Diabetes Management

SUBMITTED TO GALGOTIAS UNIVERSITY, GREATER NOIDA

IN PARTIAL FULFILLMENT OF THE REQUIREMENT FOR THE

AWARD OF THE DEGREE OF

MASTER OF SCIENCE
IN CLINICAL RESEARCH

BY

Manoranjan Nayak
1624101017

SUPERVISED BY

(Hima Baruah)
ASSISTANT PROFESSOR
CLINICAL RESEARCH
2018

SCHOOL OF CLINICAL RESEARCH AND HEALTHCARE

MANAGEMENT
GALGOTIAS UNIVERSITY
GREATER NOIDA, INDIA.

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 CANDIDATE'S DECLARATION

I hereby certify that the work which is being presented in the report entitled “Diabetes
Management ” in partial fulfillment of requirements for the award of degree of M.Sc. (Clinical
Research) submitted in the School of Clinical Research and Healthcare Management,
Galgotias University, Greater Noida, is an authentic record of my own work carried out during
a period from March 2018 to April 2018 under the supervision of Mr.Manoranjan Nayak and
is free of any plagiarism The matter presented in this report has not been submitted by me in any
other University / Institute for the award of M.Sc. Degree.

Student name/Signature/Date

This is to certify that the above statement made by the candidate is correct to the best of my/our
knowledge and belief.

Faculty Supervisor/Name/Signature/Date

The M.Sc. Viva – Voce Examination of _____________ has been held on ____________ and
accepted.

Internal Examiner Name/Signature/Date______________

______________________________

External Examiner Name/Signature/Date

Signature of HoD / Dean

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 ACKNOWLEDGEMENT

I take this opportunity to express my sincere thanks and deep gratitude to all those people who
extended their wholehearted cooperation and have helped me in completing this research work
successfully.

I wish to express my sincerest gratitude to my Faculty Supervisor Hima Baruah Snr.Drug

Safety Associate, whose guidance is truly professional, who always remained ready to extend
his/her helping hand in times of need, which has motivated me for my Dissertation work on a
very valuable topic, and whose cooperation has resulted in successful completion of this work. A
single word is not enough for her, because extra hard work, valuable guidance, perfect teaching
that encouraged me to work hard.

I also thankfully acknowledge the Neelam Bata Rd, Opp. Neelam Cinema, AC Nagar, New
Industrial Town, Faridabad, and Haryana 121001 for providing me their valuable support.

Student’s Name: Mr.Manoranjan Nayak

Enrolment number: 1624101017

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 LIST OF GRAPH(S)/FIGURE(S)

GRAPH 01: Showing daily glucose and insulin cycle…………………………….10

FIGURE 01: Showing a blood glucose test strip for an older style (i.e., optical color sensing)
monitoring system…………………………………………………………………...13

FIGURE 02: Showing a modern portable blood glucose meter (OneTouch Ultra), displaying a
reading of 5.4 mmol/L (98 mg/dL)………………………………………………….16

FIGURE 03: Showing the Bio-artificial pancreas: a cross section of tissue with encapsulated islet
cells delivering endocrine hormones in response to glucose………………………...22

FIGURE 04: Gene therapy: Designing a viral vector to deliberately infect cells with DNA to carry
on the viral production of insulin in response to the blood sugar level……………...23

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 ABSTRACT

The main goal of diabetes management is, as far as possible, to restore carbohydrate
metabolism to a normal state.

To achieve this goal, individuals with an absolute deficiency of insulin require insulin
replacement therapy, which is given through injections or an insulin pump.

Insulin resistance, in contrast, can be corrected by dietary modifications and exercise. Other
goals of diabetes management are to prevent or treat the many complications that can result from
the disease itself and from its treatment.

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 CONTENTS
Page no.

Candidate's Declaration…………………………………………………………….02 i
Acknowledgement………………………………………………………………….03 viii
List of Graph(s)/Figure(s)……………………………………………………………04 xvi xxii
Abstract……………………………………………………………………………...05

1. Introduction ……………………………………………………………………….08

2. Overview………………………………………………………………………………………………………………………..09

2.1 Goals…………………………………………………………………………………………………………………….09

2.2 Issues……………………………………………………………………………………………………………………09

2.3 Complexities……………………………………………………………………………………………………….09 & 10

2.4 Early advancements……………………………………………………………………………………………10

2.5 Modern approaches……………………………………………................................................10-12

3. Blood sugar level…………………………………………………………………………………………………………..12 & 13

3.1 Hypo and hyperglycemia……………………………………………………………………………………13 & 14

3.2 Glycemic control…………………………………………………………………………………………………14 & 15

4. Monitoring……………………………………………………………………………………………………………………...15

4.1 Personal (home) glucose monitoring………………………………………………………………….16

4.2 HbA1c test……………………………………………………………………………………………………………16

4.3 Continuous glucose monitoring………………………………………………………………………….17

5. Lifestyle modification………………………………………………………………………………………………….17

5.1 Diet……………………………………………………………………………………………………………………..17

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 5.2 Medications………………………………………………………………………………………………………..17 & 18

