Biomedical

Communication

Biosci. Biotech. Res. Comm. 9(4): 580-586 (2016)

One of the crucial proteins to in uence type 2

diabetes: The high mobility group A1

Hao Kong, Yancheng Liu, Liting Zheng, Qinglu Wang* and Yujun Zhang

Key Laboratory of Biomedical Engineering & Technology of Shandong High School, Qilu Medical University,

Zibo, 255213, China

ABSTRACT

HMGA1 have been shown to transactivate promoters through mechanisms that facilitate the assembly and stability

of stereospeci c DNA-protein complexes, which promote gene transcription in response to all kinds of signals. Some

studies have proved that HMGA1 proteins are relate to insulin resistances and type 2 diabetes. The mechanism can

connect with that HMGA1 paticipate in the expression of INSR and IGF-1R; as well as in uence insulin production,

insulin sensitivity, adipocyte differentiation. Some studies have found that human body can exist in HMGAI-p, the

abnomal increasing of HMGAl-p expression can down-regulated the levels of INSR and impair insulin binding. Low-

frequency insertion polymorphism IVS5-13insC has been identi ed and associated with insulin resistance and type

2 diabetes, but con icting results on diverse ethnic groups have caused dif culty in performing clinical translation

of HMGA1 IVS5-13insC genotyping.

KEY WORDS: HMGA1, TYPE 2 DIABETES, INSULIN RESISTANCES, HMGA1-P, HMGA1 IVS5-13INSC

580

ARTICLE INFORMATION:

*Corresponding Author: wql_zcq@126.com

Received 19

Nov, 2016

Accepted after revision 25

Dec, 2016

BBRC Print ISSN: 0974-6455

Online ISSN: 2321-4007

Thomson Reuters ISI ESC and Crossref Indexed Journal

NAAS Journal Score 2015: 3.48 Cosmos IF : 4.006

reserved.

Online Contents Available at: http//www.bbrc.in/

INTRODUCTION

THE STRUCTURE AND FUNCTION OF HMGA1

HMGA1 belongs to the high mobility group (HMG)

protein family, comprising all kinds of non-histone

proteins(Reeves, 2001). Within this family, the HMGA

proteins can prior bind to the minor groove of A/T-rich

B-form DNA sequences, because it contain three AT-

hook DNA binding motifs. Although HMGA proteins

have been predicted no intrinsic transcriptional activ-

ity, they could serve as so-called “enhanceosomes” to

promote the assembly and stability of stereospeci c

DNA-protein complexes through transactivate promot-

ers, which facilitate gene transcription in response to

a variety of signals(Reeves, 2001, Thanos, et al., 1995).

Hao Kong et al.

HMGA1 orchestrate a large quantity of various tran-

scription factors, such as Sp1, p150, NF-Y, NF-kB,

ATF-2, c-Jun, TAF3 at gene promoter and enhancer

regions, which participate in gene-speci c transcrip-

tion regulation(Currie, 1997, Leger, et al., 1995, Yie, et

al., 1997, X. M. Zhang, et al., 1999(Huth, et al., 1997,

Messineo, et al., 2016) .

Thus, it regulates the expression of an impressive num-

ber of mammalian genes. Besides, HMGA1 also involved

in many other processes, including embryogenesis, differ-

entiation, and neoplastic transformation (Cleynen, et al.,

2008, Fedele, et al., 2010, Sgarra, et al., 2004). HMGA1a

and HMGA1b were HMGA1 gene encodes spliced iso-

forms, the latter one lacking 11 amino acids between

the  rst and the second AT-hook motif than the former

one(Friedmann, et al., 1993, Nagpal, et al., 1999).

TYPE 2 DIABETES

Type 2 diabetes is one of the major and exacerbating

health problems worldwide; type 2 diabetes is shown to

affect 490 million in 2030(P. Zhang, et al., 2010). Strong

genetic in uences and many polymorphisms have been

reproducibly associated with type 2 diabetes(Herder, et

al., 2011, Voight, et al., 2010). Insulin resistance in mus-

cle, liver, and adipose tissues is a primary characteris-

tic of most patients with type 2 diabetes; as such, these

tissues become resistant to endogenous and exogenous

insulin. The interaction of insulin with target tissues

is mediated by insulin receptor (INSR), a glycoprotein

implicated in directing insulin to target cells and initiat-

ing cell responses to insulin. Many of these individuals

have point mutations in the coding sequence of INSR,

the gene that encodes insulin receptor. Receptor abnor-

malities resulting from defects in the generation of INSR

mRNA have been reported in individuals with appar-

ently normal INSR genes, suggesting defects in gene

regulation(Gold ne, 1987).

