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ANGPTL8 (Betatrophin) Role in Diabetes and Metabolic
Diseases
Mohamed Abu-Farha1*, Jehad Abubaker1, Jaakko Tuomilehto2
1Biochemistry and Molecular Biology Unit; Dasman Diabetes Institute, Kuwait City, Kuwait. Dasman
2Diabetes Institute, Kuwait City, Kuwait.
*For correspondence:
Mohamed Abufarha, PhD, Biochemistry & Molecular Biology Unit
P.O. Box 1180, Dasman 15462, Kuwait
Phone: +965 2224 2999 Ext. 3010
mohamed.abufarha@dasmaninstitute.org; mafarha@gmail.com
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Abstract
Diabetes is a major disease worldwide that is reaching epidemic stage. Its increased
prevalence as well as its association with a high number of complications such as
cardiovascular diseases, nephropathy and retinopathy makes it an important disease for
investigation. ANGPTL8 is a recently identified hormone that has been associated with two
functionally important processes in the development of type 2 diabetes, insulin resistance as
well as lipid metabolism. Initial work has showed that ANGPTL8 was expressed in liver,
white adipose and brown adipose tissues. ANGPTL8 regulates the activity of lipoprotein
lipase, which is a key enzyme in lipoprotein lipolysis pathway through its direct interaction
with ANGPTL3. It has been also reported that it regulates the replication of β-cells in
response to insulin resistance. As a result, many recent studies have focused on the
association of ANGPTL8 with diabetes and obesity as well as its association with various
metabolic markers in order to better understand its physiological role in glucose homeostasis
and lipid metabolism. In this review we will highlight some of the key clinical findings,
mainly from human studies, that investigated the role of ANGPTL8 in metabolic diseases
such as diabetes, obesity and the metabolic syndrome.
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INTRODUCTION
Diabetes is reaching an epidemic stage worldwide with International Diabetes
Federation (IDF) estimating that around 415 million adults are diabetic and this number will
increase to approximately 640 million by the year 2040 [1]. Since hyperglycaemia increases
progressively during the development of diabetes, there is a high number of people with pre-
diabetes in a population at any given time. Approximately half of these people will become
diabetic within 10 years, if no preventive intervention is provided [2]. Generally, diabetes
develops from the inability of the pancreas to cope with the increased insulin demand in type
2 diabetes (T2D) [3-7] or the inability of β -cells to produce insulin due to a destruction of β-
cells in type 1 diabetes (T1D) [8-10]. Adequate glycaemic control in diabetic patients can be
achieved through a number of approaches such as lifestyle interventions and various glucose
lowering drugs including insulin injections [11, 12] [13]. In T2D the beta-cell inability to
cope with the increased insulin demand can be caused by multiple factors including genetic
factors, aging, obesity as well as oxidative stress. Traditionally, T2D has been diagnosed as
elevated fasting blood glucose (FBG) or post-challenge glucose after an oral glucose
tolerance test (OGTT) [14], but recently also glycated haemoglobin A1c (HbA1c) has been
introduced as another measure to diagnose diabetes [15]. Since various pharmacologic and
non-pharmacologic management options are currently available, early detection of diabetes is
crucial to achieve proper control of diabetes and its complications.
Active screening for diabetes can be carried out starting with non-laboratory diabetes
risk scores that have been developed and validated in various populations. Another approach
is to identify biomarkers that predict the future development of diabetes, its severity as well
as the severity of its complications. These may offer great advantages to delay or prevent the
onset of diabetes or its complications. In this review we will focus on a recently discovered
biomarker called ANGPTL8 or betatrophin that has been shown to play a key role in lipid
metabolism as well as β-cell proliferation [16-19]. ANGPTL8 is the name that will be mostly
used in this paper. This biomarker has also been suggested to be an independent predictor of
the development of T2D [20].