5.3 Insulin…………………………………………………………………………………………………………………18

5.4 Exenatide……………………………………………………………………………………………………………19

5.5 Dental care…………………………………………………………………………………………………………19 & 20

5.6 Medication nonadherence…………………………………………………………………………………20

5.7 Psychological mechanisms and adherence…………………………………………………….20 & 21

6. Research……………………………………………………………………………………………………………………….21

6.1 Type 1 diabetes………………………………………………………………………………………………….21

6.1.1 Encapsulation approach…………………………………………………………………………21 & 22

6.1.2 Stem cells……………………………………………………………………………………………….22

6.1.3 Gene therapy………………………………………………………………………………………….22 & 23

6.2 Type 2 diabetes…………………………………………………………………………………………………23-24

7. Conclusions..............................................................................................................25

8. References……………………………………………………………………………………………………………………26-30

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 1. Introduction
The term diabetes includes several different metabolic disorders that all, if left untreated, result
in abnormally high concentration of a sugar called glucose in the blood. Diabetes mellitus type
1 results when the pancreas no longer produces significant amounts of the hormone insulin,
usually owing to the autoimmune destruction of the insulin-producing beta cells of the
pancreas. Diabetes mellitus type 2, in contrast, is now thought to result from autoimmune attacks
on the pancreas and/or insulin resistance. The pancreas of a person with type 2 diabetes may be
producing normal or even abnormally large amounts of insulin. Other forms of diabetes mellitus,
such as the various forms of maturity onset diabetes of the young, may represent some
combination of insufficient insulin production and insulin resistance. Some degree of insulin
resistance may also be present in a person with type 1 diabetes.

The main goal of diabetes management is, as far as possible, to restore carbohydrate
metabolism to a normal state. To achieve this goal, individuals with an absolute deficiency of
insulin require insulin replacement therapy, which is given through injections or an insulin
pump. Insulin resistance, in contrast, can be corrected by dietary modifications and exercise.
Other goals of diabetes management are to prevent or treat the many complications that can
result from the disease itself and from its treatment.

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 2. Overview
2.1Goals
The treatment goals are related to effective control of blood glucose, blood pressure and lipids, to
minimize the risk of long-term consequences associated with diabetes. They are suggested
in clinical practice guidelines released by various national and international diabetes agencies.
The targets are:

 HbA1c of 6%[1] to 7.0%[2]

 Pre-prandial blood glucose: 3.9 to 7.2 mmol/L (70 to 130 mg/dl)[3]
 2-hour postprandial blood glucose: <10 mmol/L (<180 mg/dl)[3]
Goals should be individualized based on: [3]

 Duration of diabetes
 Age/life expectancy
 Co morbidity
 Known cardiovascular disease or advanced microvascular disease
 Hypoglycemia awareness
In older patients, clinical practice guidelines by the American Geriatrics Society states "for frail
older adults, persons with life expectancy of less than 5 years, and others in whom the risks of
intensive glycemic control appear to outweigh the benefits, a less stringent target such as
HbA1c of 8% is appropriate"

2.2 Issues
The primary issue requiring management is that of the glucose cycle. In this, glucose in the
bloodstream is made available to cells in the body; a process dependent upon the twin cycles of
glucose entering the bloodstream, and insulin allowing appropriate uptake into the body cells.
Both aspects can require management. Another issue that ties along with the glucose cycle is
getting a balanced amount of the glucose to the major organs so they are not affected negatively.

2.3 Complexities
 The glucose cycle is a system which is affected by two factors: entry of glucose into the
bloodstream and also blood levels of insulin to control its transport out of the bloodstream
 As a system, it is sensitive to diet and exercise
 It is affected by the need for user anticipation due to the complicating effects of time delays
between any activity and the respective impact on the glucose system

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 Management is highly intrusive, and compliance is an issue, since it relies upon user lifestyle
change and often upon regular sampling and measuring of blood glucose levels, multiple
times a day in many cases
 It changes as people grow and develop
 It is highly individual

Graph.01 Daily glucose and insulin cycle

As diabetes is a prime risk factor for cardiovascular disease, controlling other risk factors which
may give rise to secondary conditions, as well as the diabetes itself, is one of the facets of
diabetes management. Checking cholesterol, LDL, HDL and triglyceride levels may
indicate hyperlipoproteinemia, which may warrant treatment with hypolipidemic drugs.
Checking the blood pressure and keeping it within strict limits (using diet
and antihypertensive treatment) protects against the retinal, renal and cardiovascular
complications of diabetes. Regular follow-up by a podiatrist or other foot health specialists is
encouraged to prevent the development of diabetic foot. Annual eye exams are suggested to
monitor for progression of diabetic retinopathy.

2.4 Early advancements

Late in the 19th century, sugar in the urine (glycosuria) was associated with diabetes. Various
doctors studied the connection. Frederick Madison Allen studied diabetes in 1909–12, and then
published a large volume, Studies Concerning Glycosuria and Diabetes, (Boston, 1913). He
invented a fasting treatment for diabetes called the Allen treatment for diabetes. His diet was an
early attempt at managing diabetes.

