The significance of the kidney in diabetes T2DM: an introduction

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What is T2DM?

Definition and diagnosis

Type 2 diabetes mellitus (T2DM) is a chronic, progressive disease,1 characterised

by hyperglycaemia. Insulin resistance (i.e., a reduced cellular

response to the hormone)2 and impaired pancreatic β-cell function

are the chief pathogenetic mechanisms.3 They often occur in concert,

resulting in over-production of glucose from the liver, diminished glucose

uptake in tissues throughout the body, and consequently a net increase

in blood glucose levels.

Simple blood tests allow for the diagnosis of T2DM as well as prediabetes,

which is a condition of milder dysglycaemia at high risk of progressing

to overt T2DM. The criteria for the diagnosis of prediabetes and

diabetes are presented in Table 1 and 2.

a Defined using the 2h oral glucose tolerance test (OGTT) after ingesting the 75g glucose load.4
b The test should be performed in a laboratory using a method that is NGSP certified and
standardised to the DCCT assay.5 IFG and IGT represent intermediate states of abnormal
glucose regulation that exist between normal glucose homeostasis and diabetes.6 Impaired
fasting glucose (IFG) is now defined by an elevated fasting plasma glucose (FPG) concentration
(≥100 and <126 mg/dl; ≥5.6 and <7 mmol/l).7 Impaired glucose tolerance (IGT) is defined by an
elevated 2-h plasma glucose concentration (≥140 and <200 mg/dl; ≥7.8 and <11.1 mmol/l)
after a 75-g glucose load on the oral glucose tolerance test (OGTT) in the presence of an FPG
concentration <126 mg/dl.7 8

a Defined using the 2h oral glucose tolerance test (OGTT) after ingesting the 75g glucose load.4
B The test should be performed in a laboratory using a method that is NGSP certified and standardised
to the DCCT assay.5
c In a patient with classic symptoms of hyperglycaemia or hyperglycaemic crisis.5
* In the absence of unequivocal hyperglycaemia, FPG, PPG and HbA1c should be confirmed by
repeat testing.

Glucose metabolism: an overview
T2DM is a disease of glucose homeostasis, so it is pertinent here to briefly
review the basics of glucose metabolism. ATP, the universal energy currency
of life, is generated via the oxidation of glucose, non-esterified
fatty acids (NEFA) and, to a lesser extent, amino acids. Glucose can
be obtained from food via digestion or it can be synthesised in the
body. Glucose obtained from carbohydrates in the diet is actively
transported from the lumen of the intestine into the blood by the main
transporter protein, sodium-glucose transport protein 1 (SGLT-1)9 10 The
majority of absorbed glucose reaches the liver where it is in part stored
as glycogen (glycogen synthesis), whilst the remainder is taken up by
peripheral tissues for both oxidative and non-oxidative (storage) use;
excess glucose is converted into lipids (de novo lipogenesis) in the liver
and, to a lesser degree, in adipose tissue.11 12

The many roles of insulin
Insulin is the key hormone in glucose homeostasis. This peptide has a
number of key functions, including promoting the uptake of glucose by
cells throughout the body. Insulin, secreted by the b-cells of the pancreas,
is transported to and binds to its receptor, a tyrosine kinase enzyme
consisting of two extracellular α-subunits and two b-subunits that
span the cell membrane. These receptors are ubiquitous, with almost
every cell in the body expressing them.9 10
When insulin binds to the receptor, it phosphorylates various intracellular
proteins, activating a cascade of events resulting, among other
effects, in stimulated glucose uptake via active transport (Figure 1).9 10

As a first step, insulin activates the hexokinase enzyme, which phosphorylates
glucose, effectively trapping it within the cell.12 In hepatocytes,
insulin inhibits the activity of glucose-6-phosphatase, the enzyme
responsible for liberating free glucose from the glucose-6-phosphate
originating from glycogen (glycogenolysis) and de novo glucose synthesis
(gluconeogenesis).12 As well as preventing the release of glucose
from the hepatocytes, insulin also activates several of the enzymes
that are directly involved in glycolysis and glycogen synthesis, including
phosphofructokinase and glycogen synthase, respectively.12 When
glucose is abundant, insulin stimulates the liver to convert it to glycogen
for storage and later use.12

The synthesis of glycogen cannot continue unabated and as the stores
of this molecule reach around 10% of the liver’s entire mass, further glycogenesis
is strongly suppressed and any additional glucose taken up
by the liver cells is shunted into pathways leading to the production of
fatty acids.12 13 Once synthesised, these fatty acids are exported from
the liver as lipoproteins, which are degraded in the circulation into free
fatty acids that can be used by a number of tissues.12 13
In addition to regulating the uptake of glucose and the synthesis of fatty
acids, insulin also promotes the accumulation of triglycerides in adipocytes.
Insulin facilitates the entry of glucose into adipocytes where it is
broken down to glycerol-phosphate, which esterifies fatty acids (synthesised
in the liver) yielding a triglyceride.12 13
These processes highlight the importance of insulin in everything to do
with how the body stores, mobilises and utilises its energy sources. Furthermore,
in regulating these process, insulin also stimulates the uptake of
amino acids, increases the permeability of many cells to potassium,
magnesium and phosphate ions, and activates sodium-potassium ATPase
enzymes in many cells, causing a flux of potassium into cells.12 14
The pathophysiology of T2DM
In essence, the pathophysiological mechanisms involved in the development
of T2DM are the deterioration of b-cell function accompanied
by a reduced incretin effect, an over-activity of a-cells resulting in hyperglucagonaemia,
and insulin resistance. Simply stating these mechanisms
belies the true complexity of T2DM pathophysiology. We are still
a very long way from a complete understanding of the processes that
lead to the development of this disease, but with each new advance
in understanding there comes a better appreciation of how to tackle
T2DM.
Insulin resistance
Insulin resistance at the tissue level contributes significantly to hyperglycaemia
by impeding the degree to which target cells respond to
the presence of insulin.9 10 15-17 For example, with respect to hepatocytes
and adipocytes, insulin resistance reduces glucose uptake with a consequent
increase in glucose and free fatty acid output, respectively
(Figure 2).15 16 18 Elevated levels of glucose and free fatty acids are believed
to negatively impact b-cell function (discussed below), underlining
the intimate relationship between these two pathophysiological
mechanisms.

