Best Practice & Research Clinical Endocrinology & Metabolism 30 (2016) 345e355

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Best Practice & Research Clinical

Endocrinology & Metabolism
journal homepage: www.elsevier.com/locate/beem

Detecting people at high risk of type 2

diabetes- How do we find them and who
should be treated?
Alice P.S. Kong, MBChB, MD, Associate Professor a, b, c,
Andrea O.Y. Luk, MBChB, Associate Professor a, b, c,
Juliana C.N. Chan, MBChB, MD, Professor a, b, c, *
a
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital,
Hong Kong Special Administrative Region, China
b
Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital,
Hong Kong Special Administrative Region, China
c
Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales
Hospital, Hong Kong Special Administrative Region, China

a r t i c l e i n f o
Diabetes is a chronic disease characterized by its silent and
Article history: progressive nature. The prevalence of type 2 diabetes (T2DM)
Available online 11 June 2016 increases with age but with a worrying trend of increasingly young
age of diagnosis. Compared to their counterparts with late onset of
Keywords: disease, these younger subjects face long disease duration with
detect increased risk of diabetes-related complications. Besides, there is
high risk marked phenotypic heterogeneity which can interact with
T2DM different interventions to give rise to variable clinical outcomes.
Recognized at-risk groups include those with known atheroscle-
rosis and vascular disease, genetic background (family history and
non-White ethnic groups), phenotypes of insulin resistance
(obesity, metabolic syndrome, women with gestational diabetes or
polycystic ovarian syndrome, and men with androgen deficiency)
and “pre-diabetes” (impaired glucose tolerance and impaired
fasting glucose). These risk factors interact to amplify the risk for
diabetes, thus emphasizing the importance of comprehensive
assessment. Raising awareness and health literacy, regular
screening of high risk subjects, structured lifestyle modification

* Corresponding author. Department of Medicine and Therapeutics, The Chinese University of Hong Kong, 9/F, Clincial
Sciences Building, Prince of Wales Hospital, Shatin, N.T., Hong Kong Special Administrative Region, China. Tel.: þ86 852 2632
3138; Fax: þ86 852 2637 3852.
E-mail address: [email protected] (J.C.N. Chan).

http://dx.doi.org/10.1016/j.beem.2016.06.003
1521-690X/© 2016 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).
346 A.P.S. Kong et al. / Best Practice & Research Clinical Endocrinology & Metabolism 30 (2016) 345e355

program including early use of pharmacological agents, targeting

at predominant pathophysiological defects offers a personalized
approach to prevent this global hazard.
© 2016 The Authors. Published by Elsevier Ltd. This is an open
access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Diabetes is both a public and personal health disaster if not diagnosed early, treated promptly and
managed properly. Over 60% of all cause deaths and disabilities, including stroke, leg amputation, heart
disease, cancer, kidney disease, depression, to name but a few, are causally linked to diabetes [1e3].
T2DM is a silent and progressive disease with insidious onset characterised by many years of hyper-
glycemia culminating in multi-organ failure. Based on cohort analysis, about half of the pancreatic beta
cell function are lost upon diagnosis of T2DM [4]. Increasing evidence, including genetic analysis,
support the pivotal role of pancreatic beta cell dysfunction in disease progression, with more than one
third of type 2 diabetic patients eventually requiring insulin therapy [5,6]. In Asian populations, ge-
netic, epigenetic, and environmental factors driven by rapid nutritional transition against a backdrop of
pathogen-rich environment may lead to pancreatic beta cell dysfunction and chronic inflammation
with early onset of disease despite body leanness [7].
In type 2 diabetic patients with insulin deficiency, insulin therapy is the natural treatment option,
although hypoglycemia and weight gain are major barriers to optimal glycemic control [8,9]. New anti-
diabetic drugs which have low risk of hypoglycemia and weight gain allow optimal control of glycemia
and reduce insulin requirement in patients with established disease [10,11]. On the other hand,
detection of diabetes in high risk subjects followed by early intervention may preserve beta cell
function and reduce risk of complications [10].