2.5 Modern approaches

Modern approaches to diabetes primarily rely upon dietary and lifestyle management, often
combined with regular ongoing blood glucose level monitoring.
Diet management allows control and awareness of the types of nutrients entering the digestive
system, and hence allows indirectly, significant control over changes in blood glucose levels.
Blood glucose monitoring allows verification of these, and closer control, especially important
since some symptoms of diabetes are not easy for the patient to notice without actual
measurement.
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Other approaches include exercise and other lifestyle changes which impact the glucose cycle.
In addition, a strong partnership between the patient and the primary healthcare provider –
general practitioner or internist – is an essential tool in the successful management of diabetes.
Often the primary care doctor makes the initial diagnosis of diabetes and provides the basic tools
to get the patient started on a management program. Regular appointments with the primary care
physician and a certified diabetes educator are some of the best things a patient can do in the
early weeks after a diagnosis of diabetes. Upon the diagnosis of diabetes, the primary care
physician, specialist, or endocrinologist will conduct a full physical and medical examination. A
thorough assessment covers topics such as:

 Medical history
 Family history of diabetes, cardiovascular disease, and stroke
 Eating and exercise habits; growth and development in children and adolescents
 Diabetes education history
 Review of previous treatment regimen and response to therapy (HbA1c records)

A list of current medications, including:

 Prescription medications
 Over-the-counter medications
 Vitamin, mineral or herbal supplements

 Smoking history, including encouragement of smoking cessation (if applicable)

 Current treatment plan, including medications, medication compliance and barriers, meal
plan, physical activity patterns, readiness for behavior change
 Results of glucose monitoring and patient's use of data
 Diabetic ketoacidosis frequency, severity, and cause
 Hypoglycemic episodes and awareness
 History of diabetes-related complications
 Micro vascular: retinopathy, nephropathy, neuropathy
 Macro vascular: coronary artery disease, cerebrovascular disease, peripheral artery
disease
 Urination abnormalities, which can indicate kidney disease
 Signs of complications with pregnancy or trying to get pregnant for women patients
 Physical examination
 Height, weight, body mass index
 Blood pressure measurements
 Funduscopy
 Thyroid palpation
 Skin examination at insulin injection sites
 Comprehensive examination of hands, fingers, feet, and toes for circulatory
abnormalities
 Additional laboratory evaluation
 If results not available within past 3 months

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  HbA1c
 If results not available within past year
 Fasting lipid profile: including total, LDL, HDL cholesterol and triglycerides
 Liver function test
 Test for urine albumin excretion with spot urine albumin/creatinine ratio
 Thyroid-stimulating hormone in type 1 diabetes, dyslipidemia, or women over 50
years old
 Referrals
 Eye care profession for annual dilated fundus examination
 Family planning for women of reproductive age
 Registered dietitian for medical nutrition therapy
 Diabetes self-management education (DSME)
 Dentist for comprehensive periodontal exam
 Mental health professional if needed
Diabetes can be very complicated, and the physician needs to have as much information as
possible to help the patient establish an effective management plan. Physicians may often
experience data overload resulting from hundreds of blood-glucose readings, insulin dosages and
other health factors occurring between regular office visits which must be deciphered during a
relatively brief visit with the patient to determine patterns and establish or modify a treatment
plan.[5]
The physician can also make referrals to a wide variety of professionals for additional health care
support. In the UK a patient training course is available for newly diagnosed diabetics
(see DESMOND). In big cities, there may be diabetes centers where several specialists, such as
diabetes educators and dietitians, work together as a team. In smaller towns, the health care team
may come together a little differently depending on the types of practitioners in the area. By
working together, doctors and patients can optimize the healthcare team to successfully manage
diabetes over the long term.
The 10 countries with the largest populations of diabetic patients are China, India, the U.S.,
Brazil, Russia, Mexico, Indonesia, Germany, Egypt and Japan.

3. Blood Sugar level

Blood sugar level is measured by means of a glucose meter, with the result either in mg/dL
(milligrams per deciliter in the US) or mmol/L (millimoles per litre in Canada and Eastern
Europe) of blood. The average normal person has an average fasting glucose level of 4.5 mmol/L
(81 mg/dL), with a lows of down to 2.5 and up to 5.4 mmol/L (65 to 98 mg/dL).[7]
Optimal management of diabetes involves patients measuring and recording their own blood
glucose levels. By keeping a diary of their own blood glucose measurements and noting the
effect of food and exercise, patients can modify their lifestyle to better control their diabetes. For
patients on insulin, patient involvement is important in achieving effective dosing and timing.
Some edible mushrooms are noted for the ability to lower blood sugar levels
including Reishi,[8][9] Maitake[10][11][12][13][14][15] Agaricus blazei[16][17][18][19] as well as some others.

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3.1 Hypo and hyperglycemia
Levels which are significantly above or below this range are problematic and can in some cases
be dangerous. A level of <3.8 mmol/L (<70 mg/dL) is usually described as a hypoglycemic
attack (low blood sugar). Most diabetics know when they are going to "go hypo" and usually are
able to eat some food or drink something sweet to raise levels. A patient who is hyperglycemic
(high glucose) can also become temporarily hypoglycemic, under certain conditions (e.g. not
eating regularly, or after strenuous exercise, followed by fatigue). Intensive efforts to achieve
blood sugar levels close to normal have been shown to triple the risk of the most severe form of
hypoglycemia, in which the patient requires assistance from by-standers in order to treat the
episode.[20] In the United States, there were annually 48,500 hospitalizations for diabetic
hypoglycemia and 13,100 for diabetic hypoglycemia resulting in coma in the period 1989 to
1991, before intensive blood sugar control was as widely recommended as today. [21] One study
found that hospital admissions for diabetic hypoglycemia increased by 50% from 1990–1993 to
1997–2000, as strict blood sugar control efforts became more common. [22] Among intensively
controlled type 1 diabetics, 55% of episodes of severe hypoglycemia occur during sleep, and 6%
of all deaths in diabetics under the age of 40 are from nocturnal hypoglycemia in the so-called
'dead-in-bed syndrome,' while National Institute of Health statistics show that 2% to 4% of all
deaths in diabetics are from hypoglycemia. [23] In children and adolescents following intensive
blood sugar control, 21% of hypoglycemic episodes occurred without explanation. [24] In addition
to the deaths caused by diabetic hypoglycemia, periods of severe low blood sugar can also cause
permanent brain damage.[25] Interestingly, although diabetic nerve disease is usually associated
with hyperglycemia, hypoglycemia as well can initiate or worsen neuropathy in diabetics
intensively struggling to reduce their hyperglycemia. [26]

