A COMPREHENSIVE OVERVIEW ON

DIABETES

A Review Project, submitted to KBC North Maharashtra University, Jalgaon.

In Partial Fulfillment of the requirement for award of the Degree of,

BACHELOR OF PHARMACY

Submitted By:
PATIL DIVYANK RAJENDRA
PATIL GANESH UKHARDU

(Final Year B. Pharm.)

University Seat No.-
561300, 561301

Under the Guidance Of:

PROF. MR. AKASH.S. INGALE

KYDSCT’s College Of Pharmacy, Sakegaon, Bhusawal

2023-24
 CERTIFICATE
This is to certify that Research Project entitled, “A Comprehensive
Overview on Diabetes “By PATIL DIVYANK RAJENDRA, PATIL
GANESH UKHARDU in the partial fulfillment of Degree Of Bachelor
of Pharmacy, has been carried out in KYDSCT’s College Of
Pharmacy, Sakegaon, under my guidance and to my satisfaction.

Prof. Mr. Akash. S. Ingale Dr. P. R. Patil

Guide Principal
 ACKNOWLEDGMENT
NO research is ever they outcome of single individual’s efforts. This work is also no exception. Some
of the personalities known and unknown have contributed to and made it possible for me to present
in this shape. I am heartily grateful to all of them.

I am highly thankful to Dr. Parag R. Patil, Principal, KYDSCT’s college of Pharmacy, Sakegaon (Bhusawal)
who continuous help and providing valuable suggestion forcompleting this project.

At the outset, I express my deep heartfelt and sincere thanks to my Guide Prof. Mr. Akash. S. Ingale for
guiding me to accomplish the project work. He was there always his enthusiastic suggestion, despite of
his extremely busy schedule. Iam extremely grateful for her kindness, expert advice, support and
patience throughout the duration of my research.

I am very thankful to staff members of KYDSCT’s college of pharmacy, Sakegaon (Bhusawal), who are
great support and very helpful to me throughout my entire project.

Last, but not the least, I express my gratitude and apologize to anybody who contribution, I could not
mention in this page.

PATIL DIVYANK RAJENDRA

PATIL GANESH UKHARDU

 OVERVIEWOF NOVEL TRANSDERMALDRUGDELIVERY SYSTEM

INDEX

Sr. No. Title Page. No.

1. Abstract 1

2. Introduction 2-7

3. Literature Of Review 7

4. Insulin 8-18

5. Advances In Insulin Delivery 19-24

6. Enzyme Inhibitors 25

7. Pharmacology Of Inhaled Insulin 26

8. Pharmacokinetics Of Inhaled Insulin 27-28

9. Use Of Inhaled Insulin In Treatment Of 29-30

Diabetes

10. Conclusion 31

11. References 32-33

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 ABSTRACT:-
Diabetes is a chronic disease characterized by inadequate insulin secretion with resulting
hyperglycemia. Diabetes complications include both microvascular and macrovascular disease,
both of which are affected by optimal diabetes control. Many individuals with diabetes rely on
subcutaneous insulin administration by injection or continuous infusion to control glucose levels.
Novel routes of insulin administration are an area of interest in the diabetes field, given that
insulin injection therapy is burdensome for many patients. This review will discuss pulmonar y
delivery of insulin via inhalation. The safety of inhaled insulin as well as the efficacy in
comparison to subcutaneous insulin in the various populations with diabetes are covered. In
addition, the experience and pitfalls that face the development and marketing of inhaled insulin
are discussed. Diabetes mellitus is a serious pathologic condition which is responsible for major
healthcare problems worldwide and costing billions of dollars annually. Insulin replacement
therapy has been used in the clinical management of diabetes mellitus for more than 84 years.
Insulin has remained indispensable in the management of diabetes mellitus since its discovery in
1921. Comparatively, a large percentage of world population is affected by diabetes mellitus,
out of which approximately 5- 10% with type 1 diabetes while the remaining 90% with type 2.
The present mode of insulin administration is by the subcutaneous route through which insulin is
introduced into the body in a non-physiological manner having many challenges. Hence novel
approaches for insulin delivery are being explored.

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 INTRODUCTION:-

Diabetes and pre-diabetes are serious conditions in which people have high levels of sugar or glucose
in their blood. The World Health Organization (WHO) reports that more than 420 million people
worldwide live with diabetes. In the US, according to the US Centers for Disease Control and
Prevention (CDC), over 30 million people have diabetes, and 88 million adults have pre- diabetes
(blood sugar levels are higher than normal, but not high enough to be diagnosed with type 2 diabetes).
Diabetes is a major cause of blindness, amputation, kidney failure, and cardiovascular
disease.Glucose is a type of sugar that is used as fuel by the body. When you eat, your body
converts food into glucose. The glucose then goes into your bloodstream and is carried througho ut
the body to provide energy to all of your cells. In order for glucose to move from your bloodstream
into your cells, you need insulin. Insulin carries the glucose, or sugar, in your bloodstream into your
cells. Insulin is a hormone made by the pancreas, an organ in the upper part of your abdomen (belly).I f
your body has a problem making or using insulin, the glucose in your bloodstream cannot get into
your cells. As a result, glucose stays in the blood (high blood sugar) and the cells do not get enough
glucose. A diagnosis of pre-diabetes or diabetes is made when glucose stays at higher-than- normal
levels (also called hyperglycemia).

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There are several types of diabetes:

Type 1 Diabetes (Insulin Dependent)

The pancreas does not make any insulin

You must take insulin every day to survive

Usually begins in childhood or adolescence ,

Type 2 Diabetes (Non-insulin Dependent)

Your pancreas makes some insulin (but usually not enough), and/or the body does not respond
normally to the insulin your body does make (sometimes referred to as 'insulin resistance') Some
people with type 2 diabetes are able to control it with diet and exercise; many others need diabetes
medication, and some need insulin.Most common form of diabetes ,

Gestational Diabetes
Diabetes that starts during pregnancy due to hormones that prevent insulin from doing its job

Most women with gestational diabetes are able to control their diabetes and prevent harm to
themselves and their babies; women with gestational diabetes tend to have large babies

Pre-diabetes
Blood glucose levels are higher than normal but not high enough for a diagnosis of diabetes

Having pre-diabetes puts you at increased risk for developing type 2 diabetes . Type 2 diabetes can
often be prevented or delayed by making changes to your diet, losing weight, and increasing
physical exercise

Metabolic Syndrome
Metabolic syndrome is not a type of diabetes, but a cluster, or group, of conditions usually associated
with being overweight or obese. Metabolic syndrome is also called Syndrome X, insulin resistance
syndrome, and dysmetabolic syndrome. This group of characteristics, or traits, puts people at risk for
heart disease and type 2 diabetes. A person has metabolic syndrome if they have three of the following
five traits:

High blood pressure (hypertension)

High blood glucose (high blood sugar)

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High triglycerides (fats) in the blood

High cholesterol

Large waist (larger than 35 inches for women and larger than 40 inches for men)

Symptoms of Diabetes
Symptoms of diabetes include:

Extreme thirst

Need to urinate frequently

Unexplained weight loss

Hunger

Blurry vision

Irritability

Tingling or numbness in the hands or feet

Difficulty healingExtreme fatigue

Symptoms typically occur when glucose levels have gotten very high. If you are diagnosed while
diabetes is in its early stages, you may not have any symptoms.

