INTRODUCTION:

Diabetes mellitus is a group of diseases characterized by high levels of blood glucose resulting from defects in insulin secretion and/or action. Insulin helps metabolize carbohydrates, fats and proteins; store glycogen in the liver; and convert glucose to fat. The number of diabetes cases increases daily approximately 2,200 people are diagnosed with the disorder each day (Albright, 2000). The U.S. Centers for Disease Control and Prevention (CDC) estimates that the number of diabetes cases will double by the year 2020 (CDC, “Health,” 1999). This is due partly to the aging population and partly to a recent increase in the number of child and adolescent cases of diabetes. The two major types of diabetes are type I (insulin is not produced by the pancreas) and type 2 (insulin is produced, but the body cannot use it effectively). Type 1diabetes, often called insulin dependent diabetes mellitus (IDDM), affects 5 to 10 percent of the diagnosed U.S. diabetic population and most frequently develops during childhood or adolescence. Type 2 diabetes affects 90 to 95 percent of U.S. diabetic population and most frequent develops in people over the age of 40.

Two other types of diabetes are known as “gestational” and what is known as “other types.” Gestational diabetes affects women during pregnancy; it develops in 2 to 5 percent of all pregnancies and disappears after pregnancy. “Other types” refers to diabetes resulting from specific genetic syndromes, surgery, certain drugs, malnutrition, infections and other illnesses.

The cause of diabetes is generally unknown, although the major risk factors associated with the disease (NIDDK, 2000) are:

· Having a family history of diabetes

· Being over the age of 40

· Being overweight

· Having low HDL cholesterol

· Having a history of gestational diabetes

· Giving birth to a baby weighing 9 pounds or more

· Being in certain racial and ethnic groups, including African Americans, Hispanics/Latinos, Asian and Pacific Islanders and Native Americans

The elderly represent the largest population group with diabetes. Age impairs the body’s ability to produce insulin, which is why approximately 50 percent of all diabetes cases occur in people older than 55 years of age. Approximately 18.4 percent of the U.S. population (6.3 million people) aged 65 and older has diabetes. It is also suspected that half of the elderly population with diabetes is undiagnosed. Diabetics also represent 18 percent of all nursing home residents; diabetics in nursing homes tend be younger than nondiabetics residents (Morley, 1998). At present, diabetes is an incurable and chronic disease requiring ongoing treatment. Diabetes treatment focuses on stabilizing blood-glucose levels through insulin, diet, exercise and glucose monitoring. The treatment of type 1 diabetes always includes multiple daily insulin injections; however, other forms of insulin delivery are under study and may come to fruition soon. Human insulin (rDNA) was introduced in 1982 and is the most widely form of insulin used today. It is purer and causes fewer side effects than the animal counterpart. A strict diet, exercise and glucose monitoring are necessary components of treatment for all types of diabetes.

Forty percent of people with type 2 diabetes also require insulin injections and/or oral medication(s). The recent introduction of oral agents that control glucose levels has greatly improved and simplified the management and treatment of type 2diabetes. The recently completed United Kingdom Prospective Diabetes Study (UKPDS), a 20-year study of 5,000 people with type 2 diabetes, established the effectiveness of oral agents for that disease (DeFronzo, 1999). The remaining 60 percent of people with type 2 diabetes control their blood glucose levels with diet, exercise and monitoring alone, without medication.

Transplantation of a human pancreas is also a treatment option, although it is mostly used for patients with both diabetes and end-stage renal disease. Data show that a pancreatic transplant is far more successful if a kidney transplant is performed at the same time. Even with duel transplants, 50 percent of recipients remain dependent on insulin after five years following the transplant. There are also far more people who need pancreatic transplants than organs available.

Diabetes is associated with serious complications and can result in premature death. Diabetes is the major cause of heart disease, stroke, end-stage renal disease, adult blindness and lowerlimb amputations (Albright, 2000). Other complications resulting from diabetes include complications with pregnancy, birth defects, diabetic ketoacidosis (accumulation of acids and ketones in body tissues and fluids), , gum disease and death. Patients with diabetes are hospitalized twice as often as patients without diabetes, and their hospitalizations are 30 percent longer (Geiss, 1993).