Fig.01 A blood glucose test strip for an older style (i.e., optical color sensing) monitoring
system.

Levels greater than 13–15 mmol/L (230–270 mg/dL) are considered high, and should be
monitored closely to ensure that they reduce rather than continue to remain high. The patient is
advised to seek urgent medical attention as soon as possible if blood sugar levels continue to rise
after 2–3 tests. High blood sugar levels are known as hyperglycemia, which is not as easy to
detect as hypoglycemia and usually happens over a period of days rather than hours or minutes.
If left untreated, this can result in diabetic coma and death.
Prolonged and elevated levels of glucose in the blood, which is left unchecked and untreated,
will, over time, result in serious diabetic complications in those susceptible and sometimes even
death. There is currently no way of testing for susceptibility to complications. Diabetics are

13
therefore recommended to check their blood sugar levels either daily or every few days. There is
also diabetes management software available from blood testing manufacturers which can
display results and trends over time. Type 1 diabetics normally check more often, due to insulin
therapy.
A history of blood sugar level results is especially useful for the diabetic to present to their
doctor or physician in the monitoring and control of the disease. Failure to maintain a strict
regimen of testing can accelerate symptoms of the condition, and it is therefore imperative that
any diabetic patient strictly monitor their glucose levels regularly.

3.2 Glycemic control

Glycemic control is a medical term referring to the typical levels of blood sugar (glucose) in a
person with diabetes mellitus. Much evidence suggests that many of the long-term complications
of diabetes, especially the microvascular complications, result from many years
of hyperglycemia (elevated levels of glucose in the blood). Good glycemic control, in the sense
of a "target" for treatment, has become an important goal of diabetes care, although recent
research suggests that the complications of diabetes may be caused by genetic factors [27] or, in
type 1 diabetics, by the continuing effects of the autoimmune disease which first caused the
pancreas to lose its insulin-producing ability.[28]

Because blood sugar levels fluctuate throughout the day and glucose records are imperfect
indicators of these changes, the percentage of hemoglobin which is glycosylated is used as a
proxy measure of long-term glycemic control in research trials and clinical care of people with
diabetes. This test, the hemoglobin A1c or glycosylated hemoglobin reflects average glucoses
over the preceding 2–3 months. In nondiabetic persons with normal glucose metabolism the
glycosylated hemoglobin is usually 4–6% by the most common methods (normal ranges may
vary by method).

"Perfect glycemic control" would mean that glucose levels were always normal (70–130 mg/dl,
or 3.9–7.2 mmol/L) and indistinguishable from a person without diabetes. In reality, because of
the imperfections of treatment measures, even "good glycemic control" describes blood glucose
levels that average somewhat higher than normal much of the time. In addition, one survey of
type 2 diabetics found that they rated the harm to their quality of life from intensive interventions
to control their blood sugar to be just as severe as the harm resulting from intermediate levels of
diabetic complications.[29]

In the 1990s the American Diabetes Association conducted a publicity campaign to persuade
patients and physicians to strive for average glucose and hemoglobin A1C values below

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200 mg/dl (11 mmol/l) and 8%. Currently many patients and physicians attempt to do better than
that.

As of 2015 the guidelines called for an HbA1c of around 7% or a fasting glucose of less than
7.2 mmol/L (130 mg/dL); however these goals may be changed after professional clinical
consultation, taking into account particular risks of hypoglycemia and life
expectancy.[30][31] Despite guidelines recommending that intensive blood sugar control be based
on balancing immediate harms and long-term benefits, many people – for example people with a
life expectancy of less than nine years – who will not benefit are over-treated and do not
experience clinically meaningful benefits. [32]

Poor glycemic control refers to persistently elevated blood glucose and glycosylated hemoglobin
levels, which may range from 200–500 mg/dl (11–28 mmol/L) and 9–15% or higher over
months and years before severe complications occur. Meta-analysis of large studies done on the
effects of tight vs. conventional, or more relaxed, glycemic control in type 2 diabetics have failed
to demonstrate a difference in all-cause cardiovascular death, non-fatal stroke, or limb
amputation, but decreased the risk of nonfatal heart attack by 15%. Additionally, tight glucose
control decreased the risk of progression of retinopathy and nephropathy, and decreased the
incidence peripheral neuropathy, but increased the risk of hypoglycemia 2.4 times. [33]

4.Monitoring
Relying on their own perceptions of symptoms of hyperglycemia or hypoglycemia is usually
unsatisfactory as mild to moderate hyperglycemia causes no obvious symptoms in nearly all
patients. Other considerations include the fact that, while food takes several hours to be digested
and absorbed, insulin administration can have glucose lowering effects for as little as 2 hours or
24 hours or more (depending on the nature of the insulin preparation used and individual patient
reaction). In addition, the onset and duration of the effects of oral hypoglycemic agents vary
from type to type and from patient to patient.

