy: A new frontier in diabetes therapy. Diabetes Technology and Therapeutics 2001; 3(1): 111-123.

Cellular Activation Therapy: Cellular Activation Therapy: NephropathyNephropathy

A multi-center randomized controlled trial in patients with Type 1 A multi-center randomized controlled trial in patients with Type 1 diabetes and diabetic nephropathy compared outcomes in 23 diabetes and diabetic nephropathy compared outcomes in 23 patients treated with pulsatile intravenous insulin therapy (CIIIT) patients treated with pulsatile intravenous insulin therapy (CIIIT) plus intensive insulin therapy compared to 26 patients treated with plus intensive insulin therapy compared to 26 patients treated with intensive insulin therapy alone. Blood pressure was controlled in intensive insulin therapy alone. Blood pressure was controlled in both groups and patients were seen weekly. Hemoglobin A1c levels both groups and patients were seen weekly. Hemoglobin A1c levels declined significantly in both groups. However, the rate of decline of declined significantly in both groups. However, the rate of decline of the creatinine clearance level was significantly less (2.2 mL/min/yr) the creatinine clearance level was significantly less (2.2 mL/min/yr) in the treatment group(CAT plus intensive insulin therapy) as in the treatment group(CAT plus intensive insulin therapy) as compared to 7.7 mL/min/yr in the control group( intensive insulin compared to 7.7 mL/min/yr in the control group( intensive insulin therapy alone.) Projected average-time-until-dialysis/transplant is therapy alone.) Projected average-time-until-dialysis/transplant is 5.2 years for the control group and 18.2 years for the CAT treatment 5.2 years for the control group and 18.2 years for the CAT treatment group. group. Conclusion: Pulsatile intravenous insulin therapy (CAT) appears to Conclusion: Pulsatile intravenous insulin therapy (CAT) appears to markedly reduce the progression of diabetic nephropathy.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: Cellular Activation Therapy: NephropathyNephropathy

In patients with advanced diabetic kidney disease, the In patients with advanced diabetic kidney disease, the gradual deterioration of kidney function (decrease of gradual deterioration of kidney function (decrease of creatinine clearance [CrCl] by 8-10 ml/min/year) cannot creatinine clearance [CrCl] by 8-10 ml/min/year) cannot be arrested with "routine" insulin therapy. This study be arrested with "routine" insulin therapy. This study reports the treatment outcome of an average of 37 reports the treatment outcome of an average of 37 months (range 1-7 years) of CIIIT in 31 patients with months (range 1-7 years) of CIIIT in 31 patients with Type I diabetes and advanced diabetic renal disease. Type I diabetes and advanced diabetic renal disease. The CrCl at the end of the treatment period was The CrCl at the end of the treatment period was essentially unchanged, suggesting that adding weekly essentially unchanged, suggesting that adding weekly CIIIT to daily intensive insulin therapy could arrest or CIIIT to daily intensive insulin therapy could arrest or markedly delay progression to the end stage renal markedly delay progression to the end stage renal disease, when kidney dialysis or transplantation is disease, when kidney dialysis or transplantation is required.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: Cellular ActivationTherapy: Glycemic AwarenessGlycemic Awareness

A study of 20 diabetic patients over 42 months showed A study of 20 diabetic patients over 42 months showed that hepatic activation (CAT) resulted in a 98 percent that hepatic activation (CAT) resulted in a 98 percent decrease in major hypoglycemic reactions. On treatment decrease in major hypoglycemic reactions. On treatment with CAT, patients with "brittle" diabetes and with CAT, patients with "brittle" diabetes and "hypoglycemia unawareness" gradually regained the "hypoglycemia unawareness" gradually regained the ability to detect falling blood glucose levels. ability to detect falling blood glucose levels. Results: patients went from an average of 3 severe Results: patients went from an average of 3 severe hypoglycemic reactions (requiring outside intervention) hypoglycemic reactions (requiring outside intervention) per month to an average of 0.1 episodes per month. The per month to an average of 0.1 episodes per month. The average frequency of hypoglycemic reactions returned to average frequency of hypoglycemic reactions returned to three per month when CAT was stopped.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: Cellular Activation Therapy: HypertensionHypertension

Chronic intermittent intravenous insulin Chronic intermittent intravenous insulin therapy for patients with high blood therapy for patients with high blood pressure led to a 46% decrease in the pressure led to a 46% decrease in the amount of medication required to control amount of medication required to control the patients' blood pressure in 3 months.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: Cellular Activation Therapy: HypertensionHypertension

Patients with severe diabetes often have increased night Patients with severe diabetes often have increased night time blood pressure, a condition that may worsen the time blood pressure, a condition that may worsen the complications of diabetes. Patients in randomized, complications of diabetes. Patients in randomized, controlled clinical trials comparing two treatments 1) four controlled clinical trials comparing two treatments 1) four subcutaneous insulin injections daily, vs 2) weekly CAT subcutaneous insulin injections daily, vs 2) weekly CAT added to the four subcutaneous injections daily had added to the four subcutaneous injections daily had monthly measures of 24 hour ambulatory blood monthly measures of 24 hour ambulatory blood pressure. pressure. Results: Patients treated with CAT showed a 3% decline Results: Patients treated with CAT showed a 3% decline in the night/day blood pressure ratio. In contrast, those in the night/day blood pressure ratio. In contrast, those on only four subcutaneous injections daily had a 3% on only four subcutaneous injections daily had a 3% increase in night/day blood pressure ratio. In addition, increase in night/day blood pressure ratio. In addition, the group on CAT had an significant improvement in the the group on CAT had an significant improvement in the average HbA1c levels.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: Cellular Activation Therapy: HypotensionHypotension

On CAT therapy, patients reported On CAT therapy, patients reported complete relief from dizziness and fainting complete relief from dizziness and fainting when they stood up and blood pressure no when they stood up and blood pressure no longer dropped precipitously with upright longer dropped precipitously with upright posture.  posture. 

