WHAT YOU NEED TO KNOW ABOUT DIABETES
Author: Nicolene Naidu
Bachelor of Biological Science (Cellular Biology), Bachelor of Medical Science (Medical
Microbiology) (Honours)
During the second century A.D., a Greek physician named Aretus the Cappadocian
came up with the term “diabainein”, which in Greek means siphon, to describe
patients presenting with polyuria (ie. passing too much water – like a siphon). This
term later became translated from medieval Latin to the English translation of
diabetes.
The term mellitus was added in 1675 by Thomas Willis, because of the excess
glucose found in the blood and urine of diabetic patients - mel in Latin literally means
honey.
Diabetes mellitus is used to describe a group of metabolic disorders characterised by
chronic hyperglycaemia as a result of defects in insulin secretion, insulin action or
both.
Three main types of diabetes exist:
1. Type 1 diabetes where the body does not produce any insulin at all.
2. Type 2 diabetes where the body either does not produce enough insulin or the
insulin that is produced does not function as it should.
3. Gestational diabetes, a transient form of diabetes that usually presents only during
pregnancy and then corrects itself after birth.
There is no known cure for diabetes, however treatment became possible in 1921
when insulin became medically available due to the combined efforts of Frederick
Banting, Charles Best, J.B. Collip and J. MacLeod.
The characteristic symptoms of this metabolic disease include weight loss, blurred
vision, polyuria and thirst. Often the pathological and functional changes brought
about by diabetes may lead to long term complications such as potential blindness,
renal failure, foot ulcers (with risk of amputation) and features of autonomic
dysfunction (including sexual dysfunction). In severe cases, stupor, coma and even
death may result from ketoacidosis (a consequence of insulin deficiency).
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THE ODDS AND ENDS YOU NEED TO SEE THE BIGGER PICTURE...
Glucose is a simple sugar that provides fuel to ALL the cells in our body. Cells like
our brain cells and red blood cells rely solely on glucose for their energy, thus it is
essential for a mechanism to maintain constant glucose levels, so that cells do not
have an overconcentration of glucose during a meal and then starve between meals
(or overnight).
Figure 1: Shows the location of the pancreas in relation to other body organs along with a close up
view of the cells that make up the pancreas and consequently, aide in its role in glucose regulation.
(http://health.howstuffworks.com/diseases-conditions/diabetes/diabetes1.htm )
Under normal circumstances, the pancreas produces two hormones that help
regulate blood glucose levels....insulin and glucagon. These two hormones work
opposite each other to maintain constant glucose levels. It is also worth mentioning a
third hormone, somatatastin, which counter-regulates insulin and glucagon.
Figure 2: Diagram showing the regulation of glucose levels by the pancreatic hormones insulin and
glucagon. These hormones effect changes in the liver, fatty tissue and muscle tissue as demonstrated
in the diagram above to either raise or lower overall blood sugar levels.
(http://www.lef.org/magazine/mag2004/jun2004_report_diabetes_01.htm)
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All these hormones are produced by the cells of the islets of Langerhans in the
pancreas. Beta cells produce insulin, which is used by most cells in the body. It
stimulates adipose cells to convert fatty acids and glycerol into fats, liver and muscle
cells to convert amino acids to proteins and glucose to glycogen and inhibits the liver
and kidney cells from making glucose via gluconeogenesis. Insulin has direct effects
on glucose, lipoprotein, ketone and protein metabolism...but its primary function in
glucose metabolism is to allow glucose to enter the body’s cells.
Table 1: The effects of insulin on metabolism and consequences of its deficiency.
TYPE OF METABOLISM
GLUCOSE
MAJOR METABOLIC EFFECTS


LIPOPROTEIN

Inhibits production of glucose by the liver

cells
Stimulates the uptake of glucose into
muscle and fat cells
Inhibits lipolysis in adipose tissue.

