Page 1, 2

The Effect of Inhaled Insulin on Anatomical Structures
When one takes a breath of insulin powder/liquid via an inhaler or a spray, only a small part of insulin reaches the depth of the alveoli, is absorbed by blood in the lungs (pulmonary circulation), and is distributed throughout the body by the circulating blood.

Before insulin enters the blood, it comes in contact with and gets deposited in various concentrations on the following:

1. Oral and nasal cavities: many particulates get attached to the lining of nasal and oral cavity (vestibule of the mouth).

2. Tongue: villi on the tongue captures insulin as one inhales.

3. Tonsils: particles can enter the crevices and crypts of the tonsils, which are attached to the lining of the tonsil cells.

4. The epiglottis is constantly exposed to insulin particles during inhalation and exhalation.

5. Larynx and vocal cords: the space between the vocal cards is narrow and creates a bottleneck for air passage that all inhaled and exhaled insulin particles have to pass through. Thus, the lining of the vocal cords gets the largest deposits of any structure.

6. Pharynx: some insulin particles can stick to pharyngeal wall as the powder enters the upper airway.

7. Trachea and bronchial air conducting tubes before alveoli: air passages get most of the inhaled insulin. There is ciliated epithelium lining the surface of the trachea, bronchus, and bronchiole air passages. These particles get picked up by the cilia and taken inside the lining cells -- think sea anemones picking up their food.

8. Esophagus: some insulin powder is dissolved in the saliva and mucosa in the mouth and ingested. Some insulin will be deposited on the esophageal surface as this insulin-containing saliva is swallowed.

9. Stomach: insulin is dissolved in the secretion of the oral and nasal cavity. As these secretions are swallowed, the insulin coats the esophagus inner surface before reaching the stomach and is inactivated by the acidity of the stomach.

10. As one exhales the air though the nose, insulin-containing exhaled insulin enters nasal passages, olfactory mucosa, and nasal air sinuses, all of which pick up insulin particulates.

You can see by this analysis that just to get enough insulin into blood through the deeper depths (alveoli) of lungs or mucous membrane of the mouth and nose, these insulin treatments have to pass through many anatomical and histological cell structures. In the process, these structures are coated with large doses of unneeded insulin, which can lead to cell division and cancers. More or less the same fate also results when the nasal or oral insulin sprays are used.

Ultimate Long-Term Effects of Using Inhalation and Oral And Nasal Spray Insulin Methods
Without going into great detail, let us describe the cells in the above exposed anatomical structures that are constantly exposed to the following onslaughts:

1. Infection, including viruses from air and through personal contact

2. Chronic irritation from working in dirty, dusty, smoky environment

3. Tobacco smoking, snuff use, and tobacco chewing

4. Mechanical and chemical irritation by heat and cold, chemicals, noxious fumes, etc.

5. Exposure to chemicals, including carcinogenic hydrocarbons in the workplace, chemicals due to tobacco use, and breathing dry or humid air daily

6. Trauma to the oral cavity by tooth damage and to the oral cavity due to passage of hot and cold foods; effects on the esophagus and stomach of the passage of acidic and alkaline food and drinks

Due to these exposures, the structures affected by inhaled and nasal and oral sprayed insulin can undergo changes such as the following:

1. Metaplasia change is a situation where cells have changed from their original mature differentiated type into another mature differentiated cell type as an adaptive response.

2. Dysplasia changes: dysplasia is a combination of two Greek words: dys-, which means difficult or disordered; and plassein, to form (from "bad form," in Greek). In other words, dysplasia is the abnormal or disordered organization of cells in the tissues. This abnormality in the appearance of cells is indicative of an early step towards transformation into a tumor (cancer) development – a precancerous change. More dysplasia develops in the body with advancing age which can turn to cancer in above described anatomical sites. Leukoplakia (white patches) of the mouth (oral cavity) is a good example. All these abnormal cells have more insulin receptors on their walls to support their division and rapid growth.