Benefits of early detection of T2DM

Both epidemiological and clinical trials have shown that the onset of T2DM can be delayed and may
be preventable through lifestyle modification and/or pharmacological intervention by preserving or
reducing the rate of decline of beta cell function [10,12e15]. In the United Kingdom Prospective Dia-
betes Study (UKPDS) which recruited patients with newly-diagnosed T2DM, early intensive glycemic
control with mean 0.9% HbA1c lower than conventional treatment, translated into a 12e25% reduction
in microvascular complications after a median duration of 10 years [16]. In the 10-year post-trial
follow-up period of UKPDS, early intensive glycemic control had a legacy effect with reduced risk of
cardiovascular complications and all-cause death [17]. These results are in contrast to the ACCORD
(Action to Control Cardiovascular Risk in Diabetes) study where intensive treatment was introduced
after 10 years of diagnosis when many patients had developed complications with poor tolerance to
hypoglycemia [6]. Thus, early intensive treatment at a stage when complications are less likely and side
effects are better tolerated is preferable to delayed intensive treatment when side effects may lead to
adverse consequences [18,19]. Given that 20e50% of people with T2DM remain undiagnosed on a
worldwide basis especially in low-to-middle-income countries, early detection is particularly impor-
tant since treatment is relatively inexpensive and effective compared to late-stage disease when
treatment tend to be more complex [20e22].

Who is at risk of T2DM?

T2DM is a complex disease with interplay between genetic and environmental factors. Well
recognized risk factors include positive family history and ethnicity which may be closely related to
genetic susceptibility [23,24]. In these high risk subjects, shared environments and culture with similar
 A.P.S. Kong et al. / Best Practice & Research Clinical Endocrinology & Metabolism 30 (2016) 345e355 347

lifestyles may be contributory factors. Other factors include obesity, insulin resistance and metabolic
syndrome, notably dyslipidemia and hypertension [25e27]. Overweight and obesity during childhood
and adolescence are important risk factors due to substantial tracking of obesity trait and its associated
cardiovascular risk factors into adult life [28e30]. Men with testosterone deficiency [31e35] and
women with gestational diabetes mellitus [36] and polycystic ovarian syndrome [37] have reduced
insulin sensitivity and increased risk of T2DM. Another important at-risk group which deserves clinical
attention is “prediabetes” which include impaired glucose tolerance (IGT) and/or impaired fasting
glucose (IFG). These high risk subjects often harbor multiple risk factors which amplify their risk for
developing diabetes (Fig. 1). The use of risk scores has been recommended to increase the yield of
positive cases of screening program. For instance, in a Hong Kong Chinese population of working age,
we used a validated risk score (including age, body mass index, hypertension, dyslipidemia, family
history of diabetes and gestational diabetes) and identified 10e20% of subjects with a risk score 12
who had high likelihood of having diabetes on 75 g oral glucose tolerance test [38,39]. Besides, these
subjects often have varying degrees of insulin deficiency and resistance calling for more detailed
phenotyping and personalized intervention [40].

Individuals with strong family history and genetic risks

The American Diabetes Association recommended testing for diabetes in asymptomatic adults who
have first degree relatives with diabetes and high risk ethnic groups including Pacific Islander, Latino,
Asian, African and Native Americans [41]. In a meta-analysis of 3813 individuals (19 African, 31
Caucasian and 24 East Asian cohorts), Africans and East Asians exhibited hyperbolic relationships
between insulin sensitivity and insulin response compared to their Caucasians counterparts [42]. In
this analysis, the authors demonstrated ethnic differences in the stabilization points of insulin

Fig. 1. A conceptual framework showing the interactions amongst various risk factors in causing prediabetes and diabetes
(PCOS¼polycystic ovarian syndrome, GDM¼gestational diabetes)
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sensitivity and insulin response in maintaining normal blood glucose levels with Asians having low
beta cell function which often decompensate in the presence of insulin resistance [42]. For individuals
with a strong family history of diabetes, the possibility of monogenic diabetes and LADA (latent
autoimmune diabetes of adults) should be considered as these subtypes of diabetes are not uncommon
in certain ethnic groups such as Asian populations [43,44].