CONSEQUENCES OF INSULIN
DEFICIENCY
Hyperglycaemia - osmotic diuresis and
dehydration
Elevated Free Fatty Acid levels
(ie. triglyceride breakdown)
KETONE

Inhibits the process whereby fatty acids

are broken down to produce ketone
bodies (ketogenesis)
ketoacidosis
PROTEIN


Inhibits protein degradation

Stimulates amino acid uptake and protein
synthesis
Regulates gene transcription
Among others, muscle wasting

Alpha cells produce glucagon, which acts on the liver to lower insulin levels by
converting glycogen to glucose when blood sugar levels are too low.
Delta cells produce somatatastin which, as already mentioned, helps balance insulin
and glycogen levels.
The release of insulin into the bloodstream lowers blood glucose levels by a variety
of mechanisms including stimulating uptake of glucose by the tissues, suppressing
free fatty acid release from adipose cells and suppressing glucose production by the
liver. Its secretion is regulated by blood glucose levels. When blood glucose levels
are elevated, insulin levels increase and when blood glucose levels are lowered,
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insulin levels decrease. It is the only hormone that directly decreases blood
glucose levels.
While not all cells depend on insulin for enabling glucose to enter, those that are,
dependent on insulin to allow glucose enter freely (eg. Eyes, kidneys, brain, nerves,
erythrocytes) are usually the sites associated with complications from diabetes.
As mentioned three types of diabetes exist, type 1, type 2 and gestational diabetes.
Hyperglycemia in all diabetic patients is due to a functional deficiency in insulin
action, either due to:
1. A decrease in insulin secretion by the pancreatic cells.
2. Insulin resistance (lowered response to insulin by target cells).
3. An increase in the counter-regulatory hormones that oppose the effects of
insulin.
These three factors help classify diabetes mellitus into its various types and also
helps explain the clinical presentations of each type of diabetes.
TYPE 1 DIABETES
Type 1 diabetes accounts for between 5 – 10 % of all diabetes cases and was
formerly known as insulin dependent diabetes (because patients produce little or
no insulin) or juvenile onset diabetes (because onset of this type of diabetes
usually occurs early in life – between 8 and 14 years of age, with most patients
presenting before the age of 30).
It results from autoimmune mediated destruction of the insulin producing beta cells of
the pancreas. 85 – 90 % of patients presenting with Type 1 diabetes may carry
markers for immune destruction upon presenting with diabetic fasting
hyperglycaemia. These markers include antibodies to glutamic acid decarboxylase,
islet cell antibodies and or antibodies to insulin (Verge et al, 1996).
Autoimmune destruction of the pancreatic cells may be rapid in some patients and
slow in others (Zimmet et al, 1994). The rapidly progressive form of autoimmune
mediated destruction is most common in children, but may occur in adults
(Humphrey et al, 1998).
Latent autoimmune diabetes is the term given to adults presenting with this type
of diabetes as autoimmune destruction generally occurs at a much slower pace in
such patients. Adults presenting with this form of diabetes are frequently initially
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misdiagnosed as having type 2 diabetes based on age rather than the cause of
disease.
It is likely that Type 1 diabetes is initiated by exposure of a genetically susceptible
individual to an environmental trigger.
While some patients (namely children and adolescents) present with ketoacidosis as
the first manifestion of type 1 diabetes (Japanese survey, 1985), others may retain
enough beta cell function to prevent ketoacidosis for years (particularly adults)
(Zimmet et al, 1995) and some might maintain moderate hyperglycaemia (fasting)
until an infection or other trigger causes a change to severe hyperglycaemia with
may be accompanied by ketoacidosis.
It is important to note that some forms of Type 1 diabetes are idiopathic.
`
FIGURE 3:Showing the mechanism of diabetic ketoacidosis. The hormone insulin is used to regulate
glucose levels. In its absence, the body is forced to try and regulate glucose levels via alternate
pathways, ketoacidosis is a consequence of such an attempt at regulation and the conditions that
lead to this process can be seen in steps 1 – 6 above.
http://diabeticexchange.blogspot.com/2011/04/diabetic-ketoacidosis-treatments.html
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A lack of insulin in the body leads to an increase in the release of glucose from the
liver via the process of gluconeogenesis (ie. the conversion of glycogen to glucose in
the presence of glucagon). This causes osmotic diuresis when glucose “spills” into
the urine along with solutes like sodium and potassium, causing the characteristic
symptoms of diabetes (ie. polyuria, dehydration and compensatory polydipsia and
polyphagia).
Free fatty acids are released from adipose tissue via the process of lipolysis and are
converted in the liver to ketone bodies (ketoacidosis), thus ketoacidosis results from
the use of fat for energy when the body can no longer properly metabolise glucose
on its own. Symptoms of ketoacidosis include nausea, vomiting, “fruity” breath,
kussmaul’s breating (breathing is laboured and characterised by deep breaths).
Patients presenting with type 1 diabetes are prone to ketoacidosis when insulin
treatment is withheld or under conditions of severe stress with an excess of counterregulatory hormones. These patients are often thin in appearance.
Characteristics of type 1 diabetes include:




