CHAPTER TWO: LITERATURE REVIEW

2.0 INTRODUCTION

Diabetes mellitus can be defined as a group of metabolic disease characterized by

increased levels of glucose in the blood (hyperglycaemia) resulting from defects in insulin

secretion, insulin action or both American Diabetes Association, (2009). Consequently,

diabetes carries an increase rise of morbidity and disability from neuropathy especially

diabetic foot ulcer. All forms of diabetes are characterized by chronic hyperglycaemia,

ketoacidosis, hypoglycaemia which are macrovascular complications as well as the

development of diabetes-specific microvascular pathology in the retina, renal glomerulus

and peripheral nerve Centre for Disease Control and Prevention (CDC), (2007). As a

consequence of its microvascular pathology, diabetes is a leading cause of blindness, end-

stage renal disease and a variety of the debilitating neuropathies. Diabetes is also

associated with accelerated artherosclerosis micro vascular disease affecting arteries that

supply the heart, brain and lower extremities. As a result, patients with diabetes have a

much higher risk of myocardial infarction, stroke and limb amputation Brownlee, (2001).

It is sixth leading cause of death in the U.S and incurs annual medical cost of over $100

billion Agency for health research and quality (AHRQ), (2007). Diabetes is associated

with increased risk of cardiovascular diseases, such that a person with diabetes has a risk

of myocardial infarction (MI) as high as that of a non-diabetic person with a previous MI.

Infact, cardiovascular disease accounts for >50% of all deaths in the diabetic population

Calkinet al., 2006). The diabetic control and complication trial (DCCT) and the UK

prospective diabetes study (UKPDS) established that hyperglycaemia is the initiating

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cause of the diabetic tissue injury that we see in daily clinical practice. Although this

process is modulated by genetic determinants of individual susceptibility and by

independent accelerating factors such as hypertension and dyslipidaemia, glycaemic

control remains crucial for preventing such diseases Schiavoniet al., (2007).

Adherence refers to the willingness and ability of an individual patient to follow health-

related advice, take medication as prescribed, attend scheduled clinic appointments, and

complete recommended tests and consultations Osterberg, (2005). Although often used

interchangeably with compliance, adherence also refers to the extent to which patients

follow through decisions about medicines taking (i.e leaving open the question of who

makes these decisions or how they are made, the patient has a choice of decision.) Horne

et al.,(2005). The importance of optimizing treatment adherence rises in proportion to the

potential benefit from therapy. As to whether patients achieved goal blood glucose

despite not having fully complied with prescriptions, or failed to achieve goal blood

glucose (in part) because of imperfect adherence the first implication is that optimal

compliance with prescribed medications should not be assumed, since it seems not to

occur about half the time Osterberg, (2005). Prominent reasons for low adherence

included forgetfulness, lack of funds, high pill burden, feeling of well-being and cure, and

side effects of medications. Premature discontinuation of treatment due to drug side

effects and lack of money to buy drugs interrupted consistent use of antidiabetic

medications. However, The most common discouraging factors cited in the literature such

as forgetfulness, side effects, cost of medication and lack of access to medication have

not shown any statistically significant associations with non-adherence Hashmiet al.,

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( 2007). Factors showing significant

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 associations with adherence are age, number of drugs prescribed and patients‟ knowledge

of the disease and treatment, including their beliefs and practices Hashmiet al., (2007).

