INT J CURR SCI 2014, 12: E 110-127

REVIEW ARTICLE ISSN 2250-1770

Type 2 Diabetes Mellitus: Impact of genetics and environment

Md. Shamim Hossaina*, Md. Saidul Islama,b, Mst. Touhida khatuna and Md. Ashrafuzzaman Sapona

aDepartment of Biotechnology and Genetic Engineering, Faculty of Applied Science and Technology

Islamic University, Kushtia-7003, Bangladesh

bLaboratory of Microbiology and Genetics, Department of Biomedical Sciences, Medical School

Chonbuk National University, Jeonju, 561-712, Republic of Korea

*Corresponding author: shamim_btge@yahoo.com; Phone: +8801719409846

Abstract

Type 2 diabetes (T2D) develops while the body can still produce insulin, but not enough, or when the insulin produced

doesn’t work properly. It has become a health-care problem worldwide, with the raise in disease prevalence being all the

more worrying as it not only affects the developed world but also developing nations with fewer resources to cope with yet

another major disease burden. Furthermore, the problem is no longer restricted to the ageing population, such as young

adults and children are also being diagnosed with T2D. Genes play an important role in the development of diabetes

mellitus. Type 2 diabetes is a polygenic disorder with multiple genes located on different chromosomes contributing to its

susceptibility, including TCF7L2, KCNJ11, PPARG, ENPP1, Adiponectin, Calpain 10, PTPN1, CDKAL1, ABCC8, HNF4A,

SLC2A2, UCP2, INS, PIK3R1 and SOS1 gene. The environmental factor (arsenic, pesticides, selenium, bisphenol A,

phthalates and microorganism) also associated with Type 2 diabetes. Researchers found that taking proper exercise,

vaccination against causing enterovirous, regulation of taking diet and keep away from smoking are the best away prevent

from type 2 diabetes. This review aims to provide the link of causative factor to develop type 2 diabetes and search the

possible away of prevention against type 2 diabetes.

Keywords: Type 2 diabetes, insulin resistance, gene, environmental factor

Received: 04thMay; Revised: 18thJune; Accepted: 07thJuly © IJCS New Liberty Group 2014

Introduction

Diabetes mellitus type 2 also known as noninsulin-

dependent diabetes mellitus (NIDDM) or adult-onset

diabetes is a metabolic disorder that is characterized by

high blood glucose level in the context of insulin

resistance and relative insulin deficiency (Vinay et al.,

2005). Insulin resistance is a term that describes the

reduced ability for cells to store away blood sugar. In

essence, the hormone insulin, which activates the blood

sugar storage process, becomes increasingly ineffective.

Type 2 Diabetes has a complex pathogenesis that was

classically characterized by pancreatic β-cell dysfunction

followed by decrease of the beta cell mass, peripheral

insulin resistance and raised hepatic glucose production.

β-cell dysfunction is occurred initially by diminished

firstphase insulin response after glucose stimulation but

also following stimulation with nonglucose

secretagogues such as the incretin hormone glucagon-

like peptide-1 (GLP-1) ( Guja et al., 2012). This type of

diabetes is in contrast to diabetes mellitus type 1 where

causes an absolute insulin deficiency due to destruction

of islet cells in the pancreas. Type 2 diabetes makes up

about 90% of cases of diabetes with the other 10% due

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primarily to diabetes mellitus type 1 and gestational

diabetes. Obesity is thought to be the primary cause of

type 2 diabetes in people who are genetically predisposed

to the disease. Rates of type 2 diabetes have elevated

markedly over the last 50 years. As of 2010 there are

approximately 285 million people with the disease

compared to around 30 million in 1985 (Smyth and

Heron, 2006). Long-term complications from high blood

sugar can result in heart disease, strokes, diabetic

retinopathy where eyesight is affected, kidney failure

which may require dialysis, and poor circulation of limbs

leading to amputations. Diabetes mellitus affects people

of every age, race, and background, and is now a major

modern cause of premature death in many countries

around the world, with someone dying from Diabetes

Type 2 every 10 seconds worldwide (Gillespie, 2008).

Genetic factor

Type 2 diabetes is a polygenic disease that different

kinds of genes are involved to its expression. On the

basis of locus or combination of loci, it may be

dominant, recessive, or between of them. Though the

identifying of a complex disease is challenging but

different strategies have been used in efforts to identify

type 2 diabetes susceptibility genes.