Obesity is known to be the most common cause of insulin resistance.16
The exact relationship between the two is not fully understood, but it
is thought to involve a number of processes, involving excessive storage
of triglycerides in the liver (steatosis).19 Lipids are more abundant
in obese individuals and it is thought that these may interfere with the
signalling processes crucial to the correct functioning of insulin.20 Obesity
also triggers inflammatory responses, some of which are important in
intracellular signalling within insulin-responsive cells.20 Furthermore, the
adipose tissue is far from being an inert storage ‘depot’ (see below).20

β-cell dysfunction
The b-cells of the pancreas do not respond to rising glucose levels or
other stimuli that regulate insulin secretion to match the current metabolic
requirements. This results in a relative lack of insulin contributing
to chronic hyperglycaemia, especially in the situation of insulin resistance
with its higher insulin needs.16 In the early stages of T2DM, with
the advent of resistance, there is a compensatory increase in insulin
secretion in an attempt to maintain glucose and lipid homeostasis.17
However, the time dynamics of insulin release is abnormal even at this
stage because of a reduced sensitivity of b-cells to glucose. This defect
is accentuated in overt T2DM. In long-standing disease, there is
usually a reduction in the islet number and/or diminished b-cell mass
in the pancreas of people with T2DM due to increased apoptosis and
inadequate regeneration.22 Why this should occur is not clear, but it
is likely to be due to a combination of genetic susceptibility and acquired
factors. Many b-cell ‘aggressors’ have been identified, such as
elevated glucose and free fatty acid levels (Figure 3), all of which lead
to b-cell damage and apoptosis. For example, increased levels of free
fatty acids within b-cells can inhibit proper glucose utilisation, disrupt
normal cell signalling cascades and damage mitochondria due to the

generation of reactive oxygen species.16 Interestingly, b-cells have a
very low antioxidant capacity.23

Reduced incretin effect
The incretin system and the defects therein observed in people with
T2DM are reviewed in Chapter 4. Incretins are a quantitatively important
stimulus to insulin secretion after meals, so that defects in this
entero-insular axis will contribute to relative insulin deficiency in type 2
diabetes.
The scope of the T2DM problem
Epidemiology
T2DM is a huge public health problem, the growth of which shows no
signs of abating. The epidemiological statistics of this disease are staggering.
Every ten seconds two people develop diabetes.26 Globally, it is
estimated that 285 million people have this disease (just over 6% of the
global population) and by 2030, there are projected to be more than
430 million people with this disease.26 The rise of T2DM as a global epidemic
has accompanied the rapid cultural and social changes - shifting
demographics, increasing urbanization, dietary changes, reduced
physical activity and other unhealthy lifestyle and behavioural patterns
- that have taken place over the last five decades or so.26
Globally, diabetes is the fourth leading cause of death. Every year,
diabetes kills nearly four million people, almost half of whom are less
than 70 years old.26 An even greater number die from cardiovascular
disease made worse by diabetes-related complications.26 T2DM alone

constitutes about 85% to 95% of all diabetes cases in developed countries
and accounts for an even higher percentage in developing countries.26
The impact of T2DM is certainly comparable to other diseases of modern
society, such as hypertension and obesity, and often coexists with
these other conditions.
When we think of diabetes we tend to imagine a disease that afflicts affluent,
western societies, but increasingly T2DM respects neither wealth
nor social status and the places with the most serious T2DM are countries
such as India (see below). Indeed, almost 80% of diabetes deaths
occur in low- and middle-income countries as these countries often
lack the necessary healthcare resources to manage this disease effectively.
26 These developing countries are also likely to see the largest increases
in the prevalence of T2DM in the coming years and decades.26
A silent disease
The epidemiological figures certainly make disturbing reading, but they
are not the whole story. T2DM, especially in its early stages, is a silent
disease. Symptoms, even if they occur, are mild and are easily overlooked
even though hyperglycaemia and the consequences thereof
are insidiously causing damage. At least 50% of all people with diabetes
are unaware of their condition and in some countries this figure may
reach 80%.26
By the time they are diagnosed, a considerable proportion of people
have already started to develop diabetes-associated complications,
such as retinal abnormalities with a potential to lead to visual
impairment in the long run, initial damage to the kidneys (albuminuria)
eventually threatening kidney function, heart disease, stroke and nerve
damage.26 Studies suggest that the typical patient with new-onset
T2DM has had the disease for at least 4–7 years before it is diagnosed.27
It seems that undiagnosed T2DM is far from being a benign condition.27
Clinically significant morbidity is present at diagnosis and for years
before diagnosis.27 Among people with T2DM, 25% are believed to have
retinopathy; 9%, neuropathy; and 8%, nephropathy at the time of
diagnosis.28
Economic burden
T2DM and its complications (considered later in this chapter) have a
significant economic impact on individuals, families, health systems
and countries. Costs include those for healthcare, loss of earnings, and
economic costs to society in terms of loss of productivity and associated
lost opportunities for economic development.29 The CODE study
revealed that hospitalisations account for 55% of all T2DM expenditure
in Europe.30

In developing countries such as India, where almost 51 million people
have T2DM,26 lack of access to health care services, as well as lack of
national welfare schemes and health insurance coverage for diabetes
make treatment unaffordable for the masses resulting in late diagnosis
and the early onset of complications, with their heavy economic burden.31
In the United States, almost 27 million people have diabetes and an additional
57 million are estimated to have pre-diabetes, putting them at
an increased risk for developing diabetes.26 29 The total cost of diabetes
in 2007 was $174 billion, including $116 billion in excess medical expenditures
and $58 billion in reduced national productivity.32 Medical costs
attributed to diabetes include $27 billion for care to directly treat diabetes,
$58 billion to treat the chronic complications that are attributed
to diabetes, and $31 billon in excess general medical costs.32 The largest
components of medical expenditures attributed to diabetes are
hospital inpatient care (50% of total cost), diabetes medication and
supplies (12%), retail prescriptions to treat complications of diabetes
(11%), and physician office visits (9%).32 Of the chronic complications
of diabetes, peripheral vascular disease accounts for the greatest proportion
of expenditure in that category (Figure 4).32