2.0 Classification of Diabetes Mellitus

The Canadian Diabetes Association (2013) classified diabetes as below;

1. Type 1 (Juvenile onset or insulin-dependent) diabetes mellitus

2. Type 2 (Maturity onset or Noninsulin-dependent) diabetes mellitus

3. Gestational diabetes mellitus and Others

Others are;

1. Genetic defects of beta-cell function

3. Genetic defect in insulin action

3. Diseases of the exocrine pancreas

4. Endocrinopathies

5. Drug or chemical induced e.g. Nicotinic acid, Glucocorticoids, high dose thiazides,

pentamidine, interferon-alpha

6. Infections

2.0.1 Type 1 Diabetes Mellitus

This results from the body’s failure to produce insulin and presently requires a person to

inject insulin. Type 1 diabetes is an auto immune disease that is a condition in which the

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Body’s disease fighting immune system goes awry and attacks healthy tissues. Scientists

have so far identified 20 genes that play a role in diabetes such as HLA-DQA1, HLA-

DQB1, HLA-DRB1 IDDM2, and CTLA4 genes, these genes provide instructions for

making proteins (including insulin) and have regulatory roles in immune responses. In

addition to causing hyperglycaemia, type 1 diabetes if left untreated affects fat

metabolism.

2.0.2 Type 2 Diabetes Mellitus

Referred to as non-insulin dependent diabetes mellitus formally is more common above

the age of 40 with a peak age of onset in developed countries of between 60 and 70 years.

It is caused by a relative insulin deficiency and or insulin resistance. It can progress to the

extent whereby exogenous insulin is required to maintain blood glucose levels Elizabeth

et al., 2008). Of the nearly 21million people in the US with diabetes, 90-95% have type 2

diabetes. In addition, there is a strong relationship between obesity and type 2 diabetes

with about 80%diabetics with this form of disease being overweight.

2.0.3 Gestational diabetes mellitus

This type of diabetes develops only during pregnancy, it occurs more in African

Americans, American Indians, and among women with a family histoFry of diabetes.

Women who have had gestational diabetes have 20-50% chance of developing diabetes

within 5-10 years National Institute of Health, (2012.) This form of diabetes could pose

risks to the baby such as macrosomia (high birth weight), respiratory distress etc

(www.diabetes.co.uk, 2016).

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2.1 Prevalence of Diabetes Mellitus

The prevalence of DM is increasing globally, the worldwide prevalence was 171

million in the year (2000) and is estimated to rise to 366 million in (2030), but in

Nigeria, the prevalence is between 2-7% WHO, (2016). The overall prevalence of

diabetes is 2% in Dakace village near Zaria. Dahiru, et al. (2008). Despite

advances in diabetes therapy, control rates continue to be sub-optimal. Programs

that improve diabetic control and prevention of its complication are urgently

needed.

2.2 Risk Factors in Diabetes

In majority of patients, risk factors associated with diabetes are either of genetic

or environmental origin. Type 1 diabetes mellitus is mostly genetic while type 2

diabetes is due to some physical factors. Some conventional risk factors includes;

dyslipidaemia, hypertension, coagulopathy. Calking et al., (2006). Other possible

risk factors include; obesity, alcohol use, family history, smoking and diet.

2.2.1 Obesity

Being overweight is one of the strongest predictors of developing diabetes. Lack of physical activity

(Sedentary lifestyle) leads to poor weight management and increases the risk of diabetes and many

heart conditions. Maintaining a normal body and daily exercise such as walking and jogging increase

metabolic as well as cardiovascular efficiency. Malka, et al, (2000).

2.3.2 Diet

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Excessive carbohydrate intake results in hyperglycaemia where the insulin

present is inadequate for normal glucose metabolism. Also saturated fats

accumulate over time resulting in hypercholesterolemia which can subsequently

lead to artherosclerosis and ketoacidosis. Malka, et al, (2000).

2.3.3 Smoking

Cigarette smoking results in vasoconstriction due to release of chemo mediators

which activates the sympathetic nervous system thus increases the risk of heart

diseases and eventually diabetes. Nicotinic acid from tobacco is an important

chemical which induces diabetes. Smoking therefore should be avoided in

diabetic patients. Malka, et al, (2000).

2.3.4 Alcohol Abuse

Consumption of large amount of alcohol increases the risk of diabetes. Alcohol

interferes with steroid production (Glucocorticoids) which could induce

hyperglycaemia where control is inadequate. Reduction or total withdrawal from

alcohol intake will help in lowering blood glucose in predisposed individuals.