4.1 Personal (home) glucose monitoring

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Fig.02 A modern portable blood glucose meter (OneTouch Ultra), displaying a reading of
5.4 mmol/L (98 mg/dL).

Control and outcomes of both types 1 and 2 diabetes may be improved by patients using
home glucose meters to regularly measure their glucose levels. Glucose monitoring is both
expensive (largely due to the cost of the consumable test strips) and requires significant
commitment on the part of the patient. The effort and expense may be worthwhile for patients
when they use the values to sensibly adjust food, exercise, and oral medications or insulin. These
adjustments are generally made by the patients themselves following training by a clinician.

4.2 HbA1c test

A useful test that has usually been done in a laboratory is the measurement of
blood HbA1c levels. This is the ratio of glycated hemoglobin in relation to the total hemoglobin.
Persistent raised plasma glucose levels cause the proportion of these molecules to go up. This is
a test that measures the average amount of diabetic control over a period originally thought to be
about 3 months (the average red blood cell lifetime), but more recently[when?] thought to be more
strongly weighted to the most recent 2 to 4 weeks. In the non-diabetic, the HbA1c level ranges
from 4.0–6.0%; patients with diabetes mellitus who manage to keep their HbA1c level below
6.5% are considered to have good glycemic control. The HbA1c test is not appropriate if there
has been changes to diet or treatment within shorter time periods than 6 weeks or there is
disturbance of red cell aging (e.g. recent bleeding or hemolytic anemia) or
a hemoglobinopathy (e.g. sickle cell disease). In such cases the alternative Fructosamine test is
used to indicate average control in the preceding 2 to 3 weeks.

4.3 Continuous glucose monitoring

The first CGM device made available to consumers was the GlucoWatch biographer in 1999.
This product is no longer sold. It was a retrospective device rather than live. Several live

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monitoring devices have subsequently been manufactured which provide ongoing monitoring of
glucose levels on an automated basis during the day.

5.Lifestyle modification
5.1 Diet
For Type 1 diabetics there will always be a need for insulin injections throughout their life.
However, both Type 1 and Type 2 diabetics can see dramatic effects on their blood sugars
through controlling their diet, and some Type 2 diabetics can fully control the disease by dietary
modification. As diabetes can lead to many other complications it is critical to maintain blood
sugars as close to normal as possible and diet is the leading factor in this level of control.
Recent research shows that the first step in Diabetes management should be for patients to be put
on a low carb diet. Patients that are put on a high carb diet find it very difficult to maintain
normal blood glucose levels. Patients that are put on a low carb or restricted carbohydrate diet,
manage to maintain near normal blood glucose levels and A1cs. [41][42][43][44][45][46][47][48][49]

5.2 Medications
Main article: Anti-diabetic drug

Currently, one goal for diabetics is to avoid or minimize chronic diabetic complications, as well
as to avoid acute problems of hyperglycemia or hypoglycemia. Adequate control of diabetes
leads to lower risk of complications associated with unmonitored diabetes including kidney
failure (requiring dialysis or transplant), blindness, heart disease and limb amputation. The most
prevalent form of medication is hypoglycemic treatment through either oral
hypoglycemics and/or insulin therapy. There is emerging evidence that full-blown diabetes
mellitus type 2 can be evaded in those with only mildly impaired glucose tolerance. [50]
Patients with type 1 diabetes mellitus require direct injection of insulin as their bodies cannot
produce enough (or even any) insulin. As of 2010, there is no other clinically available form of
insulin administration other than injection for patients with type 1: injection can be done
by insulin pump, by jet injector, or any of several forms of hypodermic needle. Non-injective
methods of insulin administration have been unattainable as the insulin protein breaks down in
the digestive tract. There are several insulin application mechanisms under experimental
development as of 2004, including a capsule that passes to the liver and delivers insulin into the
bloodstream.[51] There have also been proposed vaccines for type I using glutamic acid
decarboxylase (GAD), but these are currently not being tested by the pharmaceutical companies
that have sublicensed the patents to them.
For type 2 diabetics, diabetic management consists of a combination of diet, exercise, and weight
loss, in any achievable combination depending on the patient. Obesity is very common in type 2
diabetes and contributes greatly to insulin resistance. Weight reduction and exercise improve
tissue sensitivity to insulin and allow its proper use by target tissues. [52] Patients who have poor
diabetic control after lifestyle modifications are typically placed on oral hypoglycemics. Some
Type 2 diabetics eventually fail to respond to these and must proceed to insulin therapy. A study
conducted in 2008 found that increasingly complex and costly diabetes treatments are being

17
applied to an increasing population with type 2 diabetes. Data from 1994 to 2007 was analyzed
and it was found that the mean number of diabetes medications per treated patient increased from
1.14 in 1994 to 1.63 in 2007.[53]
Patient education and compliance with treatment is very important in managing the disease.
Improper use of medications and insulin can be very dangerous causing hypo- or hyper-glycemic
episodes.