Obesity and risk of T2DM

Obesity and overweight are associated with insulin resistance, even in young people, which can lead
to clustering of cardiometabolic risk factors [28,45]. This abnormal internal milieu can lead to hyper-
insulinemia with progressive beta cell secretory failure leading to early onset of diabetes [27]. Besides,
there are ethnic differences in body fat distributions, with Asians having more visceral fat and reduced
glucose disposal rates than non-Asians [46]. Together with reduced beta cell function and rapid
economical transitions and affluent lifestyles, Asians are a particularly high risk group for early
intervention [42]. However, commonly used clinical tools such as body weight and body mass index
might not be sufficiently sensitive to differentiate obese people who are metabolically healthy from
those with insulin resistance [47]. Epidemiological data from the United States have identified
discordance between body weight and cardiovascular risk profile, with some normal-weight in-
dividuals having clustering of cardiometabolic abnormalities while some overweight and obese people
are metabolically healthy [47]. It is also increasingly recognized that sub phenotypes of obesity, such as
ectopic fat in the liver, may be more important than subcutaneous fat in determining an individual's
risk to have insulin resistance and metabolic consequences [48]. Our group has reported the inde-
pendent role of mesenteric fat measured by ultrasound scan on predicting metabolic syndrome, fatty
liver and carotid atherosclerosis in healthy Chinese subjects [49e52]. That said, given the resource
implications required for detailed sub phenotyping, cost-effective analysis for including these strati-
fication tools, such as imaging for ectopic fat, will be needed, especially in developing areas.

Men with testosterone deficiency should be screened for diabetes

Testosterone is the primary male sex hormone responsible for development and maintenance of
masculine characteristics and sexual function. Testosterone deficiency in men refers to a state of
insufficient testosterone production and action and is manifested by low circulating testosterone with
symptoms and signs. Classical testosterone deficiency results from testicular pathology or impaired
release of gonadotropin due to disruption of the hypothalamusepituitary axis. Gradual decline in
circulating testosterone occurs with natural ageing and contributes to physiological changes in elderly
men, including body composition with increased body fat and reduced lean muscle mass [53]. The
overall prevalence of androgen deficiency ranges from 6 to 40% depending on the age group, clinical
setting and comorbidities of the surveyed populations [31,54,55].
Men with testosterone deficiency are more likely to develop metabolic syndrome and diabetes, in
part due to changes in body composition and insulin resistance [56]. Men with non-metastatic prostate
cancer treated with testosterone deprivation therapy have increased abdominal fat and reduced lean
muscle mass within months of testosterone withdrawal [57]. This is often associated with increased
incidence of T2DM over time with progressive decompensation of insulin secretion to overcome
insulin resistance [58,59]. There is now a wealth of literature on the association between low testos-
terone and diabetes [31e35]. In a cross-sectional analysis of 1413 men who participated in the Third
National Health and Nutrition Examination Survey in the United States, those in the lowest tertile of
free testosterone levels were four times more likely to have diabetes compared to those in the top
tertile after adjustment for other risk factors [32]. The European Male Ageing Study, which enrolled
2966 older men, showed that subjects with total testosterone levels <11.0 nmol/L and sexual symp-
toms (decreased sexual interest, reduced morning erection and erectile dysfunction), had higher fre-
quencies of both diagnosed and undiagnosed diabetes and metabolic syndrome than men with normal
testosterone levels [33]. In men with testosterone insufficiency, 20e30% have diabetes and up to two
third have metabolic syndrome [31,33]. In addition to these cross-sectional surveys, in the Massa-
chusetts Male Aging Study of 1156 men followed for 7e10 years, free testosterone and sex hormone
 A.P.S. Kong et al. / Best Practice & Research Clinical Endocrinology & Metabolism 30 (2016) 345e355 349