IDENTIFICATION OF ANGPTL8
One of the recent biomarkers that has been recognized to play a role in glucose as
well as lipid homeostasis is ANGPTL8 [19-24]. This protein is an atypical ANGPTL protein
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as it lacks the fibrinogen-like domain and only possesses the N-terminal coiled-coil domains
[21, 24]. This protein has been given many names, in addition to ANGPTL8, it has been
called “hepatocellular carcinoma-associated gene” (TD26) as well as “refeeding induced in
fat and liver” (RIFL) [22] and “lipasin” [24, 25]. RIFIL and lipasin names were given based
on its function in fasting/feeding regulation as well as lipoprotein lipase (LPL) activity
regulation respectively [22], [24, 25]. Initial work in mice has shown that mice lacking the
ANGPTL8 (or Gm6484, as referred to in mice) had low triglyceride (TG) level in blood
circulation [26]. This gene was earlier named RIFL by Ren et al. where they showed that it
was mainly expressed in white and brown adipose tissues (WAT and BAT, respectively) as
well as liver tissues and was regulated by nutrients and hormonal factors [22]. They showed
that TG level in ANGPTL8-null mice was only one third of that found in the wild type.
Knocking down RIFL in 3T3-L1 cells resulted in around 35% reduction in TG concentration.
ANGPTL8 expression was increased over 100 folds during 3T3-L1 cells adipogenesis.
Furthermore, ANGPTL8 expression was increased by about eight times in WAT of ob/ob
mice (an obesity mouse model) compared to wild type mice. Moreover, both WAT and liver
RIFL gene expression was increased by about 100 and 12 times, respectively, after feeding
and fasting conditions in mice. RIFL was induced by insulin and suppressed by forskolin,
isoproterenol and dibutyryl-cAMP in 3T3-L1 cells. Taken together, the data by Ren et al.
confirmed the involvement of RIFL in adipogenesis and lipid metabolism.
Concurrently, a second research group also showed that ANGPTL8 or lipasin, as they
referred to it, was capable of inhibiting LPL activity in vitro [23]. Overexpressing ANGPTL8
in mice lead to about a 5-fold increase in plasma TG. Furthermore, ANGPTL8 expression
was increased in liver during a high fat diet and reduced after fasting. They also showed that
ANGPTL8 is thermo-modulated by cold as its expression was induced in BAT after cold
exposure [24]. It can be concluded from these previous studies that ANGPTL8 is mostly
expressed in liver, WAT and BAT [21-24]. The level of ANGPTL8 can be induced by high
fat feeding and exposure to cold. Also, ANGPTL8 is involved in regulating plasma TG level
through its inhibition of LPL activity, which results from its interaction with the N-terminal
domain of ANGPTL3 [21-24].
A third critical paper was published by Quagliarini et el. also in 2012 showing similar
tissue distribution with particular enrichment in liver and adipose tissue [21]. ANGPTL8 was
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given this name based on its sequence similarity to members of the angiopoietin-like protein
family mainly ANGPTL3, which was also recognized as an interaction partner for
ANGPTL8. Adding further support to ANGPTL8 role in lipid metabolism, Quagliarini et el.
showed that a non-synonymous SNP (R59W) was associated with lower LDL-C and HDL-C.
Using the Dallas Heart Study (DHS), this variant was associated with lower plasma levels of
LDL-C and HDL-C in African Americans and Hispanics but not European Americans [21].
Their results were replicated in African Americans in the Atherosclerosis Risk in
Communities (ARIC) study [21]. No association was observed between this variant and TG
level in any ethnic group [21]. We have recently shown that people of Arab origin who
carried this variant had higher FBG [27]. In addition, Quagliarini et al. showed that the
overexpression of ANGPTL8 lead to increased TG level that was further increased in the
presence of ANGPTL3 [21]. This suggested that the two proteins maybe acting in synergy to
control TG level. Indeed, this was validated when they showed that ANGPTL8 protein was
physically interacting with ANGPTL3, which resulted in regulating the plasma lipoprotein
level. They also showed that overexpressing ANGPTL3 alone in wild type mice did not result
in increased TG while it was true for the overexpression of ANGPTL8. Collectively, their
findings suggested that ANGPTL8 plays a role in regulating the level of TG through its
interaction with ANGPTL3 forming a complex that might act as a LPL inhibitor.