3. Heteroplasia is the abnormal cell growth of cytologic and histologic elements. Insulin can enhance the growth of normal tissue, ultimately leading to pathological disease conditions such as thickening of the blood vessels; and to cardiovascular diseases; the tracheo-bronchial tree causing obstructive restriction to oxygen flow; and to the formation of benign and malignant tumors. That is why high levels of blood insulin in type 2 diabetes contribute to the development of cardiovascular diseases.

The dysplasic cells are precancerous, and we should worry when we use inhalation and nasal and oral spray insulin (as well as oral and rectal insulin delivery systems, which we will discuss later) for diabetes. Some of these cells already may be undergoing microscopic cancerous changes, especially in those who are chronic smokers, nasal snuff users, and tobacco chewers. The deposition of insulin on these dysplastic abnormal precancerous and cancerous cells will stimulate multiplication, resulting in full-blown cancers and their spread.

End Result of Long-Term Use of Inhalation and Nasal and Oral Spray Insulin

1. An initial and transient irritation causing cough, sneezing, shortness of breath, sore throat, and dry mouth

2. After inhalation and nasal and oral spray insulin use, many of the insulin particles are deposited on the oral-pharyngeal-laryngeal-tracheo-bronchial tree, mouth, and nose lining. This high concentration of insulin is picked up by the insulin receptors acting as tumor promoter. This will increase the incidence of tumors of the oral cavity, tongue, larynx, pharynx, trachea, bronchial tree, tonsils, nasal mucosa, nasal air sinuses, and all the structures where the insulin particulates are deposited.

3. Increased incidences of lung cancer, oral and tongue cancers, pharyngeal cancers, nose cancers (especially among those who smoke and are exposed to irritants, such as miners, granite workers, workers at petrochemical factories, and other dusty occupations). Existing cancers of the lungs and mouth and nasal cavities grow rapidly and spread farther. Inhalation and nasal and oral spray insulin acts like a "miracle grow plant growth food" for growing cancer cells, making it more deadly in the nose, mouth, respiratory tract, and lungs.

4. Increased incidence of cancer at the lower end of the esophagus due to their exposure to gastroesophageal reflex disorder (GERD) and Barrette's disease by swallowed insulin dissolved in saliva

5. More nasal polyps and infection of the nasal sinuses and conversion of polyps to cancers due to stimulation by insulin growth factors

6. In smokers, excess of insulin enters into bloodstream, resulting in hypoglycemia. Inhalation and nasal and oral spray insulin can increase the transport of insulin resulting in hypoglycemic effects.¹⁶

7. A compromise lung, air passages, oral and nasal cavity functions is a real possibility.

8. Insulin, a growth promoting protein, can increase the amount of lung tissue and tracheo bronchial passages, due to the increase in smooth muscle cells in air passages, increase in number of fibroblasts, many types of white blood cells in the lungs (including phagocytes, mast cells becoming larger). Overgrowth of tissues in the respiratory tracts can narrow these resulting in the following: 1. High resistance to the passage of air in the respiratory tract, making inhalation insulin unsuitable for patients with obstructive lung diseases including asthma; 2. Modifications of the lung alveoli lining (where gas exchange takes place), thus affecting the gas exchanges (absorption of oxygen and elimination of carbon dioxide) through alveoli —the primary function of lungs.

9. There are high levels of inhaled insulin inside the peripheral lungs and oral and nasal mucosa where insulin particles are deposited. Blood vessels (smooth muscle cells) and other cells (fibroblasts) come directly in contact with the insulin, similar to insulin in the blood. It is possible that insulin growth promoting effect may result in pulmonary (nasal or oral) blood vessel thickening and other cellular elements surrounding these blood vessels, resulting in pulmonary hypertension, and ASVD.¹⁷

10. Inhalation, nasal and oral spray insulin may have longer-lasting respiratory, (oral and nasal cavity) changes in people with pre-existing respiratory diseases.¹⁸ Singers may develop more vocal card nodules and laryngeal tumors.

11. May aggravate asthma, pulmonary fibrosis, sarcoidosis, tuberculosis, chronic pulmonary afflictions, sinusitis, chronic infection of oral and nasal cavities, and exacerbation of existing chronic lung and oral and nasal cavity diseases.

