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Diabetes is a disease in which the body does not produce or properly use insulin. According to the American Diabetes Association, 20.8 million people in the United States, or seven percent of the population, have diabetes. About1.5 million new cases were diagnosed in people aged 20 years or older in 2005. The World Health Organization (WHO) recently compiled data that estimates that, worldwide,180 million people have diabetes, and that number is expected to double by 2030. Diabetes is no longer mainly a disease of the aged; increasingly, more young people are diagnosed with diabetes due to rampant obesity. Diabetes is the next great lifestyle disease pandemic. One out of every ten health care dollars spent in the United States goes to treat diabetic patients. It is estimated that, in 2002, diabetes care cost a total of $132 billion, of which $92 billion was spent on direct medical costs and $40 billion on indirect costs, such as disability payments, loss of work income, and premature mortality. Health care costs for a person with diabetes in the US are three times more than the health care costs of a healthy non-diabetic.

Since 1922 and its discovery by Canadian doctors Banting and Best, the use of subcutaneous insulin injections has been the most important treatment for diabetes. However, its use is often associated with lack of compliance, due to the pain associated with multiple daily injections. Hence, there is a big demand for an insulin delivery system that can be administered without painful shots. Development of such an insulin delivery system promises a multibillion dollar market and greater patient compliance. Below, we look at diabetes in general, then discuss the dangers of new methods of self-administering insulin: inhalation insulin, nasal and oral spray insulin, oral insulin, and insulin suppositories.

Definition and Causes
Diabetes is a life-long, life-threatening chronic disease marked by high levels of sugar in the blood. The pancreatic endocrine gland, which produces insulin, and cells that use insulin for the uptake of glucose from blood are at the root of this life-threatening pandemic. All racial groups are affected. People with diabetes have high blood sugar because their pancreas does not make enough insulin or because their muscle, fat, liver, and other body cells do not respond to blood insulin (insulin resistance) as do those of healthy non-diabetics. Diabetes, then, is caused by too little or no insulin produced in the pancreas, cell resistance to the biologic effects of insulin, or both.^1,2 To understand diabetes, it is important to understand the normal process of food metabolism. Several things happen when food is digested:

1. After food is digested, sugar (glucose) enters the bloodstream from the intestines. Glucose is a source of fuel for the body, producing energy in cells for all bodily activities.
2. The pancreas makes insulin in its endocrine gland (islets of Langerhans) in response to a blood sugar rise after meal. The role of insulin is to move glucose from the bloodstream into muscle, fat, and liver cells, where it can be used as fuel for immediate energy needs and/or stored as glycogen (mainly in the liver) to be released for energy between meals as needed when the blood sugar falls.

Types of Diabetes
· Type 1 diabetes results from selective beta cell destruction in the islets, which results in severe or absolute natural insulin production deficiency. Type 1 diabetes is known as juvenile diabetes, afflicts children, comprises less than ten percent of total diabetic cases, and is a lifelong condition. It is an autoimmune disease in which the immune system attacks and kills insulin-producing cells. Repeated daily injections of insulin are needed to sustain life and prevent life-threatening raise of blood sugar. At any given time, the entire human pancreas contains up to 8 mg of insulin, representing approximately 200 biologic units not found in the pancreas of type 1 diabetics.