Glucose (Blood Sugar) Tests

Since diabetes does not always have obvious symptoms, it is important to have regular lab tests to
check your blood sugar or glucose levels. The most common glucose tests are:

Fasting glucose test: measures the glucose in a blood sample taken when you have not had anything
to eat or drink (except water) for at least eight hours. Hemoglobin A1C test: measures your average
blood sugar or blood glucose over the last two to three months. This test does not require fasting. It
is used to monitor diabetes control as well as to help diagnose it.To find out if you have diabetes or
pre-diabetes, you will usually have a fasting glucose test. A glucose tolerance test may be ordered to
help diagnose diabetes and as a follow-up to a high fasting glucose level. A glucose tolerance test
looks for abnormalities in the way your body handles glucose after eating.A diagnosis of diabetes

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can be made based on either of the following test results, confirmed by retesting on a different day:
A fasting blood glucose level of 126 milligrams per deciliter (mg/dL) or higher

An A1C of 6.5 percent or more (an A1C of 5.7 - 6.4 suggests pre-diabetes)

Who Is at Risk for Diabetes?

Anyone can get diabetes. However, certain factors may increase your risk:

Being over 40 years old

Being overweight or obese

A family history of the disease

A poor diet

Not being physically active

Smoking or using tobacco

A lot of fat around the belly (sometimes called 'central obesity;' having an apple-shaped body)

Hepatitis C or liver damage

High cholesterol level

High blood pressure

Having had gestational diabetes while pregnant

Taking certain HIV drugs (see below)

HIV and Diabetes

High glucose levels can be a side effect of HIV drugs. Specifically, certain protease inhibitors (PIs),
nucleoside reverse transcriptase inhibitors (NRTIs) and possibly integrase inhibitors can make it
difficult for insulin to get glucose into the cells. This is called insulin resistance. It can lead to pre-
diabetes and diabetes. If you need to take these drugs for your HIV treatment, your blood sugar should
be checked frequently. Pregnant people who need to take PIs to prevent transmitting HIV to their
babies should also have their glucose levels followed very closely. Some people living with HIV
experience changes in the location of their body fat (lipodystrophy). Lipodystrophy syndrome
sometimes comes with high glucose levels, unwanted changes in body fat, and increases in fat
(cholesterol and triglyceride) levels in the blood.

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Regardless of the HIV drugs you take, there are things you can do to make diabetes less likely:

Eat a healthy diet

Get regular exercise

Stop smoking

Lose weight if you are overweight or obese

Control your blood pressure and cholesterol levels – if necessary, with medications

What Problems Can Diabetes Cause?

Diabetes can lead to serious illness and even death. It is a major cause of heart disease and stroke,
and the ninth leading cause of death in the US. Worldwide, the World Health Organization (WHO)
estimates that diabetes was the seventh leading cause of death in 2019. Some of the serious
complications of diabetes are:

Blindness

Kidney failure

Blood vessel disease that requires an amputation

Nerve damage (neuropathy)

Cardiovascular disease (damage to your heart and/or blood vessels) which increases the risk of
heart attacks and stroke

How Are Diabetes and Pre-Diabetes Treated?

Although diabetes can be a very serious disease, it can be treated. It is important to manage diabetes
by checking your blood glucose regularly and keeping it under control. Many people control their
glucose levels by maintaining a healthy weight, changing their diet, and increasing exercise. A healthy
diet for people with diabetes involves reducing sugar and starchy foods (carbohydrates), such as
candy, pastries, chips, sugary drinks, bread, potatoes, rice, and corn. If possible, see a registered
dietitian to help you plan your meals. Many AIDS service organizations have registered dietitians on
staff who will see you free of charge. Sometimes, despite eating well and being physically active,
blood sugar levels cannot be controlled without the help of medications and/or insulin. There are a
number of medications available that lower blood glucose levels. Because these medications act in
different ways, they may often be used together. Some of the diabetes
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medications may interact with HIV drugs. To reduce the chance of drug interactions, make sure your
health care provider knows about all medications you take. Pre-diabetes People with pre- diabetes are
likely to develop type 2 diabetes unless they take action. The good news is that if you have pre-
diabetes, you can do a lot to prevent or delay diabetes. Studies have shown that people can lower their
risk of developing diabetes by losing weight through diet and increased physical activity. One study
found that diet and exercise leading to five to seven percent weight loss (about ten to 14 pounds in a
person who weighs 200 pounds) lowered the chances of getting type 2 diabetes by nearly 60 percent.
Study participants lost weight by cutting fat and calories in their diet and by exercising (mostly
walking) at least 30 minutes a day, five days a week.

Taking Care of Yourself

While diabetes is a serious condition, people living with HIV and diabetes can make lifestyle changes
and work with their health care providers to control their diabetes and prevent many of its
complications.

Steps to staying healthy:

Regular medical check-ups and lab work that includes glucose tests

Control blood pressure and fat levels in your blood to lower the risk for heart disease and stroke

Eat a healthy diet (see our fact sheet on Nutrition)

Get regular physical activity (see our fact sheet on Exercise)

Stop smoking (see our fact sheet on Smoking)

Diabetes is a common disease. Many people with diabetes live full, active, healthy lives. There is also
a lot of ongoing research about the best way to prevent diabetes. If you start by taking the steps above,
you may be on your way to living well with diabetes.

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 LITERATURE OF REVIEW:-

1. The antiquity of early descriptions of diabetes underscores the importance of the observation
and recording of medical conditions as humans evolve. Early physicians used whatever was
in their capacity (smell or even taste!) in pursuit of knowledge, skills and diagnosis.

