medicina

Review
From Pre-Diabetes to Diabetes: Diagnosis,
Treatments and Translational Research
Radia Marium Modhumi Khan 1,† , Zoey Jia Yu Chua 2,† , Jia Chi Tan 3,† , Yingying Yang 4,5 ,
Zehuan Liao 3,6, * and Yan Zhao 3, *
1 School of Chemical and Biomedical Engineering, Nanyang Technological University, 62 Nanyang Drive,
Singapore 637459, Singapore
2 School of Physical and Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link,
Singapore 637371, Singapore
3 School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive,
Singapore 637551, Singapore
4 Tongji University School of Medicine, Shanghai 201204, China
5 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 65 Solna, Sweden
6 Department of Microbiology, Tumor, and Cell Biology (MTC), Karolinska Institutet, Biomedicum,
Solnavägen 9, SE-17177 Stockholm, Sweden
* Correspondence: [email protected] (Z.L.); [email protected] (Y.Z.)
† Contributed equally to this work.




Received: 29 June 2019; Accepted: 23 August 2019; Published: 29 August 2019


Abstract: Diabetes, a silent killer, is one of the most widely prevalent conditions of the present time.
According to the 2017 International Diabetes Federation (IDF) statistics, the global prevalence of
diabetes among the age group of 20–79 years is 8.8%. In addition, 1 in every 2 persons is unaware of
the condition. This unawareness and ignorance lead to further complications. Pre-diabetes is the
preceding condition of diabetes, and in most of the cases, this ultimately leads to the development
of diabetes. Diabetes can be classified into three types, namely type 1 diabetes, type 2 diabetes
mellitus (T2DM) and gestational diabetes. The diagnosis of both pre-diabetes and diabetes is based on
glucose criteria; the common modalities used are fasting plasma glucose (FPG) test and oral glucose
tolerance test (OGTT). A glucometer is commonly used by diabetic patients to measure blood glucose
levels with fast and rather accurate measurements. A few of the more advanced and minimally
invasive modalities include the glucose-sensing patch, SwEatch, eyeglass biosensor, breath analysis,
etc. Despite a considerable amount of data being collected and analyzed regarding diabetes, the actual
molecular mechanism of developing type 2 diabetes mellitus (T2DM) is still unknown. Both genetic
and epigenetic factors are associated with T2DM. The complications of diabetes can predominantly
be classified into two categories: microvascular and macrovascular. Retinopathy, nephropathy,
and neuropathy are grouped under microvascular complications, whereas stroke, cardiovascular
disease, and peripheral artery disease (PAD) belong to macrovascular complications. Unfortunately,
until now, no complete cure for diabetes has been found. However, the treatment of pre-diabetes has
shown significant success in preventing the further progression of diabetes. To prevent pre-diabetes
from developing into T2DM, lifestyle intervention has been found to be very promising. Various
aspects of diabetes, including the aforementioned topics, have been reviewed in this paper.

Keywords: diabetes; pre-diabetes; insulin resistance; hyperglycemia

1. Introduction
Diabetes mellitus (DM) is a form of metabolic disorder whereby the patients suffer high blood
sugar levels because their bodies do not respond to, or produce inadequate, insulin—a hormone that

Medicina 2019, 55, 546; doi:10.3390/medicina55090546 www.mdpi.com/journal/medicina

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helps to stabilize the blood sugar (glucose) level by directing the cells to take up glucose and inhibit
hepatic glucose production [1]. There are generally 3 types of diabetes: Type I, II and gestational
diabetes but more emphasis is placed on the first 2 types of diabetes. Type I diabetes is a form of
autoimmune disease whereby the cells that produce insulin are destroyed by its own immune system
whereas type II diabetes, being more common than type I, happens when the body does not respond
to the insulin produced. In chronic conditions, diabetes can lead to long-term damage, dysfunction,
and failure of different organs, especially the eyes, kidneys, nerves, heart, and blood vessels [2,3]. A few
typical complications of diabetes are blindness (retinopathy), renal failure, diabetic foot disorders
(severe infections on the legs, which will eventually lead to amputation) and cardiovascular diseases [4].
Despite the tremendous effort put into prolonging the lives of patients with DM, diabetes has
remained as the 5th leading cause of death worldwide and has directly resulted in 1.6 million deaths [5,6].
Diabetic patients are reported to have a 15% increased risk of premature death and life expectancy
reduced by approximately 10 and 20 years for type I and type II diabetes, respectively [7,8]. According
to the 2017 International Diabetes Federation (IDF) statistics, the global prevalence of diabetes among
the age group of 20–79 years is 8.8%. In addition, 1 in every 2 persons is unaware of the condition [9].
By 2030, diabetes is estimated to affect 439 million adults, up from the previous estimation of 366
million [10,11]. However, statistics show that the number of diabetic patients worldwide was 422
million in 2014 [6]. Thus, a new report has estimated that there will be at least 592 million diabetes
cases worldwide in 2035 [12]. Diabetes is also reported to be more prevalent in the urban population
when compared to the rural population, and affects more men than women [13]. Diabetes can affect
anyone, but many studies that date back to as early as 1969 show that Asians, people who origin from
Far East, Southeast Asia, or the Indian subcontinent, particularly South Asian, are more susceptible to
diabetes than people from other ethnicities [14–19].
A study conducted in 1985 at Southall, West London, demonstrated that the prevalence of diabetes
in Asians was at least 3.8-fold higher than Europeans and 5-fold higher for patients aged between 40 to
64 years old [20]. Ramachandran et al., published in 2012, stated that more than 60% of the world’s
diabetic population were from Asian countries, as Asians are genetically and ethnically predisposed
to diabetes and thus have a lower tolerance for environmental risk factors. The paper reported that
Asians develop diabetes at a lower body mass index (BMI) as well as a smaller waist circumference, as
compared to the Western population, and have a younger onset age for diabetes [21]. This is mirrored
in a study conducted in the United States, where Asian Americans were shown to be at a higher risk
of getting diabetes, despite having lower rates of obesity than non-Hispanic whites [22]. Another
study of a total combined sample size of 54,326 people was also conducted in the United States. In this
large-scale study, the prevalence of diabetes in foreign-born South Asians (13.6%) was almost 2 times
more than foreign-born other Asians (7.4%), and more than twice that of U.S.-born non-Hispanic
whites (5.6%). Among the patients with normal BMI, the prevalence in foreign-born South Asians was
at least 5-fold higher than U.S.-born non-Hispanic whites at 14.1% and 2.7%, respectively. Although
foreign-born South Asians have a prevalence similar to that of U.S.-born Hispanics, only 45.6% of the
foreign-born South Asian diabetic populations are considered as overweight or obese, compared to
67.1% of the U.S.-born Hispanics [23]. This is in line with the claim made by Ramachandran et al.
As diabetes is a worldwide epidemic, and more prevalent in South Asian ethnicity, Asian countries
will not be spared by this disease, and some would label Asia as the epicenter of this epidemic [24].
The International Diabetes Federation (IDF) reported that in 2013, nearly 382 million people worldwide
suffered from diabetes and 60% of them reside in Asia [25]. IDF also predicted that by 2035, the number
will go up to 592 million people. In contrast to the statistics found in the Western countries, where
diabetes is more common in elderly, research has shown that the Asian population has a high incidence
rate of diabetes even in young or middle-aged adults [26]. This further supports the idea that people
of South Asian ethnicity are more vulnerable towards diabetes. At the same time, there is growing
evidence showing that Asian countries are experiencing a faster rate and higher burden of diabetes
patients than any other regions [10,27–29]. According to a nation-wide survey conducted in Singapore,
Medicina 2019, 55, 546 3 of 30

a total of 440,000 Singaporeans has been diagnosed with diabetes and this number is expected to grow
up to 1 million by 2050, which is 15% of the population [30]. This is strong evidence that diabetes is
an urgent health concern in Asia, which must be addressed immediately. It is important to raise the
awareness of the public and draw attention to the adverse effects of diabetes, as well as gather national
support to tackle diabetes.
To be diagnosed as diabetic, one’s blood glucose level needs to be equal to or above a certain value.
According to the American Diabetes Association (ADA), there are four methods for the diagnosis of
diabetes and the same methods are used for the screening of pre-diabetes in patients [31]. The methods
are:

(1) Fasting plasma glucose test (FPG): where fasting refers to the absence of food and drink intake,
apart from water, for at least 8 h before the test; or
(2) Oral glucose tolerance test (OGTT): where a patient consumes a glucose syrup solution containing
75 g of glucose before which a blood test is carried out to determine 2-hr plasma glucose (PG); or
(3) A1C (Glycated hemoglobin or hemoglobin bounded to glucose) levels via a laboratory test; or
(4) Random PG of more than or equal to 200 mg/dL or 11.1 mmol/L in patients that displayed
symptoms of hyperglycemia or hyperglycemic crisis.