Subsequent publications showed that ANGPTL8 was involved in β-cell proliferation
in response to treatment with insulin receptor antagonist (S961). In a study by Yi et al. it was
reported that a 17 fold increase in β-cell proliferation was observed upon overexpression of
ANGPTL8 “betatrophin” in mouse liver, leading to a 3-fold increase in β-cell mass. They
also showed that ANGPTL8 was released into circulation, and then binds to β-cells through
an unidentified receptor leading to increased β-cell proliferation and mass [19]. Furthermore,
they reported that mice overexpressing ANGPTL8 had improved glucose tolerance and lower
FBG [19]. These conclusions were however questioned by other studies that showed that
mice lacking ANGPTL8 had normal glucose and insulin tolerance [28]. Furthermore, one
study showed that ANGPTL8 did not have any effect on β-cell expansion in mice and further
confirmed that blood TG was reduced by ANGPTL8 deletion and increased after its
overexpression [29]. The only consistent finding reported by different studies is that showing
that knocking down ANGPTL8 expression in mice results in disrupted TG delivery to
adipose tissues [21, 28]. Another study by Jiao et al. showed that transplantation of human
and mice islets treated with S961 under the kidney capsule in mice resulted in increased
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ANGPTL8 level, which in turn caused an increase in beta-cell proliferation in the
transplanted mice islets [30]. However, this effect was not observed in human transplanted
islets. In conclusion, the role of ANGPTL8 in beta-cell proliferation in humans as well as
mice has been challenged, however, its role in insulin resistance is becoming well established
even though more studies investigating its mechanism of action remain to be conducted [29,
31]. This review will focus more on the clinical studies that looked at the plasma level of
ANGPTL8 and its possible association with lipid and glucose profiles as well as other
diabetes and obesity related biomarkers.
ANGPTL8 ROLE IN OBESITY
Obesity is the major risk factor for T2D that leads to increased insulin demand and
insulin resistance. In combination with lack of physical activity and genetic predisposition,
obesity will stress beta-cells to increase insulin production reaching a point where beta-cells
fail to compensate for the increased insulin demand leading to permanently elevated glucose
concentration in blood circulation, i.e. the development of T2D [13]. ANGPTL8 is produced
by two of the key tissues in the insulin resistance pathways, liver and adipose tissue. Liver is
one of the main tissues involved in glucose metabolism. Adipose tissues also plays a major
role in insulin resistance through the increased inflammation, free fatty acids release, and
reduced adiponectin production [32, 33]. Given the connection between obesity and insulin
resistance as well as lipid metabolism, it’s imperative that ANGPTL8 would be regulated by
obesity.
Studies in rodents has shown that ANGPTL8 level was increased in obesity [21-23].
We have recently published a large human cohort study that showed a positive association
between ANGPTL8 and BMI, and also with waist/hip ratio in non-diabetic people [20]. In
another study we also showed that ANGPTL8 was increased in obese people, but its level
was reduced after exercise [34]. In this study we looked at both forms of ANGPTL8 which
has been called the C-terminal 139-198 and the full length form of ANGPTL8 due to the
different ELISA antibodies used to measure its plasma level. The full length level of
ANGPTL8 was measured using ELISA (Wuhan EIAAB Science co) (catalogue number
E1164H) as described previously. Whereas, the C-terminal 139-198 form was measured
using ELISA kit recognizing the C-terminal domain of ANGPTL8 from 139 to 198 amino
acid manufactured by Phoenix Pharmaceuticals (catalogue number EK-051-55). The use of
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multiple ELISA kits has been suggested as the cause of some of the discrepancies in the
reported data regarding ANGPTL8 level under various conditions such as obesity as well as
its association with FBG [35]. The accuracy of both full length and C-terminal 139-198
ELISA kits has been evaluated by Fu et al. showing that the correlation coefficient between
both kits was 0.99. It was also shown that the C-terminal kit gave higher values for
ANGPTL8 plasma level when compared with the levels obtained from the full length form.