In the UK, the cost of diabetes to the National Health Service is approximately
£1 million per hour, and is increasing rapidly.33 Around 2.1 million
people in the UK have diabetes, which is forecast to rise to 2.5 million
by 2030.26 Diabetes accounts for approximately a tenth of the NHS’
budget each year, a total exceeding £9 billion.33 In 2004-2005, primary
care units in England dispensed by prescription 24.8 million items for the

drug management of diabetes (to control hyperglycaemia), costing
the NHS £458 million.34 In 2009-2010 this had risen by more than 40% to
more than 35.5 million different items prescribed, at a cost of nearly
£650 million.34
The largest increase in diabetes prevalence is predicted to occur in
India and China. By 2030, there are predicted to be 62 million and 87
million people with diabetes in China and India, respectively.26 The
WHO estimates that in the period 2006–2015, China will lose $558 billion
in national income due to heart disease, stroke and diabetes alone. A
2007 study from India shows that total, annual median expenditure on
diabetes health care was $227 in urban areas and $142 in rural areas.35
This not may seem a great deal, but when we consider that the mean
annual income in urban areas is $2,273 and $818 in rural areas we get
a sense of how economically debilitating this condition is for people
in developing countries.35 People with diabetes in urban India spend
around a tenth of their income on diabetes healthcare, whereas those
in rural areas spend around a fifth. In developing countries, grinding
poverty and an extreme shortage of state healthcare collude to reveal
the huge burden of diabetes.
Societal burden
Aside from the obvious economic burden of T2DM there are the negative
impacts on society that are much harder to quantify. The complications
of T2DM and the treatments patients have to take for the rest
of their life can lead to depression, which has ramifications for the way
in which an individual interacts with family and friends. Similarly, family
members may be placed under great pressure by the need to juggle
family life, their career and the needs of a spouse or child with T2DM.
Quantifying these aspects of the T2DM burden is practically impossible,
but they must be considered in the development of disease management
strategies and in attempts to define the full impact of the disease.

Risk factors in the development of T2DM
Genetic predisposition
Genetics are of fundamental importance in the emergence and the
progression of T2DM, but deciphering which genes code for which
proteins in the bewildering complexities of the metabolic regulatory
mechanisms and how they interact will take many more years of intense
study to fully elucidate. This area has been further complicated
by our growing understanding of epigenetics. Epigenetics relates to
heritable differences that are not caused directly by underlying genetic
mechanisms.36 Typically, these can be caused by methylation of
the genome causing some genes to be activated and others to be
deactivated, although other mechanisms are also possible.36
Epigenetics aside, around 50 candidate genes involved mainly in pancreatic
b-cell function, but also in insulin action/glucose metabolism
and other metabolic mechanisms that increase T2DM risk have been
identified,37 but their individual role enhances the risk for T2DM by less
than 20-30 %. Thus multiple polymorphisms must be present to substantially
influence individual diabetes risk.
The more well-known candidate genes include transcription factor
7-like 2 (TCF7L2) gene, peroxisome proliferator-activated receptor-γ
(PPARγ), ATP binding cassette, subfamily C, member 8 (ABCC8) and
CAPN10. It has been postulated that TCF7L2 gene variants may affect
the susceptibility to T2DM by indirectly altering GLP-1 levels.38 The
PPARγ gene is important in adipocytes and lipid metabolism, with one
form (Pro) decreasing insulin sensitivity and increasing T2DM risk several
fold.37 ABCC8 codes for the receptors and potassium channels that
regulate the release of hormones from the pancreas. A mutation in the
receptor or channel can affect the secretion of hormones, such as insulin.
37 CAPN10 codes an enzyme (calpain 10), variations in the activity
of which can affect insulin secretion.37
Obesity
Obesity is the most potent risk factor for developing T2DM. The correlation
between diabetes and obesity is well-known (Figure 5).39 In an
evolutionary context, the obesity epidemic is a consequence of maladaptation,
i.e. the human genotype has not adapted to the modern
lifestyle with food abundance relative to shortage (as was typical for
our ancestors). Evolution equipped humans with the ability to survive
on meagre, albeit intermittently abundant, food resources – a situation
that prevailed for the vast majority of human evolution. Compared with
our ancient ancestors, our anatomy and physiology are unchanged,
but in recent centuries, lifestyles have changed immeasurably in the

vast majority of cultures. Today, humans are largely sedentary with
easy access to an abundance of energy-rich, processed foods.
The physiological links between obesity and diabetes are poorly understood,
but what is important is that obesity leads to insulin resistance in
the majority of cases.20 It is generally thought that defects in lipid metabolism
in obese patients are the root cause of T2DM in these patients.20
In the obese patient, lipid molecules may leak from the adipocytes
into the bloodstream where they are eventually taken up by liver and
muscle cells.20 Once inside these cells, the lipids interfere with signalling
processes crucial to the correct functioning of insulin.20 In addition,
insulin resistance is associated with subclinical inflammatory responses
throughout the body.20 Furthermore, it is also becoming increasingly
clear that adipose tissue is far more than just a storage tissue, acting
in many ways like an endocrine organ. In obesity, the para-endocrine
functions of this tissue may be impaired.20

Increasing age
T2DM can develop at any age. Typically, however, the prevalence of
this disease increases with age (Figure 6) and one reason why T2DM is
such a rapidly growing problem is the aging population.40 Internationally,
T2DM is most common in the 40-59 age group, but the incidence
of the disease is increasing more rapidly in adolescents and young
adults.41 The fact that T2DM prevalence typically increases with age is
probably a result of the progressive loss of b-cell function that occurs
with age, particularly in susceptible individuals who have other risk factors,
e.g. poor diet, sedentary lifestyle, etc.