THE RELATIONSHIP BETWEEN HMGA1 AND

TYPE 2 DIABETES

HMGA1 proteins are over-expressed in virtually every

type of cancer, where their expression levels correlate

with tumor malignancy and a poor outcome for patients

suffering from that particular type of tumor(De Rosa,

et al., 2016, Huso, et al., 2014). But, some studies have

also proved that low-expressed HMGA1 proteins are

relate to insulin resistances and type 2 diabetes(Aiello,

et al., 2010, Foti, et al., 2005) The mechanism can con-

nect with that HMGA1 paticipate in the expression of

INSR and isulin-like growth factor 1 receptor (IGF-1R);

and in uence insulin production, insulin sensitivity,

adipocyte differentiation.

HMGA1 POSITIVELY REGULATE THE

EXPRESSION OF INSR AND IGF-1R VIA

INFLUENCING GENE TRANSCRIPTION

HMGA1 assemble polyprotein-DNA complexes with

protein polymer to positively regulate the activity of

INSR promoter, which bind to the transcription start site

of INSR. Finally, resulting in the positive regulation of

INSR expression and insulin signal transduction(Foti,

et al., 2005, Kolb, et al., 2007, Paonessa, et al., 2006).

Moreover, HMGA1 have also effected on insulin signal

transduction through the positive regulation of IGF-1R

expression(Aiello, et al., 2010). Foti and his colleagues

have found HMGA1 mutation in peripheral blood lym-

phocyte from subjects with insulin resistance and type

2 diabetes, which result in HMGA1 protein were pre-

sent at low expression. Restoration of HMGA1 pro-

tein expression in subjects’ cells enhanced INSR gene

transcription, and restored cell-surface insulin recep-

tor protein expression and insulin-binding capac-

ity. These results show that the decrease of HMGA1

is likely to cause insulin resistances and human type

2 diabetes. In animal study, HMGA1 knock-out mice

were present at considerably decreased insulin recep-

tor expression in the major targets of insulin action,

largely impaired insulin signaling, causing a pheno-

type characteristic of human type 2 diabetes(Foti, et al.,

2005).

HMGA1 CAN FACILITATE INSULIN

PRODUCTION VIA REGULATING PDX-1 AND

MAFA

Arcidiacono and his colleagues provided evidence that

HMGA1 physically interacts with PDX-1 (the pancre-

atic and duodenal homeobox factor-1) and MafA (V-maf

musculoaponeurotic  brosarcoma oncogene homolog A),

two critical transcription factors for insulin gene expres-

sion and beta-cell function, both in vitro and in vivo(Hay,

et al., 2006). They also show that the over-expression

of HMGA1 signi cantly improves the transactivating

activity of PDX-1and MafA on human and mouse insu-

lin promoters, while HMGA1 knockdown considerably

decreased this transactivating activity. In addition, they

demonstrate that HMGA1 may act as a glucose-sensitive

element controlling the transcription of the insulin gene,

because high glucose stimulus remarkably increases

the binding of HMGA1 to the insulin gene promoter.

According to the above analysis, HMGA1, by regulating

PDX-1- and MafA-induced transactivation of the insulin

gene promoter, is witnessed by affected pancreatic beta-

cell function and insulin production(Arcidiacono, et al.,

2014).

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Hao Kong et al.

HMGA1 PARTICIPATE IN THE REGULATION

OF INSULIN HYPERSENSITIVITY TO ADAPT

IMPAIRED GLUCOSE TOLERANCE

Due to the restriction of medical ethics, we could not do

an in-depth study for  nite patients with HMGA1 muta-

tion. Thus, some researchers carry on depth studies via

animal model. A study showed that the expression of

insulin receptor is off by 90% and appear to hypergly-

cemia simultaneously in Hmga1-knockout mice. But, in

Hmga1-knockout mice peripheral insulin hypersensitiv-

ity paradoxically coexisted with a condition of impaired

glucose tolerance and overt diabetes. Moreover, the

expression of the insulin-regulatable glucose transporter

4 (Glut4) was increased in muscular tissue (Foti, et al.,

2005). We could not precisely explain that the sensitivity

to insulin emerged discrepancy between peripheral tis-

sues from human and mouse.