· Type 2 diabetes is more common than type 1, comprising more than 90% of cases of diabetes, and usually occurs in adults. Increasing obesity from overeating and failure to exercise are important predisposing risk factors. Conventionally, type 2 diabetes is viewed as high blood sugar (hyperglycemia) as a primary disease caused by an etiologically uncertain combination of obesity-associated insulin resistance with gradual reduction in insulin production due to the gradual loss of beta cells that produce insulin. The latest research points to the novel "lipocentric" theory, which states that high blood sugar (hyperglycemia) associated with type 2 diabetics, insulin resistance, and beta cell loss is secondary to the metabolic trauma caused by outside (ectopic) lipid (fat) deposition or fat toxicity (lipotoxicity) due to excess caloric intake.^3-5 Fat is at the center of the cause for this condition (i.e., lipocentric). It is interesting to note that the studies by Dixon et al. and Unger provide support for the "lipocentric" hypothesis by demonstrating that the weight loss that follows gastric banding in morbidly obese is accompanied by remission of diabetes in 73% of obese patients with type 2 diabetes. This finding supports 45 years of biochemical, physiological, and clinical research pointing to lipid overload as the underlying cause of this disease.³ A molecular pathway to insulin resistance seems to be due to outside (ectopic) accumulation of unoxidized fatty acids. Surplus lipids arising from overeating are in fact the link between obesity, hyperglycemia, and insulin resistance.⁴ In 1994, Lee et al. demonstrated that outside (ectopic) lipids that accumulate in pancreatic insulin-producing islets parallel with other tissues lipid deposits can cause the subtotal lipotoxic destruction of insulin-producing beta cells that precipitates the hyperglycemia, thereby providing the final evidence for the lipocentric theory of type 2 diabetes.⁵ Other studies point out that the root cause of insulin resistance is a breakdown in inside cell (intercellular) signaling. Insulin is a biochemical key messenger. It signals proteins called GLUT-4 transporters (residing within the cell) to rise up to the cell's membrane (cell wall), where they can grab onto glucose and take it inside the cell. In patients with insulin resistance, the cells don't get the message. They simply can't hear insulin key opening or "knocking" on the door. This results in elevated blood sugar and insulin. There could be other additional factors due to lipotoxicity as described above. Recent studies show high incidence of type 2 diabetes due to drinking water contaminated with inorganic arsenic; the etiology of environmental causes of type 2 diabetes is beginning to unravel.⁶

The liver (as well as intestines and kidneys) which stores the glucose as glycogen, releases it into the blood during fasting (postprandial) as glucose in spite of elevated blood sugar and high or low blood insulin levels. Whatever the causative factor, elevated blood sugar should be investigated and if found as the problem, therapeutic agents to reverse or prevent such metabolic change in liver cells need to be developed. For this we need other therapeutic agents besides those currently on the market that prevent glucose phosphatase action and so prevent the conversion of glycogen to glucose and its subsequent release into the blood. We also need insulin with different molecular make up (change in the two amino acid chains and its disulfide bond) that alters this metabolic change, breaks insulin resistance, and stops the leaking of the glucose form the liver cells at the same time. Such therapeutic agent (s) when effectively developed as an oral treatment would be received as "God's Gift" to diabetics.

· Gestational diabetes is high blood glucose that develops at any time during pregnancy in about four percent of all US pregnancies due to insulin resistance caused by placenta and placental hormones. This condition reverses after birth of the baby.

· Miscellaneous group: diabetes stemming from genetic defect-related metabolic syndromes, surgery, drugs, malnutrition, infections, and other illnesses.

Diabetes: Symptoms and Diagnostic Tests
Patients develop symptoms over a short (in type 1) or long period of time (in type 2). These symptoms include increased thirst, urination, weight loss, increased appetite, fatigue, blurred vision, dry skin, numbness and tingling in limbs, slow-healing wounds and more infections than usual, disturbed sleeping, impotence in men, etc.

A urine test alone cannot diagnose diabetes, although it can show levels of sugar and ketone bodies. The following blood glucose tests are used to diagnose diabetes:

· Fasting blood glucose level -- Diabetes is diagnosed if higher than 126 mg/dL on two occasions. Levels between 100 and 126 mg/dl are considered pre-diabetic and considered as risk factors for type 2 diabetes.

· Random (non-fasting) blood glucose level -- Diabetes is suspected if higher than 200 mg/dL and accompanied by the some of the above symptoms.

· Oral glucose tolerance test -- Diabetes is diagnosed if glucose level is higher than 200 mg/dL after two hours (This test is used more for type 2 diabetes.)

· Blood test: The HbA1c is a measure of average blood glucose during the previous two to three months. It is a very helpful way to determine how well treatment is working. Ask your doctor to check it every three months.