2. Age is no bar to contributing significantly to the profession; Langerhans, was a 22 year old
student when he wrote a thesis identifying the cells that were later known to be the source of
insulin production.

3. Despite accounts of the acrimonious ‘team’ interactions building up to and following the
groundbreaking discovery of insulin, the acknowledgement of fellow professionals is
illustrated in Banting and Macleod’s (Noble laureates) recognition of Best and Collip’s
immense contributions by sharing their Noble prize money with them.29

4. The refusal to patent insulin but to share this miraculous therapy freely with the world will
remain an outstanding example of unreserved generosity towards mankind in the history of
medical disease. Banting’s colossal contribution has been globally recognised by the
declaration, since 2007, of his birthday (14th November) as World Diabetes Day.

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 INSULIN: -

History of Insulin:-

History of Insulin The discovery of insulin was a seminal event in both the study of diabetes and the
care of diabetic pa tients. The development of procedures for purifying and modifying insulin took
an additional 30 years. In his masterful rendition of these developments, Mi chael Bliss recounts the
remarkable story surrounding the discovery of insulin and notes that the discovery of insulin at the
University of Toronto in 1921-22 was one of the most dramatic events in the history of the treatment
of disease.1 Insulin received its name before it was discovered in 1889. In Germany, Oskar
Minkowski and Joseph von Mering observed that total pancreatectomy in ex perimental animals leads
to the development of severe diabetes mellitus and begun the speculation that a mysterious substance
produced by the pancreas is responsible for metabolic control.1 By the first decade of the Twentieth
Century it was widely hypothesized that an “internal solution” of the pancreas controls carbohydrate
metabolism.1 Even so there was so much impressionistic evi dence supporting the existence of
pancreatic internal secretion emanating from the islet cells that in 1907 a Belgian investigator J de
Meyer proposed it be named “insulin”. In 1916, Sharpey Schafer in Britain inde pendently suggested
the same name. Much truth is in the notion again clarifi ed by hindsight, that insulin was sitting there
waiting to be isolated or “discov ered”. It almost certainly would have been found during the second
decade of the 20th Century, but the work of Central European researchers, such as Zuelzer and the
Romanian physiologist, NC Paulesco was ut terly disrupted by World War I.1 In 1920, Frederick
Grant Banting a 22 years old orthopedic surgeon was attempting to launch general practice in the
small Canadian city of London, On tario. With time on his hands he accepted a demonstratorship in
surgery and anatomy at London’s Western University. OnMonday 31st October he had to talk to
physiology students about carbohydrate meta bolism, a subject with which he was not particular ly
familiar. Late Sunday night, as part of his preparation he read the leading article in the November
issue of Surgery, Gynecology and Obstetrics a discussion of “The relation of the Islets of Langerhans
to diabetes with special reference to cases of Pancreatic Lithiasis” by Moses Barron. Barron’s
unremarkable report stimulated a train of thought in Banting’s mind that caused him, sometime after
mignight, to jot down this idea: “Diabetus Ligate pancreatic ducts of dog. Keep dogs alive till acini
degenerate leaving islets. Try to isolate the internal secretion of these to relieve glycosuria”.1 Banting
enjoyed dabbling in research and returned to his alma mater, the University of Toronto and ap
proached JJR Macleod professor of physiology, with a proposal to engage in summer research to
test his “Di abetus” idea. Macleod a noted expert in
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carbohydrate metabolism, doubted that a novice could succeed where masters had failed however
he may have seen some value in Banting’s hypothesis that the internal solution was somehow being
nullifi ed in pancreatic extracts by the action of the externally secreted diges tive ferments. By ligating
the pancreatic ducts Banting hoped to induce atrophication of the acinar cells and eliminate the
external solution. Banting’s training as a surgeon would serve him well in such research; it also
predisposed him to an interest in grafting experiments as the second stage in his work in an age before
the re jection phenomenon was understood. Several experts had suggested pancreatic dissection in
the search for the elusive secretion. With surplus facilities at hand in his very well - equipped
laboratory Macleod agreed to give Banting spare dogs, and a student assistant for a “Summer” thing
to the problem. One of the Macleod’s summer students Charles Best, reluctantly won a coin toss to
see who would start work with Banting.1 Banting began his research assisted by Best on 17th May
1921. Macleod was both the formal supervisor and an active advisor before leaving the city in mid-
June. The casualty rate among Banting’s dogs was high, some depancreatized, others duct ligated.
At the end of July, he and Best began intravenous injections into depancreatized animals of saline
extracts of chilled atrophied pancreas. They observed a pattern of hypoglycemic effects. When
Macleod returned in Sep tember, he urged Banting and Best to repeat and amplify their experiments.
He discouraged Banting from returning down the grafting road and after some friction with the
young doctor supplied more space and dogs. By December, Banting and Best had accumulated further
evidence that their extract reduced the blood glucose of diabetic dogs. After experiments with fetal
calf pancreas and then with fresh beef pancreas, Banting found he could dispense with the
cumbersome duct-ligation/atrophication procedures (though he never quite realized that in doing so
he had disproven his original hypothesis of an antagonism between the pancreatic secretions).
Because of Best’s inexperience Macleod and Banting decided to add JB Collipinexperience Macleod
and Banting decided to add JB Collip to the research team. Collip the biochemist from the Univers ity
of Alberta, was visiting Toronto to work with Macleod and had expressed an interest in the pancreas
work. The fi rst presentation of the Toronto research, read at the New Haven meeting of the American
Physi ological Association on 30th December 1921 was not well received. In their inexperience and
haste. Banting and Best had been sloppy and muddled. Their lack of data on the side effects of their
extracts (which were almost certainly pyrogenic, as others had been), meant that it was diffi cult to
convince anyone that their fi ndings were better than those of Killner and others. The team’s recent
experiments notably evi dence complied by Collip on the extracts, apparent restoration of glycoge n
mobilization in the liver and its ability to clear ketones, may have seemed more promising.