Polyuria – excessive urination resulting from a large loss of water.
Polydipsia – excessive thirst resulting from intracellular dehydration.
Polyhagia – excessive hunger
Weight loss – despite an increase in food consumption.
These, as mentioned, are related to elevated blood glucose levels and glucosuria
(“spilling of glucose into the urine”).
Possible triggers for the activation on Type 1 diabetes in those with a genetic
predisposition include viruses, drugs and environmental toxins. These individuals are
also prone to other autoimmune disorders like those of the thyroid (Grave’s Disease,
Hashimoto thyroiditis), Addison’s Disease, vitilgo and pernicious anaemia.
TYPE 2 DIABETES
Type 2 diabetes is the most prevalent form of diabetes mellitus and accounts for
approximately 90 % of all diabetic cases. It is often diagnosed in adults above the
age of 40 and is thus referred to as “adult onset diabetes”. While it is more common
in adults, there has been an increase in adolescent Type 2 diabetes, thought to be
associated with an increased sedentary lifestyle and obesity in addition to an
inheritable genetic propensity for the disease.
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Risk factors for type 2 diabetes include obesity, family history, habitual sedentary
lifestyles, race or ethnicity, hypertension, dyslipidemia, polycystic ovary disease and
a history of gestational diabetes mellitus.
Type 2 diabetes was previously called non insulin dependent diabetes and while
ketoacidosis might occur, patients with type 2 diabetes are generally not prone to
this disorder because they usually possess sufficient insulin to prevent the
breakdown of excess fat to supply energy. This type of diabetes progresses through
multiple phases and evolves gradually
Patients presenting with Type 2 diabetes are characterised by defects in insulin
secretion and insulin resistance
The pancreatic cells usually have enough insulin stored to compensate for insulin
resistance however the reserve insulin is generally not enough to fully compensate
for insulin resistance.
As type 2 diabetes evolves and progresses, the beta cells become impaired and
over the course of time are no longer able to compensate for insulin resistance. In
the end, it is hepatic glucose production that determines plasma glucose
concentrations. In the final stages of type 2 diabetes the liver becomes insulin
resistant....so basically clinical type 2 diabetes sets in when the pancreas becomes
exhausted and can no longer compensate for insulin resistance. Insulin resistance
and insulin levels are generally high for years before the onset of clinical type
2 diabetes.
IMPAIRED INSULIN SECRETION
The pancreas of individuals with normal cell function, insulin secretion is adjusted to
maintain normal glucose tolerance. Basically, glucose tolerance describes the
processes that occur to move glucose from the blood into your cells once you’ve
eaten.
In non-diabetic individuals, insulin secretion rises in proportion to the severity of
insulin resistance....and glucose tolerance remains normal.
INSULIN RESISTANCE
Simply put, insulin resistance in type 2 diabetics, refers to the fact that while their
body’s might possess sufficient insulin, there do not possess sufficient receptors for
insulin to bind to.
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Most people exhibiting type 2 diabetes are obese and this is thought to be an
important contributing factor to insulin resistance. The increased adipose tissue
(adiposity) in obese individuals is associated with increased free fatty acid levels in
the plasma. This inhibits the use of peripheral glucose and promotes glucose
production in the liver (glycogen to glucose). In addition, the expanded fat cell mass
and adiposity in obese individuals are resistant to insulin’s antilipolytic effects.
Chronically elevated plasma free fatty acid concentrations are now recognised in
aiding in impairing insulin secretion and leading to insulin resistance in the muscle
and liver. Increased fat content closely correlates with insulin resistance in these
tissues.
In “normal” individuals, glucose injestion results in insulin cells being secreted into
the portal vein and carried to the liver. Here it suppresses glucagon secretion and
reduces hepatic glucose output.
Patient’s exhibiting type 2 diabetes fail to suppress glucagon upon glucose injestion.
This means that insulin resistance in the liver along with hyperglucagonemia, leads
to the continued production of hepatic glucose.
So...type 2 diabetics have 2 sources of glucose:


Glucose in the post prandial state (directly from what is consumed).
From continued hepatic glucose production.
About 80 % of total body glucose uptake occurs in the skeletal muscle (muscle is the
major site of glucose disposal). In type 2 diabetes, the primary site of insulin
resistance resides in muscle tissue.
Normally, increased insulin concentrations in the plasma, lead to a linear increase in
glucose uptake by the muscles. This contrasts with type 2 diabetics in whom the
onset of insulin action is delayed (by approximately 40 minutes) and its ability to
stimulate glucose uptake is halved. Usually, the kidneys are unable to reabsorb all
the glucose from the blood it filters and so some glucose will “pass” into the urine.
Insulin resistance is associated with a number of cardiovascular risk factors.
These include hyperinsulinemia, coagulation abnormalities, dyslipidemia,
hypertension and abdominal obesity. This association is referred to as THE
METABOLIC SYNDROME. Simply put, it is a combination of medical conditions that,
when occurring together increase the risk of developing cardiovascular disease and
diabetes.
While lethargy, polyuria, nocturia, & polydipsia can be seen at diagnosis in type 2
diabetes, significant weight loss is less common.
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GESTATIONAL DIABETES
This form of diabetes complicates roughly 7 % of all pregnancies. It refers to,
carbohydrate intolerance that results in hyperglycaemia with onset of pregnancy.
This definition is irrespective of whether or not insulin therapy is required or whether
the condition persists after pregnancy. It should be noted however, that women that
present with diabetes before the onset of pregnancy do not have gestational
diabetes...they have diabetes mellitus and pregnancy and are usually closely
monitored before and after pregnancy.
Complications from gestational diabetes for the foetus include neonatal death and
foetal overgrowth leading to abnormally foetus for the gestational age
(macrosomia). Complications for the mother include among other things a
caesarean section birth and hypertension.
DIABETIC COMPLICATIONS
Table 2: The clinical manifestations of type 1 and type 2 diabetes mellitus.
CHARACTERISTIC
AGE
ONSET
PHYSICAL TRAITS
INSULIN RESISTANCE
AUTO ANTIBODIES
KETONES AT DIAGNOSIS
SYMPTOMS
INSULIN
THERAPY REQUIREMENTS
ACUTE COMLICATIONS
MICROVASCULAR
COMPLICATIONS
MACROVASCULAR
COMPLICATIONS
TYPE 1 DIABETES
< 3O
TYPE 2 DIABETES
>30
Abrupt
Gradual
Lean
Obese or history thereof
Absent
Present
Often present
Rarely present
Present
Absent
Symptomatic
Asymptomatic
Immediate
May take years after diagnosis
Diabetic ketoacidosis
No
Rare


Hyperosmolar
Hyperglycaemic state
Common
Common
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ACUTE COMPLICATIONS OF DIABETES
Hyperglycaemia



As mentioned earlier, glucosuria causes osmotic diuresis (ie. increased urination as
a result of certain substances that are either non-absorbable or poorly absorbed by
the kidneys) which results in dehydration.
Dehydration stimulates thirst (polydipsia)
Glucosuria can lead to significant calorie loss, hence the excessive hunger
(polyphagia) that accompanies hyperglycaemia.
Polyuria, polydipsia and polyphagia are common in type 1 diabetes and symptomatic
in type 2 diabetes.

Dehydration, calorie loss (in urine) and muscle wasting account for the characteristic
weight loss exhibited by type 1 diabetics.
Diabetic ketoacidosis
 Diabetic ketoacidosis is routinely treated with potassium (K+) supplements, because
vomiting and diuresis deplete K+ stores in the body.
 Acidosis and hyperglycaemia however, maintain normal to slightly elevated K+
levels until corrected, by causing a shift of potassium out of the cells.
 Serum K+ levels drop and K+ moves back into cells upon administration of insulin
and correction of acidosis.
 If left untreated potassium levels can drop so low that they cause fatal cardiac
complications.
Hyperosmolar coma




Occurs in type 2 diabetics
Often occurs because there is sufficient insulin to suppress lipolysis and prevent
ketogenesis.
Because of the lack of ketoacidosis and its accompanying symptoms, these patients
often exhibit more profound hyperglycaemia and dehydration, because they present
much later.
Higher incidence for coma occurs in type 2 diabetes because glucose levels are so
high that effective osmolality is often > 340 mOsm/L, as compared to patients
presenting with ketoacidosis and its symptoms much earlier on.
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CHRONIC COMPLICATIONS OF DIABETES
There is a direct relationship between the long term elevation of blood sugar levels
and the most serious complications of diabetes.
Microvascular and microvascular disease are chronic circulatory conditions
associated with diabetes.
Microvascular disease, also known as small vessel disease, occurs when the small
capillaries at nerve endings become inflamed and engorged.
Retinopathy:


Present in both type 1 and type 2 diabetes
Refers to damage to the eyes retina that usually results from long term diabetes.
Nephropathy:


End stage renal disease occurs more frequently in type 1 diabetes (as compared to
type 2 diabetes), however type 2 diabetes accounts for more than half the diabetic
population with this disease because of the greater prevalence of type 2 diabetes.
Hypertension speeds up disease
Neuropathy:


Occurs in approximately 60 % on type 1 and type 2 diabetics.
High morbidity
In macrovascular disease, also known as large vessel disease, plaque formation in
the large vessels causes them to close.