· The Ketones test is done using a urine sample. Ketones are produced by the breakdown of fat and muscle, and they are harmful at high levels, producing a condition called ketoacidosis.

Consequence of Diabetes
The public perceives diabetes as a simple raise in blood sugar that can be cured, curtailed, or controlled by popping a pill or getting a shot. They fail to realize the lifelong list of debilitating diseases and deadly complications that afflict diabetics unless proper levels of blood sugar are maintained with antidiabetic therapy and proper diet, weight control, and exercise. The following is partial list of such health problems:

1. Heart disease up to four times higher among diabetics, resulting in atherosclerosis and coronary artery heart disease

2. Stroke is two to four times higher in diabetics.

3. Diabetic retinopathy, leading to blindness in uncontrolled diabetes

4. Peripheral neuropathy, leading to pain or a loss of feeling in the limbs, foot ulcers and foot infections, and the possibility of an amputation

5. Nerves that control a single muscle or group of muscles can lose their function resulting in eye movement problems with double vision or drooping of the cheek on one side of the face due to Bell's palsy.

6. Kidney diseases needing dialysis (nephropathy)

7. Hypertension and increased cholesterol (hyperlipidemia),which can lead to ASVD, myocardial infarction (MI), stroke, blood clots.

8. Gangrene and chronic infection of limbs with non-healing wounds needing surgical intervention such as amputations

9. Congenital birth defects and high incidence of still births among diabetic pregnant women

10. Infection of the body, especially respiratory system (influenza and pneumonia), due to less resistance to infection.

11. Stomach and bowel affliction can result in nausea, constipation, or diarrhea; a stomach that is slow to empty it contents in diabetics is called gastroparesis.

12. Impotence is common due to nerve and blood vessel damage from diabetes.

13. The most important painful complication of diabetes is increased incidence of cancers of every kind.

14. Premature Death: According to National Institute of Diabetes and Digestive and Kidney Diseases, diabetes is a seventh-leading cause of death, causing 193,140 deaths in 1996. Think about this: in middle-aged non-diabetics, the early death rate is 50% less compared than that in similarly aged diabetics.

15. Every year, 10,000-30,000 people with diabetes die of complications from flu or pneumonia. They are roughly three times more likely to die of these complications than people without diabetes.

Complications of diabetes are attributed to excessive sugar in the blood and tissues binding to proteins called excessive glycosylation, especially in blood vessels, peripheral nerves, brain, eyes, etc., as well as excessive build-up of sorbitol inside cells. Glycosylation is a biological and biochemical chronic process through which sugar molecule binds irreversibly to a protein. Because diabetics have higher levels of glucose in their blood for longer durations, compared to non-diabetics, this results in a higher degree of glycosylation – a abnormal protein complex structure laid all over body tissues. Excessive glycosylation leads to multiple cellular dysfunctions including inactivation of enzymes, inhibition of regulatory molecule binding, decreased susceptibility to proteolysis, abnormalities of nucleic acid function, altered macromolecular recognitions, etc.

Sorbitol is produced as a byproduct of glucose metabolism inside every cell in the body through the action of aldose reductase enzyme. In non-diabetics, sorbitol is converted to fructose and is excreted from the cells. Inside the cells of diabetics, however, when glucose levels become elevated, sorbitol is produced faster than it can be broken down and expelled. Since sorbitol cannot cross the cell membrane or break down to fructose to be expelled, it builds up to a toxic level inside the cells, creating an imbalance that results in loss of electrolytes and other minerals. This accumulated sorbitol draws water into the cell by the simple process of osmosis, leading to the collapse of its architecture and loss of its function, especially in peripheral nerves (neuropathy), blood vessels (ASVD, coronary artery disease), the cells of the retinal blood vessels (diabetic retinopathy), the lens of the eye (cataract), the pancreas (pancreatitis), the kidneys (nephropathy with kidney failure), and the heart (myocardial infarction and other organ diseases). The changes in the genetic material in the cells caused by the rapid division of cells stimulated by high levels of blood and tissue insulin also may ultimately lead to cancers and their spread.