A comparison between results for normal, diabetes and pre-diabetes diagnoses based on the first
three criteria can be summarized as in Table 1 [32].

Table 1. A comparison between normal, pre-diabetes and diabetes based on three diagnosis methods.

FPG PG in OGTT A1C

Normal <100 mg/dL or 5.5 mmol/L <140 mg/dL or 7.8 mmol/L <5.7% or 39 mmol/mol
Pre-Diabetes ≥100 mg/dL or 5.5 mmol/L ≥140 mg/dL or 7.8 mmol/L ≥5.7% or 39 mmol/mol
Diabetes ≥126 mg/dL or 7.0 mmol/L ≥200 mg/dL or 11.1 mmol/L ≥6.5% or 48 mmol/mol

There are pros and cons in these different diagnostic methods. FPG ≥ 140 mg/dL is a highly specific
but rather insensitive test for the diagnosis of DM [33]. Almost all subjects with FPG ≥ 140 mg/dL will
have PG in OGTT ≥ 200 mg/dL, but a significant portion of subjects (depending on the population)
with PG in OGTT ≥ 200 mg/dL will not have an FPG ≥ 140 mg/dL. A1C test measures the glycation
of proteins and can potentially indicate chronic hyperglycemia, but this test does not directly prove
high blood glucose levels—the clinical definition of DM [34]. Furthermore, measuring PG in OGTT
is a more accurate method than measuring FPG and A1C in diagnosing DM [35]. However, PG in
OGTT ≥ 200 mg/dL may also indicate impaired glucose tolerance, rather than full-blown diabetes.
Therefore, it is recommended that more than one test is used in diagnosing DM.
Many studies, as reported above, have been done on diabetes patients. However, little is known
about the pre-diabetic conditions. Pre-diabetes is a term used to describe the buffer period before
the onset of type II diabetes, where the blood sugar level is higher than normal but lower than the
diagnostic criteria of type II diabetes. Impaired β-cell function and increased insulin resistance are two
pathological pathways that lead to pre-diabetes, and subsequently, diabetes. The onset of increased
insulin resistance starts years before diabetes and even pre-diabetes [36]. More specifically, insulin
resistance in skeletal muscle tissues can be regarded as the initiating factor that is present decades
before impaired β-cell function [37]. Additionally, in a study conducted by Cerasi et. al., it was
observed that there was a decrease in glucose-induced insulin release of the pancreatic β-cells in
diabetic and pre-diabetic patients [38]. The dose–response curve for glucose-induced insulin release
shifted to the right and further right for pre-diabetic and diabetic patients, respectively, as compared to
normal individuals [38]. Moreover, it was also reported that there was a significant increase in β-cell
function 3 to 4 years before diabetes diagnosis, followed by a steep decrease [36]. Combining the
continued increase in insulin resistance with a decrease in β-cell function, glucose levels in the blood
become unregulated and pre-diabetes then evolves into full-blown diabetes.
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It has been estimated that the number of pre-diabetic cases will increase to more than 470 million
people worldwide, and this is understandably a worrying trend [39]. The Centers for Disease Control
and Prevention (CDC) reported that in 2015, almost half (48.3%) of the adult population aged 65 and
above had pre-diabetic conditions and that approximately 84.1 million people in the U.S. were already
pre-diabetic. In accordance with the higher prevalence of diabetes in South Asian ethnicity, the Asian
population indeed showed a higher prevalence in pre-diabetes than the Western population [40].
Studies have shown that non-East Asian countries such as Saudi Arabia (6.8%), India (6.3%) and
South Latin America (17.8%) have pre-diabetes prevalence 2 to 5-fold lower than East Asian countries
as China (35.7%). A total of 37% of pre-diabetic patients who leave their condition untreated may
see themselves develop diabetes in 4 years [13,41–45]. Moreover, if lifestyle changes were adopted,
long-term studies have shown that the risk of this progression—from pre-diabetes to diabetes—can
be lowered for an extended period of 10 years [41]. Pre-diabetes is seen as the critical phase, because
studies have shown that at this stage, the condition is reversible and could serve as a potential route to
combat diabetes [41,45]. Thus, in this paper, we conduct a general review which includes pre-diabetic
conditions, by pooling together publications that discuss diabetes from different perspectives, in the
hope that, with a better understanding of this disease, we can provide invaluable insight as to how we
can combat diabetes around the world.

2. Risk Factors of Type II Diabetes

Diabetes is one of the most prevalent diseases worldwide. Even though a considerable amount
of data has been collected and analyzed regarding diabetes, the actual molecular mechanism of
developing type 2 diabetes mellitus (T2DM) is still unknown. Although the mechanism behind this
disease has yet to be fully understood, according to most researchers, certain factors play a key role in
driving the onset of T2DM. Both genetic and epigenetic factors are associated with T2DM.

2.1. Evidence for Lifestyle and Environmental Risk Factors

2.1.1. Obesity
T2DM occurs due to various factors that cause insulin resistance and β-cell dysfunction. Various
cross-sectional and prospective studies have unanimously confirmed that obesity is one of the
environmental factors that has a correlation with T2DM. A total of 50% of people with T2DM are obese
(BMI > 30 kg/m2 ). A total of 90% of diabetic patients are overweight (BMI > 25 kg/m2 ). Therefore, even
just a moderate weight loss can have an immense impact in controlling diabetes [46,47]. Due to obesity,
the levels of adipocytes, cytokines (interleukin-1 (IL-1) and interleukin-6 (IL-6)), and tumor necrosis
factor alpha (TNFα)) increases in the body. The increased amount of these components triggers a
signaling pathway which represents an inflammatory action of the adipose tissue [48]. This chronic
low-grade inflammatory action might promote insulin resistance in cells [49]. Indeed, in a study
conducted by Barbarroja et al., it was found that the level of mRNA expression of IL-1β and IL-6 among
insulin resistant obese people was high in comparison to non-insulin resistant obese patients [48]. In a
study conducted on the health of nurses, as reported by Wild and Byrne, it was found that women
whose BMI was greater than 35 had a 49-times more chance of developing T2DM compared to those
whose BMI was less than 22. Studies on men have shown similar results. Wild and Byrne also reported
that men with a BMI greater than or equal to 35, had a 42-times higher chance of developing the disease
than men with a BMI less than 23. This study was conducted on a cohort of men from the United States
of America. For Asians (mostly Indians), the onset of higher risk of diabetes starts at an even lower
BMI value (15–20). However, recent studies have shown that larger waist circumference could be a
better indication of developing T2DM than BMI. Several studies in China, the U.S., and Finland state
that the risk of developing T2DM can be lowered through decent weight loss [50].
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2.1.2. Sedentary Lifestyle

Through various studies, a sedentary lifestyle has been proven to be one of the major causes of
developing T2DM. Watching television is one of the major sedentary activities. Watching television is
worse than any other sedentary activity, such as playing board games, sewing, reading, writing or
driving a car. This is because the metabolic rate while watching television is the lowest among the
mentioned sedentary activities [51]. A meta-analysis was conducted with 10 studies, which consisted
of 505,045 participants in total. In the analysis, it was found that people with longer TV time had a
112% higher pool for T2DM compared to the people with shorter TV time [52]. The explanation for this
can be found in BMI. As people tend to spend more time watching TV, they are less physically active.
Hence, their BMI increases. The physiological reasoning is that during acute contraction of active
muscles, there is an immediate uptake of plasma glucose, and when someone is physically inactive,
this does not happen often enough. The decrease in insulin sensitivity is another reason. A study was
conducted by Balkau et al. with 801 apparently healthy volunteers, to find a relation between sedentary
time and insulin sensitivity. In the study, sedentary time was measured with accelerometry and insulin
sensitivity was measured with a hyperinsulinemic-euglycemic clamp. The study concluded that there
was an inverse relationship between sedentary time and insulin sensitivity. The difference between the
most and least physically active hours was only 4 h; however, the insulin sensitivity ranged around
40% [53]. Therefore, by replacing just 30 min of sedentary lifestyle with moderate to vigorous physical
activities, it can improve insulin sensitivity by 15% [54]. Moreover, since a sedentary lifestyle is strongly
correlated with weight gain or obesity, the pathophysiological paths of obesity causing diabetes may
also be applicable to a sedentary lifestyle.