However, most of these side effects are slowed down and/or prevented through early detection and treatment. A major clinical study conducted from 1983 to 1993 by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) showed that maintaining blood sugar levels in diabetics as close to normal as possible slows the onset and progression of eye disease (76 percent reduced risk), kidney disease (50 percent reduced risk) and nerve disease (60 percent reduced risk) (NIDDK, 1994). The CDC believes that 90 percent of adult blindness associated with diabetes is preventable (Geiss, 1993).

Diabetes is the seventh leading cause of death in the United States, taking 193,000 lives a year (ADA, 2000). Overall, the life expectancy for people with diabetes is 10–15 years shorter than the general population. Research shows that the death rate of middle-aged diabetics is twice that of middle-aged nondiabetics (Brenneman, 1999).

Studies show that people with diabetes have worse QoL than people without diabetes, but better QoL than people with most other serious chronic diseases. Several studies assert that people with type 1 diabetes have a poorer QoL than people with type 2 diabetes (Rubin,1999). Maintaining glycemic control is often associated with better QoL. Complications of diabetes are the most important disease-specific determinant of QoL for those with the disease. Interestingly, intensive treatment regimens for type 1 diabetes do not impair QoL. These regimens consist of three to four insulin injections daily, frequent glucose monitoring, diet and exercise (Grant, 1999).

A 1999 study of glucose tolerance and QoL among non-institutionalized elderly people (73 years or older) in Finland concluded that subjects with previously diagnosed diabetes had a poorer QoL compared with those with undiagnosed diabetes, impaired glucose tolerance, or normal glucose tolerance. Using the Nottingham Health Profile (NHP) instrument, the study found that a greater number of diabetic patients reported problems on all three energy item indicators, nearly all physical mobility indicators and half of the pain indicators (Hiltunen, 1999).

The total cost of diabetes in the United States was estimated at $98.2 billion in 1998. This includes direct medical costs of approximately $44 billion for medical care, hospitalizations and treatment supplies, and indirect costs of approximately $54 billion for disability payments, time lost from work and premature death. A 1994–96 study found that per capita expenditure among diabetic Medicare beneficiaries was 1.7 times greater than among Medicare beneficiaries without diabetes (Krop, 1999).

In 1997, per capita health-care costs for people with diabetes were $10,071, compared with $2,699 for nondiabetics. A reported 74,927 persons were permanently disabled by diabetes. On average, people with diabetes aged 18–64 lost 8.3 days from work in 1997, while the same group of people without diabetes lost 1.7 days from work (NIDDK, 2000).

A 1997 study on the direct cost of diabetes for the elderly (age 65 and over) found that $4.11 billion was spent on hospital care, $255 million on physician visits and $306 million on nursing home visits (Weinberger, 1997). However, the full economic and societal cost of diabetes is difficult to measure because mortality records fail to assess the impact of the disease on the proximate cause of death and costs associated with undiagnosed patients are not quantifiable (CDC, Diabetes, 1999).

Impact of Current Biotechnology Products:

Biotechnology is changing the composition of pharmaceuticals used in the treatment diabetes. Recombinant DNA (rDNA) uses insulin engineered from human cells rather than animal cells, the previous treatment option, and is associated with better health outcomes. Studies indicate that problems with immunogenicity (provoking an immune response) are less likely with rDNA than with insulin derived from animals (Eli Lilly and Company, Humulin package insert, 1994).

PRANDIN™ (REPAGLINIDE):

Prandin, an oral blood glucose-lowering drug (benzoic acid derivative) used to treat type 2 diabetes, was introduced by Novo Nordisk, Inc. in December 1997. Taken two to four times a day, the tablet stimulates the production of insulin in the pancreas. Prandin reduces the incidence and severity of hypoglycemic side effects compared with other Oral hypoglycemic agents. The FDA advisory committee called for additional postmarketing surveillance for adverse cardiovascular events. Labeling advises that increases in dosage be made carefully in patients with impaired renal function or renal failure necessitating dialysis (Vinson, 1998).

In one-year clinical trials, Prandin was not associated with excess mortality rates compared with other oral hypoglycemic agents. Reported adverse side effects included upper respiratory infection, 16 percent (placebo, 8 percent); sinusitis, 6 percent (placebo, 2 percent); and arthralgia, 6 percent (placebo, 3 percent) (The Pink Sheet, “Novo Nordisk,” 1998). Prandin™ is used frequently in combination therapy with (Glucophage® (metformin). However, Glucophage treatment should be avoided in patients over 80 years of age because of declining kidney function (Morley, 1998).