Treatment Outlines
For type 1 diabetes, the only treatment is insulin injections. Pregnancy diabetes is treated with insulin and a change in diet. For type 2 diabetes, the treatment is threefold:

1. Exercise, reduce body weight, eat less calories, control refined sugar intake, and take proven over-the-counter supplements that may cure the condition. Consider drinking arsenic-free water.

2. Take oral medications that increase insulin production (glimepiride, glipizide, glyburide, repaglinide, nateglinide, and sitaglyptin) or reduce resistance to insulin at cellular level and increase sensitivity (metformin, rosiglitazone, and pioglitazone) or medication that reduces sugar absorption from the intestines (acarbose and miglitol). Inhalable insulin does not replace natural insulin production. The alterations in the lifestyle – a balanced diet and good exercise – along with anti-diabetic therapy are the most effective way of controlling this chronic disease. Consider taking one of the alternative over-the-counter supplements listed below.

3. Persons with type 2 diabetes may not require insulin to survive, although about 30% will benefit from insulin therapy to control the blood glucose. It is estimated that up to 20% of individuals in whom type 2 diabetes was the initial diagnosis may in reality have both type 1 and type 2 or type 2, slowly leading to type 1, requiring full insulin replacement. This is said to be due to destruction of insulin-producing cells by high lipids (lipocentric theory).^3-5 A combination of above treatment modalities with addition of insulin injections may be called for. These patients along with the type 1 diabetics are targeted for use of inhaled insulin, oral and nasal insulin sprays, and oral-rectal insulin.

How Insulin Transports Blood Sugar into Cells
The role of insulin is a very complex biological and biochemical one at cellular levels. The liver plays a primary role in removing and storing glucose from the blood after a meal and releasing it for energy needs when the blood sugar level drops between meals. Each cell in the body has a cell membrane around it much like the thin covering on a grape. These cell membranes are the gatekeepers for various substances in and out of cells including sugar. These membranes have various kinds of receptors (locked doors) that open or shut for the entry and exit of these biological and nutritional substances. These doors are unlocked by specific biological keys (such as insulin).

Cells have insulin receptors (IR) and insulin-like growth factor receptors (IGFR-l, II) – locked doors on the cell membrane that can be opened (i.e., activated) by the insulin key. Without these, sugar, proteins, and fats cannot enter the cell through the cell membrane. Once insulin activates the activity on the surface and inside the cell, a small protein (polypeptide-GLUT-4) molecule moves towards the cell membrane, binds to these opened receptor doors, locks onto the cell membranes, binds to the glucose outside the cell membrane, and literally drags the sugar-bound protein through these biologically insulin-activated unlocked doors into the cell to be used for energy production. Insulin activates various biological activities, resulting in a host of biochemical reactions and allowing large amounts of sugars, amino acids, and other nutrients, including electrolytes (needed for cell energy, protein production, and cell division to maintain the healthy body) into the cell. Insulin also helps store sugar in the liver (mainly) and in other cells as glycogen to be released between meals when blood sugar falls and/or to be used as needed by the cells. Sugar's entry into the liver (some in other cells) from the blood reduces the circulating elevated blood sugar after meal. Elevated blood sugar after meal also triggers the release of insulin (from the pancreas to portal circulation), which enters the liver and clears the elevated blood sugar. Insulin increases the rate of glucose transport by ten times or more. That tells us what an important role insulin plays in lowering the blood sugar.

Cancer and Insulin Receptors
Cancer and precancerous cells develop anaerobic (less oxygen) metabolism, as described by Nobel laureate Otto Warburg almost 75 years ago. Due to this metabolic defect, cancer cells only produce 15% of the energy needed for cellular activity and multiplication. To overcome the energy deficit, these cells need more sugar. If they have normal insulin receptors like normal healthy cells, they will be starved to death and will not grow or spread to distant organs. As normal cells change to anaerobic factory (cancer) needing lots of sugar, they develop almost three to ten times more insulin and insulin-like growth factor receptors, allowing three to ten times more sugar into cells to meet this metabolic demand. More insulin receptors mean more insulin binds on the cancer cell surface and more glucose and amino acid enters the cell to meet the metabolic need to multiply and spread.