Ethnicity
The prevalence of T2DM around the world is heavily influenced by
race/ethnicity. For example, the incidence of T2DM in white Europeans
is relatively low compared with Asian/Pacific Islanders (Figure 7).41 Exactly
why there should be such variation is not fully understood, but it is
more than likely to be due to a complex interplay of factors involving
genetic and environmental elements.
Even in children, the prevalence of T2DM varies with ethnicity, as exemplified
in Figure 8.42 The pattern in Figure 7 can be explained to some
extent by the prevalence of obesity in these ethnic groups. For example,
in children between the ages of 2 and 5 years, the prevalence
of obesity in white non-Hispanics, black non-Hispanics and Mexican
Americans was 8.6%, 8.8% and 13.1%, respectively.43 As children grow
older (adolescents 12–19 years old), the differences in the prevalence
of obesity become even more marked: 12.7% in white non-Hispanics;
23.6% in black non-Hispanics and 23.4% in Mexican Americans.43

Lifestyle
A variety of lifestyle factors are known to influence the risk of developing
T2DM. Exercise has a definite effect on T2DM. Studies have shown
that exercise appears to reduce the risk of developing T2DM even after
adjusting for body-mass index (Figure 9).44 The relative risk of developing
this disease in those people exercising vigorously once a week,
2–4 times a week and ≥5 times a week is 0.77 (95% CI: 0.55–1.07), 0.62
(95% CI: 0.46–0.82) and 0.58 (95% CI: 0.40–0.84), respectively.44 Exercise

appears to optimise the ways in which our body uses glucose, such as
enhancing the uptake of this sugar by muscle cells.
The effect of alcohol on the risk of developing T2DM appears to be
less clear cut. A meta-analysis of 15 prospective cohort studies demonstrates
a U-shaped relationship between alcohol consumption and the
risk of developing T2DM.45 In those people who consume a moderate
amount of alcohol (6–48 g/day) there is highly significant, 30% reduced
risk of T2DM, but no risk reduction is observed in heavy consumers (≥48
g/day) or those who abstain from alcohol.45
Exactly why there should be such a relationship between alcohol
consumption and risk of T2DM is not fully understood. Moderate alcohol
consumption is known to increase HDL cholesterol concentration,
46 whereas, higher consumption is known to be associated with increased
body weight, triglyceride concentration and blood pressure
increase.47-50 Alcohol also has anti-inflammatory effects and these may
provide some degree of protection from the inflammatory mechanisms
involved in the development of T2DM.51 52 Enhanced insulin sensitivity
with lower plasma insulin concentrations is another potential mechanism
that explains this relationship.48

Smoking is also known to increase the risk of developing T2DM. Tobacco,
or at least some of the biologically active compounds in commercial
tobacco, can result in high blood sugar levels and insulin insensitivity.
53 54 A study in US male physicians showed that in past smokers and
those who smoked <20 or ≥20 cigarettes per day the relative risk of
developing T2DM was 1.2 (95% CI: 1.0–1.4), 1.4 (95% CI: 1.0–2.0) and 2.1
(95% CI: 1.7–2.6), respectively.55

Other risk factors
A number of other factors are known to increase the risk of developing
T2DM. For example, individuals with impaired glucose tolerance (IGT)
or impaired fasting glucose (IFG) are at an increased risk of developing
this disease.28 IGT and IFG are pre-diabetic states characterised by the
same pathophysiological abnormalities of T2DM, only milder in degree.
A history of gestational diabetes mellitus is known to increase the risk
of developing T2DM later on in life.28 In around 3-8% of pregnancies,
impaired glucose tolerance or full gestational diabetes can develop.56
The reason for this is not clear, but it is thought that the hormones produced
during pregnancy, notably progesterone, can worsen insulin
resistance in susceptible individuals, resulting in raised blood glucose
levels.57 The transient demand on glucose-regulating mechanisms may
contribute to T2DM later on.57 Additionally, an abnormal metabolic intrauterine
milieu affects foetal development by permanently modifying
expression of key genes regulating b-cell development (Pdx1) and
glucose transport (Glut4) in muscle.58 Ultimately, this can lead to the
development of T2DM in adulthood.58 This observation reinforces the
importance of epigenetics in the development of T2DM (see Genetic
predisposition section earlier in this chapter).
Women with polycystic ovarian syndrome are also at an increased risk
of developing T2DM.28 It is thought the hormonal imbalances associated
with this condition, notably the overproduction of androgens can
impair carbohydrate metabolism, ultimately leading to impaired glucose
tolerance and T2DM.59
T2DM complications
Underlying aetiology
T2DM causes a number of complications that together account for
much of the morbidity, mortality and burden associated with this disease.
These complications can be broadly divided into two categories:
microvascular and macrovascular. Regardless of the classification, all
complications of T2DM are a consequence of chronic hyperglycaemia
and the other metabolic and haemodynamic abnormalities that
accompany this disease such as central obesity, dyslipidaemia and
hypertension.60 Several of these diabetic complications can also occur
in patients with normal glucose tolerance and prediabetes.28

Elevated levels of glucose are found throughout the body of an individual
with T2DM from the blood in their arteries supplying oxygen
and substrates to the fluid that bathes their cells. If these elevated glucose
levels persist for an extended period of time then cellular damage
ensues. Exactly how elevated glucose levels damage cells is not
fully understood, but a number of candidate mechanisms have been
identified. Elevated glucose levels result in the non-enzymatic formation
of glycated proteins and, ultimately, advanced glycosylated end
products (AGEs), the accumulation of sorbitol and fructose, increased
hexosamine pathway flux and the activation of protein kinase C.61-63
One consequence of this over-abundance of sugars is an increase in
oxidative stress, i.e. increased concentrations of free radicals generated
during the metabolism of the overly abundant sugars.61 62 Similarly,
this excess of sugars causes osmotic stress, i.e. the reduced ability of the
cell to regulate its water and solute levels.61 62
The damage sustained by cells and tissues accumulates until compensatory
mechanisms are insufficient to prevent a decline in function and
diabetic complications become symptomatic (Figure 10).61 The cells
particularly affected by hyperglycaemia are capillary endothelial cells
throughout the body, mesangial cells in the renal glomerulus and neurons
and Schwann cells in the autonomic and peripheral nerves.61 Unlike
most other cells, the cell types above are unable to reduce their
uptake of glucose when they are exposed to hyperglycaemic conditions.
61
Figure