binding globulin (SHBG) at baseline were independently and inversely related to incident T2DM after
adjustment for age and anthropometric indices [34]. In the Kuopio Ischemic Heart Disease Risk Factor
Study which enrolled a longitudinal cohort of 702 middle-aged men residing in Finland, total but not
free testosterone independently predicted incident metabolic syndrome and T2DM [35]. The exact
underlying mechanisms by which testosterone modifies the amount and distribution of fat is not well
understood. It has been suggested that testosterone may promote the differentiation of pluripotent
stem cells to bias commitment towards myogenic lineage while inhibit their development into
adipocytes [60]. Testosterone may also modulate gene expression implicated in insulin action and
glucose metabolism through androgen receptor signaling in liver and skeletal muscle [61,62].
The relationship between T2DM and testosterone deficiency is complex. Men with T2DM are more
likely to have low testosterone levels compared to their age-matched non-diabetic counterparts
[63e65]. In a meta-analysis of cross-sectional and prospective studies involving over 6000 men, serum
total testosterone was consistently lower in men with T2DM than those without [66]. While the risk
relationship of diabetes with low total testosterone level may be confounded by obesity, which reduces
SHBG, a significant proportion of non-obese men with T2DM also had low testosterone levels [64].
These risk associations between low testosterone and T2DM have also been validated using more
robust measurements of free or bioavailable testosterone, which are less influenced by changes in
SHBG levels [63]. Although hypogonadotropic hypogonadism is the most common pattern of testos-
terone deficiency in men with diabetes, this invariably occurs in the absence of gross structural lesion
on pituitary imaging [64,67]. Pro-inflammatory cytokines, such as tumour necrosis factor-a and
interleukin-1 b, can inhibit gonadotropin-releasing hormone and luteinizing hormone (LH) in vivo [68].
Furthermore, deletion of insulin receptors in animal models has been shown to reduce LH and
testosterone levels, suggesting that insulin insufficiency in T2DM may alter the activity of the hypo-
thalamusepituitaryegonadal axis [69].
The link between testosterone insufficiency and premature mortality has been extensively
reported. In the European Prospective Investigation into Cancer in Norfolk Study, which followed up
11,606 men aged 40e79 years residing in the United Kingdom for 7 years [70], total testosterone was
inversely related to all-cause mortality as well as mortality due to cardiovascular disease and cancer.
The association remained robust after exclusion of deaths that occurred within 2 years of enrolment,
minimizing the possibility of low testosterone being an epiphenomenon of ill-health. In an updated
systematic review of 21 studies comprising over 20,000 men observed for 10 years, an increase of
35% and 25% in all-cause and cardiovascular mortality respectively was found for each 2.2 standard
deviation decrease in total testosterone [71].

Women with polycystic ovarian syndrome or gestational diabetes

While low testosterone levels are associated with increased risk of T2DM in men, high testosterone
levels are linked with increased risk of T2DM in women, as supported from a meta-analysis including
80 published articles (43 prospective and 37 cross-sectional studies) comprising 6974 women and
6427 men [66]. In this meta-analysis, cross-sectional studies showed that men with T2DM had lower
testosterone levels than men without diabetes, and that women with T2DM had higher testosterone
levels than controls [66]. In a similar vein, prospective studies demonstrated that men with higher
testosterone levels had a 42% lower risk of T2DM (95% CI 0.39 to 0.87) while testosterone increased risk
of T2DM in women albeit statistically not significant (p ¼ 0.06) [66].
Polycystic ovarian syndrome is a common endocrine disorder associated with testosterone excess
in women, albeit with considerable phenotypic variability and ongoing controversies regarding its
clinical definition [37]. Similar to men with testosterone deficiency, women with excess testosterone
are often obese and insulin resistant with a high risk for T2DM, which needs to be taken into
consideration during the treatment of polycystic ovarian syndrome [37,72].
During pregnancy, insulin resistance increases with advancing gestational age and changing
hormonal patterns. Women with a prior history of gestational diabetes had a higher rate of glucose
intolerance and T2DM compared to pregnant women with normal glucose tolerance [36]. In a pro-
spective study involving 139 Chinese pregnant women who underwent 75 g oral glucose tolerance
tests at 24e28 weeks gestation between 1992 and 1994 (45 with gestational diabetes and 94 with
350 A.P.S. Kong et al. / Best Practice & Research Clinical Endocrinology & Metabolism 30 (2016) 345e355