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Discovery of Insulin :-

On 11th January 1922, clinicians at Toronto Gen eral Hospital injected a 14 year old, severely diabetic
boy Leonard Thompson with 15 ml of pancreatic ex tract made by Banting and Best. This clinical test
was a failure. The injection caused only slight reductions of glycemia and glycosuria, had no effect
on ketoacidosis or the patient’s subjective presentation, and resulted in the formation of a sterile
abscess. These re sults were not as encouraging as those obtained by Zuelzer in 1908, Banting later
wrote treatment was immediately discontinued.1 On January 23rd, a new series of injections began.
Thompson responded immediately. His glycosuria almost disappeared, his ketonuria did disappear,
his blood glucose dropped to normal. He was brighter and stronger. For the first time in history there
was clear unambiguous evidence that scientists were able to re place the function impaired in
diabetes. This was the demonstration of the isolation of the internal secretion of the pancreas that the
world had awaited for 30 yrs.1 It was JB Collip the biochemist who had produced the successful
extract. He had developed a method of extraction that involved changing the concentrations of
slightly acidic alcohol solutions of chilled beef pan creas. It is not clear which members of the research
team fi rst suggested using acid alcohol until he was able to precipitate out the active princip le
relatively free from toxic contaminants. It was a major improve ment on Banting and Best’s methods,
the single most important step forward in the discovery process.1 Banting and Best were particular ly
confused and self serving in their refusal to recognize their collabo rators contributions to the work,
as Newelyn Barker put it that “in insulin there is glory enough for all”.1 The glory came almost
immediately. On 3rd May, 1922, Macleod delivered a complete summary of the Toronto work at the
Washington meeting of the Asso ciation of the American Physicians. By now it had been decided to
name the active principle “insulin”. Macleod suggested the Latin root for islands without knowing of
Meyer’s and Schaeffer’s earlier proposals. The audience agreed that the Toronto team had made one
of the greatest breakthroughs in modem medicine and gave them a standing ovation. Eighteen months
later, in area of the fastest recognitions of a medical discovery in its history the Nobel committee of
the Caroline Institute awarded the 1923 Nobel Prize in Physiology or Medicine to Banting and
Macleod. Banting divided his prize money equally with Best, Macleod split his with Collip. The
Nobel committee was probably mistaken in not having named Collip as a co-recepient of the prize.1
For further reading on the exiting story of insulin discovery book by Michael Bliss may be referred.

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Structure of Insulin
Like most of the other hormones, insulin is a protein comprising of 2 polypeptide chains A (with 21
amino acid residues) and B (with 30 amino acid residues) [Fig. 1]. Chains A and B are linked by
disulphide bridges. In addition A-chain contains an intra-chain disulphide bridge linking residue 6
and 11. The structure of insulin is shown in the fi gure 1 below. C-chain, which connects A and B
chains is liberated along with insulin after breakdown of proinsulin. Insulin monomers aggregate to
form dimers and hexamers.3 Zn hexamer is composed of three insulin dimmers associated threefold
symmetrical pattern.

Biosynthesis of Insulin
Insulin is synthesized in the beta cells of pancreas in the form of preproinsulin which is the ultimate
precursor and gene for the same is located on chromosome 11 close to that for insulin like growth
factor-2 (IGF-2) [Fig.2].2 Within a minute after synthesis it is discharged into cisternal space of rough
endoplasmic reticulum where it is cleaved into proinsulin by proteolytic enzymes. Proinsulin with a
C (connecting) chain linking A and B chains is then transported by microvesicles to the Golgi
apparatus. Proinsulin is released in vesicles. Conversion of proinsulin to insulin continues in maturing
granules through the action of prohormone converatse 2 and 3 and carboxy peptidase H.4 Maturing
granules are translocated with the help of microtubules and microfi laments.

Insulin secretion
Insulin is secreted from the beta cells in response to various stimuli like glucose, arginine,
sulphonylureas though physiologically glucose is the major determinant. Various neural, endocrine
and pharmacological agents can also exert stimulatory effect. Glucose is taken up by beta cells
through GLUT-2 receptors. After entering the beta cell, glucose is oxidized by glucokinase, which
acts as a glucose sensor. Glucose concentration below 90 mg/dl do not cause any insulin release. At
such substimulatory glucose concentrations, K+ effl ux throughopen KATP channels keeps the ß cell
membrane at anegative potential at which voltage-gated Ca2+ channels are closed. As there is
increase in plasma glucose, glucose uptake and metabolism by the ß .

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cell is enhanced. Ri se in ATP concentration result in closure of KATP channels, leading

to a membrane depolarization, opening of voltage-gated Ca2+ channels, Ca2+ infl ux, a rise
in intracellular calciumconcentration, and ultimately exocytosis of insulin granules.
Structurally, the pancreatic KATP channel consists of two unrelated subunits: a sulfonylurea
receptor (the SUR1 isoform) and a potassium channelsubunit (Kir6.2) that forms the central
ion-conducting pathway(Fig 3). The mature KATP channel exists as an octamer of Kir6.2and
SUR1 subunits in a 4:4 stoichiometry (Fig 3). A sub unit specifi c site specifi c to pancreatic
KATP channel, confers glimepiride an advantage over the other sulfonylurea secretagogues.
Sulfonylurea
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and non-sulphonylurea drugs act as insulin secretogogues by closing KATP channels bypassing the
ß cell metabolism. Diazoxide is a K channel opener and inhibits insulin secretion,independent of
blood glucose levels.

Pharmacology of Insulin

Human insulin is now produced by recombinant DNA technology. Various companies differ in their
methodology but the basic principal is introduction of human insulin or proinsulin gene into organis ms
like E coli or Yeast. Yeast based technology may offer physio-chemical structural and protein folding
advantages though, this may not be clinically meaningful. The organisms keep on multiplying and in
turn producing insulin or proinsulin which is converted to insulin by enzymatic cleavage. Dry human
insulin is a microcrystalline powder with a molecular weight of 5808. Insulin precipitates at its
isoelectric pH of 5.4, while it is soluble at a pH of 2-3. 1 IU of insulin corresponds to 38.5 µg dry
substance.7 Insulin is available in the market in the strength of 40U and 100U i.e. 40U/ml and 100
U/ ml respectively. Even U500 is available in US and U10 is sometimes formulated individually for
use in infants with diluents provided by manufacturer. Half life of injected insulin is about 40 min.
Insulin preparations Porcine insulin has been withdrawn from the market globally and bovine is
expected to be extinct very soon. Human insulin is available in the short acting i.e. regular and
intermediate acting i.e. Neutral Protamine Hagedorn (NPH) forms.