This finding suggested to result from the possibility that the full length ANGPTL8 might be
degraded, therefore its level will be less than those obtained for the C-terminal 139-198 form
[35]. We have shown that both forms were increased in obese people. However, only the full
length ANGPTL8 form was positively associated with FBG [34]. Similarly, other studies
reported increased ANGPTL8 level in obesity as shown in Table 1. For example, Fu et al.
showed that ANGPTL8 level was positively correlated with BMI (rho=0.49, P<0.001) [36].
Taken together, our data suggest that kit variations can explain the differential association
between ANGPTL8 and FBG but not the changes in obesity level as both kits showed a
similar trend. Ethnic variations or other unmeasured factors might be responsible for some of
these changes.
Guo et al. showed that ANGPTL8 was increased in overweight people compared
with lean controls [37], but obese people, on the other hand, had a lower ANGPTL8 level
than overweight people [37]. Moreover, in another study by Fenzl et al. the ANGPTL8 level
between lean and morbid obese people was compared, but they did not observe a significant
difference between the groups [38]. Only one study has reported reduced ANGPTL8 level in
obesity; ANGPTL8 level was reduced in obesity and even more so in obese people with
insulin resistance [39]. One of the main differences observed with this study was the use of a
different kit, which was purchased from CUSABIO/ Aviscera Bioscience, than what has been
used in most other studies. Their ANGPTl8 levels were ranging from 45.1-8.8 ng/mL, which
is roughly 10-40 times higher than levels observed by other kits [39].
The varying results observed in the reported ANGPTL8 levels may also be in part due
to other comorbidities that can play a role in regulating the ANGPTL8 levels. For example it
has been reported that ANGPTL8 level may be affected by thyroid function [40], polycystic
ovary syndrome [41] as well as metabolic syndrome (MetS) [42, 43]. We have also recently
shown that ANGPTL8 was higher in people with MetS than those without. When stratified
according to the number of MetS components, people with higher number of MetS
components had significantly higher level of ANGPTL8 [44]. Similarly, Crujeiras et al. have
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recently shown that ANGPTL8 was increased in obese people with MetS and it was
associated with less reduction in adiposity and dyslipidemia after a weight-loss program [42].
ANGPTL8 ROLE IN DIABETES
T2D develops as a result of the failure of beta-cells to compensate for the increased
insulin demand caused by hyperglycemia and insulin resistance [45-48]. The search for
agents that promote beta-cell proliferation has been very active yet elusive [17, 18]. The
discovery of ANGPTL8 as a hormone that is capable of increasing beta-cell proliferation has
been hailed as a scientific breakthrough [16-18]. It has been shown that ANGPTL8 was
increased under states of insulin resistance to increase beta-cell proliferation and increase
insulin production [19]. ANGPTL8 was increased in ob/ob mice and in the db/db diabetic
mouse model [19]. These findings, particularly the ability of ANGPTL8 to increase beta-cell
proliferation was later challenged [29, 49, 50]. Similarly, many studies have shown that
levels of ANGTPL8 was increased in people with T2D subjects as summarized in Table 1.
This is contrary to its proposed role in increasing beta-cell proliferation where a decrease in
its level is expected. It can be speculated that a state of ANGPTL8 resistance is observed in
these people with T2D where beta-cells are not responsive to the increased ANGPTL8 level.