5.3 Insulin
Insulin therapy requires close monitoring and a great deal of patient education, as improper
administration is quite dangerous. For example, when food intake is reduced, less insulin is
required. A previously satisfactory dosing may be too much if less food is consumed causing
a hypoglycemic reaction if not intelligently adjusted. Exercise decreases insulin requirements as
exercise increases glucose uptake by body cells whose glucose uptake is controlled by insulin,
and vice versa. In addition, there are several types of insulin with varying times of onset and
duration of action.
Several companies are currently working to develop a non-invasive version of insulin, so that
injections can be avoided. Mannkind has developed an inhalable version, while companies like
Novo Nordisk, Oramed and BioLingus have efforts undergoing for an oral product. Also oral
combination products of insulin and a GLP-1 agonist are being developed.
Insulin therapy creates risk because of the inability to continuously know a person's blood
glucose level and adjust insulin infusion appropriately. New advances in technology have
overcome much of this problem. Small, portable insulin infusion pumps are available from
several manufacturers. They allow a continuous infusion of small amounts of insulin to be
delivered through the skin around the clock, plus the ability to give bolus doses when a person
eats or has elevated blood glucose levels. This is very similar to how the pancreas works, but
these pumps lack a continuous "feed-back" mechanism. Thus, the user is still at risk of giving too
much or too little insulin unless blood glucose measurements are made.
A further danger of insulin treatment is that while diabetic microangiopathy is usually explained
as the result of hyperglycemia, studies in rats indicate that the higher than normal level of insulin
diabetics inject to control their hyperglycemia may itself promote small blood vessel
disease.[26] While there is no clear evidence that controlling hyperglycemia reduces diabetic
macrovascular and cardiovascular disease, there are indications that intensive efforts to
normalize blood glucose levels may worsen cardiovascular and cause diabetic mortality. [54]

5.4 Exenatide
The U.S. Food and Drug Administration (FDA) has approved a treatment called Exenatide,
based on the saliva of a Gila monster, to control blood sugar in patients with type 2 diabetes.

18
5.5 Dental care
High blood glucose in diabetic people is a risk factor for developing gum and teeth problems,
especially in post puberty and aging individuals. Diabetic patients have greater chances of
developing oral health problems such as tooth decay, salivary gland dysfunction, fungal
infections, inflammatory skin disease, periodontal disease or taste impairment and thrush of the
mouth.[69] The oral problems in persons suffering from diabetes can be prevented with a good
control of the blood sugar levels, regular check-ups and a very good oral hygiene. By
maintaining a good oral status, diabetic persons prevent losing their teeth as a result of various
periodontal conditions.
Diabetic persons must increase their awareness towards the oral infections as they have a double
impact on one's health. Firstly, people with diabetes are more likely to develop periodontal
disease which causes increased blood sugar levels, often leading to diabetes complications.
Severe periodontal disease can increase blood sugar, contributing to increased periods of time
when the body functions with a high blood sugar. This puts diabetics at increased risk for
diabetic complications.[70]
The first symptoms of gum and teeth infections in diabetic persons are decreased salivary flow,
burning mouth or tongue. Also, patients may experience signs as dry mouth which increases the
incidence of decay. Poorly controlled diabetes usually leads to gum problems recession
as plaque creates more harmful proteins in the gums.
Tooth decay and cavities are some of the first oral problems that individuals with diabetes are at
risk for. Increased blood sugar levels translate into greater sugars and acids that attack the teeth
and lead to gum diseases. Gingivitis can also occur as a result of increased blood sugar levels
along with an inappropriate oral hygiene. Periodontitis is an oral disease caused by untreated
gingivitis and which destroys the soft tissue and bone that support the teeth. This disease may
cause the gums to pull away from the teeth which may eventually loosen and fall out. Diabetic
people tend to experience more severe periodontitis because diabetes lowers the ability to resist
infection[71] and also slows healing. At the same time, an oral infection such as periodontitis can
make diabetes more difficult to control because it causes the blood sugar levels to rise.[72]
To prevent further diabetic complications as well as serious oral problems, diabetic persons must
keep their blood sugar levels under control and have a proper oral hygiene. A study in the
Journal of Periodontology found that poorly controlled type 2 diabetic patients are more likely to
develop periodontal disease than well-controlled diabetics are.[70] At the same time, diabetic
patients are recommended to have regular checkups with a dental care provider at least once in
three to four months. Diabetics who receive good dental care and have good insulin control
typically have a better chance at avoiding gum disease to help prevent tooth loss.[73]
Dental care is therefore even more important for diabetic patients than for healthy individuals.
Maintaining the teeth and gum healthy is done by taking some preventing measures such as
regular appointments at a dentist and a very good oral hygiene. Also, oral health problems can be
avoided by closely monitoring the blood sugar levels. Patients who keep better under control
their blood sugar levels and diabetes are less likely to develop oral health problems when
compared to diabetic patients who control their disease moderately or poorly.
Poor oral hygiene is a great factor to take under consideration when it comes to oral problems
and even more in people with diabetes. Diabetic people are advised to brush their teeth at least