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Insulin analogues which are synthetically modifi ed with some changes in the amino acid sequence
are also available. Rapid acting insulin analogues Lispro (Eli Lilly) and Aspart (Novo Nordisk) are
already in the market while glulisine (Sanofi -Aventis) is to be launched shortly. Glargine (Sanofi
-Aventis) and Detemir (Novo Nordisk) are the long acting analogues available. Ultralente is now
withdrawn. Regular insulin Regular insulin is available as a clear solution at neutral pH. 0.4% of zinc
is added to allow the insulin molecules to self associate into hexamers. For the prevention of growth
of micro-organisms phenol or m-cresol is added. Regular insulin has its onset of action within 15-30
min after subcutaneous injection, maximum activity peaks at 120-150 min while the action lasts for
6-8 hours. In order match the peaks of glucose and insulin, subcutaneous injection is advised to be
taken 30-40 min prior to meals. NPH or isophane insulin Isophane insulin is known as NPH insulin
as it was developed in Denmark at the Hagedorn Laboratory in 1940s.8 In order to prolong the action
of insulin, a positively charged protein, protamine is added in a molar ratio of 1:6 to regular insulin.
It binds with the negatively charged insulin at neutral pH. Neutral ph value is achieved by use of
phosphate buffer. Zn and m-cresol are also added. NPH insulin is slowly absorbed from subcutaneous
tissue with peak at 5-7 hours and the action lasts for 12-15 hours. This insulin is most commonly used
at bedtime to control fasting blood sugar. Lente insulin If zinc is added in excess amount (10 times
that added in NPH), at neutral pH and if acetate is used as a buffer in stead of phosphate, it forms
insoluble insulin- zinc complexes. This property is exploited for the production of lente insulins. The
action profi le of these preparations depends upon the physical conditions of insulin. Semilente is
amorphous and has biphasic absorption kinetics with short duration of action. Ultralente is long acting
crystalline suspension. These insulins cannot be mixed with regular insulin due to their zinc content
and are not very popular. Premixed formulations Regular and NPH insulin are available in a premixed
formulation with 30:70, 50:50, 25:75 proportions. These preparations are very popular as there is no
mixing involved. Patients of type 2 diabetes on split mix regime may be shifted to premixed
preparation if they are on approximately similar proportion. Rapid acting Analogues Regular insulin
when injected is in hexamer form, which slowly releases into monomers and is responsible for delay
in the action. Analogues are synthesized by modifying the amino acid sequence so as to keep insulin
molecule in monomeric form which has rapid onset of action and peak resembling physiology. After
subcutaneous injection the action starts at 30 min, peaks at 60-90 min and is over by 4 hours. This
action profi le is very effi cient in controlling postprandial glycemic excursions without any risk of
delayed hypoglycemia. 10,11 Long acting analogues Long acting analogues are designed in an
attempt to obtain a steady basal insulin level without any peak unlike NPH, which has a risk of late
night hypoglycemia. In insulin glargine, the amino acids sequence is altered so as to change

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isoelectric pH of insulin to 7.4 from 5.4. It is clear and soluble at an acidic pH. After injection in
subcutaneous space it gets precipitated and is released slowly, making its action last for even more
than 24 hours. Most of the patients require a single dose for basal cover. Insulin detemer has a long
action by virtue of a fatty acid chain attached to it. Premixed Analogue preparations Insulin glargine
cannot be mixed with any other insulin by virtue of its acidic pH and high Zn content i.e. 30 µg/ml.
Premixed preparations are available with protamine insulin. In these preparations the protamine -
insulin part has to be formulated with the same insulin analogue like lispro or aspart. These
preparations are available in 25:75, 30:70, 50:50 proportions .

Selection of insulin
Species Porcine insulin is no more available. Bovine insulin, the most economical option for non-
affording patients will be out of market very soon, due to ecological and environmenta l
considerations. Human insulin should be preferred for management of GDM, diabetic women
considering pregnancy, individuals with allergy or immune resistance to animal derived insulins,
those initiating insulin therapy and those expected to use only intermittently. Changing insulin species
and brands should be avoided as it may affect blood glucose control. Types of insulin (Conventiona l)
[Physical Appearance & Colour Code] Conventional Regular insulin – it s clear and watery, short
acting. NPH insulin – Cloudy, intermediate acting. Semelente, Lente and Ultralente are insulin
formulations with varying concentration of zinc, their actions being short, intermediate and long
acting respectively. Premixed preparations – with regular and NPH insulin mixed in fi xed proportions
viz.30/70,50/50,25/75 are available. These combinations are not physiological. They should be used
if there is doubt about patient’s compliance or feasibility of mixing insulins. Insulin Analogues Insulin
analogues have been synthesized by modifying structure of insulin so the action profile mimic s
physiology. Rapid acting analogues – Aspart, Lispro, Glulisine Long acting analogues – Glargine &
Detemir

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rofiles of Human Insulins and Analogues

Strengths available (U-40, U-100)

U40 i.e. 40 U/ml of insulin is the most widely used in India. U100 can be used for patients requiring
very high doses. Even U500 is available in US and U10 is sometimes formulated individually for use
in infants with diluents provided by manufacturer. Vials are U-40, U-100 and rarely U-10, U- 500 but
cartridges are always U-100. WHO recommend eventually all insulins across the globe to be U-100.

Storage
Vials & cartridges not in use should be refrigerated. Extremes of temperature 300 C and excess
agitation should be avoided to prevent loss of potency, clumping, frosting or precipitation. Vials &
cartridges in use, used for > 1 month may loose potency specially if not stored at room temperature.
They should be kept away from direct sunlight.

Syringes (U-40, U-100)

Though syringes are available in varying capacities viz. 0.3, 0.5, 1 and 2 ml; in our country 1 ml is
the most commonly used. Different syringes are available for use with 40U and 100U vials, differ ing
in markings, though both may be of 1 ml capacity. Syringe of corresponding strength only should be
used. Needles are available with thickness varying from 26 to 31 Gz. While changing from one length
to another, blood sugar should be monitored. 30 or 31 Gz needle can bend in a single use. Syringe s
must not be shared. Bending or breaking needle should be avoided. Syringes and needles should be
disposed in a puncture resistant container. Though the manufacturers recommend single use, reuse
is widely practiced and supposed to be safe as most insulin

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 ADVANCES IN INSULIN DELIVERY:-

NEEDLE AND SYRINGE

A common way of administering is with the needle and syringe. Syringes come in range of

capacities (1ml, 0.5ml, 0.3ml) with different needle types. Needles have very fine points and

special coating to make injections pain free.

INSULIN PENS
Insulin pen injectors are convenient and discreet way of administering insulin. They have a built-

in dial that allows us to determine the amount of insulin to be injected, a short needle one end and

a plunger at the other. Insulin pens are particularly useful if we need to take premixed insulin.