Cancer cells also need insulin and insulin-like growth factors for protein synthesis, which is needed for growth, multiplication, and spread. Insulin with growth hormone and insulin-like growth factors enhance the uptake of amino acids into cancer cells, increases the translation of messenger RNA (thus forming new proteins), and increases the rate of transcription of DNA in the cell nuclei (thus forming increased quantities of RNA). This is the result of the evolution of normal cells to cancer cells that multiply with uncontrolled ease. In summary, insulin greatly enhances the rate of protein formation – providing sugar for energy needs – and enhances the cell division in cancer cells. That is why cancer cells grow uncontrolled with the help of numerous insulin and insulin-like growth factor receptors activated by insulin. In true sense, high levels of insulin at the cell level are carcinogenic due to the abnormal biological changes they bring in the cell lifecycle.

You can see that the abnormal precancerous cells and cancer cells flourish with an additional supply of insulin directly deposited on insulin receptors with the use of inhalation insulin, nasal and oral insulin sprays, and oral or rectal insulin. It has been shown that even the nanomolar concentration of IGF-I and IGF-II are potent mitogens, meaning that these stimulate cell division and proliferation. Can you think of what could happen to the cells of a vulnerable population, for instance, aged smokers exposed to irritations and toxic chemicals (including tobacco), which already are working to transform normal cells into cancer cells? The threat of tumors (cancers), infections, and other diseases looms with the prolonged, stand-alone use of inhalation insulin, insulin oral or nasal sprays, oral swallowed insulin and rectal suppository treatments.

Diabetes and Cancers
As you know by now, insulin is a double-edged sword: we know that it controls sugar in the blood to prevent diabetes; at the same time, insulin also contributes to many diseases in type 2 diabetics as described above. Here is the problem: as cells become resistant to insulin, type 2 diabetes results. This, in turn, results in more sugar circulating in the blood because there's no sugar uptake within insulin-resistant cells. In response to elevated blood sugar, insulin-producing cells produce more insulin. This insulin starts to circulate in the blood. As described above, abnormal cells and cancer cells have more insulin and IGF receptors. Studies have shown that cancer cells need energy in the form of sugar due to anaerobic metabolism. The circulating high insulin provides energy through glucose metabolism to these cancer and precancerous cells, which helps them to multiply rapidly by enhancing the protein syntheses and providing energy through sugar. That is why diabetics experience higher cancer rates than non-diabetics. Interestingly, insulin-producing cells reduce or stop producing insulin over time in type 2 diabetics,
which again increases blood sugar that needs exogenous insulin to control blood sugar.

Insulin and Cancers
Before you start using insulin through inhalation, oral and nasal spray, oral, or rectal suppository delivery systems, I want to offer the following. If you go online to and www. Pubmed.gov and search for "insulin and cancer," you will find 17,089 citing; if you search "insulin causes cancer," you will find 9079 citing. This indicates the intense research on the relationship of insulin to cancer. It is well-established that type 2 diabetics do develop more cancers than non-diabetics, and insulin plays a major role in multiplication of cancers cells and their spread. All cancer and precancerous cells have up to ten times more IR and IGFR-I than normal cells to which insulin does bind. Even solitary non-cancerous fibrous tumors besides prostate and other types of caners have IGF receptors.^8-12 Several epidemiological studies have shown that insulin resistance states are characterized by high levels of insulin in the blood (hyperinsulinemia) and are associated with an increased risk for a number of tumors, including carcinomas of the breast, prostate, colon, kidney, and other organs. Recent data have elucidated some molecular mechanisms by which insulin is involved in cancer. It is well-known that the insulin receptors are over-expressed in all human cancers.¹³ According to various studies, there is hardly a precancerous or cancer cell in which the insulin receptors are not over-expressed. Why do the cancers need that many insulin receptors? Without the ability to bind to the receptors on the cancer cell wall, insulin has no effect on the transport of glucose for energy production and protein synthesis – i.e., cancer will not grow and spread.