TCF7L2 gene

In 2003, a modest peak of linkage was described

on chromosome 10 by researchers at deCODE genetics

consortium on Icelandic T2D families. The exploration

of this linkage signal led to the identification of a T2D

associated gene (Grant et al., 2006), namely the gene

encoding the Transcription Factor 7-Like 2 (TCF7L2)

located at 10q25.3. TCF7L2 (also known as TCF-4) is a

transcriptional factor involved in Wnt signaling, being

able to bind b-catenin. This pathway of signaling is

connected in embryogenesis, including adipocyte and

pancreatic tissue formation. A strong association

between type 2 diabetes and variation in the transcription

factor 7-like 2 (TCF7L2) gene found in Icelandic,

Danish, and American populations (Grant et al., 2006).

Some studies confirmed TCF7L2 as the locus that

confers the strongest responsible on T2D diabetes risk,

so that some authors even stated that this could be the

biggest story in diabetes genetics since the discovery of

HLA’s in T1D (Zeggini and McCarthy, 2007). The

physiological implication of this transcription factor is

responsible in glucose homeostasis. It has been suggested

that intestinal proglucagon gene expression may be

regulated by the Wnt/TCF7L2 pathway in

enteroendocrine cells (Yi et al., 2005). Thus, TCF7L2

variants may modify type 2 diabetes susceptibility

through modulation of glucagon-like peptide-1 (GLP-1)

secretion. As for the molecular mechanism of TCF7L2

involvement in T2D pathogenesis, where found that the

risk allele leads to impaired insulin secretion by altering

three different mechanisms: glucose-stimulated insulin

secretion, incretinstimulated insulin secretion and

proinsulin-toinsulin conversion (Schafer et al., 2011).

PPARG gene

PPARG gene on chromosome 3in locus 3p25 was

an attractive candidate gene because it encodes the

molecular target for thiazolidinediones. In 1997, Yen et

al. described an association between the proline-to-

alanine change at position 12 of PPARG (Pro12Ala or

rs1801282) in and the risk of T2D (Guja et al., 2012). A

common missense variant in the g2 isoform of

peroxisome proliferator–activated receptor gamma, a

protein of PPARG gene (PPAR g) [Pro12 to Ala12

(Pro12Ala)] has shown to association with diabetes in

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multiple studies, where a meta-analysis suggesting that

the common allele is associated with an increased

diabetes risk of 25% (Altshuler et al., 2000). A major

missense mutations in this gene result in severe,

dominantly inherited insulin resistance, diabetes mellitus,

and additional features such as partial lipodystrophy and

hypertension (Barroso et al., 1999).

KCNJ11 gene

The KCNJ11 gene, located on the short arm of

chromosome 11p15.1, encodes the pore-forming subunit

of the ATP-sensitive potassium channel Kir6.2 of the

pancreatic β-cells. The ATP-sensitive potassium channel

which plays a key role in regulating the release of

hormones, such as insulin and glucagon, in the beta cell.

Gain-of-function mutations of KCNJ11 open the

potassium channel and inhibit the depolarization of β-

cells, leading to a defect in insulin secretion (Gloyn

et al., 2004). Remarkably, this gene was reported to be

involved in the pathogenesis of neonatal diabetes. A

missense Glu23Lys mutation was described (E23K or

rs5210) in which Glutamate is changed into Lysine at

codon 23 of KCNJ11. Studies in various populations

have consistently reported that substitution of lysine for

glutamic acid at the 23rd amino acid (E23K) is

associated with an increased risk of T2DM (Florez et al.,

2004; Nielsenb et al., 2003). In recent reports of large-

scale association studies and meta-analyses, the E23K

variation was found to raise the risk of T2DM with an

OR of 1.15 (Florez et al., 2006).