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INSULIN JET INJECTOR

Insulin jet injectors offer an alternative t needles and work by sending a fine spray of insulin into

theskin using a pressurized jet of air instead of a needle.

INSULIN PUMP
Insulin pumps are small devices of size of a pager that can be attached to our belt or placed in our

pocket. They are made up of an insulin reservoir connected to a tube, ending in a cannula or

catheter, which is inserted under the skin of our abdomen. They can be set to deliver insulin at a

slow, continuous rate throughout the day, or to release larger quantities at meal times or when

blood sugar is high. The main advantage of a pump is that it closely mimics the slow but continua l

release of insulin by the pancreas.

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INSULIN PATCH
Insulin patches are also currently under development, but it is difficult for insulin to be absorbed

through the skin. The patch is designed to release insulin slowly and continuous ly. Additiona l

dose can be administered by pulling off a tab on the patch.

INSULIN INHALOR
Insulin inhalers are a new way of delivering premealtime insulin. Insulin inhalers work like an

asthma inhaler, but deliver dry powdered insulin into the bloodstream via the lungs. However,

because the system can only be used to deliver fastacting insulin, long-acting insulin must still be

injected. Large doses are needed because only around 10 per cent of the dose actually reaches

the bloodstream and that amount may vary, for instance, if you have a cold or asthma. The inhalers

are not yet commercially available in Australia, but have been approved for use in the USA

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Development Of Inhaled Insulin :-

Shortly after Banting and Best discovered insulin in the early 1920s, the first studies using inhaled
insulin were performed. In these studies, it was reported that blood glucose decreased in response
to inhalation of insulin. In 1987, it was demonstrated that nebulized human insulin provided blood
sugar control comparable to subcutaneous insulin in 6 children with T1DM. However, it was
recognized that the bioavailability of inhaled insulin was significantly lower than that of
subcutaneous preparations. Consequently, it was not until the development of improved delivery

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devices and understanding of particle pharmacology that inhaled insulin became ready for clinica l
study.

Inhaled Insulin Devices:-

Devices capable of delivering particulate insulin to the alveolar space have been developed and
studied in a variety of clinical protocols. The ideal device should not only deliver insulin in a
consistent fashion in order to achieve optimal glycemic control, but also should be convenient for
patients – both portable and user-friendly. Over the course of the last 20 years, several companies
have worked to develop inhaled insulin systems for patient use.

The systems differ in the formulation of the inhaled insulin – liquid vs lyophilized powder –
and the delivery device with respect to size, mechanism of insulin release, and regulation of
insulin administration (mechanical vs electronic). The bioavailability of inhaled insulin for each
of the devices varies, but is in the range of 10% to 46%, with much of the drug being lost within
the device or in the oropharynx or upper airways. Table 1 summarizes the features of inhale d
insulin delivery systems that have been studied most extensively.

Exubera was developed through a collaboration between Nektar Therapeutics and Pfizer and, in
2006, was approved by the Food and Drug Association (FDA) and the European Medicines
Agency (EMEA) for treatment of both T1DM and T2DM. The insulin delivered by this device is
a dry powder formulation packaged in blister packets containing 1 mg or 3 mg of regular human
insulin. The unit doses are delivered via a mechanical inhaler and are equivalent to 3 units and 8
units of subcutaneously delivered short-acting insulin, respectively. Much of the medical
literature describing the pharmacokinetics, glucodynamics, and safety profiles of inhaled insulin
was obtained from studies using Exubera.

However, in October 2007, Pfizer announced that it would no longer be selling Exubera
secondary to poor sales and acceptance.

The AERx insulin diabetes management system (AERx iDMS) was developed by both Aradigm
Corporation and Novo Nordisk. This system creates an aerosol of insulin droplets from a liquid
insulin preparation. The device has electronic controls that guide the user to inhale the insulin in
a reproducible fashion.

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In addition, the device offers the capability to download dosing, use frequency, and inhalatio n
patterns to aid the prescriber and patient in monitoring adherence and treatment goals. Although
the AERx system was in phase III trials, Novo Nordisk elected to discontinue further study

This system is currently in phase III trials and is unique in that the partners have developed a
placebo formulation for inhalation, allowing for design of double-blind, placebo controlled
studies in patients with T2DM. Technosphere compares favorably to regular insulin administrated
subcutaneously in controlling postprandial hyperglycemia, suggesting that this formulation may
provide improved blood sugar control. While there are other inhaled insulin devices/systems that
have been developed,

TABLE 1 – INHALED INSULIN SYSTEM:-

Inhalatio n Insulin Insulin Inhaler Method Device Device Current

system Formulati Equivale Device Inhalati Size Benefits Status
on nts on
Exubera Dry 1 mg =3U Mechani User 20cm*4 Collapsi FDA-
powder 3mg=8U cal Depend cm ble approved off
blisters ed market

AER*iD MS Liquid 1AER Elecroni Guided 8cm*4c Downloa

insulin *unit=1U c System m d No further
blister capabilit developm ent
AIR y
Dry 6mg=2U Mechani Breath 7cm*2c Small No further
powder, 9mg=6U cal actuate m device developm ent
Capsules size

Technosp here Dry 6TU=1.56 Machani User 10cm*5 Placebo Phase 3 trials
powder U cal depende cm formulat FDA –
Microsphe 12TU*3.1 nt ion new drug
res, 2U application
cartridges
24TU=6.2
4U

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 ENZYME INHIBITORS:-
Researchers have evaluated the use of protease inhibitors with an aim to slow the rate of
degradation of insulin. They hypothesized that the slow rate of degradation will increase the
amount of insulin available for absorption. As discussed previously, enzymatic degradation of
insulin is mediated by serine proteases trypsin, achymotrypsin, and thiol metalloproteinase IDE.
Consequently, stability of insulin has been evaluated in the presence of excipients that inhib it
these enzymes. Representative inhibitors of trypsin and achymotrypsin include pancreatic
inhibitor , soybean trypsin inhibitor , camostat mesylate , and aprotinin . Inhibitors of insulin-
degrading enzyme include 1,10 phenanthroline ,
pchoromericuribenzoate, and bacitracin . Enzyme inhibitors have been associated with systemic
intoxication if they are absorbed. If they are not absorbable, then the digestion of nutritive proteins
may be disturbed.