This phenomenon showed that the existence of

molecular adaptation mechanisms in Hmga1-knockout

mice. Two systems are now considered to explain this

phenomenon.

1. The cAMP-HMGA1-RBP4 system: adipose tissue

can release of the adipose-derived serum RBP4,

which its amounts have a negative correlation

with the expression of Glut4 (Yang, et al., 2005).

RBP4-knockout mice appear to insulin hypersen-

sitivity. Provided exogenous RBP4 or over-expres-

sion RBP4 in body can induce insulin resistance.

However, HMGA1-knockout mice really existed the

decreasing of RBP4 mRNA and peripheral blood

RBP4 levels. Then, exogenous RBP4 were correct-

ed the enhancing of Glut4 in the muscle tissue

of HMGA1-knockout mice, and correspondently,

the unusual high effect of insulin reduces blood

sugar was declined remarkably. In the study on

wild-type mice, found that glucagon can stimulate

the expression of HMGA1 and RBP4, whereas this

situation could not emerge on HMGA1-knockout

mice. Thus, HMGA1 plays an direct role in RBP4

promoter to paticipate in pancreatic glucagon

stimulate the expression of RBP4. Because pan-

creatic glucagon release is regulated by the cAMP

pathway, hence, thinking of that cAMP is regula-

tory factor for HMGA1 and RBP4 gene(Chiefari,

et al., 2009).

2. (2)The HMGA1-IGF-I/IGFBP System: Numerous

results of experimental and clinical studies evi-

dence that IGF-I plays a vital role in normal car-

bohydrate metabolism(Woods, et al., 2000, Yakar,

et al., 2001). The IGF-binding proteins 1 (IG-

FBP1) and 3 (IGFBP3), two major members of the

IGF-binding protein superfamily, by in uencing

both the bioavailability and distribution of IGF-I

in the extracellular environment, hold a crucial

position in IGF-I ligand-receptor interactions,

(Baxter, 2000, Clemmons, 1997). They demonstrat-

ed that IGF-I’s bioactivity was increased, but levels

of IGFBP1 and IGFBP3 are considerably decreased

in Hmga1-knockout mice. They hypothesize that,

under certain adverse metabolic conditions, func-

tional inactivation of HMGA1, by adversely affect-

ing the expression of both IGFBP proteins, may

re ect an adaptive mechanism to increase IGF-1’s

bioactivity, ensuring recruitment of Glut4 to mus-

cle plasma membrane and tissue glucose disposal.

However, the precise mechanisms by which these

compensatory circuits of glucose uptake are ac-

tivated and provide signals for the translocation

remain to be fully characterized and elucidated

(Iiritano, et al., 2012).

HMGA1 CAN INVOLVE IN FORMING INSULIN

RESISTANCE VIA INHIBITING ADIPOCYTE

DIFFERENTIATION

The importance of poorly adipocyte differentiated for

development and progression of insulin resistance is

witnessed (Gustafson, et al., 2015). HMGA1 can pro-

mote adipocyte differentiation, enhance the ability to

store fat, improve body of insulin sensitivity (Melillo,

et al., 2001). Two transcriptional factor, CCAAT/

enhancer-binding protein (C/EBP) and retinoblas-

toma protein (RB), been considered plays an important

role in the process of adipocyte differentiation(Chen, et

al., 1996). A study found that HMGA1 is pivotal pro-

tein in adipocyte differentiation due to it involve in the

formation of the RB-C/EBP complex. They also found

that Hmga1-knockout embryonic stem cells dif cult to

undergo this process. This provided a result that HMGA1

may plays a crucial role in adipocyte differentiation,

in other words, pool adipocyte differentiation induce

insulin resistance and type 2 diabetes may relate to the

abnormal decreasing of HMGA1(Esposito, et al., 2009).

However, in the other study, they generated aP2-

HMGA1 transgenic mice which over-express HMGA1

in adipose tissues to discover the function of HMGA1

in vivo. They found that the genes involved in adipo-

cyte differentiation were down-regulated and preadi-

pocyte marker genes were up-regulated in white (WAT)

and brown (BAT) adipose tissue from aP2-HMGA1

transgenic mice. So, over-expression of HMGA1 lead

to impaired WAT and BAT creation through inhibiting

the adipogenic process and increasing adipose precursor.