19
twice a day, and if possible, after all meals and snacks. However, brushing in the morning and at
night is mandatory as well as flossing and using an anti-bacterial mouthwash. Individuals who
suffer from diabetes are recommended to use toothpaste that contains fluoride as this has proved
to be the most efficient in fighting oral infections and tooth decay. Flossing must be done at least
once a day, as well because it is helpful in preventing oral problems by removing the plaque
between the teeth, which is not removed when brushing.
Diabetic patients must get professional dental cleanings every six months. In cases when dental
surgery is needed, it is necessary to take some special precautions such as adjusting diabetes
medication or taking antibiotics to prevent infection. Looking for early signs of gum disease
(redness, swelling, bleeding gums) and informing the dentist about them is also helpful in
preventing further complications. Quitting smoking is recommended to avoid serious diabetes
complications and oral diseases.
Diabetic persons are advised to make morning appointments to the dental care provider as during
this time of the day the blood sugar levels tend to be better kept under control. Not least,
individuals who suffer from diabetes must make sure both their physician and dental care
provider are informed and aware of their condition, medical history and periodontal status.

5.6 Medication nonadherence

Because many patients with diabetes have two or more comorbidities, they often require multiple
medications. The prevalence of medication nonadherence is high among patients with chronic
conditions, such as diabetes, and nonadherence is associated with public health issues and higher
health care costs. One reason for nonadherence is the cost of medications. Being able to detect
cost-related nonadherence is important for health care professionals, because this can lead to
strategies to assist patients with problems paying for their medications. Some of these strategies
are use of generic drugs or therapeutic alternatives, substituting a prescription drug with an over-
the-counter medication, and pill-splitting. Interventions to improve adherence can achieve
reductions in diabetes morbidity and mortality, as well as significant cost savings to the health
care system.[74] Smartphone apps have been found to improve self-management and health
outcomes in people with diabetes through functions such as specific reminder alarms, [75] while
working with mental health professionals has also been found to help people with diabetes
develop the skills to manage their medications and challenges of self-management effectively.[76]

5.7 Psychological mechanisms and adherence

As self-management of diabetes typically involves lifestyle modifications, adherence may pose a
significant self-management burden on many individuals.[77] For example, individuals with
diabetes may find themselves faced with the need to self-monitor their blood glucose levels,
adhere to healthier diets and maintain exercise regimens regularly in order to maintain metabolic
control and reduce the risk of developing cardiovascular problems. Barriers to adherence have
been associated with key psychological mechanisms: knowledge of self-management, beliefs
about the efficacy of treatment and self-efficacy/perceived control.[77] Such mechanisms are
inter-related, as one's thoughts (e.g. one's perception of diabetes, or one's appraisal of how
helpful self-management is) is likely to relate to one's emotions (e.g. motivation to change),

20
which in turn, affects one's self-efficacy (one's confidence in their ability to engage in a behavior
to achieve a desired outcome).[78]
As diabetes management is affected by an individual's emotional and cognitive state, there has
been evidence suggesting the self-management of diabetes is negatively affected by diabetes-
related distress and depression.[79] There is growing evidence that there is higher levels of
clinical depression in patients with diabetes compared to the non-diabetic
population.[80] Depression in individuals with diabetes has been found to be associated with
poorer self-management of symptoms.[81] This suggests that it may be important to target mood
in treatment.
To this end, treatment programs such as the Cognitive Behavioural Therapy - Adherence and
Depression program (CBT-AD) [76] have been developed to target the psychological mechanisms
underpinning adherence. By working on increasing motivation and challenging maladaptive
illness perceptions, programs such as CBT-AD aim to enhance self-efficacy and improve
diabetes-related distress and one's overall quality of life. [82]

6. Research
6.1 Type 1 diabetes
Diabetes type 1 is caused by the destruction of enough beta cells to produce symptoms; these
cells, which are found in the Islets of Langerhans in the pancreas, produce and secrete insulin,
the single hormone responsible for allowing glucose to enter from the blood into cells (in
addition to the hormone amylin, another hormone required for glucose homeostasis). Hence, the
phrase "curing diabetes type 1" means "causing a maintenance or restoration of
the endogenous ability of the body to produce insulin in response to the level of blood glucose"
and cooperative operation with counter regulatory hormones.
This section deals only with approaches for curing the underlying condition of diabetes type 1,
by enabling the body to endogenously, in vivo, produce insulin in response to the level of blood
glucose. It does not cover other approaches, such as, for instance, closed-loop integrated
glucometer/insulin pump products, which could potentially increase the quality-of-life for some
who have diabetes type 1, and may by some be termed "artificial pancreas".

6.2 Encapsulation approach

A biological approach to the artificial pancreas is to implant bioengineered tissue containing islet
cells, which would secrete the amounts of insulin, amylin and glucagon needed in response to
sensed glucose.
When islet cells have been transplanted via the Edmonton protocol, insulin production (and
glycemic control) was restored, but at the expense of
continued immunosuppression drugs. Encapsulation of the islet cells in a protective coating has
been developed to block the immune response to transplanted cells, which relieves the burden of
immunosuppression and benefits the longevity of the transplant. [83]

21
Fig.03 the Bio-artificial pancreas: a cross section of tissue with encapsulated islet
cells delivering endocrine hormones in response to glucose.