Penetration Enhancers:-

Permeation enhancers improve the absorption of proteins by increasing their paracellular and
trancellular transports. An increase in paracellular transport is mediated by modulating tight
junctions of the cells, and an increase in transcellular transport is associated with an increase in
the fluidity of the cell membrane. Permeation enhancers that fall into the former category include
calcium chelators, and those that fall into the latter category include surfactants. Calcium
chelators act by inducing calcium depletion, thereby creating global changes in the cells,
including disruption of actin filaments, disruption of adherent junctions, and diminished cell
adhesion. Surfactants act by causing exfoliation of the intestinal epithelium, thus compromis ing
its barrier functions. This raises questions about the toxicity and long-term clinical use of
permeation enhancers. Most literature studies on the use of these permeation enhancers have
demonstrated that their enhancement is dose and time dependent. Examples of permeation
enhancers used include sodium laurate and cetyl alcohol, sodium cholate
ethylenediaminetetraacetic acid (EDTA) , and zonula occludens toxin (ZOT) clinical.

Role of Polymer Systems-

The use of polymer systems both alone and concurrent with absorption modifiers such as enzyme
inhibitors and permeation enhancers has been evaluated. In the former system, the drug is released
after uptake of the polymer system intact from the GIT. In the latter system, the drug is released
in the lumen before being absorbed.

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 PHARMACOLOGY OF INHALED INSULIN:-

Discussion of the pharmacology of inhaled insulin involves both the study of

pharmacokinetics measurement of serum insulin levels following administration of the

drug and pharmacodynamics – measurement of onset and duration of hypoglycemic

effect. Most of the inhaled insulin devices are designed to be used in conjunction with

carbohydrate consumption, targeting control of prandial glucose excursions. The ideal

system would closely mimic β-cell secretion of insulin with rapid onset of action

followed by sustained activity over a period of 2– 3 hours to control rising glucose

concentrations while limiting delayed hypoglycemic effects. The majority of studies

compare different inhaled insulin delivery systems to regular insulin administered

subcutaneously which has a peak effect on glycemia 30–60 minutes after administration

and duration of action up to four hours.

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 PHARMACOKINETICS OF INHALED INSULIN:-

Studies to assess serum concentrations of insulin following inhalation have been performed in
healthy volunteers as well individuals with both T1DM and T2DM. A summary of the
pharmokinetic parameters for various inhaled insulin devices is provided by Patton et al. In a
comparison of Exubera and regular insulin in healthy nonsmoking males, the total insulin
exposure was similar for inhaled insulin and regular insulin. However, the time to maxima l
insulin concentration (Cmax) was more rapid for inhaled insulin vs regular insulin. (55 min vs
148 min). In an open-label 4-way crossover study in healthy volunteers comparing 3 differe nt
Technosphere inhaled insulin doses and regular insulin, similar results were found– Cmax was
12 to 17 min for Technosphere insulin and 134 min for regular insulin. Studies performed with
the AERx system in patients with T1DM also revealed there was a more rapid rise in serum
insulin in the inhaled group vs regular insulin group. However, the intrasubject variability with
respect to total insulin exposure was ∼26% for the inhaled group, indicating that consistent
inhalation techniques could play a significant role in diabetes control. Rave et al compared
Technosphere insulin to regular insulin in 16 patients with T2DM.24 Cmax was reached earlier
(15 min vs 120 min) and was 45% greater for inhaled insulin compared to regular insulin.

Glucodynamics Of Inhaled Insulin-

Glucodynamics is measured by determining the infusion rate of glucose necessary to mainta in
euglycemia following the administration of insulin. This parameter determines the hypoglyce mic
effect of therapy. In healthy males receiving inhaled insulin, rates of glucose infusion were higher
in the first hour after dosing than in those receiving regular insulin by injection, correlating with
the more rapid rise in serum insulin levels.This maximal effect on glycemia is comparable to
short-acting insulin analogs. Total glucose consumption was comparable for bioequivalent doses
of inhaled vs regular insulin over the entire clamp period. In individuals with T1DM, the glucose
infusion rate profile showed an early peak rate with inhaled insulin (AERx) vs regular insulin
with a similar glucose consumption. Rave et al performed mixed-meal tolerance tests in 16
individuals with T2DM and compared the ability ofTechnosphere insulin and regular insulin to
control postprandial glucose levels. Both maximal postprandial glucose excursion and total blood
glucose area under the curve were significantly lower following use of inhaled insulin in this
group, indicating that for similar insulin exposure, glycemic control was improved with inhaled
insulin.The rapid onset of action coupled with the ability to exert an effect on glucose levels for
several hours after administration, makes inhaled insulin a good candidate for control of meal-
time glucose levels.

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Equivalence Dosing Of Inhaled Insulin :-

Pharmacokinetic and glucodynamic studies have been performed to determine the equivale nce
of each inhaled insulin formulation relative to subcutaneous insulin. These results are
summarized in Table 1. In order for patients to receive the appropriate amount of insulin to
cover carbohydrate ingestion, they must perform a series of inhalations using the doses
available for each delivery system. For example, a patient normally requiring 10 units of
regular insulin could inhale either three 1 mg blisters (9 unit equivalents) or one 1 mg blister
and one 3 mg blister (11 unit equivalents) of Exubera to achieve a comparable insulin dose. A
study was performed in healthy nonsmoking adults to determine whether different dose
combinations of AIR capsules were interchangeable. The pharmacokinetic and glucodyna mic
results demonstrated that combinations of different AIR capsule dose strengths were equivale nt.
Thus, there is greater flexibility with insulin dosing as well as less glycemic variability when
equivalent dose strengths are interchanged in this system.

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 USE OF INHALED INSULIN IN TREATMENT OF DIABETES:-

Multiple studies have been performed in patients with both T1 and T2DM to assess the efficacy
of inhaled insulin in controlling diabetes. Inhaled insulin has been compared to regular insulin
or short-acting insulin analogs in patients with T1DM. Studies including individuals with
T2DM have assessed the effect of inhaled insulin on diabetes control when added to oral
therapy as well as in comparison to short-acting insulin. Outcome measures have included
HbA1c, pulmonary function, weight gain, and patient satisfaction.
Type 1 Diabetes-

Current strategies to control blood glucose levels in individuals with T1DM involve subcutaneous
insulin injections given multiple times per day (2 to 5) or insulin pump therapy via CSII. In
patients receiving injection therapy, they generally receive long-acting (basal) insulin 1 or 2
times/day and short-acting insulin with meals to cover post-prandial meal excursions. Multip le
daily injection therapy places a burden on patients and is a significant barrier to optimizing
adherence to diabetes regimens aimed at improving glycemic control. Inhaled insulin has the
potential to replace shortacting insulin analogs, eliminating as many as 4 injections per day.
Inhaled insulin administered before meals has been compared in a randomized controlled fashio n
to regimens using regular insulin preprandially and either NPH (twice daily) or ultralente (once
daily).