Development of Inhaled Insulin and Nasal and Oral Insulin Spray Therapies for Diabetes
Unprecedented demand for insulin-dependent diabetes mellitus therapy coupled with the unmet need for non-invasive alternatives to subcutaneous insulin injection make diabetes one of the most attractive profitable therapy areas for the pharmaceutical industry to develop inhalation, oral and nasal spray insulin, and oral or rectal pill hormone delivery of insulin-based products. (Exubera was the first such FDA-approved product in the market to deliver the insulin by inhalation insulin. Exubera has now been withdrawn from the market for safety reasons.) Important routes targeted for developing alternative (to subcutaneous injection) insulin delivery systems are the nose, mouth, lungs, skin, and digestive system.

The following are some of the research centers and pharmaceutical companies that are experimenting to provide inhaled insulin, oral and nasal sprays, and oral and rectal insulin pills with diverse delivery systems.

1. Pfizer and Aventis collaborated with Nektar Therapeutics (formerly Inhale Therapeutics), a company that specializes in finding delivery solutions for oral, injectable, and pulmonary drug administration. They marketed the FDA-approved "Exubera inhaler" to deliver insulin content that coats the anatomical structures before it reaches the deeper depths of alveoli; only ten percent of the insulin is absorbed, and the rest is lost.

2. Eli Lilly, along with Alkermes, is developing "AIR Insulin," which is expected to be submitted for approval in 2009; this treatment has been under development since 2001.

3. Mannkind and Technosphere Insulin System are developing a palm-sized inhaler device with a special formulation that allows pH sensitive carrier particles to be carried deep into the lungs and release insulin. This is a powder that will be deposited on the air passages before it reaches the lung alveoli.

4. Novo Nordisk has partnered with Aradigm to produce the only inhaled insulin in clinical trials that uses a liquid formulation. Known as AERx Insulin Diabetes Management System, again it sticks to various anatomical structures before it reaches lung alveoli and has the same adverse effect as inhaled insulin powder.

5. Andaris, in Nottingham, England, acquired in 2003 by Cambridge-based Quadrant developed a 5 micron hollow microcapsule of insulin using a low temperature, spray technique that preserves the insulin structure. This insulin microcapsule can be inhaled directly into the lungs for absorption. Quadrant is now working with Innovata, MicroDose Technologies, and Bristol-Meyers Squibb to develop this Q Dose inhaled insulin product.

6. Biodel, Inc., located in Danbury, Connecticut, is a specialty pharmaceutical company that develops novel formulations of FDA-approved Biodel's proprietary VIAdel™ technology, which allow for a more effective delivery of endocrine therapeutics as well as one with increased efficacy and safety. They are developing patented technology applicable to a wide range of peptides, proteins and other macromolecules, including insulin. Biodel's lead drug candidates VIAject™, a very rapid-acting injectable insulin, and VIAtab™ are said to utilize a rapidly acting oral sub-lingual insulin, and no one knows what else is in the works by this ingenious founder of the company.

7. Generex Biotech Pharma and many other drug companies are working on different ways to deliver insulin. Generex, a biotechnology company, has developed rapid mist oral delivery insulin (Oral-Lyn) that is absorbed by the buccal mucosa and currently approved for use in Ecuador. This company has an agreement to develop the treatment for the US with insulin giant Eli Lilly. Long-term use can result in oral cancers, especially in smokers and tobacco chewers.

8. Companies like Aradigm, Novo Nordisk, Wockhardt, Emisphere, US-based Nobex in collaboration with India-based Biocon, Oramed Pharmaceutical of Israel, Sree Chitra Tirunal Institute of India, and countless others are all working to develop oral and other modes or routes for insulin delivery systems.