12. Increased incidence of infections where the insulin particles come in contact with pathological exposed surfaces.

13. Due to rapid absorption of insulin through the lungs and nasal and oral linings, some patients may develop hypoglycemia when they can't find help with life-threatening complication.¹⁹

14. The next concern we have is the uptake of aerolised insulin by the olfactory mucosa in the nose. Our studies from Emory University School of Medicine have shown the pia-arachnoid membranes of the brain extend all the way to roof of the nose, extending to the base of the olfactory mucosa in the nose.²⁰ That is why any inhaled infecting microbes (viruses and bacteria-meningococcus) from the nasal olfactory mucosa can reach the central nervous system (CNS)and distributed to cerebrospinal fluid (CSF) with ease due to the effect of inhaled and oral or nasal spray insulin on the nasal mucosa. What about the easy and rapid transfer of infection (meningococcal and viral) from olfactory mucosa to the brain in tee age school-going children who use inhalation and nasal and oral spray insulin?^20,24

15. Another outcome of inhalation and oral and nasal spray insulin is increases in the level of insulin antibodies from baseline levels of 6% to 35%. On the other hand, there is hardly any change in the patients with subcutaneous insulin therapy.²¹ The adverse effects include retarding the action of soluble insulin in the blood and its removal as immune complex by the immune (reticulo-endothelial) system, making less insulin available to lower blood sugar at cellular level.

16. The studies show that the patients with diabetes and asthma have to inhale more insulin to achieve good metabolic control of blood sugar.²² This raises the possibility of more insulin deposits before the insulin reaches the circulatory system, resulting in more adverse effects with long-term use, such as lung cancers.

These and other unknown adverse effects of inhalation and oral and nasal insulin spray may not appear for months. However, continued use will certainly result in the development of other diseases, since, in these forms, the insulin comes in direct contact with the above-mentioned structures on its way to deeper blood vessels and the lungs. We strongly recommend this method not be used in smokers, in patients with chronic oral-pharyngeal-esophageal-lung-nasal cavity diseases, or in anyone with a predisposition to dysplasia or other conditions in which abnormal cells can turn into tumors (e.g., leukoplakia of oral cavity), both benign and malignant. No one knows the long-term effects of using inhalation or nasal and oral insulin spray.

For convenience's sake, patients with type 1 diabetes or insulin-dependent type 2 diabetes mellitus who have to take insulin shots could benefit from the occasional use of inhalation and nasal and oral spray insulin therapy. Unfortunately, these insulin delivery systems are not a complete replacement for injectable insulin, and I don't believe they ever will be; they should only be used as a supplement for mealtime insulin injections. Nighttime injections of insulin are needed to keep diabetes under control. Fortunately, non-insulin-dependent diabetics (NIDDM) who can control their blood sugar levels through weight reduction and oral medications will not need inhalable or spray insulin or injectable insulin therapy unless the oral anti-diabetic medications become less effective or altogether ineffective.

Inhalation and nasal and oral spray insulin forms of diabetic therapy are expensive. So, when their metabolic effect is compared to that of cheaper methods that offer fewer adverse health ill effects (such as subcutaneous insulin therapy), why would a health care provider pay for these forms of insulin therapy? Inhalation and nasal and oral insulin spray therapies may be suitable in some situations because they're quick and easy; they may benefit those who travel frequently, those involved in sports, those who prefer another method just before meal, and those juvenile diabetics who need help in taking insulin injections. However, an endless list of drugs can interact with these insulin forms, and these therapies also come with many contraindications that a patient would need to consider before choosing inhalation or spray insulin.

What to Do if a Person Has Diabetes?
Type 1 diabetics: continue subcutaneous insulin injections; control blood sugar levels by diet and exercise in addition to injections. Type 2 diabetics: control obesity; restrict excessive caloric intake and refined carbohydrates such as sugars; exercise to burn fat and carbohydrates. Do consider taking proven over-the-counter, anti-diabetic, sugar-reducing supplements, especially the following:

· Cinnamon (acts as an insulin substitute in type 2 diabetes and triples the insulin efficiency)

· Zinc (enhances insulin production and activity of many enzymes)

· Vitamin D³ (protects from the immune system attack of insulin-producing cells)

· Alpha lipoic acid (an antioxidant) protects the insulin-producing cells.