normal glucose tolerance) [36], 26.6% of women with history of gestational diabetes and 14.9% with
normal glucose tolerance developed “pre-diabetes” 15 years later. The respective figures for incident
diabetes were 24.4% and 5.3% (all p < 0.001) [36]. In Chinese women, considered a high risk popu-
lation for diabetes, the prevalence of gestational diabetes is also rising [73]. Compared to their Eu-
ropean counterparts, pregnant women from Asia are more insulin resistant [74]. In the
aforementioned study of Chinese women with gestational diabetes followed for up to 15 years, in-
sulin resistance, as measured by Matsuda insulin sensitivity index [75]and the quantitative insulin
sensitivity check index (QUICKI) [76], was an independent predictor of T2DM and metabolic syn-
drome syndrome. The average yearly conversion rate to T2DM was 1.6% after a pregnancy affected by
gestational diabetes [36].

“Prediabetes”

Individuals with ”prediabetes”, IGT and/or IFG are estimated to have 40e50% lifetime risk of
progression to T2DM [10,77]. Individuals with IGT who are in the upper third of 2-h post oral glucose
tolerance test (OGTT) plasma glucose have lost 70e80% of their b-cell function. In these subjects,
preservation of their remaining b-cell function is critical to minimise development of T2DM [78]. There
is general consensus that targeted, rather than population, screening for diabetes or prediabetes is
preferred [20]. Many experts propose the use of risk scores such as the Finnish Diabetes Risk Score
(FINDRISC) and QDiabetes Risk Score [20] to identify high risk people for definitive testing. While there
is no perfect screening test for diabetes, HbA1c is becoming a popular screening test due to the
inconvenience and staff costs implicated with OGTTs.

Who should be treated?

Treatment of high-risk individuals to prevent T2DM has important medical and socio-economic
implications. The question of who should be treated needs to take into consideration the cost-
effectiveness and ease of implementation. Most diabetes prevention trials recruited subjects with
IGT although many of them also had metabolic syndrome [79e81]. Lifestyle modification has
consistently been demonstrated to reduce conversion of IGT to T2DM [12e14,79], although changing
and maintaining lifestyle changes are challenging [79]. Moreover, structured lifestyle modification
programs are not inexpensive often requiring a team approach including dietitians and physical
trainers especially if individual guidance and supervision is required [14]. A recent systemic review of
30 published trials studying at risk individuals with “pre-diabetes” [81] showed that both lifestyle
and pharmacological agents were beneficial in reducing the rates of conversion from “prediabetes” to
T2DM, with lifestyle interventions having a clear primary role. However, the addition of a pharma-
cological agents to a diet and exercise regimen is useful to those who are unable to follow lifestyle
changes, and in those who continue to remain glucose intolerant after a period of lifestyle modifi-
cation [81]. Pharmacological agents of choice include: 1) Metformin which reduced risk of incident
T2DM by 31% [14] accompanied by improvement in insulin sensitivity [82]; 2) Thiazolidinediones
(TZD), insulin sensitizers, which reduced the risk of incident diabetes by 23% in the US Diabetes
Prevention Program [83] with troglitazone, 62% in the DREAM (Diabetes REduction Assessment with
ramipril and rosiglitazone Medication) trial with rosiglitazone, and 72% in the ACT NOW study with
pioglitazone [84]; 3) Alpha glucosidase inhibitors which reduced risk of incident diabetes by 25% in
the STOP-NIDDM study with acarbose [85] and by 40% in a study using voglibose in Japanese patients
with T2DM [86].