Microvascular complications
The microvascular complications are retinopathy, nephropathy and
neuropathy all of which are characterised by non-inflammatory damage
to the cells in question and progressive loss of function in the
respective organs and systems.
Retinopathy is the most frequent cause of new cases of blindness
among adults aged 20-74 years of age.64 It is caused by damage to
the capillary endothelial cells in the retina and risk factors include duration
of T2DM, hypertension, and smoking.64 During the first two decades
of diabetic disease, 60% of patients with T2DM develop some degree
of retinopathy, which is often accompanied by glaucoma, cataracts
and macular disease or other eye disorders, all of which occur earlier
and more frequently in people with this disease.64 Diabetic retinopathy
is often linked with diabetic nephropathy.65 Diabetic nephropathy is discussed
in detail in Chapter 2, suffice to say here that it is a progressive
kidney disease caused by changes in glomerular structure and function
and expansion of extracellular matrix and that approximately onethird
of all people with T2DM have some degree of renal impairment.66
Neuropathy is characterised by a progressive decline predominantly
in sensation, but also in movement and other bodily functions due to
damage of the neurons and their insulating Schwann cells.61 Neuropathy
is broadly divided into peripheral and autonomic. The former
is impaired sensation in the legs, feet, arm or hands – often accompanied
by pain, carpal tunnel syndrome and erectile dysfunction,67 while
the latter is characterised by problems with breathing, blood pressure,
bladder control, vision and the gastrointestinal tract (e.g. gastroparesis).67
Neuropathy is a significant source of morbidity and mortality in people
with diabetes and T2DM is the leading cause of this condition in the
Western world.68 Recent studies have found that peripheral neuropathy
affects approximately 70% of people with T2DM.69 70 Other studies have
shown that peripheral nerve damage is a factor in 76% of all diabetic
foot ulcers, implicating this T2DM complication in 50-75% of all non-traumatic
amputations.68 71 Ulcers and amputations as a consequence of
diabetes-induced peripheral neuropathy are a huge problem. Some
estimates suggest that every 30 seconds a lower limb is lost somewhere
in the world as a consequence of diabetes.72 The mortality rate in those
diabetic patients with new-onset ulceration of the feet is 43%–55%. In
those people who undergo an amputation, this rises to almost 75% – a
mortality rate that is higher than several types of cancer.73-79
Needless to say, the burden of foot complications due to diabetesinduced
peripheral neuropathy is huge. Economic analyses have suggested
that the cost of treating diabetic foot ulcers in Europe alone
may be as high as €10 billion per year.80 For all its debilitating and eco

nomic impacts, diabetic neuropathy is a typically overlooked complication
of T2DM.
Macrovascular complications
People with T2DM are at increased risk of macrovascular complications,
such as stroke, transient ischaemic attacks, coronary artery disease,
myocardial infarction, hypertension and peripheral vascular disease.
As varied as these may seem, they are all a consequence of
hyperglycaemia-induced damage to the endothelium of blood vessels,
most notably the arteries. This injury to the endothelium triggers a
cascade of events, collectively known as atherogenesis (Figure 11).60
This process also involves an inflammatory response within the vessel
wall, which ultimately results in the formation of atherosclerotic lesions
that effectively narrow the lumen of arteries throughout the body, as
well as hardening the arterial walls (Figure 11). This narrowing impedes
blood flow and can increase the chances of clot formation. However,
the most catastrophic consequence of this inflammatory process is the
potential for the lesion to rupture with debris and associated clots occluding
a downstream portion of a blood vessel, which in some cases,
can be fatal.60
The atherogenic cascade begins with the oxidation of lipids from LDL
particles, which accumulate in the endothelial wall of arteries.60 Angiotensin
II is thought to promote the oxidation and accumulation of
lipids.60 Following this initial step, monocytes infiltrate the arterial wall
and differentiate into macrophages, which accumulate oxidised lipids
to form foam cells.60 Once formed, these foam cells stimulate macrophage
proliferation as well as attracting T-lymphocytes.60 In turn, the
T-lymphocytes induce smooth muscle proliferation and the accumulation
of collagen in the arterial walls.60 The net result of this inflammatory
cascade is the formation of a lipid-rich atherosclerotic lesion with a
fibrous cap.60
In addition to the inflammatory mechanisms outlined above, there is
also evidence of increased platelet adhesion and hypercoagulability
in people with T2DM. These phenomena may be as a result of impaired
nitric oxide generation, increased free radical formation and altered
calcium regulation in the platelets, all of which promote platelet aggregation.
Not only is platelet aggregation often increased in people
with T2DM, but there is also evidence that the process of fibrinolysis may
be impaired due to elevated levels of plasminogen activator inhibitor
type 1.60 It is very likely this combination of increased coagulability and
impaired fibrinolysis further increases the risk of vascular occlusion and
cardiovascular (CV) events in T2DM.81

The physical narrowing of the arteries and the potential for the atherosclerotic
lesion to rupture and completely occlude a blood vessel significantly
increases the risk of CV events. In people with diabetes, the
risk of myocardial infarction is comparable to the risk in non-diabetic
patients with a history of previous MI.82 T2DM increases the risk of stroke
by 150–400% and the risk of death from CV causes by two to six-fold.83
Indeed, more than 70% of patients with T2DM die of CV causes.84 Needless
to say, the societal and economic burden of macrovascular complications
in the context of overall healthcare costs attributable to
T2DM is huge. Data suggest that CV disease accounts for the largest
proportion of all diabetes-related healthcare expenditure.85 86

Chapter 1 Summary
zzType 2 diabetes mellitus (T2DM) is a chronic, progressive disease, characterised
by hyperglycaemia. Insulin resistance (i.e., a reduced cellular
response to the hormone) and impaired pancreatic β-cell function are the
chief pathogenetic mechanisms.
zzSimple blood tests allow for the diagnosis of T2DM as well as prediabetes,
which is a condition of milder dysglycaemia at high risk of progressing to
overt T2DM.
zzThe criteria for the diagnosis of diabetes are as follows:
◦◦ Fasting plasma glucose (FPG): ≥126 mg/dl (7.0 mmol/l)
◦◦ Post-prandial glucose (PPG): ≥200 mg/dl (11.1 mmol/l)
◦◦ HbA1c ≥6.5%
◦◦ Random plasma glucose: ≥200 mg/dl (11.1 mmol/l)
zzInsulin has a number of key functions, including promoting the uptake of
glucose by cells throughout the body.
zzIn essence, the pathophysiological mechanisms involved in the development
of T2DM are the deterioration of β-cell function accompanied by a
reduced incretin effect, an over-activity of a-cells resulting in hyperglucagonaemia,
and insulin resistance.
zzThe β-cells of the pancreas do not respond to rising glucose levels appropriately,
which results in a relative lack of insulin contributing to chronic
hyperglycaemia.
◦◦ Many β-cell ‘aggressors’ have been identified, such as elevated glucose
and free fatty acid levels, all of which lead to β-cell damage and apoptosis.
zzEvery ten seconds, two people develop diabetes
◦◦ Globally, it is estimated that 285 million people have this disease (just over
6% of the global population) and by 2030, there are projected to be more
than 430 million people with this disease.
zzDiabetes is the fourth leading cause of death.
◦◦ Every year it kills nearly four million people, almost half of whom are less
than 70 years old.
zzThe typical patient with new-onset T2DM has had the disease for at least
4–7 years before it is diagnosed. By the time they are diagnosed, a considerable
proportion of people have already started to develop diabetesassociated
complications.
zzThe total cost of diabetes in the US in 2007 was $174 billion.
zzIn the UK Diabetes accounts for approximately a tenth of the NHS’ budget
each year, a total exceeding £9 billion.
zzGenetics are of fundamental importance in the emergence and the progression
of T2DM and many candidate genes have been identified that
increase the risk of developing T2DM.