ENPP1gene

The gene ectonucleotide pyrophosphatase

phosphodiesterase 1 (ENPP1), also known as plasma cell

glycoprotein 1, which recently found to be associated

with both childhood and adult obesity in a French

population. A moderate excess of the risk haplotype was

also observed in adults with T2DM compared with

controls (10.7% vs 7.1%, OR 1.44), and this association

was also replicated in an Austrian cohort with similar

frequencies. The study of Mantel-Haenszel of 2,569

European subjects supported the association, with OR

1.56 and p=0.00002 (Meyre et al., 2005). The

nonsynonymous variant lysine 212 to glutamine

(K121Q) has been best studied, and also shown to be

associated with obesity but not diabetes in Caucasian and

African American subjects ascertained from the New

York Cancer Project (Matsuoka et al., 2005). Other

researchers also found a connection of K121Q with

earlier T2DM onset and coronary disease among T2DM

patients (Bacci et al., 2005). The association of K121Q

with T2DM was replicated in three relatively small

populations among them two of South Asian ancestry

and one Caucasian (Abate et al., 2005). Although the

K121Q variant appears to associate with T2DM and

obesity, additional work is needed to determine the

magnitude of the risk. In 2001, Hegele et al. described a

K121Q SNP of ENPP1 gene that was strongly associated

with insulin resistant. Though different studies on this

gene reported a positive association with type 2 diabetes

but other well-powered studies failed to replicate this

association (Florez, 2008). However, a recent

metaanalysis of about 42,000 samples (McAteer et al.,

2008) confirmed the association of this ENPP1 gene

variant with T2D in European populations under a

recessive model (OR 1.38, p < 0.005).

Calpain 10 gene

The first common diabetes gene report of a positive

result emerging from GWL scanning in T2D families

was represented by CAPN-10 (region of chromosome 2),

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the gene encoding Calpain 10. CAPN10 encodes an

intracellular calcium-dependent cysteine protease that is

ubiquitously expressed in both adult and fetal tissues

(Cox et al., 2004). A haplotype that was initially linked

to T2D included an intronic A to G mutation at position

43, which shows to be involved in CAPN10 transcription.

In 2000, Horikawa et al. reported three single nucleotide

polymorphisms (SNPs) in the CAPN-10 gene associated

with T2D: SNP-43 (G/A) in intron 3, SNP -19 (3/2) in

intron 6 and SNP-63 (C/T) in intron 13 and described

several T2D associated haplotypes. Though the exact

mechanism of CAPN-10 gene involvement in T2D

pathogenesis remains unknown but functional evidence

accumulated in recent studies suggests a potential role in

both insulin resistance and insulin secretion (Turner

et al., 2005).

Adiponectin gene

In 2000, a GWL study on French families identified

a peak of linkage on chromosome 3q27-qter (Vionnet

et al., 2000) and it was shown to segregate with T2D and

MetS on chromosome 3q27 in both French and Japanese

populations. A strong linkage was found this gene in

Hispanic Americans by the Insulin Resistance and

Atherosclerosis Study Family Study (Guo et al., 2006)

but not reconfirmed in Pima Indians and African

Americans (Grigorescu et al., 2011). Adiponectin (ApN

or ADPN or ADIPOQ or APM1) is a 30 kDa protein

structurally similar to complement 1q, secreted by

adipocytes. ApN plays an important role in insulin

action, energy homeostasis, inflammation etc. ApN

levels are declined in insulin-resistant patients with

obesity, T2D or MetS and correlate well with insulin

sensitivity. Adiponectin levels correlate negatively with

glucose, insulin and triglyceride levels as well as the

body mass index (BMI), while there is a positive

correlation with high-density lipoproteins (HDL),

cholesterol level. SNPs of APM1, the gene encoding

adiponectin, were associated with the development of

hyperglycemia (Dedoussis et al., 2007). More than 10

SNPs were described in the ADIPOQ gene with possible

correlation to the plasma ApN levels, MetS and risk to

develop T2D, the best studied being SNP-45 in exon 2

and SNP 276 in intron 2. For SNP-45T/G, the G allele

would be pathogenic in most studies and associated to

high risk of T2D and reduced insulin sensitivity (Tso

et al., 2006). In the French population, two other SNPs

(C–11377G and G-11391A) from the promoter region

were reported to be associated with hypoadiponectemia

and T2D (Vasseur et al., 2002).

PTPN1 gene

The PTPN1 gene ubiquitously expressed protein

tyrosine phosphatase-1B (PTP1B), catalyzes the

dephosphorylation of tyrosine residues from the insulin

receptor kinase activation segment (Seely et al., 1996)

and IRS1 (Goldstein et al., 2000) resulting in the down-

regulation of insulin signaling. PTP1B also shows

negative control on leptin signaling through the

dephosphorylation of JAK2 and STAT3 (Cheng et al.,

2002). The disruption of the PTPN1 gene in mice results

in elevated insulin sensitivity and in resistance to diet-

induced obesity (Elchebly et al., 1999), as well as

enabling normalization of blood glucose levels. Several

studies have investigated the association of T2DM with

genetic variants of PTPN1. When analyzing the PTPN1

gene locus, Bento et al. (2004) discovered convincing

associations between multiple SNPs and T2DM in two

independent Caucasian American case-control samples.