6.3 Stem cells

Research is being done at several locations in which islet cells are developed from stem cells.
Stem cell research has also been suggested as a potential avenue for a cure since it may permit
regrowth of Islet cells which are genetically part of the treated individual, thus perhaps
eliminating the need for immune-suppressants.[48] This new method autologous
nonmyeloablative hematopoietic stem cell transplantation was developed by a research team
composed by Brazilian and American scientists (Dr. Julio Voltarelli, Dr. Carlos Eduardo Couri,
Dr Richard Burt, and colleagues) and it was the first study to use stem cell therapy in human
diabetes mellitus This was initially tested in mice and in 2007 there was the first publication of
stem cell therapy to treat this form of diabetes. [84] Until 2009, there were 23 patients included and
followed for a mean period of 29.8 months (ranging from 7 to 58 months). In the trial, severe
immunosuppressant with high doses of cyclophosphamide and anti-thymocyte globulin is used
with the aim of "turning off" the immunologic system", and then autologous hematopoietic stem
cells are reinfused to regenerate a new one. In summary it is a kind of "immunologic reset" that
blocks the autoimmune attack against residual pancreatic insulin-producing cells. Until
December 2009, 12 patients remained continuously insulin-free for periods ranging from 14 to
52 months and 8 patients became transiently insulin-free for periods ranging from 6 to 47
months. Of these last 8 patients, 2 became insulin-free again after the use of sitagliptin, a DPP-4
inhibitor approved only to treat type 2 diabetic patients and this is also the first study to
document the use and complete insulin-independendce in humans with type 1 diabetes with this
medication. In parallel with insulin suspension, indirect measures of endogenous insulin
secretion revealed that it significantly increased in the whole group of patients, regardless the
need of daily exogenous insulin use.[85]

6.4 Gene therapy

Technology for gene therapy is advancing rapidly such that there are multiple pathways possible
to support endocrine function, with potential to practically cure diabetes. [86]

22
Fig.04 Gene therapy: Designing a viral vector to deliberately infect cells with DNA to carry on
the viral production of insulin in response to the blood sugar level.

 Gene therapy can be used to manufacture insulin directly: an oral medication, consisting of
viral vectors containing the insulin sequence, is digested and delivers its genes to the upper
intestines. Those intestinal cells will then behave like any viral infected cell, and will
reproduce the insulin protein. The virus can be controlled to infect only the cells which
respond to the presence of glucose, such that insulin is produced only in the presence of high
glucose levels. Due to the limited numbers of vectors delivered, very few intestinal cells
would actually be impacted and would die off naturally in a few days. Therefore, by varying
the amount of oral medication used, the amount of insulin created by gene therapy can be
increased or decreased as needed. As the insulin-producing intestinal cells die off, they are
boosted by additional oral medications. [87]
 Gene therapy might eventually be used to cure the cause of beta cell destruction, thereby
curing the new diabetes patient before the beta cell destruction is complete and
irreversible.[88]
 Gene therapy can be used to turn duodenum cells and duodenum adult stem cells into
beta cells which produce insulin and amylin naturally. By delivering beta cell DNA to the
intestine cells in the duodenum, a few intestine cells will turn into beta cells, and
subsequently adult stem cells will develop into beta cells. This makes the supply of beta cells
in the duodenum self replenishing, and the beta cells will produce insulin in proportional
response to carbohydrates consumed.[89]

6.5 Type 2 diabetes

Type 2 diabetes is usually first treated by increasing physical activity, and eliminating saturated
fat and reducing sugar and carbohydrate intake with a goal of losing weight. These can restore
insulin sensitivity even when the weight loss is modest, for example around 5 kg (10 to 15 lb),
most especially when it is in abdominal fat deposits. Diets that are very low in saturated fats have
been claimed to reverse insulin resistance. [90] [91]
Cognitive Behavioral Therapy is an effective intervention for improving adherence to
medication, depression and glycaemic control, with enduring and clinically meaningful benefits
for diabetes self-management and glycaemic control in adults with type 2 diabetes and comorbid
depression.[82]

23
Testosterone replacement therapy may improve glucose tolerance and insulin sensitivity in
diabetic hypogonadal men. The mechanisms by which testosterone decreases insulin resistance is
under study.[92] Moreover, testosterone may have a protective effect on pancreatic beta cells,
which is possibly exerted by androgen-receptor-mediated mechanisms and influence of
inflammatory cytokines.[93]
Recently[when?] it has been suggested that a type of gastric bypass surgery may normalize blood
glucose levels in 80–100% of severely obese patients with diabetes. The precise causal
mechanisms are being intensively researched; its results may not simply be attributable to weight
loss, as the improvement in blood sugars seems to precede any change in body mass. This
approach may become a treatment for some people with type 2 diabetes, but has not yet been
studied in prospective clinical trials. [94] This surgery may have the additional benefit of reducing
the death rate from all causes by up to 40% in severely obese people.[95] A small number of
normal to moderately obese patients with type 2 diabetes have successfully undergone similar
operations.[96] [97]
MODY is a rare genetic form of diabetes, often mistaken for Type 1 or Type 2. The medical
management is variable and depends on each individual case. [98]

24
7. Conclusions
Diabetes management is, as far as possible, to restore carbohydrate metabolism to a normal
state. To achieve this goal, individuals with an absolute deficiency of insulin require insulin
replacement therapy, which is given through injections or an insulin pump. Insulin resistance, in
contrast, can be corrected by dietary modifications and exercise. Diabetes management is to
prevent or treat the many complications that can result from the disease itself and from its
treatment.

25
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Thank you

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