In studies performed using Exubera®, inhaled insulin was noninferior with respect to HbA1c
changes, although 2-hour postprandial and fasting plasma glucose levels were lower in the groups
receiving inhaled insulin.34,35 In a recent study reported by Garg et al 385 individuals with
T1DM were randomized to receive either inhaled insulin (AIR®) or regular/lispro insulin before
meals with glargine serving as the basal insulin.36 After 2 years of study, only 20% of study
subjects reached a target HbA1c of 7%, and inhaled insulin was demonstrated to be inferior to
preprandial subcutaneous insulin with respect to change in HbA1c. When individuals with T1DM
were treated with glargine as basal insulin and randomized to either Technosphere inhaled insulin
or rapid acting insulin analog, both groups had comparable decreases in HbA1c at 1 year;
however, the inhale .insulin group had significantly lower fasting plasma glucose and 1 hour
postprandial glucose levels compared to those on subcutaneous insulin.37 The discrepancie s
between the studies related to effects of inhaled insulin on HbA1c may be related either to the
inhaled insulin formulation itself or to the basal insulin used in each study.

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Type 2 Diabetes-

Individuals with T2DM often have complicated medication regimens when the addition of insulin
is considered. Patients may be taking several different classes of drugs in an effort to control
blood sugars – oral hypoglycemic agents (sulfonylureas or meglitinides) and insulin sensitizers
(biguanides or thiazolidindiones). Rosenstock et al performed a trial in T2DM patients on dual
oral agent therapy who continued to have poor glycemic control (HbA1c 8%). Patients were
randomized to continued oral therapy, oral therapy plus Exubera, or Exubera alone. HbA1c
improved by 1.4% (inhaled) and 1.9% (inhaled plus oral agents) compared to oral agents alone.
This suggests that some patients may achieve adequate glycemic control on inhaled insulin alone,
thereby simplifying their treatment regimen. In addition, individuals randomized to inhaled
insulin plus oral agents had a greater likelihood of reaching glycemic targets compared to those
on oral agents alone (32% vs 1%). As discussed above, Mannkind Corporation has developed a
placebo based device for use in clinical trials as a comparator to Technosphere inhaled insulin.
This controls for the attention received by subjects within a study as well as the motivation factor
ascribed to subjects who are randomized to inhaled insulin, in contrast to subcutaneous insulin,
that may bias study outcomes.

Individuals with T2DM suboptimally controlled on oral agents were randomized in a double -
blind fashion to receive either placebo Technosphere powder or Technosphere insulin before
meals. Use of inhaled insulin resulted in a significant decline in HbA1c compared to those using
placebo, taking into consideration that HbA1c was mildly elevated in all subjects at baseline (8%,
inhaled insulin group; 7.8% placebo group). In a study of patients with T2DM on insulin therapy,
subjects received either pre-meal Exubera plus ultralente (subcutaneous) or twice daily injectio ns
of regular and NPH insulin. There was no difference in the reduction in HbA1c between the
groups, although those randomized to inhaled insulin were more likely to achieve HbA1c 7%
(odds ratio 2.27, 95% confidence interval 1.24 to 4.14). In a similar population of patients with
T2DM, AERx® premeal inhaled insulin was compared to premeal subcutaneous regular insulin,
both in combination with bedtime NPH insulin.

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 CONCLUSION:-
Several important issues remain with respect to the likelihood that inhaled insulin will be used

clinically in the future. The first is the significant impact that the launch and subsequent

withdrawal of Exubera from the market had on the continued study and development of

competing inhaled insulin devices. The second major development is the report from Pfizer that

there is an increased incidence of lung cancer among former smokers who were treated with

Exubera. As a consequence of this revelation, it is likely that the FDA will limit the use of inhale d

insulin to individuals who have never smoked and require extensive postmarketing studies to

address issues related to carcinogenicity risk. Finally, with the continued development of devices

that have improved the ability to deliver subcutaneous insulin, including insulin pumps and

insulin pens, the niche in the diabetes market which inhaled insulin is likely to occupy may be

limited. Although the concept of inhaled insulin is attractive, the availability of subcutaneous

insulin regimens that provide intensive diabetes care and the concern about pulmonary functio n

and health will significantly affect future development in this area. In conclusion, inhaled insulin

is a novel route of insulin administration which has the potential to become a therapeutic option

in the treatment of both T1DM and T2DM. improved diabetes control and decrease the risk of

long-term diabetes complications.

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2. Bakker W, Eringa EC, Sipkema P, vanHinsbergh VW. Endothelial dysfunction and

diabetes: roles of hyperglycemia, impaired insulin signaling and obesity. Cell Tissue Res.
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6. UK Prospective Diabetes Study (UKPDS) Group. Intensive bloodglucose control with

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7. Zambanini A, Newson RB, Maisey M, Feher MD. Injection related anxiety in insulin-
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8. Prentki M, Matschinsky FM. Ca2+, cAMP, and phospholipid-derived messengers in

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9. Porte D, Sherwin R, Baron A. Ellenberg and Rifkin’s Diabetes Mellitus. 6th ed. New York:
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11. Logtenberg SJ, Kleefstra N, Houweling ST, et al. Improved glycemic control with
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13. Gänsslen M. Uber inhalation von insulin. Klin Wochenschr.

14. Patton JS, Byron PR. Inhaling medicines: delivering drugs to the body through the lungs.

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16. Elliott RB, Edgar BW, Pilcher CC, Quested C, McMaster J. Parenteral absorption of
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18. Rosenstock J, Bergenstal R, DeFronzo RA, et al. Efficacy and safety of Technosphere
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19. Rave K, Heise T, Pfutzner A, Boss AH. Coverage of postprandial blood glucose
excursions with inhaled Technosphere insulin in comparison to subcutaneously injected regular
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25. Cefalu WT, Skyler JS, Kourides IA, et al. Inhaled human insulin treatment in patients with
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26. Rave K, Nosek L, De la Pena A, et al. Dose response of inhaled drypowder insulin and
dose equivalence to subcutaneous insulin lispro. Diabetes Care.

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