Malka, et al, (2000).

2.3.5 Ageing and Family History

Over time, the number of collagen fibre in artery and wall increases making blood

vessels stiffer. The reduced elasticity brings about a smaller cross-sectional area

in systole leading to hypertension Akubue, (2006). Hypertension is an important

risk factor for the development of diabetes. Children from parent with diabetes
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have higher risk of developing hyperglycaemias compared to those without

family

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history of the disease. This is as a result of genetic transfer from one generation to the

other Malka, et al, (2000).

2.4 Diagnosis of diabetes

The Clinical Practice Guidelines for Diabetes Management in Nigeria adopted the WHO

criteria for diagnosing diabetes WHO, (2016). They consist of the following;
Diabetes symptoms (polyuria, polydipsia, and unexplained weight loss) plus:

A random venous plasma glucose concentration of > 11.1mmol/L.A fasting plasma

glucose concentration of 7.0mmol/L (6.1mmol/L for whole blood).Plasma glucose

concentration of > 11.1mmol/L 2 hours after 75g anhydrous glucose in an oral glucose

tolerance test.With no symptoms, diagnosis should not be based on a single glucose

determination but requires confirmatory plasma venous determination. At least one

additional glucose test result on another day with the value in diabetic range is essential.

Current recommendation are that the diagnosis is confirmed by a glucose measurement in

an accredited laboratory on a venous plasma sample. A diagnosis should never be made

on the basis of glucosuria or a stick reading of a finger prick blood glucose alone.

Glycated haemoglobin (HbA1c) is not used alone as diagnostic tool. Hackett et al.,

(2008).

2.5 Management of Diabetes Mellitus

The main goal of diabetes management is to restore carbohydrate metabolism to a normal

state as possible. To achieve this goal, individuals with an absolute deficiency of insulin

require insulin replacement therapy, which is given through injections or an infusion

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pump. Insulin resistance, in contrast can be corrected by dietary modification and

exercise. Other goals of diabetes management are to prevent and/or treat the many

complications that can result from the disease itself and from the treatment. American

Diabetes Association, (2008). Treatment of diabetes includes pharmacological and non-

pharmacological approaches.

Goals of Diabetic Management;

1. To achieve normal to near-normal glycaemic control

2. To prevent complications
3. To reduce morbidity and mortality from the disease
4. To improve patient’s quality of life

2.5.1 Pharmacological Management of Diabetes

Diabetes treatment are organised by pharmacological action with regards to the ability to

address basal glucose needs, prandial needs or insulin resistance. Oral anti-

hyperglycaemic therapies and new injected hormonal therapies lower glycosylated

haemoglobin (HbAlc) levels only 1-2% at best ADA, (2009). For patients with HbAlc

levels >9%, combination therapies or early introduction of insulin may be essential for

achieving adequate diabetes control.

Pharmacologic treatment of Type 1 diabetes

Keeping blood sugar levels under control can prevent or minimise complications. Insulin

treatment is one component of a diabetes treatment plan for people with type 1 diabetes.

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 Insulin treatment replaces or supplement the body’s own insulin, restoring normal or

near-normal blood sugar level. Many different types of insulin treatment can successfully

control blood sugar levels; the best option depends upon a variety of individual factors.

McCulloch, (2012).