9. Many companies are developing or have developed devices for transdermal delivery of insulin without pain, using passive delivery systems with a patch, cream, spray, continuous infusion, micro needle patch, rapid injectors, etc. The skin is a formidable barrier. Active transdermal delivery involves a chemical or mechanical disruption of the skin barrier by an applied force, such as ultrasound or an electrical current, as well as through chemicals. These developments include Dermisonics, which has integrated microelectronics and ultrasonic science into a skin pad called the U-Strip; the Medi-Cap, a transdermal patch that holds the insulin and is applied to the skin; the Ultrasonic Applicator and Dose Controller generates ultrasonic transmissions to dilate the pores and allow large molecule drugs to enter the bloodstream; the Medingo insulin-dispensing patch, called the Solo™, adheres directly to the skin with no tubing or other connections (the Solo™ system includes the patch and a separate remote control unit); Vyteris transdermal drug delivery uses an Iontophoretic delivery technology that delivers drugs comfortably through the skin using low-level electrical energy; and continuous subcutaneous insulin delivery pumps are also available and in use by many type 1 diabetics. Many such devices are in the horizon. Most of these devices are cumbersome to wear and difficult to operate and, hence, are not popular.

Distribution of High Dose of Inhalation Insulin Used to Achieve Blood Levels in the Lungs to Lower Blood Sugar
Inhalation and nasal and oral spray insulin is effective only when the calculated dose is at least three to five times the amount given by injection under the skin. Only little more than ten percent of inhaled or aerolised or swallowed insulin is bio-available and able to reduce blood sugar. These therapy modes do not yield 100% dose-dependent effects in lowering the sugar. Further, insulin has to be tagged to other substances to reach alveolar, mouth and nasal surfaces, be absorbed, and effectively reduce blood sugar in insulin-dependent diabetes.

Let's look at what happens to insulin delivered through inhalation and nasal and oral spray delivery systems:¹⁴

1. Some insulin remains in the original container after inhalation or spray.

2. Some insulin adheres to the inner surfaces of the inhaler and delivery tubing.

3. Larger particles (containing a lot of insulin) are deposited in the mouth, throat, Nose, and tracheo-bronchial tree (breathing tubes).

4. Some insulin particles are exhaled through the nasopharyngeal outlet without being deposited in the alveoli.

5. When insulin passes through the nasal passage in exhaled air, some particles enter the nasal air passages (sinuses) and nasal lining as well as landing on the olfactory mucosa which has direct connection to the brain.¹⁵

6. Some insulin deposited in the alveoli is taken up by macrophages and other lining cells.

7. Finally, the aerolised insulin-containing particles deposited on the deepest part of the lungs (alveolar mucosa), oral, and nasal mucosa are absorbed by the systemic circulation. They enter the heart, then circulate all over the body, binding to insulin receptor, and performing the physiologic function of reducing blood sugar and enhancing the protein synthesis.

8. It is interesting to note only 25% of this insulin reaches the liver (due to 25% of cardiac output reaching liver), whereas 100% of the endogenous natural insulin produced in response to high blood sugar after meal passes through the liver where an estimated 60% of it is used by liver cells and the rest enters the systemic circulation from the liver. Even oral insulin does not reach liver like natural pancreatic insulin. Only 30-40% of orally absorbed insulin reaches the liver.

It is obvious that only a small part of inhaled insulin and nasal and oral insulin spray gets into circulating blood to reduce blood sugar. Because of the reasons detailed above, to achieve the proper levels in blood, inhalation or spray methods are formulated with far more insulin so that they can achieve the concentration needed to lower blood sugar. This makes make these products very expensive to produce. The onset of action with inhaled insulin and nasal and oral insulin spray is more rapid than that found with the use of subcutaneously administered rapid-acting analogue due to the difference between the large absorbing surface of the lung alveoli, oral and nasal mucosa affected by the former as compared to the areas affected by subcutaneous injection.¹⁵

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