· Chromium and vanadium (helps insulin transport sugar to the cells by binding the insulin to cell membrane)

· Banaba leaf extract (hypoglycemic activity), bilberry, goat's rue, garlic, mulberry leaves, olive leaves, and ginseng

· Gymnema sylvestre (Indian herb promote insulin secretion and hypoglycemic)

· Momordica also known as bitter gourd (Hypoglycemic compounds in this vegetable stimulate the glucose receptor protein GLUT-4 to move from the cell interior to the cell surface, thus promoting more effective glucose absorption and metabolism. Diabetes Care. 2003; 26[4]: 1277-1294).

· Fenugreek (promotes insulin secretion, lower blood glucose with reduction of insulin levels, lowers total cholesterol and triglycerides, and increases HDL– the good cholesterol), fish oil, CoQ10, Omega 3.

· Consider taking testosterone if blood hormone levels are low. According to the latest studies, this hormone can lower the high blood sugar and ameliorate early diabetic condition.²³

· Use supplements of vitamin B6 (50 mg a day), biotin, vitamins B, E, and C, magnesium, potassium, essential fatty acids, and flaxseed oil; artichokes as part of the diet, a mixture of Chinese herbs, digestive enzymes to aid digestion, amino acid to facilitate manufacture of insulin.

· Intravenous chelation therapy using EDTA to clean the blood is also indicated.

There are other alternative therapies indicated, such as acupuncture and unproven herbs. If these measures fail to control blood sugar, resort to physician-prescribed anti-diabetic oral medications. If all these measures fail to control blood sugar, add injectable insulin to the regimen.

Future of Antidiabetic Therapies
In spite of breakthrough claims in the news media, insulin injection still is the main therapy for insulin-dependent diabetics. Inhalation insulin has been withdrawn from the market due to increased incidence of lung cancer by its use as reported by us and confirmed by Pfizer.¹⁷ Nasal and oral insulin sprays have similar effects to inhaled insulin and should not be FDA-approved. Transdermal patches using absorption enhancers, ultrasound, iontophoresis, and various transdermal devices used to deliver insulin are cumbersome, unreliable, and not practical. Neutralizing the auto antibodies before they attack the insulin production of beta cells in type 1 diabetes and implantation insulin production of stem cells are still experimental and do hold promise. Important advancement can be made if we develop bioactive therapeutic agents that would stimulate the multiplication and the differentiation of new insulin-producing islets from preexisting pancreatic progenitor cells in islets and pancreatic ducts. Development of altered insulin protein that works even with the insulin resistance needs to be considered. Attempts are being made to develop long-acting subcutaneous injections of insulin, and other antidiabetic therapeutics agents are also on the horizon. Nothing safe yet exists to replace insulin shots. My advice to type 2 diabetics, "Heed the weight and cure the disease," still holds good.

At present, we have two patents pending for the painless delivery of insulin by subcutaneous injections and also a new locally applied transmucosal insulin delivery system, using existing insulin formulations that are safe and have been in use for decades. We hope to bring them to the market so that they will make insulin-dependent diabetics more compliant in the testing blood sugar and in using insulin – without the fear of painful shots.

Part II is also online.

T.R.Shantha, MD, PhD, F.A.C.A
Jessica G. Shantha, Medical Student,
115 Bayberry Hills
McDonough, Georgia 30253
Phone/Fax: 770-507-6564, Cell: 678-640-7705
shantha35@aol.com

Dr. Shantha has published more than 125 research papers in distinguished journals such as Nature, Science, New England Journal of Medicine, Journal of Cell Biology, and others. He is the author of six books and the holder of seven patents. In 2005, Dr. T. R. Shantha received the distinguished physician award from the 42,000-member physician organization Association of Physicians from India (AAPI), and he was nominated for the Nobel Prize in physiology and medicine in 2007. Dr. Shantha is also the discoverer of the drug Terbutaline, which is used all over the world for treating priapism. A pioneer in alternative medicine, he has designed many innovative therapies, utilizing both traditional and alternative approaches, for the treatment of cancers and many other incurable diseases. Dr. Shantha has spent 53 years in medical research and in practice, is triple boarded, and is considered by many to be an expert on insulin potential therapy, hyperbaric therapy, and the treatment of both hyperthermia and pain.