Insulin is classified into the following depending on whether they would be given as

bolus or basal regimen;

1. Rapid-acting e.g. Insulin lispro (Humalog), Insulin aspart (Novolog), and Insulin

glulisine (Apidra)

2. Short-acting e.g. Insulin regular

3. Intermediate-acting e.g. Insulin NPH

4. Long-acting e.g. insulin glargine (lantus), Insulin determir

(uremir) Insulin Regimens consist of;

1. Intensive insulin Treatment

2. Conventional Insulin Treatment

Pharmacological management of type 2

Diabetes

About 80% of patients with type 2 diabetes are overweight at diagnosis, and this is

known to cause insulin resistance. This means that higher dose of medication may be

required to control blood glucose levels Wahrenberg et al., (2005).The drugs used are

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classified as follows;

Biguanides

Metformin is the only biguanide available for use in Nigeria. The mechanism of action is

still not completely understood. However, the principal mode of action is via potentiation

of insulin at an unknown intracellular locus, resulting in decrease hepatic glucose

production by both gluconeogenesis and glycogenolysis Bailey, (2004). Metformin also

stimulates tissue uptake of glucose, particularly in muscle, and is thought to reduce gastro

intestinal absorption of carbohydrate. Metformin has advantages over other insulin

secretagogues and sulfonylureas in particular, as it does not usually cause hypoglycaemia

and weight gain. Metformin is short acting with half-life of 6 hours Bailey, (2004). It

does not bind to plasma protein. It is not metabolized and is totally renally eliminated.

Side effects include; anorexia, nausea, abdominal discomfort and diarrhoea. A suggestive

regimen is to start with 500mg daily for one week, then 500mg twice daily for one week.

Increasing the dosage at weekly intervals until desired glycaemic response is achieved.

The maximum licensed dose is 3g/day but doses of more than 2g/day often cause

intolerance Bailey, (2004).

Recently, a modified-released preparation of metformin has become available that

permits once daily dosing. This formulation has fewer gastro intestinal side effects. The

maximum licensed dose for the formulation is 2g/day. Other previously available

biguanides, phenformin and buformin were withdrawn due to deaths associated with

lactic acidosis

Sulfonylureas
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The major actions of this class of drug rely on the ability of pancreas to secrete insulin

and hence require functioning beta-cells to exert a beneficial effect. Sulfonylureas lower

blood sugar by increasing pancreatic beta-cell sensitivity to glucose, allowing more

insulin to be released from storage granules for a given glucose load. Studies also suggest

that sulfonylureas may promote an increased systemic bioavailability of insulin due to

reduced hepatic extraction of the insulin secreted from the pancreas Campbell et al.,

(2015).The frequency of adverse effects from this class of drugs is low, they are usually

mild and reversible on drug withdrawal. The most common adverse effect is

hyperglycaemia,

which may be profound and long lasting. The major risk factors for the development of

hypoglycaemia include, use of long acting agents, increasing age, renal or hepatic

dysfunction and inadequate carbohydrate intake. Other adverse effects are weight gain,

blood dyscreasias and rashes. Campbell et al., (2015).

Sulfonylurea dosage should be individualized for each patient. The lowest possible

choice required to attain the desired levels of blood glucose without producing

hypoglycaemia should be used. For many agents, the maximum effect is seen if the dose

is taken half an hour before a meal; rather than with or after food. Examples of

sulphonylureas include; Glibenclamide, Glimepiride, Gliclazide.

Meglitinides

The meglitinides are insulin-releasing agents (insulin secretagogues), also called post

prandial glucose regulators. They are characterized by a more rapid onset and shorter
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duration of action than sulfonylureas. Their site of action is pharmacologically distinct

from that of sulfonylureas. Repaglinide, a benzoic acid derivative was the first member of

the class. It is licensed for use as a single agent when diet control, weight reduction and

exercise have failed to regulate glucose levels, or in combination with metformin.