We have recently published the largest cohort study showing that ANGPTL8 was
increased in people with T2D [20]. We compared the level of ANGPTL8 in 556 people with
T2D with that of 1047 non-diabetic people: ANGPTL8 level was about three times higher in
people with T2D. We also showed that ANGPTL8 was an independent predictor of T2D.
People in the highest tertiles of ANGPTL8 had about 6-fold risk of developing T2D after
adjusting for multiple factors such as age, gender, ethnicity and lipid profile. In our
population, ANGPTL8 was positively associated with many factors such as age, BMI,
waist/hip ratio, FBG, HbA1c, HOMA-IR in non-diabetic people. Our results suggested that
the increased ANGPTL8 level in people with T2D was not effective in increasing insulin
production and was not affecting plasma glucose level [20]. This conclusion was further
supported by the finding that ANGPTL8 was not associated with C-peptide level in the
people with T2D unlike the non-diabetic people in whom ANGPTL8 was positively
associated with the C-peptide level [51].
Other studies have also shown that ANGPTL8 was increased in people with T2D [36,
52-55]. Espes et al. showed that plasma ANGPTL8 was increased in 27 people with T2D vs.
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18 gender, age, and BMI matched controls [52]. In an earlier study they also looked at the
changes in ANGPTL8 level in people with T1D and showed that ANGPTL8 was increased
among them [56]. However, this increase in ANGPTL8 level was not associated with any
increase in residual C-peptide level. Fu et al. showed that serum ANGPTL8 (or lipasin as
they referred to it) was increased in 14 diabetic people compared with 15 BMI and age
matched non-diabetic people, and it was correlated with plasma glucose [36]. Hu et al.
looked at ANGPTL8 in 83 newly diagnosed people with T2D and 83 age, sex and BMI
matched healthy controls; ANGPTL8 level was about two times higher in people with T2D,
and that ANGPTL8 was positively associated with post-challenge serum 2-h OGTT and
insulin [53]. Similarly, Chen et al. measured ANGPTL8 in a subset of 330 individuals from
the Risk Evaluation of Cancers in Chinese Diabetic Individuals. They were divided into four
groups matched for age, sex, BMI, and lipid profile. The group 1 comprised 137 people with
normal glucose tolerance, the group 2 69 people with isolated impaired FBG, the group 3 120
people with isolated impaired glucose tolerance and the 4th group 112 people with newly
diagnosed T2D. The ANGPTL8 level in people with T2D was the highest amongst all groups
and associated with insulin resistance indices [54]. A Japanese study comprising 12 healthy
controls, 34 people with T1D and 30 people with T2D showed that ANGPTL8 was higher in
both T1D and T2D subjects than in non-diabetic controls [55]. On the other hand, some
studies have found ANGPTL8 level decreased in people with T2D. Gomez-Ambrosi et al.
studied 153 people (75 obese normo-glycemic, 30 obese with impaired glucose tolerance and
15 obese with T2D) matched for sex, age and body adiposity and compared to 33 normo-
glycemic lean subjects. However, as highlighted earlier, they used different ELISA kit to
measure the plasma level of ANGPTL8 [39]. Their data showed that ANGPTL8 was
decreased in obese people and further decreased in people with T2D subjects. They also
showed that ANGPTL8 was positively associated with the insulin sensitivity as measured by
QUICKI index (r=0.46, P<0.001). In another study, also using the same ELISA kit
manufactured by CUSABIO/ Aviscera Bioscience, it was shown that ANGPTL8 was
increased in overweight people with T2D compared to their lean counterparts
[37];ANGPTL8 was not significantly different between the people with T2D and the non-
diabetic people in their population, andANGPTL8 was positively correlated with insulin and
insulin resistance as measured by HOMA-IR. One of the main reasons for the different
results reported by these two groups [39, 57] compared with other researchers is likely the
different ELISA kit they used.