Prandin enables patients to reach ideal glucose levels and reduce the subsequent risk of complications. In patients with type 2 diabetes, complications from the disease affect QoL (U.K. Prospective Diabetes Study Group, 1999). The QoL of people with type 2 diabetes taking insulin has been reported to be poorer than those taking oral agents or diet alone (Jacobson, 1997; Diabetes Control and Complications Trial Research Group, 1996). New diabetes guidelines recommend using oral agents (such as Prandin) to achieve glycemic control and to prevent cardiovascular complications (Garber, 1999). Studies also show that the medication is costeffective (Riddle, 1999).

HUMALOG® (INSULIN LISPRO RDNA ORIGIN):

Humalog, introduced by Eli Lilly and Company in June 1996, is a rapid-acting parenteral blood glucose-lowering agent with a short-acting duration that is used to treat type 1 diabetes (Eli Lilly and Company, 1999). It is primarily used subcutaneously through a prefilled pen device and must be used with longer-acting insulin. It was the first insulin analog to closely parallel the way the body itself makes insulin. The dosage varies from patient to patient depending on their needs, disease state, diet, other medications and activity. Humalog can also be used intravenously for a longer-acting effect.

Humalog is effective insulin for achieving short-acting hypoglycemic control. A 1997 randomized crossover study of IDDM patients found that Humalog is associated with lower risk of severe hypoglycemia and coma (Benelux-UK Study Group, 1997). An article reviewing 22 controlled trials provided ample documentation that Humalog is effective in achieving metabolic control and further correlated these results with improved QoL. Episodes of mild hypoglycemia were reduced in 22 percent of the studies, although no change in the frequency of severe hypoglycemia was observed. However, there was a lower incidence of episodes of severe hypoglycemia at nighttime (Heinmann, 1999).

A multinational 1997 QoL study comparing Humalog with Humulin® showed a statistically significant higher satisfaction rate for those using Humalog. The QoL domains studied included energy/fatigue, health distress, treatment satisfaction and treatment flexibility (Kotsanos, 1997).

HUMULIN® (HUMAN INSULIN, RDNA ORIGIN):

Humulin, introduced by Eli Lilly and Company in October 1982, is a polypeptide hormone found to be chemically, physically, biologically and immunologically equivalent to pancreatic human insulin. Humulin is a synthesized, non-disease-producing, special laboratory strain of Escherichia coli bacteria that is purer than insulin from animal origins.

Humulin is intermediate-acting insulin combined with the more rapid onset of action of regular insulin. Humulin comes in seven formulations of human insulin, isophane suspension and zinc suspension that have different durations of action. The dosage varies from patient to patient depending on their needs, disease state, diet, other medications and activity. The reported side effects are local and systemic allergic reactions (Eli Lilly and Company, Humulin® package insert, 1994). The only recent literature on Humulin is a short-term comparison that found Humulin to be better tolerated than Humalog. Glycemic control and incidence of hypoglycemia and adverse effects were similar in both products (Daniels, 1997).

NOVOLIN® (HUMAN INSULIN, RDNA ORIGIN):

Novolin, introduced in 1982 by Novo Nordisk, Inc., was the first human insulin (rDNA origin) approved. It is available in eight formulations and several delivery mechanisms, although it is delivered primarily through the NovoPen®, a disposable, prefilled insulin pen. According to a manufacturer’s survey, 86 percent of Novolin insulin users found the delivery mechanism to be easier to use than syringes. The survey also found that patients were 100 percent compliant with their insulin regimen when using the NovoPen. Respondents also stated that the product improved their QoL (Novo Nordisk, Novolin package insert, 1982).

The Promise of Future Biotechnology Products:

In 1997 the NIH convened a team of experts to analyze diabetes and future research prospects. Their findings identified biotechnology as the primary area of impact on diabetes advances. This includes genetics autoimmunity and the beta cell, cell signaling and cell regulation (Albright, 1999). In addition to the biotechnology product trials listed below, two major studies sponsored by NIH will be conducted on the molecular genetics of insulin secretion and action (NIDDK, 1994). Recruitment is now under way. The long-term goal of this research is diabetes immunization/prevention.