2.1.3. Ageing
A considerable number of studies have found that the chances of T2DM increase with the increase
in age. According to the National Diabetes Statistics Report of the United States of America, it was
found that about 4.0% of people had diabetes in the age group 18–44 years. This number increased to
17.0% in the age group 45–64 years, and the percentage further rose to 25.2% for the age group ≥65
years [55]. Similar results were found in a survey conducted in England. According to the Health
Survey for England (2006), the highest prevalence of diabetes existed in the age group 65–74 years.
A total of 15.7% of the surveyed men in that age group had diabetes, whereas, in the same age group,
10.4% of women had diabetes [56]. In another study conducted by Suastika et al. on a cohort in Bali,
it was found that the prevalence of T2DM was more than 2-fold in the older generation compared
to younger people [57]. A study was conducted on elderly Chinese in 2000 in Taiwan. In the study,
Peng et al. found that 16.9% of them had T2DM. After 5 years, a follow-up survey was done on the
same group of people and it was found that the prevalence of diabetes rose to 23.7% [58]. The most
likely pathophysiological reason behind this is that the human body gets less sensitive to insulin as
it ages. In addition to this, the β-cells get altered or show insufficiency in insulin production as the
human body ages [59].

2.1.4. Sex and Gender

According to a report published by International Diabetes Federation (IDF) in 2017, the total
number of adults (20–79 years) diagnosed for T2DM was 425 million, which is 8.3% of the total
population. The distribution was not equal between men and women. There were 17.1 million more
men diagnosed with diabetes than women (221.0 million were men and the rest, 203.9 million, were
women). This number, both men and women together, is expected to rise to as high as 629 million
by the year 2045, which is 48% more than in 2017 [9]. The imbalance in the prevalence of diabetes
based on gender is yet to be understood. Though more men are diagnosed with T2DM, women
have more cases of obesity which is one of the major causes of T2DM. The probability of diabetes
according to sex and gender arises from various biological and environmental factors. In endocrinology,
Medicina 2019, 55, 546 6 of 30

the most prominent effect of sexual dimorphisms is expressed through T2DM. This might be due
to the difference in sex chromosomes, sex-specific gene expression of autosomes, sex hormones and
their effects on organ systems. Anatomically, men and women have different body fat distribution
and brown adipose tissue (BAT). The healthy range of BMI value of men and women is also different.
The onset of risk of diabetes starts at a lower BMI value for men compared to women. [60]. Conversely,
women have more obesity induced diabetes compared to men. In terms of fat distribution, men
have more trunk and visceral fat (VAT), and liver fat, in comparison to women of the same BMI and
age [61,62]. Moreover, men have a higher amount of VAT for any amount of total fat [63]. Women
have more deposition in leg fat tissue [64]. This difference in fat distribution might be one of the
underlying reasons for the difference in diabetes prevalence among the genders. Recent studies have
found that the different level and activity of brown adipose tissue (BAT) in the genders may play a
role as well [65]. There is a negative relation between the activity of BAT and diabetes risk. Increased
activity of BAT reverses obesity, increases adiponectin and reduces insulin resistance [66]. Besides all
of the aforementioned reasons, the difference in diabetes pattern among the genders may also be due
to different exposures to environmental factors, such as nutrition, health care facilities for prevention
or treatment of diseases, lifestyle, socioeconomic status, psychosocial stress, sleep deprivation, work
stress and many more [67–69]. The extent of the effect of the factors is different for males and females.

2.1.5. Hypertension
The cases of diabetes and hypertension overlap significantly. Therefore, it is very difficult to
understand if diabetes causes hypertension, or if hypertension causes diabetes. Recently, the American
Heart Association regarded diabetes to be a risk, rather than a risk factor, of coronary heart diseases
after recent studies showed that the risk of having myocardial infarction in diabetic individuals is equal
to that of patients who had a history of previous myocardial infarction [70]. Nonetheless, Cheung
and Li have suggested that both the diseases might carry the same or similar etiology and disease
mechanisms [71]. In the Hong Kong Cardiovascular Risk Factor Prevalence Study, Cheung found that
only 42% of the diabetes patients had normal blood pressure and 56% of the hypertension patients had
normal blood glucose level [72]. Cheung and Li have concluded that both diabetes and hypertension
are the results of a metabolic syndrome which is caused by obesity [71]. Therefore, obesity is a risk
factor for both diseases.

2.1.6. Smoking
Several long-term studies have concluded that people who are chronic smokers have a higher
risk of developing T2DM as compared to nonsmokers [73–76]. In one of the studies, it was found that
people having 20 cigarettes a day had 61% higher risk of developing T2DM, whereas, people having
less than 20 cigarettes a day had only 29% higher risk of developing T2DM [74]. The difference is
evident and has been backed by various studies; a higher dose of insulin was needed to achieve the
same metabolic control in smokers as compared to nonsmokers. This risk arises due to the insulin
insensitivity resulting from nicotine, one of the active chemicals in cigarettes [77]. Additionally, it is
not only smoking, but also nicotine patches, that have been found to decrease the effect of insulin [78].
This further confirms that nicotine is an active compound that causes diabetes. Smoking is found to
have severely aggravated glucose tolerance and the insulin sensitivity index [79]. Bergman et al. found
that smokers have reduced expression of peroxisome proliferator-activated receptor-gamma (PPAR-γ),
a transcription factor that promotes insulin sensitivity. They also found that smokers have increased
Serine 636 phosphorylation of insulin receptor substrate IRS-1 [80]. The phosphorylation of this
serine residue results in decreased insulin signaling. Among people with normal BMI, studies have
found that smokers have higher abdominal obesity than nonsmokers, which is a key risk factor for
diabetes [74,81]. Yun et al. conducted a study in which they found that people smoking more than 20
cigarettes had a 1.93 abdominal obesity ratio compared to people who had never smoked [82]. Smoking
is linked to causing detrimental changes in body composition which might lead to the development of
Medicina 2019, 55, 546 7 of 30

diabetes [83]. Through research, Yoshikawa et al. have found that there are nicotine receptors on the
pancreatic insulin-producing β-cells. Evidence from the same research indicates that, not only does
chronic exposure to nicotine increase the risk of T2DM, but also that acute exposure causes a reduction
in insulin sensitivity [84]. Results from a study conducted by Bruin et al. have also shown that nicotine
could cause pancreatic β-cell apoptosis and a reduction in pancreatic β-cell mass [85].
Studies conducted specifically on Asians have also found the positive correlation between smoking
and diabetes. For example, such a trend has been reported by studies in China, Taiwan and Korea.
The majority of Asian men (50% to 60%) are smokers [86–88]. China is both the largest producer and
largest consumer of cigarettes in the world, followed by India, another Asian country. More than 33%
of cigarettes is consumed by people in China alone [89,90]. In a study conducted on 513 Japanese
men, there was a positive correlation between smoking and higher waist-to-hip ratio (visceral adipose:
subcutaneous adipose) [83]. Therefore, the impact of smoking on diabetes is likely to be intense among
the Asian nations.

2.1.7. Alcohol
Alcohol is another risk factor for T2DM when consumed above a certain threshold value.
However, when alcohol is consumed below the threshold value, it reduces the risk of T2DM. The latest
meta-analysis to find the relation between alcohol consumption and T2DM was carried out by
Knott et al. The meta-analysis reviewed 38 studies consisting of 1,082,639 male subjects and 819,966
female subjects. Knott et al. found that when alcohol was consumed at any amount below 63 g/day,
there was a reduction in the risk of T2DM. Moreover, when alcohol consumption was 10–14 g/day,
the reduction was highest. To conclude, when alcohol consumption increases above 63 g/day there is a
positive correlation with the risk of T2DM [91].