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A recent meta-analysis has investigated the association between ANGPTL8 level and
T2D through searching PubMed and Embase for studies published comparing ANGPTL8
level between people with and without T2D; nine studies met their criteria and were included
in this meta-analysis [58]. The level of ANGPTL8 was found higher in people with T2D and
that ANGPTL8 level was higher in non-obese people with T2D than non-diabetic non-obese
people. On the other hand, ANGPTL8 was not significantly different in obese people with
T2D compared to obese non-diabetic people. It is important to highlight that our more recent
data, where we showed that ANGPTL8 level was higher in people with T2D, was not
included in their meta-analysis. Our study included a larger sample than these previous
smaller studies. A small sample size is always an important factor in the interpretation of
results from meta-analyses, and it was correctly mentioned by Li et al. as one of the main
limitations of the studies in their meta-analysis [58]. Another limitation was the use of
variable ELISA kits to measure the level of ANGPTL8 and the wide variation in actual
ANGPTL8 levels reported among different studies [58].
In addition to its increased level in people with T2D, ANGPTL8 has been found to be
increased in women with gestational diabetes (GDM) either in blood circulation [57, 59-61]
or cord blood [60, 61] as summarized in Table 2. Consistently, ANGPTL8 has been initially
shown to be increased during gestation in a mouse model [19]. Yi et al showed that
ANGPTL8 was almost 20 times higher in 18.5 dpc (date post-conception) mice compared
with non-pregnant female mice or mice in their early pregnancy [19]. The increased
ANGPTL8 level during pregnancy has been suggested to stem from a physiological
compensatory mechanism to increase beta-cell proliferation. During pregnancy females
experience a change in hormonal balance that results in a progressive decline in insulin
sensitivity to a level that imitates insulin resistance observed in T2D. The majority of females
do not exhibit changes in their blood glucose throughout pregnancy due to the adequate β-cell
compensation. In the situation where insulin resistance is stronger than what the β-cells can
compensate for, or the β-cell function declines, GDM may develop. It has been suggested that
increased ANGPTL8 level will promote beta-cell proliferation in order to compensate for the
increased insulin demand. In concordance with this argument, Ebert et al. showed that
ANGPTL8 level was higher in women with GDM compared with healthy pregnant women
[62]. Additionally, they showed that ANGPTL8 level was generally lowered postpartum from
its level during pregnancy. Similarly, Erol et al. found the ANGPTL8 level was significantly
higher in 45 pregnant women diagnosed with GDM compared with 45 healthy pregnant
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women matched for BMI and gestational age [59]. Other studies have shown that ANGPTL8
level was increased in the cord blood from women with GDM compared with healthy women
at delivery [57, 60, 61].
ANGTPL8 AND ITS INTERACTION WITH OTHER BIOMARKERS
In addition to its association with ANGPTL3 [21, 28] and insulin [19, 20, 22], the
association of ANGPTL8 with other metabolic markers such as high sensitivity C-reactive
protein (hsCRP), C-Peptide and irisin has been investigated [42, 51, 52, 56, 57, 60, 62, 63].
We found an association between ANGPTL8 and C-peptide in an attempt to understand
whether the increase in ANGPTL8 production will have an impact on the endogenous insulin
production as measured by plasma C-peptide. Comparing ANGPTL8 level in 535 non-
diabetic and 214 T2D people ANGPTL8 was significantly associated with C-peptide level in
the non-diabetic group only [51]. The lack of such association in the T2D group suggested
that the increased ANGPTL8 level observed in people with T2D was not due to increased C-
peptide production [51]. Espes et al. showed that increased ANGPTL8 in people with T1D
was not associated with an increased C-peptide level [56]. They also showed that ANGPTL8
did not correlate with C-peptide in either non-diabetic or T2D people in a small study [52].
On the other hand, Trebotic et al. showed an inverse correlation between ANGPTL8 and C-
peptide in pregnant women, both in non-diabetic pregnant women and those with GDM [57].