Over-expression of HMGA1 can decrease body-weight

gain, reduce fat mass, but improve insulin sensitivity

and glucose tolerance when fed a high-fat diet. Interest-

582 ONE OF THE CRUCIAL PROTEINS TO INFLUENCE TYPE 2 DIABETES: HMGA1 BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS

Hao Kong et al.

ingly, this provide an evidence that aP2-HMGA1 trans-

genic mice were protected against diet-induced obesity

and insulin resistances (Arce-Cerezo, et al., 2015).

THE ABNOMAL EXPRESSION OF HMGA1-P

CAN CAUSE TYPE 2 DIABETES VIA COMPETING

WITH HMGA1

Some studies have found that human body can exist in

HMGAl-pseudogene (HMGA1-p), the abnomal increasing

of HMGAl-p expression can have effect on the expres-

sion of HMGA1 protein(Esposito, et al., 2015, Espos-

ito, et al., 2014). Targeted knockdown of HMGA1-p in

patient lymphoblasts can results in reciprocally increas-

ing HMGA1 mRNA stability and expression levels with

a parallel correction in cell-surface INSR expression and

insulin binding. A recombinant plasmid carrying the

entire HMGA1-p was generated and transiently trans-

fected into cultured human HeLa cells, caused decrease

in HMGA1 mRNA levels and in uence INSR gene tran-

scription. When silent HMGAl-p expressed, the level of

HMGA1 mRNA was restored, besides, the expression

of INSR mRNA and protein were up-regulated. Under

normal circumstances, CPl interacts with the region

of HMGA13’-UTR C-rich repeats, linked to stabiliza-

tion of HMGA1 mRNA. Due to the 3’terminal portion of

HMGA1-p maintains extensive sequence homology with

the HMGA1 3’-UTR. HMGA1-p can result in increased

HMGA1 mRNA degradation, decreased HMGA1 protein

expression, resulted in the deceasing of INSR expression

by competing for CP1(Chiefari, et al., 2010).

HMGA1 IVS5-13INSC ASSOCIATED WITH

INSULIN RESISTANCE AND TYPE 2 DIABETES

Strong genetic in uences and many polymorphisms

have been reproducibly associated with type 2 diabetes.

IVS5-13insC (c.136-14_136-13insC) is present at posi-

tion 13 of HMGA1 exon 6; Low-frequency insertion pol-

ymorphism IVS5-13insC has been identi ed and associ-

ated with insulin resistance and associated with insulin

resistance and type 2 diabetes among individuals of white

European ancestry and Chinese populations(Chiefari,

et al., 2011, Liu, et al., 2012, Lv, et al., 2015).

However, no similar association is observed in

another study involving Caucasians and populations of

African and Hispanic descent(Karnes, et al., 2013, Mar-

quez, et al., 2012, Pullinger, et al., 2014). Furthermore,

con icting results regarding the association of HMGA1

with type 2 diabetes and insuf cient data on diverse

ethnic groups have caused dif culty in performing clini-

cal translation of HMGA1 IVS5-13insC genotyping.

Results regarding the functional effect of the HMGA1

IVS5-13insC variant are also contradictory. On the one

hand, HMGA1 and INSR expressions decrease in dia-

betic carriers of IVS5-13insC compared with those of

wild-type diabetic and non-diabetic patients(Chiefari,

et al., 2011). INSR protein expression and insulin-bind-

ing capacity are also restored in lymphoblasts obtained

from diabetic IVS5-13insC carriers through HMGA1

DNA transfection. On the other hand, IVS5-13insC does

not affect HMGA1 or INSR expression in adipose tissues

of normoglycemic patients(Marquez, et al., 2012) and

also have not the association with the susceptibility of

DR in the Chinese T2DM cohort(Lv, et al., 2016).

Genome-wide association studies (GWAS) on patients

with type 2 diabetes have identi ed associations between

polymorphisms and mutations in some genes(Chiefari,

et al., 2013). These genes have been regarded as poten-

tial type 2 diabetes risk factors. However, current GWAS

fail to detect an association between the HMGA1 variant

IVS5-13insC and the presence of type 2 diabetes. To bet-

ter understand, some studies that include GWAS datasets

will help determine whether the IVS5-13insC shows a

consistent association with type 2 diabetes. However, the

direct mechanism by which this variant affects mRNA

expression or amino acid sequence remains unclear.