Jessica G. Shantha is a medical student at the Morehouse School of Medicine.

Notes

1. Diabetes — Definition: Diabetes is a life-long disease marked by high levels of sugar in the blood. Available at: http://www.nlm.nih.gov/medlineplus/ency/article/001214.htm. Accessed September 26, 2008.

2. Pirisi A. The diabetes epidemic. LE Magazine. December 2000; MacWilliam L. Diabetes: Understanding and preventing the next health care epidemic. LE Magazine. June 2004; Scali B. High blood sugar; Integrative strategies for supporting healthy metabolism. LE Magazine. July 2005.

3. Dixon JB, O'Brien PE, Playfair J, et al. Adjustable gastric banding and conventional therapy for type 2 diabetes: a randomized controlled trial. JAMA. 2008;299(3):316-323.
McGarry JD. What if Minkowski had been ageusic? An alternative angle on diabetes. Science. 1992;258(5083):766-770.

4. Unger RH. Minireview: Weapons of lean body mass destruction: the role of ectopic lipids in the metabolic syndrome. Endocrinology. 2003;144(12):5159-5165.
Unger RH. Reinventing type 2 diabetes: pathogenesis, treatment, and prevention. JAMA. 2008;299(10):1185-1187.

5. Lee Y, Hirose H, Ohneda M, Johnson JH, McGarry JD, Unger RH. Beta-cell lipotoxicity in the pathogenesis of non–insulin-dependent diabetes mellitus of obese rats: Impairment in adipocyte-beta-cell relationships. Proc Natl Acad Sci U S A. 1994;91(23):10878-10882.

6. Navas-Acien A, et al. Exposure and prevalence of type 2 diabetes in US adults. JAMA. August, 20, 2008;300; 814-822.

7. Guyton AC. Human Physiology and Mechanisms of Disease. 4th edition. Philadelphia, PA: W.B. Saunders Company; 1987: 595-604.

8. Li Y, Chang Q, Rubin BP, Fletcher CD, Morgan TW, Mentzer SJ, Sugarbaker DJ, Fletcher JA, Xiao S. Insulin receptor activation in solitary fibrous tumors. J Pathol. 2007 Apr;211(5):550-4.

9. Ryan CJ, Haqq CM, Simko J, Nonaka DF, Chan JM, Weinberg V, Small EJ, Goldfine ID. Expression of insulin-like growth factor-1 receptor in local and metastatic prostate cancer. Urol Oncol. 2007 Mar-Apr;25(2):134-40.

10. Mallikarjuna K, Pushparaj V, Biswas J, Krishnakumar S. Expression of insulin-like growth factor receptor (IGF-1R), c-Fos, and c-Jun in uveal melanoma: An immunohistochemical study. Curr Eye Res. 2006 Oct;31(10):875-83.

11. Dearth RK, Cui X, Kim HJ, Kuiatse I, Lawrence NA, Zhang X, Divisova J, Britton OL, Mohsin S, Allred DC, Hadsell DL, Lee AV. Mammary tumorigenesis and metastasis caused by overexpression of insulin receptor substrate 1 (IRS-1) or IRS-2. Mol Cell Biol. 2006 Dec;26(24):9302-14. Epub 2006 Oct 9.

12. Shen MR, Hsu YM, Hsu KF, Chen YF, Tang MJ, Chou CY. Insulin-like growth factor 1 is a potent stimulator of cervical cancer cell invasiveness and proliferation that is modulated by alphavbeta3 integrin signaling. Carcinogenesis. 2006 May;27(5):962-71. Epub 2006 Jan 7.

13. Belfiore A. The role of insulin receptor isoforms and hybrid insulin/IGF-I receptors in human cancer. Curr Pharm Des. 2007;13(7):671-86.

14. Heinemann L, Heise T. Current status of the development of inhaled insulin. Br J Diabetes Vasc Dis. 2004; 4(5):295-301.