ANGPTL8 expression in brown adipose tissues has been recently linked to the action
of another browning related myokine called irisin [64]. In cell models, irisin has been found
to increase the expression of ANGPTL8 during adipocyte differentiation. It has been shown
that ANGPTL8 and irisin were positively correlated with ANGPTL8 level in people with
T1D [65], and that the level of irisin was a positive and independent predictor of the post-
delivery ANGPTL8 level [66]. In another study of 120 people with T2D, ANGPTL8 was not
shown to be associated with irisin in T2D people [67]. Taken together, these inconsistent
findings between ANGPTL8 and irisin highlight the need for more studies to address this
issue.
Based on its role in lipid regulation, ANGPTL8 has been also suggested as a potential
therapeutic target for dyslipidemia [21, 68]. In addition, since the ANGPTL8 level has been
shown to be increased in obesity and in people with MetS [43] we evaluated the potential
association between ANGPTL8 and low-grade inflammation and found a positive association
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between ANGPTL8 and hsCRP [43]. A positive association between ANGPTL8 and
hsCRP has been also found in women diagnosed with polycystic ovary syndrome [69].
CONCLUSION
In conclusion, markers that can detect the development of diabetes can greatly
enhance our understanding of the pathophysiology of the disease and may be used to suggest
methods for prevention. ANGPTL8 is a promising biomarker for early detection of T2D as
well as for GDM in pregnant women. Most studies have shown that ANGPTL8 is increased
in people with T2D, T1D and GDM. It is also increased in obese people and those with MetS.
Nonetheless, some discrepancies in the data exist, most likely due to small sample sizes in the
early studies and due to the wide range of detection kits used to assay the levels ANGPTL8
without any standardization among them. Also, since most studies to date are cross sectional,
the exact role of ANGPTL8 in the pathophysiology of diabetes is not yet very clear and its
contribution to beta-cell proliferation and insulin resistance is far from being well understood.
Taken together, ANGPTL8 is a protein that with more novel studies may significantly
advance our understanding of the pathophysiology of the development of diabetes and other
metabolic diseases.
ACKNOWLEDGMENT
We are indebted to Kuwait Foundation for the Advancement of Sciences (KFAS) for
financial support of by the funding provided to Dasman Diabetes Institute through project
numbers (RA-2014-021 and ACC-14013003). The funding agency was not involved in any
aspect pertinent to this article. None of the authors have been paid to write this article by a
pharmaceutical company or other agency. We are also thankful to Ms. Irina Al-khairi for her
efforts in proofreading this article. None of the authors (MA, JA and JT) have any conflict of
interest or anything to disclose.
Author Contributions
MA: Wrote the manuscript. JA: Critically revised the manuscript. JT: Critically revised
manuscript.
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Table 1: A list of studies measuring the level of ANGPTL8 in people with obesity and/or
diabetes
Study
Effect of Obesity
Effect of Diabetes
Comment
Ren et al.[22]
Increased in ob/ob
mice
NA
RIFL gene expression was increased
in fat and liver of obese mice. RIFL
expression was induced by insulin
[22].
Zhang et al.
[25]
Increased
ANGPTL8 in
Obesity.
NA
Expression in mice [25].
Yi et al. [19]
Higher in the liver of
ob/ob mice.
Higher in the liver of
db/db mice.
Gene expression was increased by a
3- to 4-fold in the liver of both ob/ob
and db/db mice. Given the name
betatrophin. Its expression was also
induced by insulin resistance
increasing beta-cell proliferation and
mass [19].
Espes et al.
[56]
NA
Increased
ANGPTL8 level in
people with T1D.
The level of ANGPTL8 from plasma
samples in 33 people with T1D and
24 age-matched healthy controls.
Increased ANGPTL8 in T1D did not
protect against loss of C-peptide [56].
Phoenix Pharmaceuticals ELIS kit.