zzEpigenetics is also thought to be very important in the development of
T2DM.
zzObesity is the most potent risk factor for developing T2DM.
zzThe prevalence of T2DM around the world is heavily influenced by race/
ethnicity.
◦◦ The incidence of T2DM in white Europeans is relatively low compared with
Asian/Pacific Islanders.
zzLack of exercise has a significant impact on the risk of developing T2DM.
zzIndividuals with impaired glucose tolerance (IGT) or impaired fasting glucose
(IFG) are at an increased risk of developing T2DM.
zzRegardless of the classification, all complications of T2DM are a consequence
of chronic hyperglycaemia and the other metabolic and haemodynamic
abnormalities that accompany this disease such as central obesity,
dyslipidaemia and hypertension.
zzElevated glucose levels result in the non-enzymatic formation of glycated
proteins and, ultimately, advanced glycosylated end products (AGEs), the
accumulation of sorbitol and fructose, increased hexosamine pathway flux
and the activation of protein kinase C.
◦◦ This over-abundance of sugars causes oxidative and osmotic stress.
zzThe cells particularly affected by hyperglycaemia are capillary endothelial
cells throughout the body, mesangial cells in the renal glomerulus and
neurons and Schwann cells in the autonomic and peripheral nerves.
◦◦ These cell types above are unable to reduce their uptake of glucose
when they are exposed to hyperglycaemic conditions.
zzThe microvascular complications are retinopathy, nephropathy and neuropathy.
zzMacrovascular complications include stroke, transient ischaemic attacks,
coronary artery disease, myocardial infarction, hypertension and peripheral
vascular disease.
◦◦ As varied as these may seem, they are all a consequence of hyperglycaemia-
induced damage to the endothelium of blood vessels, most notably
the arteries.
◦◦ Data suggest that cardiovascular disease accounts for the largest proportion
of all diabetes-related healthcare expenditure.

References:
1. The American Association of Clinical Endocrinologists Medical Guidelines for the
Management of Diabetes Mellitus: the AACE system of intensive diabetes selfmanagement--
2000 update. Endocr Pract 2000;6(1):43-84.
2. Matthaei S, Stumvoll M, Kellerer M, Haring HU. Pathophysiology and pharmacological
treatment of insulin resistance. Endocrine reviews 2000;21(6):585-618.
3. Wajchenberg BL. beta-cell failure in diabetes and preservation by clinical treatment.
Endocrine reviews 2007;28(2):187-218.
4. WHO. Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia:
WHO, 2006.
5. ADA. Standards of medical care in diabetes--2010. Diabetes care 2010;33 Suppl 1:
S11-61.
6. Nathan DM, Davidson MB, DeFronzo RA, Heine RJ, Henry RR, Pratley R, et al. Impaired
fasting glucose and impaired glucose tolerance: implications for care. Diabetes
care 2007;30(3):753-9.
7. Genuth S, Alberti KG, Bennett P, Buse J, Defronzo R, Kahn R, et al. Follow-up report
on the diagnosis of diabetes mellitus. Diabetes care 2003;26(11):3160-7.
8. Mellitus ECotDaCoD. Report of the Expert Committee on the Diagnosis and Classification
of Diabetes Mellitus. Diabetes care 1997;20(7):1183-97.
9. Jung CY, Lee W. Glucose transporters and insulin action: some insights into diabetes
management. Archives of pharmacal research 1999;22(4):329-34.
10. Shepherd PR, Kahn BB. Glucose transporters and insulin action--implications
for insulin resistance and diabetes mellitus. The New England journal of medicine
1999;341(4):248-57.
11. Benardot D. Advanced Sports Nutrition. Champaign: Human Kinetics, 2006.
12. Nussey S, Whitehead S. The Endocrine Pancreas Endocrinology: an integrated approach.
Oxford: BIOS Scientific Publishers Ltd 2001.
13. Ratnayake WM, Galli C. Fat and fatty acid terminology, methods of analysis and
fat digestion and metabolism: a background review paper. Annals of nutrition &
metabolism 2009;55(1-3):8-43.
14. Williams G, Pickup JC. Handbook of Diabetes, 3rd Edition: Wiley-Blackwell, 2004.
15. DeFronzo RA. Lilly lecture 1987. The triumvirate: beta-cell, muscle, liver. A collusion
responsible for NIDDM. Diabetes 1988;37(6):667-87.
16. DeFronzo RA. Pathogenesis of type 2 diabetes mellitus. The Medical clinics of North
America 2004;88(4):787-835, ix.
17. Olatunbosun S, Dagogo-Jack S. Insulin resistance: eMedicine, WebMD, 2009.
18. Rhodes CJ, White MF. Molecular insights into insulin action and secretion. European
journal of clinical investigation 2002;32 Suppl 3:3-13.
19. Youssef W, McCullough AJ. Diabetes mellitus, obesity, and hepatic steatosis. Seminars
in gastrointestinal disease 2002;13(1):17-30.
20. Wellcome Trust. How does obesity cause ill-health?: Wellcome Trust, 2009.
21. FEND. Diabetes. The policy puzzle: Is Europe making progress. , 2008.
22. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and
increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 2003;52(1):
102-10.
23. Drews G, Krippeit-Drews P, Dufer M. Oxidative stress and beta-cell dysfunction.
Pflugers Arch 2010;460(4):703-18.
24. Boden G, Shulman GI. Free fatty acids in obesity and type 2 diabetes: defining
their role in the development of insulin resistance and beta-cell dysfunction.
European journal of clinical investigation 2002;32 Suppl 3:14-23.
25. Kaiser N, Leibowitz G, Nesher R. Glucotoxicity and beta-cell failure in type 2 diabetes
mellitus. J Pediatr Endocrinol Metab 2003;16(1):5-22.
26. International Diabetes Federation. IDF Diabetes Atlas, 4th edition, 2009.
27. Harris MI, Klein R, Welborn TA, Knuiman MW. Onset of NIDDM occurs at least 4-7 yr
before clinical diagnosis. Diabetes care 1992;15(7):815-9.
28. Votey S, Peters A. Diabetes, Type 2 - A Review: Web MD, 2010.
29. Hewitt Associates LLC. Trends in HR and Employee Benefits: Chronic disease analysis -
diabetes trends, 2009.