2.2. Evidence for Genetic Risk Factors

Genetics is another major risk factor for T2DM. Various studies found that people of certain ethnic
groups have higher chances of developing T2DM than people of other ethnic groups. For example,
Pima Indians living in Western countries have twice the risk of T2DM than native Europeans. It was
found that people whose parents have T2DM have 6 times more risk of developing T2DM, as compared
to the control group. Therefore, people with parents who have T2DM, have a 40% higher chance of
developing the same condition [92]. Over the past 35 years, numerous studies have been conducted
to find if genetics is a reasonable risk factor of T2DM. Park found that family-based linkage analysis,
candidate gene approach and genome wide-association studies (GWAS) were the three approaches
used to find if genetics is responsible. In total, more than 40 genes have been identified as being
responsible for T2DM [93].

2.2.1. Family Based Linkage Analysis

As reviewed by Park, in this kind of analysis, chromosomes of members of the same blood
relation are studied to find the genetic disposition for T2DM [93]. Of the many studies that have
been conducted, a few of them identified CAPN10 and ACRP30 as the putative diabetes susceptibility
genes [94,95]. However, the results did not show consistency over the entire study population. Hence,
these genes could not be definitively concluded as being high risk factors for T2DM [93].

2.2.2. The Candidate Gene Approach

Specific candidate genes or genetic regions of known biological functions are studied. As reported
by Altshuler et al. and Gloyn et al. certain genes such as PPARG and KCNJ11 are linked to T2DM [96,97].
The PPARG gene is responsible for coding PPAR-γ. This receptor demonstrates insulin sensitivity by
controlling the transcription of a few other genes [98]. As suggested by Altshuler et al., when the 12th
amino acid (P12A) is replaced with proline, the risk of T2DM increases significantly [96]. PPAR-γ
improves insulin sensitivity through regulation of the glucose and lipid metabolism related genes
Medicina 2019, 55, 546 8 of 30

such as glucose tranporter-2 (GLUT-2) and liver type glucokinase (LGK). As GLUT-2 and LGK are
responsible for sensing the fluctuation of glucose level in the blood, activation of GLUT-2 and LGK by
PPAR-γ may restore the glucose-sensing ability of β-cells [99]. Furthermore, activation of PPAR-γ also
upregulates the expression of proteins involved in insulin response (insulin receptor substrate 1 and 2,
phosphatidylinositol 3-kinase) and glucose transport (GLUT-4 and c-Cbl-associated protein) [100,101].
Hence, PPAR-γ plays a central role in insulin sensitivity through regulating the genes involved [102].
Apart from PPAR-γ, a polymorphic variation of KCNJ11 may also significantly increase the risk of
T2DM [103]. The pore forming subunit of the ATP sensitive potassium channel (Kir6.2) of the β-cells of
the pancreas is coded by this gene. A gain-of-function mutation of this channel makes the β-cells more
permeable to potassium, thereby making it difficult for the cells to be depolarized [104]. Florez et al. and
Nielsen et al. suggested that when the 23rd amino acid (E23K) of this gene is substituted by glutamic
acid, the risk of T2DM increases substantially [105,106]. Therefore, PPARG and KCNJ11 can be claimed
to be responsible for T2DM to some extent. Hence, some anti-diabetes medications are developed
targeting these genes.

2.2.3. Genome Wide Association Studies (GWAS)

GWAS is the latest of the three approaches in identifying the genetic link of T2DM. Not only
have new genomic regions (SLC30A8, IGF2BP2, CDKN2A/2B, CDKAL1, etc.) concerning T2DM been
detected through this approach, but the previously found genomic regions (PPARG and KCNJ11) have
also been confirmed. A few of the genes that are claimed to be associated with T2DM have been listed
below (Table 2).

Table 2. Summary of some genes responsible for diabetes mellitus.

Year of Genome
Type of Encoded Protein of Wild
Wide Significance Locus Marker Chr Trait
Mutation Type
(GWS)
Missense:
2000 PPARG rs1801282 [96] 3 PPAR-γ a T2DM
Pro12Ala
Missense:
2003 KCNJ11 rs5219 [97] 11 Kir6.2 of pancreatic β-cells a T2DM
Glu23Lys
CDK5 regulatory
CDKAL1 rs7754840 [107,108] 6 Intronic subunit-associated protein T2DM
1-like 1 [109]
2007
Islet-specific zinc
Missense:
SLC30A8 rs13266634 [110,111] 8 membrane transporter T2DM and FG
Arg325Trp
(ZnT8) a
Insulin-like growth factor 2
IGF2BP2 rs4402960 [107,108] 3 Intronic T2DM
mRNA-binding protein a
25 kb
CDKN2A/B rs10811661 [107,108] 9 p16 (INK4A) a T2DM
upstream
FG = Fasting Glucose. a All of the information has been retrieved from “Genetics Home Reference”
(https://ghr.nlm.nih.gov). Part of this table is adapted from [112].

3. Novel Methods to Monitor Blood Glucose Level

According to the ADA and the National Institute of Diabetes and Digestive and Kidney Diseases
(NIH) of the United States, diabetic patients should carry out checks on their blood glucose levels
regularly to ensure that their condition is under control, as both low and high glucose levels can have
deleterious effects on the body [113,114]. Although the exact number of times to check depends on the
type of diabetes and the patient’s medications, there are four common times suggested by the NIH for
carrying out the testing: after waking up (which models fasting), before eating, two hours after eating
and before going to sleep [115,116]. Glucose levels should be targeted at 80–130 mg/dL before eating
and at less than 180 mg/dL after eating [116]. This testing can be done by the patients themselves,
using a blood glucose meter (also known as a glucometer). Briefly, as presented by most glucose meter
brochures:
Medicina 2019, 55, 546 9 of 30

1. Hands should be washed before testing as dirt and residue can lead to inaccuracies.
2. Insert a single test strip into the glucose meter.
3. A small drop of blood should be obtained by prinking the finger-tip using the lancet (needle on
blood sampling device), where the volume of blood should be sufficient in filling the test field.
4. Place blood drop onto test strip without smearing it, as smearing can lead to inaccuracies.
5. Glucose meter will then display the blood glucose level.

The glucometer provides diabetic patients with fast and rather accurate measurements of blood
glucose levels though there are factors that can lead to inaccuracy such as errors during the application,
extreme environmental conditions, and interferences from medication which may thereafter lead to
treatment errors [117]. Moreover, such errors can be eliminated through proper storage of blood
glucose testing tools and proper education of patients as suggested by Erbach et al. [117] However,
what cannot be avoided during the patient’s self-monitoring of blood glucose (SMBC) is the need
for finger pricking. Finger pricking, when done several times a day for many years, can not only
be painful for patients—making SMBC difficult for children—but also result in the development of
massive scarring and callous formation, as well as the loss of sensibility, as previously reviewed by
Heinemann [118].
In view of this, there have been growing demands for, and numerous developments in, sensors
used to measure blood glucose, either directly or indirectly, that do not require finger pricking or that
are minimally invasive. These modern methods of glucose sensing have been previously reviewed by
Bruen et al. [119] Some of these new methods that were reviewed include a glucose-sensing patch that
detects glucose present in the interstitial fluids [120]; SwEatch, a watch platform used for the analysis
of sodium present in sweat, in place of a glucose sensor [121]; an eyeglass biosensor that contains both
lactate and potassium sensors [122]; breath analysis to detect volatile organic compounds, relating to
the detection of acetone [123] as an alternative biomarker for glucose monitoring in diabetes; a lactate
sensing mouth guard for the sensing of lactate present in saliva in place of a glucose sensor [124]; and
finally, a smart-contact lens developed by Google that could be utilized for the detection of glucose levels
present in the ocular fluids [125]. Despite these innovations, however, many are still under development
and are stricken with problems, which include sweat contamination [121] and damage to microneedles
during penetration for the glucose-sensing patches [119], skin surface contaminations [126] and low
production of sweat [127] when sweat analysis is carried out, and lastly, the non-specificity of using
acetone as a diabetes biomarker [128] and interferences from other electroactive species present
in tears [57].

4. Treatment of Pre-Diabetes
Pre-diabetes is a reversible condition. If proper measures are taken during this critical period,
then a person can be spared the long-term complications. Pre-diabetes is the early indicator of diabetes
that occurs when the patient is diagnosed with impaired glucose tolerance (IGT) and/or impaired
fasting glucose (IFG). The onset of both pre-diabetes and diabetes begin with the insulin resistance of
cells [129–131]. In most cases, at the dawn of T2DM, the individual starts to show insulin insensitivity.
To combat this inefficiency of insulin function and maintain normal blood glucose levels, the β-cells of
the pancreas start to produce more insulin, which is known as hyperinsulinemia [132]. Two of the
major attributes of IGT and IFG are insulin resistance and a decrease in pancreatic β-cell function [132].
Therefore, for the successful treatment of pre-diabetes, these two features must be addressed and
resolved promptly before it aggravates to the point when the condition is no longer reversible.