Recently published data indicate that PTPN1 variants

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might modify the lipid profile, thereby influencing

susceptibility to the metabolic syndrome (Cheyssac et al.,

2006).

CDKAL1 gene

The results of the first T2D genome-wide

association studies (GWAS) were published in 2007 in

Nature, Nature Genetics and Science and reported

CDKAL1 gene associated with T2D. CDKAL1 encodes

CDK5 regulatory subunit-associated protein 1-like 1

(Steinthorsdottir et al., 2007), which is thought to inhibit

cyclin-dependent kinase 5 (CDK5) activity by binding to

the CDK5 activator p35. A genetic variation located in

6p22.3 of the CDKAL1 gene was discovered to be sig-

nificantly associated with T2DM through the deCODE

study (Steinthorsdottir et al., 2007). CDKAL1 gene also

encodes a 579-residue, 65-kD protein sharing

considerable amino acid homology with CDK5RAP1, an

inhibitor of CDK5 activation and is expressed in human

pancreatic islet and skeletal muscle. In a recent study,

revealed that disruption of CDKAL1 in mouse β-cells

resulted in impaired first-phase insulin secretion (Ohara-

Imaizumi et al., 2010). The people who had risk variants

of CDKAL1 had decreased insulin secretion capacity.

HNF4A (hepatocyte nuclear factor 4-α)

Mutations in promoter and coding regions of the

HNF4A gene cause MODY1. HNF4A encodes an orphan

hormone nuclear receptor that, together with TCF1

(LocusLink ID 6927), encoding HNF1α, TCF2

(LocusLink ID 6928), encoding HNF1β, and FOXA2

(LocusLink ID 3170), encoding HNF3β, constitutes part

of a network of transcription factors regulating gene

expression in pancreatic β-cells, liver, and other tissues.

These transcription factors control expression of the

insulin gene as well as genes encoding proteins

associated in glucose transport and metabolism and in

mitochondrial metabolism, all of which are linked to

insulin secretion in β-cells (Fajans et al., 2001). HNF4A

maps to Chromosome 20 (Argyrokastritis et al., 1997) in

a region that has been connected to Type 2 diabetes in

multiple studies (Klupa et al., 2000; Permutt et al., 2001).

This positional information, combined with the known

role of major mutations at this gene in the causation of

autosomal-dominant maturity-onset diabetes of the

young (MODY), has led to HNF4A being thought as a

strong candidate for involvement in causing Type 2

diabetes. The heterozygous nonsense and missense

mutations in HNF4α lead to an insulinopaenic form of

MODY strongly believes that β-cell dysfunction is

sensitive to the amount of HNF4α in the β-cell and that

haploinsufficiency is the likely mode of molecular

pathogenesis in that condition (Barroso et al., 2003).

ABCC8 (ATP binding cassette, subfamily C, member 8)

The ABCC8 gene is located on chromosome

11p15.1 and several gene variants of both genes have

been associated with disorders of insulin secretion and

T2DM (Dedoussis et al., 2007). ABCC8 encodes an

ATP-sensitive potassium channel, which plays a key role

in regulating the release of hormones, such as insulin and

glucagon, in the beta cell. Mutations in either gene can

affect the potassium 7 channel’s activity and insulin

secretion, ultimately leading to the development of T2D.

ABCC8 variants have been associated with Type 2

diabetes which is shown in multiple studies (Barroso

et al., 2003). ABCC8 (Ala) genes have been associated

with T2D, as well as other diabetes-related traits.

Because of the close proximity of these gene, current

studies are evaluating whether this gene work in concert

with each other, or rather have an independent effect on

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T2D susceptibility.More recently Florez and colleagues

(2004) investigated the ABCC8 gene and tested sufficient

variants to completely tag all variation in this region.

After that the E23K variant was associated with T2DM

in 3,413 subjects, and the association was confirmed in a

meta-analysis that contained over 5000 T2DM subjects

and 4747 controls (p<10-5, OR 1.15). The E23K variant

is in nearly complete linkage disequilibrium (completely

correlated) with a Serine to Alanine change at position

1369 in exon 33 of the sulfonylurea receptor, and thus

S1369A and E23K cannot be distinguished genetically

(Das and Elbein, 2006).