30. Jonsson B. Revealing the cost of Type II diabetes in Europe. Diabetologia 2002;
45(7):S5-12.
31. Narayan KM, Zhang P, Williams D, Engelgau M, Imperatore G, Kanaya A, et al. How
should developing countries manage diabetes? CMAJ 2006;175(7):733.
32. ADA. Economic costs of diabetes in the U.S. In 2007. Diabetes care 2008;31(3):
596-615.
33. Diabetes UK. The cost of diabetes 2008.
34. Diabetes UK. Cost of diabetes to the NHS rising rapidly, 2010.
35. Ramachandran A, Ramachandran S, Snehalatha C, Augustine C, Murugesan N,
Viswanathan V, et al. Increasing expenditure on health care incurred by diabetic
subjects in a developing country: a study from India. Diabetes care 2007;30(2):252-6.
36. Feinberg AP. Epigenetics at the epicenter of modern medicine. JAMA 2008;299(11):
1345-50.
37. WHO. Genetics and Diabetes: WHO, 2009.
38. Yi F, Brubaker PL, Jin T. TCF-4 mediates cell type-specific regulation of proglucagon
gene expression by beta-catenin and glycogen synthase kinase-3beta. The Journal
of biological chemistry 2005;280(2):1457-64.
39. Maskarinec G, Grandinetti A, Matsuura G, Sharma S, Mau M, Henderson BE, et al.
Diabetes prevalence and body mass index differ by ethnicity: the Multiethnic Cohort.
Ethnicity & disease 2009;19(1):49-55.
40. Joint Health Surveys Unit. Health Survey for England 2006: Cardiovascular disease
and risk factors. Leeds: The Information Centre, 2008.
41. International Diabetes Federation. IDF Diabetes Atlas, 2nd edition, 2003.
42. Liese AD, D’Agostino RB, Jr., Hamman RF, Kilgo PD, Lawrence JM, Liu LL, et al. The
burden of diabetes mellitus among US youth: prevalence estimates from the
SEARCH for Diabetes in Youth Study. Pediatrics 2006;118(4):1510-8.
43. Hannon TS, Rao G, Arslanian SA. Childhood obesity and type 2 diabetes mellitus.
Pediatrics 2005;116(2):473-80.
44. Manson JE, Nathan DM, Krolewski AS, Stampfer MJ, Willett WC, Hennekens CH.
A prospective study of exercise and incidence of diabetes among US male physicians.
JAMA 1992;268(1):63-7.
45. Koppes LL, Dekker JM, Hendriks HF, Bouter LM, Heine RJ. Moderate alcohol consumption
lowers the risk of type 2 diabetes: a meta-analysis of prospective observational
studies. Diabetes care 2005;28(3):719-25.
46. Rimm EB, Williams P, Fosher K, Criqui M, Stampfer MJ. Moderate alcohol intake and
lower risk of coronary heart disease: meta-analysis of effects on lipids and haemostatic
factors. BMJ (Clinical research ed 1999;319(7224):1523-8.
47. Kato I, Kiyohara Y, Kubo M, Tanizaki Y, Arima H, Iwamoto H, et al. Insulin-mediated
effects of alcohol intake on serum lipid levels in a general population: the Hisayama
Study. J Clin Epidemiol 2003;56(2):196-204.
48. Kiechl S, Willeit J, Poewe W, Egger G, Oberhollenzer F, Muggeo M, et al. Insulin sensitivity
and regular alcohol consumption: large, prospective, cross sectional population
study (Bruneck study). BMJ (Clinical research ed 1996;313(7064):1040-4.
49. Thadhani R, Camargo CA, Jr., Stampfer MJ, Curhan GC, Willett WC, Rimm EB.
Prospective study of moderate alcohol consumption and risk of hypertension in
young women. Archives of internal medicine 2002;162(5):569-74.
50. Wannamethee SG, Shaper AG. Alcohol, body weight, and weight gain in middleaged
men. Am J Clin Nutr 2003;77(5):1312-7.
51. Imhof A, Froehlich M, Brenner H, Boeing H, Pepys MB, Koenig W. Effect of alcohol
consumption on systemic markers of inflammation. Lancet 2001;357(9258):763-7.
52. Sierksma A, van der Gaag MS, Kluft C, Hendriks HF. Moderate alcohol consumption
reduces plasma C-reactive protein and fibrinogen levels; a randomized, diet-controlled
intervention study. Eur J Clin Nutr 2002;56(11):1130-6.
53. Epifano L, Di Vincenzo A, Fanelli C, Porcellati F, Perriello G, De Feo P, et al. Effect of
cigarette smoking and of a transdermal nicotine delivery system on glucoregulation
in type 2 diabetes mellitus. Eur J Clin Pharmacol 1992;43(3):257-63.
54. Eliasson B, Attvall S, Taskinen MR, Smith U. The insulin resistance syndrome in smokers
is related to smoking habits. Arterioscler Thromb 1994;14(12):1946-50.
55. Manson JE, Ajani UA, Liu S, Nathan DM, Hennekens CH. A prospective study of
cigarette smoking and the incidence of diabetes mellitus among US male physicians.
The American journal of medicine 2000;109(7):538-42.