4.1. Lifestyle Intervention

Various studies have suggested that there is a genetic disposition for insulin insensitivity. Certain
epigenetic risk factors, such as obesity, lack of physical exercise, and a physically inactive lifestyle
worsens the insulin resistance [133–136]. Treatment of pre-diabetes through lifestyle intervention
Medicina 2019, 55, 546 10 of 30

targets the risk factors such as obesity and diet. Lifestyle intervention mainly comprises regular and
nutritious dietary advice, instructions for physical activities and weight loss [137]. Physical activity
improves insulin sensitivity by increasing free fatty acid oxidation and improving skeletal muscle
mitochondrial function, as well as reducing lipotoxicity in skeletal muscles and the liver [138]. Physical
exercise also increases the serum level of adiponectin, which helps to improve insulin sensitivity [139].
Physical activity acts as a physiological stressor which increases glucose uptake by the muscle cells.
When the level of physical activity is low, GLUT-4 remains inactive and does not let glucose enter
the cell. Conversely, when there is insulin or physical activity, GLUT-4 allows glucose to enter the
cell [140]. Other studies have also found that the β-cell function and glucose regulation improve
as a result of moderate to intense exercise. This improvement in function is independent of weight
loss or obesity [141,142]. However, these studies were not directly done on pre-diabetics, but rather
on people intending to prevent diabetes. Nonetheless, the references used in this review paper are
justified, because pre-diabetes is the pre-condition of diabetes and most people undergo pre-diabetes
before fully developing diabetes. Physical exercises improve β-cell function and insulin sensitivity
among pre-diabetics as well [138,143]. Various studies have found that the risk of diabetes reduces
by 18% to 40% due to the consumption of a nutritious diet that contains foods with a low glycemic
index, such as cereal fiber or a mixture of whole grain and bran [144]. Reducing the consumption
of sugar-containing beverages also significantly reduces the risk of diabetes. For example, people
drinking more than one sugar-containing beverage per day have 26% more risk of developing diabetes
compared to people who have less than one per month [142,145]. Therefore, improved diet can play a
major role in preventing the development of diabetes from pre-diabetes.
The Da Qing IGT and Diabetes Study is one of the earliest studies done in Da Qing city,
China, on pre-diabetes in order to establish a relation between lifestyle intervention and pre-diabetes
progression [146,147]. In the study, 577 pre-diabetics were studied over a period of 6 years. Each of
them was assigned to one of four groups (control, improved diet only, exercise only, improved diet with
exercise). After 6 years, data showed that 67.7% of people from the control group developed diabetes,
whereas, 46.0% of people from the improved diet with exercise group developed diabetes [147].
Ever since then, many studies and surveys have been conducted on a larger number of subjects in
different countries all around the world. The United States Diabetes Prevention Program (DPP) and
the Finnish Diabetes Prevention Study (DPS) are the two largest diabetes prevention studies which
have found promising results in terms of lifestyle intervention. The DPP study was conducted by
Knowler et al. (2002). They found that there was a 58% decrease in new diabetes cases after 3 years of
intensive lifestyle interventions (ILI). In this study, 3234 pre-diabetic individuals with a mean age 51
years were either given placebo or Metformin: 2 × 850 mg per day, or changes were made in their
lifestyles. Lifestyle modification included losing 7% of body weight, reducing 25% of total calorie
intake and doing 150 min of physical exercise per week. In the study, it was found that there was a
16% reduction in developing diabetes per 1 kg decrease in weight. The number of participants who
developed T2DM per 100 participants were 4.8, 7.8 and 11.0 for lifestyle intervention, Metformin,
and placebo respectively. Moreover, in the same study, participants who lost weight and met the
required physical activity had the risk of diabetes reduced by more than 90% [133,148]. Therefore, it is
evident that weight loss played a principal role in risk reduction.
Furthermore, in the Finnish DPS conducted by Toumilehto et al., five recommendations were
given to the intervening individuals. The benefits of lifestyle intervention were found to be dependent
on the extent of the execution of the goals. The goals included total fat intake less than 30% of total
energy intake, fiber intake greater than or equal to 15 g per 1000 kcal, saturated-fat intake less than 10
percent of energy intake, weight reduction greater than 5 percent of total body weight, and exercise of
more than 4 h/wk. A total of 522 pre-diabetic individuals participated in the study, each of them being
assigned to either the control group or the intervention group. Among the intervention individuals,
the risk of developing diabetes was 58% lower compared to the control group. Therefore, both the
Finnish DPS and DPP were consistent in results [149]. Various studies have been conducted on the
Medicina 2019, 55, 546 11 of 30

Asian population to observe the effect of lifestyle intervention in the treatment of pre-diabetes or
T2DM. In the Indian Diabetes Prevention Program (IDPP) whereby people received advice on physical
activity, the risk of developing diabetes reduced by 28.5% compared to the control group [142,150].
Another four different studies found that insulin sensitivity can be improved by losing weight and/or
exercising [151,152]. Insulin sensitivity improves 30% by losing only 5% of body weight [151]. In a
Japanese study conducted with IFG, it was found that intensive intervention has a more positive
effect than less intensive intervention [153]. To prevent pre-diabetes developing into T2DM, lifestyle
intervention has been found to be very promising. However, maintaining the final reduced weight
and continuing exercise is impractical [154]. For instance, the individuals who had participated in the
DPP study were found to regain weight after the termination of the study [155]. It is impractical for an
individual to continue maintaining a 5% weight loss in real life. Another impediment in the long-term
implementation of lifestyle intervention is the lack of patient motivation. To overcome these barriers,
a pilot study was done with an advanced version of lifestyle intervention by Pot et al. The program
was developed by Foundation Nutrition Alive and was called “Reverse Diabetes2”. Even though this
program focused on treating T2DM, the same idea could be applied for treating pre-diabetics. It was a
6-month program and was conducted with T2DM patients who had completed the “Reverse Diabetes2”
within February 2015 and March 2016. The additional developments made to the mainstream lifestyle
intervention included rigorous counselling on nutrition and lifestyle, digital coaching and education
platform, physician guided medication administration, and cooking lessons. In the study, patients
were continuously motivated, and were given required knowledge and skills to adapt to the nutritious
diet and improved lifestyle. The program was conducted by an army of trained individuals: a
dietician, a personal coach and a nurse in alliance with the patient’s general practitioner. The program
mainly focused on giving dietary advice to patients. Unlike the more prevalent and common lifestyle
intervention programs, patients were given the liberty to choose their preferred dietary option in this
program. The participating members of this study were assigned in groups. In total, 73 individuals
in four groups completed the program. Members of each group were well connected through social
network platforms such as Facebook and WhatsApp, so that they could motivate each other to continue
the intervention. The results of this study revealed that the new approach to lifestyle intervention led to
improved glucose control of the T2DM patients. In the study, there was further evidence of a reduction
in consumption of glucose lowering medication when proper lifestyle intervention was conducted.
Reducing or completely stopping the glucose lowering medication was medically justified in 49% of
the participating individuals. Furthermore, in this program, the average weight loss was 4.9 kg in 6
months [156]. This study again confirms that weight reduction plays a role in reversing T2DM. Similar
effects can also be expected for reversing pre-diabetes. Therefore, this new approach can be used while
implementing the recommendation for lifestyle intervention in treatment of pre-diabetes. This could
be an indication that lifestyle intervention, if properly implemented, is a better method for controlling
pre-diabetes or diabetes than pharmacological intervention. However, although no major research has
been carried out to date, investigating the biological mechanism behind this success, it can be concluded
from the large amount of study data that lifestyle intervention can, in fact, treat the progression of
pre-diabetes to T2DM, to a significant extent. More in-depth and rigorous research needs to be done in
this field to find the actual mechanism of action of this success. Even though a satisfying number of
studies have been conducted in different countries to find the link between lifestyle intervention and
diabetes and pre-diabetes control, no nationwide lifestyle intervention program has been successfully
implemented by the government. Many countries have taken several steps to control diabetes through
lifestyle intervention, but very few have addressed pre-diabetes, which is potentially more reversible
than T2DM.
For example, the Singapore government is carrying out various intervention programs as part
of “Singapore’s War on Diabetes” to make its people more aware of diabetes and pre-diabetes.
The program also aims to train the citizens to fight these conditions. For example, in July 2017, to
manage pre-diabetes, the Ministry of Health (MOH) published the Appropriate Care Guide (ACG).
Medicina 2019, 55, 546 12 of 30