Chronic intermittent intravenous insulin therapy CAT corrects orthostatic hypotension of diabetes. Amer.  J. Med. 1995; 99: 683-4.

Effects on Biochemistry of DiabetesEffects on Biochemistry of Diabetes

Acute insulin effects on plasma homocysteine levels in patients with Acute insulin effects on plasma homocysteine levels in patients with diabetes mellitus. Aoki TT, Grecu EO, Medina M, Goodman M.  J diabetes mellitus. Aoki TT, Grecu EO, Medina M, Goodman M.  J Invest Med (in Press).Invest Med (in Press).IGF-1 and IGFBP-1 blood levels in type 1 diabetes mellitus on IGF-1 and IGFBP-1 blood levels in type 1 diabetes mellitus on intensive intravenous insulin therapy.  Aoki TT, Grecu EO.  J Invest intensive intravenous insulin therapy.  Aoki TT, Grecu EO.  J Invest Med, 1999; 47(2) 78 A.(abstract).Med, 1999; 47(2) 78 A.(abstract).Restoration of glucose homeostasis in insulin-dependent diabetic Restoration of glucose homeostasis in insulin-dependent diabetic subjects. An inducible process. Foss MC, Vlachokosta FV, subjects. An inducible process. Foss MC, Vlachokosta FV, Cunningham LN, Aoki TT.  Diabetes 1982; 31: 46-52.Cunningham LN, Aoki TT.  Diabetes 1982; 31: 46-52.Role of muscle in CO2 production after oral glucose administration Role of muscle in CO2 production after oral glucose administration in man. Meistas MT, Vlachokosta FV, Gleason RE, Arcangeli M, in man. Meistas MT, Vlachokosta FV, Gleason RE, Arcangeli M, Aoki TT.  Diabetes 1985; 34: 960-63. Aoki TT.  Diabetes 1985; 34: 960-63. Evidence for restoration of hepatic glucose processing in type I Evidence for restoration of hepatic glucose processing in type I diabetes mellitus.  Aoki TT, Vlachokosta FV, Foss MC, Meistas MI.  diabetes mellitus.  Aoki TT, Vlachokosta FV, Foss MC, Meistas MI.  Journal of Clinical Investigation 1983; 71:837-839. 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.

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.

From young to pregnant, to old, Cellular Activation Therapy works uniformly to normalize metabolism, and provides constant benefits.

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.

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.

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.

Cellular Activation Therapy Treatment Results:

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.

.

Hypoglycemia Unawareness: Many diabetic people cannot “feel” the onset of a low blood sugar reaction (hypoglycemia).

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.

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.

Wound Healing, and the role of insulin.

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 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)

HYPERTENSION(Is hypertension, a metabolic disease? Just another form of diabetes?)

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.

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.

We Can Stop the Progression of Blindness

Diabetic Retinopathy is the leading cause of non-injury blindness.

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.

Heart Metabolism, not only diabetic but other types of cardiac dysfunction

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.

Metabolic Syndrome Studies Suggest that Non-diabetic Dysfunction Responds to CAT

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.

Nerve Damage (Neuropathy)an extremely common complication.

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.

Cellular Activation Therapy Improves Nerve Conduction Velocities (Neuropathy)

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.

Basic Quality of Life, Peace of Mind, and energy levels, as well as the ability to sleep.

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 DeviceHome Medical DeviceCurrent Bionica Device is extremely accurate Current Bionica Device is extremely accurate and has a unique safety record.and has a unique safety record.

It is also “ambulatory” and therefore is FDA It is also “ambulatory” and therefore is FDA cleared for home use. cleared for home use.

Only patients who have been treated for 6 Only patients who have been treated for 6 months will be sufficiently stabilized where their months will be sufficiently stabilized where their treatment is routine enough for them to be treatment is routine enough for them to be trained, (along with a friend) to treat at home trained, (along with a friend) to treat at home and return for verification every one to three and return for verification every one to three months.months.

Facilities and ReimbursementFacilities and Reimbursement

A clinic can be started in almost any type of facility, a A clinic can be started in almost any type of facility, a doctor’s office, a shopping mall or even just a large doctor’s office, a shopping mall or even just a large room. room. Only restrooms and a sink are required.Only restrooms and a sink are required.The Doctor prescribes the treatment, and only a trained The Doctor prescribes the treatment, and only a trained Med Tech is needed.Med Tech is needed.Billings under Medicare codes in the USA equate to Billings under Medicare codes in the USA equate to $950 to $1,200 per treatment day, insurance companies $950 to $1,200 per treatment day, insurance companies may be billed more than the Medicare (CMS) codes. may be billed more than the Medicare (CMS) codes. New law provides an incentive to employers who engage New law provides an incentive to employers who engage in cost limiting practices. in cost limiting practices. Patients will pay for 6 months and then be graduated to Patients will pay for 6 months and then be graduated to home therapy, thereby making reimbursement attractive home therapy, thereby making reimbursement attractive to insurance providers.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.