Coronary heart disease is the leading cause of death in type 2 diabetes.
Diabetes is said to be the major cause of non traumatic amputations (peripheral
vascular disease).
Risk of atherosclerosis in women is equal to that in men.
Significant morbidity in type 1 and type 2 diabetes.
Diabetics are generally more prone to severe infections, because of abnormal cell
mediated immunity, vascular lesions that could hinder blood flow and prevent
inflammatory cells from reaching possible sites of infection, also phagocytosis and
neutrophil chemotaxis are defective in poorly controlled diabetes.
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Table 3: The micro and macrovascular diseases associated with diabetes mellitus.
MICROVASCULAR DISEASE
MACROVASCULAR DISEASE
Strokes
Peripheral vascular disease
Coronary heart disease
Blindness
Stroke
Neuropathy, retinopathy, nephropathy
DIAGNOSIS AND MANAGEMENT OF DIABETES
Diabetes mellitus is characterised by persistent hyperglycaemia and is generally
diagnosed by testing glucose plasma levels, usually in one of the following ways:

Taking a fasting plasma glucose sample (2 glucose fasting levels of 7 .0 mmol/l or
higher is considered diagnostic for diabetes).
 Patients are considered to have impaired fasting glucose when their fasting
glucose levels are between 6.1 and 6.9 mmol/l.

Glucose Tolerance Test – A fasting glucose sample is taken and then a 75g glucose
load is orally administered (ie. as a drink). Glucose levels are then re-tested 2 hours
later. This helps give the physician a view of the patients ability to metabolise
glucose. A 2 hour plasma glucose of 11.0 mmol/l or higher is generally considered
an indicator of diabetes.
 Patients are considered to have impaired glucose tolerance, when glucose levels
are between 7.8 and 11.1 mmol/l 2 hours after injesting the 75g glucose load.

Glycolated haemoglobin levels (HBA1C), reflect average plasma glucose levels over
a period of between 8 to 12 weeks (the average lifespan of a red blood cell). It can
be performed any time of the day and doesn’t need special preparations and is
therefore the preferred method for monitoring glycaemic control in diabetics. Values
that are 6.5 % or higher aide in diagnosing diabetes (World Health Organisation).
The glucose fasting test is generally easier to perform as it does not require the time
commitment involved in the glucose tolerance test. For this reason and because the
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glucose tolerance test has no prognostic value over the fasting test, the glucose
fasting test is generally the preferred of the two (Saydah et al,2001).
Diabetes mellitus is a chronic condition with no known cure. Therefore effective
management is essential in treating this disease. Effective management focuses on
diet, exercise, medication and self monitoring.
Diabetic complications are far less common and severe in patients who are educated
about their disease and understand and participate in maintaining well managed
glucose levels (Nathan et al, 2005). According to the National Institute for Health and
Clinical Excellence, the goal of treatment should be HBA1C values of around 6.5 %
(not lower) and monitoring should take into account other health consideration that
may exacerbate the disease (eg.Obesity or smoking).
Medications like metformin (usually 1st line of treatment in type 2 diabetes) and
insulin are used in the treatment of diabetes.
While much research is being done and needs to be done to help elucidate the
precise mechanisms of diabetes and ways in which to further minimize its staggering
mortality rates, we should take a moment to see precisely how far we have
come....and what better way to illustrate this than the fact that before the discovery of
insulin in 1921, there was no treatment for diabetes. Diabetic children were left
comatose and dying (from ketoacidosis), until insulin was first administered on that
fateful day in 1922. With this single dose, diabetic children were able to awake from
their comas within minutes, and in that moment between unconsciousness and
consciousness, diabetes became a manageable disease instead of one with no
hope.
The scientists involved in extracting insulin from pancreatic beta cells, first tested
their ‘‘concoction” on diabetic dogs, and were able to keep a dog whose pancreas
had been removed, alive for an entire summer, by using insulin to regulate the
animals glucose levels.
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Figure 4: Two of the scientists involved in the discovery of insulin with the diabetic dog they managed
to keep alive using insulin.
(http://www.medicalnewstoday.com/info/diabetes/discoveryofinsulin.php)
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