As we have shown above, HMGA1 mainly act as an

architectural tra nscription factor involved in glucose

homeostasis. Thus, many factors can induce type 2 dia-

betes by affecting its function of transcription regula-

tion. They are some examples for that:

Disrupt Self-regulatory mechanism: The HMGA1

gene been regulated by an oct amer motif, which was

identi ed as an important element of transcriptional

regulation. Based on the present study revealing that

Oct-1 and Oct-2 is crucial in modulating HMGA1 gene

and protein expression(Chiefari, et al., 2013). However,

HMGA1 can also transactivate octamer transcription

factor promoter, providing evidence for the existence of

an auto-regulatory circuit in which HMGA1 activates its

own transcription. If this mechanism is broken, sush as

Oct-1 gene variants, can also result in type2 diabetes(Ng,

et al., 2010).

Disrupt indirect regulatory mechanism: (1)HMGA1

and PKC: Incubation of skeletal muscle cell with FFA

for 6 h reduced HMGA1 protein exprerssion. But, in the

presence of eV1, a PKC translocation inhibitor pep-

tide, neither reduction nor phosphorylation of HMGA1

protein could be observed. These results suggest that

FFA-induced PKC inhibits insulin gene transcription

through the impairment of HMGA1(Dey, et al., 2007).

Some studies indicate that SFA’s inhibitory effect on

INSR expression is mediated through the kinase inde-

pendent phosphorylation of PKC, then migrates to

the nuclear region and phosphorylates HMGA1 that

retards its migration to INSR promoter which adversely

affects INSR  mRNA expression. FRL, puri ed from

BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS ONE OF THE CRUCIAL PROTEINS TO INFLUENCE TYPE 2 DIABETES: HMGA1 583

Hao Kong et al.

the leaves of Hibiscus mutabilis, can permit HMGA1 to

activate INSR promoter in skeletal muscle cells, which

improved INSR expression de ciency though blocking

PKC activation(Dasgupta, et al., 2011, Gogoi, et al.,

2014). This report can link up HMGA1 with overweight

is the risk factors for diabetes. (2) HMGA1 and NPM1: A

research focus on two human genes, the INSR genes and

the IGFBP1 genes, whose expression is directly regu-

lated by HMGA1. A study demonstrated that occupancy

of their promoters by HMGA1 was NPM1-dependent,

however, decrease in NPM1 abundance is followed by

increase in the occupancy of promoter DNA by HMGA1,

can resulting in increased promoter activity(Arnoldo,

et al., 2015). Thus, we put a hypothesis that free HMGA1

can up-regulate NPM1 expression in turn, re sulting

in decreased promoter activity. But, if NPM1 delete or

reduce excessively, broken this regulatory mechanism,

can affect normal function of HMGA1.

FUTURE PROSPECTS

HMGAl plays a crucial role in blood sugar balance as a

structural transcription factor. HMGA1 can cause insulin

resistances and type 2 diabetes via changing it func-

tion. This is novel opinion for the pathogenesis of type

2 diabetes nearly 10 years. However, the exact biologi-

cal mechanism underlying the association between the

HMGA1 gene and risk of type 2 diabetes remains uncer-

tain. Thus, further more accurate studies on HMGA1 are

warranted to clarify in diabetes pathogenesis.

We believe that an individual with the decreas-

ing of HMGA1 has speci c clinical implications. First

of all, the presence of the levels of HMGA1 may pre-

dict responses to therapy. Type 2 diabetes treatment is

largely empirical and the prediction of speci c responses

to a therapeutic agent in any patient is dif cult(Karnes,

et al., 2013). Patients with type 2 diabetes and different

pathogeny may respond differently to speci c therapies,

such as an insulin sensitizer, because HMGA1 decrease

or variant de nes a speci c defect that decreases insulin

receptor concentrations and insulin resistance. Second,

individuals possessing functional HMGA1 and type 2

diabetes may have different clinical courses from other

patients with type 2 diabetes, including differences in

the development of complications. Third, the search for

new therapies for type 2 diabetes can include agents that

upregulate HMGA1 expression. Furthermore, HMGA1

can be regarded as a novel target of gene therapy for

type 2 diabetes and insulin resistance.

ACKNOWLEDGEMENTS

This work was supported by grants from the Natural

Scienti c Foundation of Shandong Province, China

(ZR2014CM046, ZR2010CQ031 and ZR2015CL019), the

Technology Development Project Plan of Shandong

Education Department (J13LL61 and J14LM54) and Col-

laborative Innovation Center of Chinese medicine anti-

virus in Shandong University of Traditional Chinese

Medicine (XTCX2014B01-07).

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