Abu-Farha et
al [20, 34]
Increased
ANGPTL8 in obese
people.
Increased
ANGPTL8 in people
with T2D.
Used a large cohort of 1049 non-
diabetic people and 556 people with
T2D [20]. Also showed that exercise
reduced ANGGPTL8 level in obese
people [34]. EIAAB ELISA kit.
Fu et al. [36]
Increased
ANGPTL8 level in
obesity.
Increased
ANGPTL8 level in
people with T2D.
15 non-diabetic people vs 14 people
with T2D subjects matched for BMI-
and age. 24 lean vs 29 overweight
and obese people [36]. Phoenix
Pharmaceuticals ELIS kit.
Gomez-
Ambrosi et al.
[39]
Decreased
ANGPTL8 level in
obese people.
Decreased
ANGPTL8 level in
people with T2D.
75 normo-glycemic people, 30 people
with impaired glucose tolerance and
15 people with T2D. Matched for
sex, age and adiposity. The
comparison group comprised 33
normo-glycemic lean people. A
different ELISA kit was used [39].
Cusabio ELISA kit.
Hu et al. [53]
NA
Higher ANGPTL8
level in newly
diagnosed people
with T2D.
83 newly diagnosed people with T2D
compared with83 age, sex and BMI
matched healthy controls [53].
EIAAB ELISA kit.
This article is protected by copyright. All rights reserved.
Yamada et al.
[55]
NA
Higher ANGPTL8
in people with T1D
and people with T2D
compared with
healthy controls.
12 healthy controls, 34 people with
T1D and 30 people with T2D [55].
EIAAB ELISA kit.
Guo et al. [37]
Higher ANGPTL8
level in overweight
people compared
with lean people.
Obese people had
lower ANGPTL8
than overweight
people. Higher
ANGPTL8 level in
overweight people
with T2D. No
significant
difference between
people with T2D
those without
diabetes.
60 people with normal glucose
tolerance: 17 lean, 23 overweight,
and 20 obese. 56 people with T2D:
14 lean, 23 overweight, and 19 obese
[37]. Aviscera Bioscience ELISA kit.
This article is protected by copyright. All rights reserved.
Table 2: A list of studies of the ANGPTL8 level in pregnant women.
Study
Effect of Obesity
Effect of Diabetes
Comment
Ebert et al.
[62].
NA
ANGPTL8 level was
higher in women
with GDM
compared with
healthy pregnant
women. ANGPTL8
level was decreased
postpartum
compared with its
level during
pregnancy.
74 women diagnosed with GDM vs.
74 normo-glycemic pregnant women
matched for gestational age [62].
Phoenix Pharmaceuticals ELIS kit.
Trebotic et al.
[57]
NA
Increased
ANGPTL8 in
pregnant women
with GDM
compared with
pregnant normo-
glycemic women.
21 women with GDM and 19 BMI
matched normo-glycemic pregnant
women [57]. EIAAB ELISA kit.
Erol et al. [59].
NA
Higher ANGPTL8
level in the GDM
women than normo-
glycemic pregnant
women.
45 women with GDM compared
with 45 normo-glycemic pregnant
women matched for BMI and
gestational age [59]. EIAAB ELISA
kit
Wawrusiewicz
-Kurylonek et
al. [60]
NA.
Increased maternal
and cord blood
ANGPTL8 level in
GDM women.
93 women with GDM and 97
normo-glycemic women. Cord
blood ANGPTL8 level and gene
expression was evaluated in 20
women with GDM and 20 normo-
glycemic pregnant women [60].
USCN Life Science ELISA kit.
Xie et al. [61]
NA
Higher ANGPTL8
in cord blood of
women with GDM
than in normo-
glycemic women.
A total of 54 pregnant women who
delivered by Caesarean section: 21
with GDM and 23 normo-glycemic.
ANGPTL8 level was measured in
cord blood [61]. EIAAB ELISA kit.