56. Dabelea D, Snell-Bergeon JK, Hartsfield CL, Bischoff KJ, Hamman RF, McDuffie RS.
Increasing prevalence of gestational diabetes mellitus (GDM) over time and by
birth cohort: Kaiser Permanente of Colorado GDM Screening Program. Diabetes
care 2005;28(3):579-84.
57. Rebarber A, Istwan NB, Russo-Stieglitz K, Cleary-Goldman J, Rhea DJ, Stanziano GJ,
et al. Increased incidence of gestational diabetes in women receiving prophylactic
17alpha-hydroxyprogesterone caproate for prevention of recurrent preterm delivery.
Diabetes care 2007;30(9):2277-80.
58. Pinney SE, Simmons RA. Epigenetic mechanisms in the development of type 2
diabetes. Trends Endocrinol Metab 2010;21(4):223-9.
59. Legro RS, Kunselman AR, Dodson WC, Dunaif A. Prevalence and predictors of risk
for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary
syndrome: a prospective, controlled study in 254 affected women. The Journal of
clinical endocrinology and metabolism 1999;84(1):165-9.
60. Fowler M. Macrovascular and microvascular complications in type 2 diabetes
patients. Clinical Diabetes 2008;26(2):77-82.
61. Brownlee M. The pathobiology of diabetic complications: a unifying mechanism.
Diabetes 2005;54(6):1615-25.
62. Gerich JE. Clinical significance, pathogenesis, and management of postprandial
hyperglycemia. Archives of internal medicine 2003;163(11):1306-16.
63. Brownlee M. Biochemistry and molecular cell biology of diabetic complications.
Nature 2001;414(6865):813-20.
64. Fong DS, Aiello L, Gardner TW, King GL, Blankenship G, Cavallerano JD, et al. Retinopathy
in diabetes. Diabetes care 2004;27 Suppl 1:S84-7.
65. Jawa A, Kcomt J, Fonseca VA. Diabetic nephropathy and retinopathy. The Medical
clinics of North America 2004;88(4):1001-36, xi.
66. Koro CE, et al. Antidiabetic medication use and prevalence of chronic kidney
disease among patients with type 2 diabetes mellitus in the United States. Clin.
Therapeutics 2009;31(11):2608-17.
67. ADA. Standards of medical care in diabetes--2009. Diabetes care 2009;32 Suppl 1:
S13-61.
68. Vinik AI, Park TS, Stansberry KB, Pittenger GL. Diabetic neuropathies. Diabetologia
2000;43(8):957-73.
69. Karvestedt L, Martensson E, Grill V, Elofsson S, von Wendt G, Hamsten A, et al. The
prevalence of peripheral neuropathy in a population-based study of patients with
type 2 diabetes in Sweden. Journal of diabetes and its complications 2010.
70. Lauterbach S, Kostev K, Becker R. Characteristics of diabetic patients visiting a
podiatry practice in Germany. J Wound Care 2010;19(4):140-44.
71. Gordois A, Scuffham P, Shearer A, Oglesby A, Tobian JA. The health care costs of
diabetic peripheral neuropathy in the US. Diabetes care 2003;26(6):1790-5.
72. International Diabetes Federation. Time to Act: Diabetes and Foot Care: International
Diabetes Federation, 2005.
73. Apelqvist J, Larsson J, Agardh CD. Long-term prognosis for diabetic patients with
foot ulcers. Journal of internal medicine 1993;233(6):485-91.
74. Faglia E, Favales F, Morabito A. New ulceration, new major amputation, and
survival rates in diabetic subjects hospitalized for foot ulceration from 1990 to 1993:
a 6.5-year follow-up. Diabetes care 2001;24(1):78-83.
75. Jeffcoate WJ, Chipchase SY, Ince P, Game FL. Assessing the outcome of the
management of diabetic foot ulcers using ulcer-related and person-related measures.
Diabetes care 2006;29(8):1784-7.
76. Moulik PK, Mtonga R, Gill GV. Amputation and mortality in new-onset diabetic foot
ulcers stratified by etiology. Diabetes care 2003;26(2):491-4.
77. Naschitz JE, Lenger R. Why traumatic leg amputees are at increased risk for cardio
vascular diseases. QJM 2008;101(4):251-9.
78. Resnick HE, Carter EA, Lindsay R, Henly SJ, Ness FK, Welty TK, et al. Relation of lowerextremity
amputation to all-cause and cardiovascular disease mortality in American
Indians: the Strong Heart Study. Diabetes care 2004;27(6):1286-93.
79. Schofield CJ, Libby G, Brennan GM, MacAlpine RR, Morris AD, Leese GP. Mortality
and hospitalization in patients after amputation: a comparison between patients
with and without diabetes. Diabetes care 2006;29(10):2252-6.
80. Prompers L, Huijberts M, Schaper N, Apelqvist J, Bakker K, Edmonds M, et al.
Resource utilisation and costs associated with the treatment of diabetic foot ulcers.
Prospective data from the Eurodiale Study. Diabetologia 2008;51(10):1826-34.

81. Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis: epidemiology,
pathophysiology, and management. JAMA 2002;287(19):2570-81.
82. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart
disease in subjects with type 2 diabetes and in nondiabetic subjects with and without
prior myocardial infarction. The New England journal of medicine 1998;339(4):229-34.
83. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial
intervention and cardiovascular disease in patients with type 2 diabetes. The New
England journal of medicine 2003;348(5):383-93.
84. Laakso M. Cardiovascular disease in type 2 diabetes: challenge for treatment and
prevention. J Intern Med 2001;249(3):225-35.
85. Hogan P, Dall T, Nikolov P. Economic costs of diabetes in the US in 2002. Diabetes
care 2003;26(3):917-32.
86. Paterson AD, Rutledge BN, Cleary PA, Lachin JM, Crow RS. The effect of intensive
diabetes treatment on resting heart rate in type 1 diabetes: the Diabetes Control
and Complications Trial/Epidemiology of Diabetes Interventions and Complications
study. Diabetes care 2007;30(8):2107-12.
87. Stary HC, Chandler AB, Dinsmore RE, Fuster V, Glagov S, Insull W, Jr., et al. A definition
of advanced types of atherosclerotic lesions and a histological classification of
atherosclerosis. A report from the Committee on Vascular Lesions of the Council on
Arteriosclerosis, American Heart Association. Circulation 1995;92(5):1355-74.