This guide contains advice on lifestyle intervention. An initiative by the Health Promotion Board
(HPB) is the 12-week Diabetes Prevention Program (DPP), which consists of 2 nutrition workshops,
9 exercise lessons and 1 goal setting workshop. Monthly short message service (SMS) alerts are sent
to people regarding health tips. Moreover, HPB has launched the HealthHub Track app which helps
its users to track physical activity levels. One of the latest additions to HealthHub is the Diabetes
Risk Assessment (DRA) tool, which helps young adults to determine whether they should go for
diabetes screening or not. MOH has heavily subsided diabetes screening under the Screen for Life
(SFL) program [157]. However, even after all these steps, there is no guarantee that pre-diabetes
can be completely treated, as most people are unaware that they have pre-diabetes. Also, no formal
nationwide study has been conducted to know whether most Singaporeans are aware of the facilities
provided by government and how successfully all of these have been implemented. More interactive
approaches need to be undertaken in Singapore and the maximum output of the existing facilities
need to be ensured. Nonetheless, lifestyle intervention is one of the most reasonable and safe ways to
prevent the progression of pre-diabetes to T2DM [137]. Other risk factors of diabetes such as smoking
can also be included in the intervention program to make it more effective.
However, the efficiency of improved lifestyle on the prevention of progress of pre-diabetes
depends on the extent of β-cell dysfunction and hyperglycemic nature, which varies from patient
to patient [142].

4.2. Pharmacological Interventions

The progression of pre-diabetes to T2DM can also be prevented through anti-diabetic drugs or
anti-obesity drugs.

4.2.1. Metformin
Metformin is one of the most popular and common medications prescribed to delay the
onset of diabetes. Metformin belongs to the biguanide class of anti-diabetic medication [158].
The mechanism of action of Metformin is complex and yet to be fully understood. Metformin does
not get metabolized in the human body and the concentration of Metformin remains high in the liver,
intestines, kidney and bladder [159–161]. In humans, the main site of action of Metformin is the
intestines, liver and kidney [162,163]. Metformin decreases fasting plasma glucose (PG) concentration
and hemoglobin A1c by suppressing liver glucose production (hepatic gluconeogenesis) or by restoring
β-cell function [164–167]. This drug mainly works by shrinking the rate at which hepatic glucose is
produced and enhancing the insulin action in skeletal muscles [168,169]. Two of the core mechanisms
of action of this drug are via the energy sensor enzyme adenosine monophosphate-activated protein
kinase (AMPK) and the inhibition of mitochondrial respiration [163]. Hepatic gluconeogenesis requires
the supply of a high amount of ATP. Metformin exploits this demand of ATP to reduce hepatic
gluconeogenesis. Metformin is found to inhibit the function of complex I of the mitochondrial electron
transport chain. Therefore, reducing the ATP production [170,171]. One of the drawbacks, as addressed
by many, regarding this mechanism of action is that a high amount of Metformin is required to
observe a significant reduction in hepatic gluconeogenesis [170]. The reduction of ATP production
due to the inhibition of mitochondrial respiration plays a role in the activation of AMPK as well.
As the amount of ATP decreases, to maintain the energy balance, AMPK switches on pathways
that produce ATP and switches off pathways that use ATP [172,173]. When Metformin is given at a
smaller concentration (20 µmol/L), a longer time is needed to get significant results, in comparison
to when higher concentrations are used (500 µmol/L) [174]. However, Metformin has also been
found to have AMPK independent effects on hepatic gluconeogenesis. When Metformin was given
to mice lacking AMPK subunits in the liver and to control mice, Metformin was found to improve
glucose tolerance in both groups [175]. More of the latest studies have found that Metformin controls
glucose by inhibiting fructose-1,6-bisphosphatase, the key enzyme for gluconeogenesis, rather than
solely activating AMPK [163]. Another mechanism of action is that it improves the overall action
Medicina 2019, 55, 546 13 of 30

of glucagon-like peptide-1 (GLP-1). Metformin increases the secretion of GLP-1 by the intestinal
L-cell and/or reduces the action of the enzyme (dipeptidyl peptidase-4) that breaks down GLP-1. This
improves the overall action of GLP-1 [176–178]. Apart from inhibiting liver gluconeogenesis, Metformin
also increases glucose disposal in skeletal muscle by increasing AMPK activity in skeletal muscle of
T2DM patients [179]. The increase in AMPK activity is associated with increased phosphorylation of
AMPK on Thr172 and decreased acetyl-CoA carboxylase-2 activity. Hence, Metformin reduces the
blood glucose level in the aforementioned ways.
In the DPP study conducted by Knowler et al. (2002), it was found that Metformin, at a dose
of 2 × 850 mg/day reduced the chances of development of T2DM from IGT. A total of 7.8 per 100
pre-diabetics developed diabetes when Metformin was prescribed, whereas, a total of 11.0 per 100
pre-diabetics developed the same when a placebo was prescribed. Furthermore, Metformin also
improves insulin sensitivity and reduces new cases of T2DM. However, in the DPP study (Knowler et al.,
2002) conducted in the USA, Metformin was found to be not as effective as lifestyle intervention [133],
while in the Indian DPP conducted by Ramachandran et al. (2006) over a three years period, Metformin
was found to be as effective as lifestyle intervention. The study was conducted on 531 Asian Indians,
each being assigned to one of four groups (control, lifestyle modification only, Metformin only,
and lifestyle modification with Metformin). The results of the lifestyle modification group and
Metformin group were very similar [150]. Additionally, Knowler et al. concluded that in people
with a BMI higher than 35, aged less than 65 years, and having a fasting PG higher than 110 mg/dL,
Metformin reduced the chances of developing T2DM as effectively as lifestyle intervention [133].
Overall, Metformin is a relatively safe drug. Hence, it is advised to people who are aged less than 60
years, with a BMI more than 35 kg/m2 and with IGT or IFG, by the ADA [180].

4.2.2. Thiazolidinediones
Thiazolidinediones target PPAR-γ. PPAR-γ are ligand activated transcription factors and
activation of PPAR-γ results in insulin sensitization and increases glucose metabolism [181,182].
Thiazolidinediones work by making the adipocytes, liver and muscle cells more sensitive to insulin
and by conserving the β-cell function. Insulin sensitivity is determined by the efficacy of the
PPAR-γ receptors of adipocytes and muscle cells [183–185]. A considerable number of studies
have also found that thiazolidinediones improve insulin sensitivity by decreasing plasma free fatty
acid and intramyocellular lipid content. Thiazolidinediones also redistribute fats from visceral to
subcutaneous adipose sites which might help to control diabetes [183–185]. Troglitazone, pioglitazone,
and rosiglitazone are the common drugs belonging to this group and all have shown similar results in
improving insulin sensitivity [186–188]. In the DPP, Troglitazone reduced the progression of T2DM
in IGT individuals by 23% within 3 years [134]. In another study, called the Diabetes Reduction
Assessment with ramipril and rosiglitazone Medication (DREAM) trial, rosiglitazone reduced the
progression of T2DM in IGT individuals by 62% [135]. Pioglitazone and troglitazone have been found
to control the progression of gestational diabetes as well [189–191]. However, rosiglitazone might have
some side-effects. A double-blind study was conducted with Ramipril and rosiglitazone. Even though
there was a decrease in diabetes incidence by 60%, there were a few side-effects. The side-effects
included an average increase in weight by 2.2 kg, and a higher risk of the cardiovascular incident
including heart failure [135,136].