15. Heise T, Rave K, Bott S, et al. Time-action profile of an inhaled insulin preparation in comparison to insulin lispro and regular insulin. Diabetes. 2000;49:A10.

16. Himmelmann A, Jendle J, Mellen A, Petersen AH, Dahl UL, Wollmer P. The impact of smoking on inhaled insulin. Diabetes Care. 2003;26:677-82.

17. Aye M, Sheedy W, Harrison R, Thompson JS, Morice AH, Masson EA. Pulmonary vasodilation in the rat by insulin in vitro could indicate potential hazard for inhaled insulin. Diabetologia. 2003;46:1199-202.

18. Available at: www.Insulin news.com-Inhalation insulin therapy.

19. Heise T, Rave K, Bott S, et al. Time-action profile of an inhaled insulin preparation in comparison to insulin lispro and regular insulin. Diabetes. 2000;49:A10.

20. Shantha TR, Bourne GH. The "Perineural Epithelium": A new concept. Its role in the integrity of the peripheral nervous system. In: GH Bourne, ed. Structure and Function of Nervous Tissues. Volume I. New York: Academic Press; 1969: 379-459.
Shantha TR, Nakajima Y. Histological and histochemical studies on the rhesus monkey (Macaca mulatta) olfactory mucosa. Z. Zellforsch. 1970;103:291-319.

21. Hermansen K, Ronnemaa T, Petersen AH, Bellaire S, Adamson U. Intensive therapy with inhaled insulin via the AERx insulin diabetes management system: A 12-week proof-of-concept trial in patients with type 2 diabetes. Diabetes Care. 2004;27:162-7.

22. Henry RR, Mudaliar SR, Howland WC, et al. Inhaled insulin using the AERx Insulin Diabetes Management System in healthy and asthmatic subjects. Diabetes Care. 2003;26:764-9.

23. Lichten EM. Testosterone's overlooked role in the treatment of diabetes in men. Life Extension. July 2007: 23-29.

24. Shantha. TR. Unknown health risks of inhaled insulin. Life Extension. September 2007; 79-82.

Postscript:
Word of Caution to Pharmaceutical Industry and FDA on the Development and Approval of Nasal and Oral Insulin Sprays and Oral and Rectal Insulin

Dr. T. R. Shantha has sent detailed letters and published material to various drug companies involved in developing inhaled insulin and to FDA about the dangers of inhaled insulin and possible development of cancers between the years 2005-2007.²³ In October 2007, the Pfizer pharmaceutical company withdrew the only FDA-approved inhaled insulin (Exubera) from the market, taking a 2.5 billion dollar loss. Some of the other pharmaceutical companies stopped developing inhaled insulin also. Supporting Dr. T. R. Shantha's research findings, on April 9, 2008, Pfizer announced findings of a connection between the development of six lung cancer cases and the short-term use of inhalation insulin.²⁵

This is great victory for Dr. T. R. Shantha and his research findings (Shantha TR, Unknown health risks of inhaled insulin, Life Extension, September 2007: 79-82).²³ Can you imagine thousands of diabetics developing lung, gastrointestinal, oral and nasal cancers from the use of inhaled insulin? Dr. T. R. Shantha's timely report on the dangers of inhaled insulin saved thousands of diabetics from developing lung cancer and billions of dollars in their health care and litigation costs. We thank him for his research genius and for preventing this evolving health disaster and saving many hundreds from developing and suffering from lung, bronchial, oral, laryngeal, pharyngeal, and nasal cancers. The FDA should consider seriously his warning in this two-part series on insulin and take all precautions before they approve alternative methods to replace the subcutaneous insulin delivery system. Dr. T. R. Shantha firmly believes that nasal- and oral-sprayed insulin, oral insulin, or rectal insulin suppositories have similar effects to inhaled insulin. If these products are approved, there will be meteoric rise in oral, tongue, gum, cheek, tonsilar, pharyngeal, laryngeal, nasal cavity, gastrointestinal tumors (cancers), and infections, and countless other health hazards. FDA approval should be considered only after all the concerns are addressed. These insulin deliver systems should be approved for use under special circumstances only; not as replacements for subcutaneous insulin daily injections.

Page 1, 2