INHALED INSULIN (RDNA):

Inhaled Therapeutics Systems Inc., in collaboration with Pfizer Inc., is in Phase III testing of new insulin that is inhaled, making possible reproducible delivery of rapid-acting insulin into the lungs. A dry powder is delivered through the mouth to the deep lung through a portable aerosol system. The aerosolized insulin is transported through the lung tissue to the bloodstream for systemic distribution. Thus far, the product has tested favorably, and the company expects FDA approval in three to five years (Roller, 1998).

Results from a Phase II study found that the inhaled product was as effective as injected insulin in treating both type 1 and type 2 diabetes. In addition, a 56-patient Phase II study found that patients unresponsive to an oral insulin product responded satisfactorily to the inhaled version (The Pink Sheet, “Pfizer/Hoechst,” 1998).

AI-401 (RDNA):

Eli Lilly and AutoImmune Inc. are currently testing AI-401, an oral tolerance product for stopping the progression of diabetes. AI-401 is an oral form of rDNAthat the manufacturers believe will modify the immune system to stop the destruction of insulin-producing cells (The Pink Sheet, “In Brief,” 1994).

INSULINOTROPIN:

Insulinotropin, developed by Scios, Inc. and licensed by Norvo Nordisk, Inc., is being developed for treatment of type 2 diabetes. This product is a naturally occurring peptide hormone that stimulates the release of insulin in response to higher blood sugar levels (Health Daily News, 1996).

SOMATOKINE® (IGF-I/BP3):

SomatoKine, being developed by Celtrix Pharmaceuticals Inc., is an insulin-like growth factor/BP3 complex that specifically treats debilitating and degenerative conditions associated with diabetes and osteoporosis. The product is delivered through Elan Corporation’s Medipad®, a disposable microinfusion pump. It is currently in Phase II trials. Phase II trial results have already shown that severely osteoporotic hip fracture patients treated with subcutaneous infusions of SomatoKine lost about 2 percent of hip-bone mineral density at six months compared with a 6 to 7 percent loss for placebo (The Pink Sheet, “Elan,” 1999).

ALTERED PEPTIDE LIGANDS (APL):

APL’s are peptides corresponding to T-cell epitopes with one altered amino acid. Trials using APL-based insulin have focused on the body’s immune system (Smets, 1998). Several manufacturers are testing variations of this ligand for diabetes.

SYMLIN™ (PRAMLINTIDE):

Amylin Pharmaceuticals, Inc. is conducting Phase III trials with SYMLIN, an orally administered synthetic analog of human amylin (a peptide that is normally co-secreted with insulin by pancreatic beta cells but may be deficient in diabetic patients). The agent appears to display efficacy in both type 1 and type 2 diabetes. Early results from Phase III trials indicate that the agent improved glycated hemoglobin levels after six months when added to insulin regimens of type 1 patients (Portyansky, 1999; Medical Industry Today, “Study,” 1999).

AC2993 (EXENDIN-4):

AC2993 (exendin-4), also from Amylin Pharmaceuticals, is in Phase I testing as an investigational drug for type 2 diabetes. The product was originally isolated from the salivary secretions of the Gila monster. A synthetic version of the peptide is being tested in subcutaneous form (Roller, 2000).

BIOARTIFICIAL PANCREAS:

The development of a bioartificial pancreas is a promising treatment option for type 1 diabetes. Experiments are being conducted with a tissue-engineered pancreatic construct based on immunoisolated, insulin-secreting cells (Pappas, 1999).

The QoL for patients with type 1 diabetes can be significantly improved through pancreas transplantation. Implanting an artificial pancreas would eliminate the need for insulin injections, frequent self-monitoring of blood glucose levels and dietary restrictions. It would also be more cost-effective than authentic pancreatic transplantation, and would eliminate the wait for a transplant. Increasing evidence also suggests that an artificial pancreas may slow the progression of long-term diabetic complications. However, patients would risk the adverse effects of lifelong immunosuppression (Mayes, 2000).

CONCLUSION:

Over the past 25 years many new biotechnology products have been developed to treat the growing health-care needs of human. This paper demonstrates that biotechnology products have a substantial impact on treating human being in the diabetes mellitus disease. The data also present examples of the numerous new products under development that hold even greater promise for improving the health and quality of life of human being. This study represents a snapshot of biotechnology’s contributions and promise after a quarter century of research and development. The future is even more exciting based on the rapid rate of progress in genetic research human genome sequence, which will accelerate the search for disease causes and cures.

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Received on 15.10.2011 Accepted on 20.11.2011

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