4.2.3. α-Glucosidase Inhibitors

This group of drugs may ameliorate T2DM by prolonging the overall carbohydrate digestion time
and decreasing the rate of glucose absorption [192]. In the STOP Non-Insulin-Dependent Diabetes
Mellites (STOP-NIDDM) trial, over a 3.3 year follow up, acarbose reduced the progression of IGT to
T2DM by 25% [193,194]. In another study in Japan, voglibose reduced diabetes progression by 40% in
a period of 48 weeks. However, both studies have shown notable side effects among the individuals.
The major side effects were related to the gastrointestinal system that included flatulence and diarrhea.
Medicina 2019, 55, 546 14 of 30

In the STOP-NIDDM study and the Japanese study, 37% and 7% participants respectively terminated
the trial before the completion of the program due to the side effects [193–195]. Although α-glucosidase
inhibitors alone can improve glycemic variability, it should be noted that they do not improve insulin
sensitivity [196]. Combination with other groups of anti-diabetic drugs may be necessary to effectively
inhibit the progression of T2DM.

4.2.4. Incretins
Gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are two of the major
stimuli for insulin secretion. GLP-1 slows down diabetes progression by reducing glucagon secretion,
keeping the stomach full for a longer period, and shrinking the appetite. This limits food intake and
leads to weight loss. However, both GIP and GLP-1 get broken down by Dipeptidyl Peptidase-IV
(DPP4). Therefore, GIP and GLP-1 cannot be used as a means of therapy for preventing diabetes
progression. To overcome this hurdle, a GLP-1 receptor agonist is used. Two such common agonists
are liraglutide and exenatide. These agonists are not broken down by DPP4 and can accomplish similar
results to GLP-1. In a study, exenatide was found to be improving β-cell function and playing a role
in reducing weight [197]. However, no study has yet been carried out to track the effect of GLP-1 on
the progression of IGT to T2DM. But a study over a period of 2 years has been conducted on obese
individuals, and exenatide and liraglutide have been shown to cause weight loss [198].

4.2.5. Sodium-Glucose Cotransporter (SGLT) 2 Inhibitors

SGLT 2 inhibitors are one of the latest additions to pharmacological interventions in treating
pre-diabetes and T2DM. Canagliflozin, dapagliflozin and empagliflozin are the common approved
drugs belonging to the class of SGLT 2 inhibitors [44,199,200]. SGLT 2 inhibitors can be recommended
alone or in combination with other glucose controlling medications [201]. The doses of different SGLT
2 inhibitors are different [202]. Some of the most common side effects of this class of medication is
urogenital tract infection, genital infection, breast and bladder cancer [203,204]. Because of all these,
more serious research needs to be carried out to verify the safety of this class of medication. SGLT 2
inhibitors mainly work by interfering with the SGLT 2 in the kidneys. In a healthy individual, glucose
is filtered and reabsorbed by the kidneys. SGLT 2 is responsible for the reabsorption of glucose in
the kidney [205]. In pre-diabetics and diabetes, the expression of SGLT 2 increases, resulting in more
reabsorption of glucose by the kidney [206]. When SGLT 2 inhibitors are used, they tend to decrease
this reabsorption of glucose and reduce FPG and HbA1c [207]. Therefore, this increases urinary glucose
elimination and decreases blood glucose level.

4.2.6. Anti-Obesity Drugs

Orlistat is an anti-obesity drug which works by reducing the absorption of fat by almost 30%. In a
study over a period of 1.5 years, it was found that the progression of IGT to diabetes was reduced
when orlistat was given to individuals while the subjects maintained a low-calorie diet and lost weight.
According to the XENial in the Prevention of Diabetes in Obese Subjects (XENDOS) trial, orlistat
reduced diabetes development by 37% over a 4-year treatment [208].

4.3. Bariatric Surgery

Bariatric surgery mainly works by targeting the calorie intake of the subject which ultimately results
in weight loss. As reviewed by Bansal, the most common modalities under bariatric surgery include
Roux-en-Y gastric bypass, laparoscopic adjustable gastric banding, sleeve gastrectomy, and duodenal
switch with biliopancreatic diversion [209].
A Swedish Obese Study conducted by Sjostrom et al., tracked the weight of subjects who underwent
a bariatric surgery and compared the data with the control group. A total of 4047 individuals were
followed up after two years, and 1703 individuals were followed up after ten years. There was a 23.4%
and 16.1% decrease in weight for the 2 years and 10 years follow up groups respectively. On the other
Medicina 2019, 55, 546 15 of 30

hand, there was an increment in weight for the control group. There was a 0.1% increase after 2 years
follow up, and a 1.6% increase after 10 years follow up [210]. Overall, there was a 75% reduction in risk
for developing diabetes after bariatric surgery was performed [209,210]. In another study reported by
Pories et al., it was found that 78% of diabetic and 98% of pre-diabetic subjects restored normal glucose
level after gastric bypass surgery [211]. Therefore, bariatric surgeries provide promising methods for
the treatment of pre-diabetes as they target obesity, which is one of the major risk factors of diabetes.

5. Complications
Pre-diabetes progresses to diabetes if left untreated. Moreover, if diabetes is left unmanaged and
untreated, various chronic complications can develop, increasing the diabetic patient’s discomfort and
could even lead to death. A list of some known diabetes complications that have been previously
researched
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5.1. Cancer
Cancer is a genetic disease resulted from both internal factors and external factors [212,213]. It is a
less-explored complication that can result from diabetes. With 80% of pancreatic cancer patients
presenting with impaired glucose tolerance, and because one major pathophysiology of diabetes is
the impaired β-cell function, there appears to be an association between T2DM and pancreatic cancer
[214]. While there are many studies that establish diabetes as a risk factor of pancreatic cancer, where
Medicina 2019, 55, 546 16 of 30

5.1. Cancer
Cancer is a genetic disease resulted from both internal factors and external factors [212,213]. It is
a less-explored complication that can result from diabetes. With 80% of pancreatic cancer patients
presenting with impaired glucose tolerance, and because one major pathophysiology of diabetes is the
impaired β-cell function, there appears to be an association between T2DM and pancreatic cancer [214].
While there are many studies that establish diabetes as a risk factor of pancreatic cancer, where 1% to
2% of patients who had recently suffered from diabetes were reported to develop pancreatic cancer
in 3 years [215], this relationship also works vice versa, such that pancreatic cancer can be the cause
of diabetes. In fact, type 3 diabetes is a form of diabetes that is caused by the loss of function of the
pancreas, which occurs in up to 30% of pancreatic cancer patients [215]. In addition to pancreatic
cancer, diabetes can increase the risks, by twice or more, of developing liver cancer—since the liver
is also exposed to high levels of insulin for diabetic patients—and endometrium cancer, as well as
increase the risk of developing cancers of colon and rectum, breast, and bladder by 1.2 to 1.5 times [216].
However, in two meta-analysis on diabetes and prostate cancer, diabetes lowered the risk of developing
prostate cancer by 9% [217] and 16% [218]. This is further affirmed by a case study conducted by
Coker et al. which saw a stronger protective effect against prostate cancer in patients suffering from
diabetic complications and also for African American men, although the study concurred that more
research is still required to establish the biological mechanisms between diabetes and prostate cancer
risk [219].

5.2. Depression
Depression is a psychological complication that can result from diabetes, and the relationship
between the former and the latter is often regarded to be bi-directional. While different studies
report different levels of risk of diabetic patients developing depression, it is generally more likely
for diabetic individuals to be found depressed, as compared to non-diabetic individuals under the
same settings [220,221]. Complex mechanisms behind the association of diabetes and depression
remain understudied. However, it has been suggested that the consumption of atypical antipsychotic
medications [221], the patient’s sufferings caused by advanced diabetes, as well as diabetic abnormalities
in neurohormonal and neurotransmitter function [220] could be reasons for this association. Conversely,
depression is a risk factor that can rivals other factors such as smoking [221] in causing diabetes,
as depression makes it difficult for diabetic patients to adhere to medical treatments and glycemic
controls [220], thereby furthering diabetes complications.

5.3. Alzheimer’s Disease

Recent studies proposed Alzheimer’s disease to be “Type 3 Diabetes” resulting from impaired
insulin signaling [222]. Arvanitakis et al. have concluded in their study that there is a 65% higher
risk level for diabetic patients to develop Alzheimer’s disease than non-diabetic individuals [223].
The relationship between the two, however, is uncertain. Moreover, in a review on Alzheimer’s disease
and diabetes, it was suggested that Type 2 diabetes itself was not sufficient to cause Alzheimer’s
disease, although diabetes could have served as a pathogenesis and progression co-factor [222].