Nateglinide was introduced later and is a derivative of D-phenylalanine to be used with

metformin when metformin alone is inadequate. Like sulfonylureas, the meglitinides

stimulate first-phase insulin secretion by inhibiting ATP-sensitive potassium channels in

the membrane of the pancreatic beta-cells. This cause depolarization and opening of

voltage gated calcium channels and subsequent stimulation of insulin release. Most

common side effects of meglitinides are; Hypoglycaemia, visual disturbance, abdominal

pain, diarrhoea, constipation, nausea, vomiting and rarely hyper sensitivity Marino,

(2009). Thiazolidinediones. Recent research into the action of the thiazolidinedione

(glitazones) has led to greater understanding of the development of type 2 diabetes. Two

glitazones are currently available, Rosiglitazone and pioglitazone. Pioglitazonehas been

shown to have a significant benefit on macrovascular morbidity and mortality

demonstrating the benefit of a glucose-lowering agent on macro vascular disease

dormandy et al., (2005). The glitazones act as agonists of the nuclear peroxisome

proliferator-activated receptor-alpha (PPAR-alpha) which is mostly expressed in adipose

tissues, but also found in pancreatic beta-cells, vascular endothelium and macrophages. It

is also expressed weakly in skeletal muscles, liver and heart Hauner, (2002). The

thiazodidinediones lower fasting and post prandial glucose levels in addition to lowering

free fatty acid and insulin concentrations. They enhance insulin sensitivity and promote

glucose uptake and utilization in peripheral tissues. The primary side effects of both
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rosiglitazone and pioglitazone is oedema, particularly in patients with hypertension and

congestive cardiac failure. Others are weight gain, headache, myalgia, abdomimal pain

and upper respiratory tract infection, both drugs cause elevated liver transaminases.

Another glitazone, troglitazone was withdrawn from the UK in 1997 because of liver

failure and thus liver function should be checked during initiation of therapy Hauner,

(2002).

Alpha Glucosidase Inhibitors Acarbose reduces carbohydrate digestion by interfering

with gastro intestinal glucosidase activity. Although overall carbohydrate absorption is

not significantly altered, the post prandial hyperglycaemic peaks are markedly reduced.

The

most common adverse effect of acarbose is abdominal discomfort associated with

flatulence and diarrhoea. Others are idiosyncratic elevation of plasma hepatic

transaminase levels Bischoff, (1995).Incretin-Based therapies incretin mimetics and

inhibitors of the protease dipeptidyl peptidase (DPP)-4 are new classes of antidiabetic

agents first introduced in ( 2005) (Exenatide) and ( 2007) (Sitagliptin), respectively.

They both use the properties of the incretin hormone, glucagon-like peptide (GLP)-1

Michael et al., (2009.) They work by increasing the levels of hormones called „Incretins‟.

These hormones help the body produce more insulin only when needed and reduce the

amount of glucose produced by the liver when not needed. They reduce the rate at which

stomach digests food and empties, and can also reduce appetite Bailey, (2014).

Sodium glucose Co-transporter 2 (SGL T2) Inhibitors

A new class of oral antidiabetic agents. They include; Canaglifozin, Empaglifozin, and
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Dapaglifozin. They inhibit SGL T2 thereby preventing glucose reabsorption and

increasing its excretion in urine. As glucose is excreted, its plasma levels fall leading to

improvement in all glycemic parameters. The most common adverse effects of this class

of drugs is Uro-genital infections especially in women and in uncircumcised men.

Bailey, (2015).

Insulin Therapy in type 2 Diabetes

Evidence has shown that overweight patients who are not acutely unwell should be

initiated on once daily basal insulin (usually at night) with continuation of metformin.

The basal insulin is titrated to achieve normal fasting glucose levels and the patient may

be taught this self-titration protocol Davies et al., (2005).

Non-Pharmacological Management of Diabetes

1. Smoking cessation

2. Reduction of alcohol consumption

3. Cutting down high calorie diets

4. Avoiding fat intake

5. Improved personal hygiene to prevent infections

6. Eating vegetables and fruit

7. Drinking water to remain hydrated

Role of Education in Diabetes

Management

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According to Bonsignore, (2017). Diabetes education is the cornerstone of diabetes

management because diabetes requires day-to-day knowledge of nutrition, exercise,

monitoring of blood glucose and medication adherence. Diabetes education makes you

more aware of diabetes, what it takes to treat it, and gives you the power to control it.

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