Other treatment considerations in special at-risk groups

For other at risk groups not reaching the state of “prediabetes”, such as women with polycystic
ovarian syndrome, tackling obesity is the core consideration for intervention. Recent advances using
non-targeted metabolomic approaches indicated that obesity is the major determinant of the
metabolic heterogeneity including insulin resistance [87]. As such, strategies which can reduce body
weight such as lifestyle modification, possibly anti-obesity drugs and bariatric surgery in people
 A.P.S. Kong et al. / Best Practice & Research Clinical Endocrinology & Metabolism 30 (2016) 345e355 351

with severe obesity may be considered [37]. A recent meta-analysis of 12 randomized controlled
trials, comprising 608 women with polycystic ovarian syndrome, metformin in combination with
lifestyle modification was thought to be an effective weight management strategy in this population
[88].
The risk association of testosterone deficiency with premature mortality in men with or without
diabetes has been well reported although the underlying mechanism requires further exploration
[89]. Although there are ongoing controversies regarding the place of testosterone replacement
therapy in men with testosterone deficiency not due to primary testicular or pituitary pathology
[90], some experts hold the view that, in subjects with low testosterone who also have metabolic
abnormalities including T2DM, testosterone replacement therapy may be indicated. In observa-
tional cohorts and small scale trials [89], treatment with testosterone in elderly men and men with
T2DM with testosterone deficiency have been shown to reduce glycemia and compensatory
hyperinsulinemia, although larger scale randomized studies are needed to confirm these findings
[91, 92].
In the American Diabetes Association Treatment Guideline [41], screening for T2DM is recom-
mended in over-weight or obese adults aged 45 years, or persons with risk factors for diabetes
regardless of age. This guideline highlighted that any conditions associated with insulin resistance are
considered risk factors, although there is no specific reference made to testosterone deficiency. Given
the consistent evidence regarding the unfavourable metabolic effects of low testosterone and the
predisposition of men with low testosterone for T2DM, there is strong argument for regular screening
for diabetes and early intervention in this high risk population.

Fig. 2. A proposed flow chart for the detection and management of high risk people for diabetes. GDM, gestational diabetes; HbA1c,
glycated haemoglobin; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; OGTT, oral glucose tolerance test; PCOS,
polycystic ovarian syndrome.
352 A.P.S. Kong et al. / Best Practice & Research Clinical Endocrinology & Metabolism 30 (2016) 345e355

Conclusions

There are many risk factors which frequently cluster to amplify the risk of developing T2DM.
An individual with multiple risk factors deserves regular surveillance and clinical assessment to
detect “prediabetes” or diabetes to enable early intervention. Similar to diabetes management
[8,11,19,41,93,94], screening and treatment of high risk patients should be personalized and be
implemented as soon as possible. Regular screening, lifestyle modification and behavioural changes
remain the cornerstones for diabetes prevention (Fig. 2). For high risk people who cannot afford
intensive lifestyle modifications, or in areas where implementation of such programs are not without
challenge, early intervention with pharmacological agents targeting the underlying pathophysiological
mechanisms may be an option.

Research agenda
Areas for future research:

C Cost-effectiveness analysis of screening at-risk individuals to develop T2DM

C Cost-effectiveness analysis of the use of pharmacological agents, such as the use of met-
formin, for high risk groups.
C Personalized approach including the incorporation of genetic analysis in the treatment of
high risk groups.

Disclosure

JCNC has received research grant and/or honorarium for consultancy or giving lectures, from Bayer,
Boehringer Ingelheim, Daiichi-Sankyo, Eli-Lilly, GlaxoSmithKline, Merck Sharp & Dohme, Merck
Serono, Pfizer, Astra Zeneca, Sanofi, Novo-nordisk and/or Bristol-Myers Squibb. APSK has received
honorarium for consultancy or giving lectures from Abbott, Astra Zeneca, Sanofi, Novo Nordisk,
Eli-Lilly, Merck Serono, Pfizer and Nestle. The proceeds have been partially donated to the Chinese
University of Hong Kong, American Diabetes Association and other charity organizations to support
diabetes research and education.

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