5.4. Diabetic Ocular Diseases

There are several types of ocular diseases that can arise from diabetes, eventually causing vision
loss. Among the numerous ocular complications, most research focuses on diabetic retinopathy, since
even the World Health Organization estimated it to cause blindness in 5% of blind people [224].
Moreover, more than 60% of Type 2 diabetes patients develop some form of diabetic retinopathy within
a decade of diabetes incidence [225] and nearly all Type 1 diabetes patients suffer this two decades
after puberty [226]. Although the pathophysiological cause behind diabetic retinopathy is unclear,
several mechanisms have been proposed. Nine biochemical pathways that are the main contributors to
Medicina 2019, 55, 546 17 of 30

diabetic retinopathy have been extensively reviewed by Tarr et al. [224]. The pathways that associate
retinopathy with diabetes, reviewed by Tarr et al. include: an increased polyol pathway, activation of
protein kinase C, increased expression of growth factors, hemodynamic changes, accelerated formation
of advanced glycation end-products, oxidative stress, activation of the renin–angiotensin–aldosterone
system, subclinical inflammation and capillary occlusion [224]. Other less commonly known diabetic
ocular diseases that are known to directly cause, link and possibly link to diabetes have also been
previously classified by Jeganathan et al. [227] and are summarized as follows (Table 3):

Table 3. Table showing ocular diseases other than diabetic retinopathy that can arise as complications
of diabetes, adapted from the review by Jeganathan et al. [227].

Direct Causes Known Links Possible Links

Development of Cataracts Glaucoma Retinal vein occlusion
Ischemia caused by anterior optic nerve Ocular ischemic syndrome Retinal arteriolar emboli
Diabetic papillopathy Retinal artery occlusion
Ocular movement disorders Corneal diseases

5.5. Taste Loss

Rarely are diabetes complications associated with taste. However, altered taste and a preference for
sweet food were presented in a case study by Bhandare et al. where a newly diagnosed diabetes patient
was found to suffer from blunted taste, which could partially be reversed when hyperglycemia was
corrected. Therefore, altered taste has been proposed as an indicator of blood sugar fluctuations [228].

5.6. Cardiovascular Diseases

Cardiovascular diseases are the main contributor of death and disability in diabetic
patients [229,230]. Cardiovascular diseases were reported to account for more than 50% of deaths, by
Einarson et al., after they reviewed the prevalence of cardiovascular diseases in Type 2 diabetic patients,
recorded in 57 studies published from 2007 to 2017 [230]. More specifically, the American Heart
Association regarded diabetes to be a risk, rather than a risk factor, of coronary heart diseases after
recent studies showed that the risk of having myocardial infarction in diabetic individuals equals that of
patients who had a history of previous myocardial infarction [70]. Additionally, while Type 2 diabetic
patients showed an increased risk of 15–400% of developing stroke [70], Type 1 diabetic patients suffer
higher mortality from ischemic heart disease, as compared to the rest of the population [70]. This is
because numerous cardiovascular diseases risk factors are present in diabetic patients such as obesity,
hypertension, and dyslipidemia [229,231]. Moreover, diabetes can also contribute to cardiomyopathy
as well as coronary artery disease directly, rather than indirectly through the risk factors [231].

5.7. Diabetic Kidney Diseases

Diabetic kidney disease or diabetic nephropathy is another common microvascular diabetic
complication where it has been estimated to be prevalent in 30% and 40% of Type 1 and Type 2
diabetic patients respectively [232]. Diabetic nephropathy was characterized by Nazar C.M.J. as
having protein albumin found in the urine, coupled with a decrease in glomerular filtration rate
and an increase in arterial blood pressure [233]. The development of diabetic nephropathy, similar
for both types of diabetes, starts with albuminuria or known as incipient nephropathy—moving
from microalbuminuria to macroalbuminuria [234]—then to overt nephropathy, eventually leading to
end-stage renal disease [235]. In fact, diabetes is known to become the most frequent cause of end-stage
renal disease globally, where countries such as Malaysia, Mexico, and Singapore see diabetes being
the main cause of end-stage renal disease in 60% of their diabetic patients [236]. While end-stage
renal disease develops in 50% and more than 75% of Type 1 diabetic patients after they develop
overt nephropathy 10 and 20 years later respectively, only 20% progress from overt nephropathy after
20 years for Type 2 diabetic patients [235]. Moreover, it should be noted that the incidence of diabetic
Medicina 2019, 55, 546 18 of 30

nephropathy is higher and developed at a faster rate in Type 2 than Type 1 diabetic patients, as Type 2
diabetic patients often have their diagnosis delayed [235].

5.8. Sexual Dysfunction

Higher prevalence of sexual dysfunction as a complication arising from diabetes have been
reported in both men and women, although the association is less conclusive for women [237]. While
sexual dysfunction for men results from more physiological reasons, female sexual dysfunction was
found to be more related to social and psychological reasons [237]. Among the various sexual problems,
erectile dysfunction was the most common dysfunction in men [238], with diabetic men experiencing
it three times more than non-diabetic men [239], where the association between erectile dysfunction
and diabetes is multifactorial [240]. For women, a few types of sexual dysfunction have been reported,
such as lower sexual desire, genital arousal disorder, orgasmic disorder and pain [239]. Additionally,
although a study presented by Ahmed et al. concluded that female sexual dysfunction was more
prevalent in Type 1 than Type 2 diabetic women in Egypt [241], there is still generally a lack of studies
in comparing the prevalence of sexual dysfunction between the two types of diabetes [237,238].

5.9. Skin Disorder

A complication of diabetes that is highly prevalent, but often goes undiagnosed is skin disorders,
with its reported prevalence at 51–97% in both Type 1 and Type 2 diabetes in different regions
worldwide [242]. Although various studies presented different statistical data on skin disorder in
diabetic patients, cutaneous infection, xerosis, and inflammatory skin diseases were the most common
types of skin disorders reported for diabetic individuals [242,243]. Skin disorders usually occur in
poorly controlled diabetic patients, which is expected, since diabetic skin disorders are found to be
highly correlated to glycemic control [242].

5.10. Diabetic Neuropathy

Diabetic neuropathy is the most common complication of diabetes, for both Type 1 and Type 2
since it has been reported in 90% of diabetic patients [244]. Among the various neuropathy syndromes,
the most common syndrome is diabetic polyneuropathy, which accounts for 75% of the syndromes [245].
Diabetic polyneuropathy is defined as a peripheral nerve dysfunction [246] and is the main contributor to
disability in diabetes, stemming from foot ulceration and amputation, gait disturbance, and fall-related
injury [245]. Pain, another main symptom of diabetic neuropathy [244] is experienced by 20–30% of
patients suffering from diabetic polyneuropathy [246]. Diabetic neuropathic pain is characterized
by Schreiber et al. as a “tingling, burning, sharp, shooting, and lancinating or even as electric shock
sensations” which often worsen in the night [244]. Pain can also be a complication that is associated
with depression, as mentioned earlier, as it decreases the quality of life and influences the mood of
diabetic patients [244]. Moreover, the pathological reasoning behind diabetes and pain has yet to be
fully established [244,245].

6. Conclusions
With every nation’s attention on diabetes mellitus, there is an urgent need for a multidimensional
insight into this disease. In this review, many possible genetic and epigenetic markers as well as
lifestyle and environmental factors have been explored to provide a better understanding of the risk
factors of T2DM. Simultaneously, we have discussed the novel diagnostic methods of T2DM for a
more sensitive and specific approach towards identifying diabetic patients and pre-diabetic population.
Different treatment options have been comprehended and included in this review for comparison
among the treatment regimes. Additionally, some of the more common complications resulting from
diabetes have also been reviewed. By establishing this thorough review on diabetes, we hope to
provide invaluable insight as to how we can combat diabetes and pre-diabetes around the world.
Medicina 2019, 55, 546 19 of 30

Funding: This project was funded by Nanyang Technological University (NTU), Singapore (URECA 2018–2019:
SBS18005).
Acknowledgments: We wish to acknowledge the funding support for this project from Nanyang Technological
University under the Undergraduate Research Experience on CAmpus (URECA) program. Z.L. is a recipient of
the NTU Research Scholarship and NTU-KI Joint PhD Scholarship from the School of Biological Sciences, Nanyang
Technological University, Singapore. Z.L. mentored R.M.M.K., Z.J.Y.C., J.C.T. and Y.Y. In completion of this review
article under the Graduate Assistantship Program (GAP) of Nanyang Technological University, Singapore.
Conflicts of Interest: The authors declare no conflict of interest.

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