Jack Spratt gene (new diabetes Gene identified)

It has long been hypothesized that type 2 diabetes in

lean people is more genetically driven. A new study

found from a research team which was led by the

Peninsula College of Medicine and Dentistry (PCMD),

University of Exeter. This research institutions from

around the world, has for the first time proved that lean

type 2 diabetes patients have a larger genetic disposition

to the disease than their obese counterparts. Their study

has also identified a new genetic factor associated only

with lean diabetes sufferers. The study is published in

PLoS Genetics. Using genetic data from genome-wide

association studies, the research team tested genetic

markers across the genome in approximately 5,000 lean

patients with type 2 diabetes 13,000 obese patients with

the disease and 75,000 healthy controls. The team

revealed differences in genetic enrichment between lean

and obese cases which support the hypothesis that lean

diabetes sufferer have a greater genetic predisposition to

the disease. This is in contrast to obese patients with type

2 diabetes, where factors other than type 2 diabetes genes

are more likely to be responsible. In addition, genetic

variants near the gene, LAMA1 were linked to type 2

diabetes risk for the first time, with an effect that

appeared only in the lean patients (Perry et al., 2012).

SLC2A2 (encoding GLUT2)

SLC2A2 encodes the glucose transporter GLUT2, a

member of the facilitative glucose transporter family that

is highly expressed in pancreatic β-cells and liver. It is a

highly plausible candidate gene for Type 2 diabetes, as it

is a high Km transporter that regulates entry of glucose

into the pancreatic β-cell. This initiating the cascade of

events, leading to insulin secretion. GLUT2 is also

highly expressed in the liver, where it is associated in the

regulation of both glucose uptake and output. It is

notable that the alleles that associated with increased

diabetes risk were also all linked with lower fasting

insulin levels, suggesting that these may influence basal

insulin secretion. In 2003, Barroso et al. typed six SNPs

in SLC2A2, three of which SNP21, SNP23, and SNP24

and found significantly associated with diabetes status

with an OR of approximately 1.4-1.5. In the QT study,

all three disease-associated SNPs were also associated

with lower levels of fasting plasma insulin. Rather

surprisingly allele 2 (A) at T198, which was connected

with increased disease risk, was associated with lower 2-

h plasma glucose. No other significant associations with

intermediate phenotypes were found (Barroso et al.,

2003).

UCP2 gene

UCP2 gene located on chromosome 11q13 (SNP,

rs659366). It is responsible for impaired insulin secretion

hat has been shown to predominate over insulin

resistance in individuals with early onset T2D. The

UCP2 variant has a strong predictor of T2D with earlier

onset. The promoter variant in the UCP2 gene has been

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associated with increased expression of the gene in

adipose tissue. If this variant is associated with increased

UCP2 mRNA levels in human pancreatic β-cells (which

is not known), this could result in increased uncoupling

and, in turn, in decreased formation of ATP and impaired

insulin secretion. In 2005, Lyssenko et al. revealed that

fifty-eight (44.3%) of the converters were homozygous

for the risk genotype (GG) of the UCP2 −866G>A

variant and this GG genotype was associated with a

modestly increased risk of T2D (HR 1.4, p = 0.049).

Though this risk was not influenced by BMI and FPG at

baseline whereas the GG genotype was also associated

with increased risk of developing T2D in patients with

earlier onset of diabetes (HR 2.0, 95% CI 1.2–3.3, p =

0.0057).

INS (encoding insulin)

The INS (LocusLink ID 3630) gene encodes the

hormone preproinsulin, which upon proteolytic cleavage

creates mature insulin and C-peptide. Barroso et al.

(2003) tested a single SNP in the 3′-UTR (SNP72) of the

insulin gene (INS) with disease status and found this

SNP, significantly associated with increased Type 2

diabetes risk under a recessive model for the T allele (OR

2.02, p = 0.0258). The insulin gene variable number

tandem repeat (INS–VNTR) has been extensively studied

and is proposed to exert pleiotropic effects on birth

weight and diabetes susceptibility (Huxtable et al., 2000).

The data for the single SNP Barroso et al. (2003) tested

suggest that either the insulin gene or other loci in LD

may be involved in Type 2 diabetes risk.

PIK3R1 and SOS1 gene: The gene PIK3R1, encoding the

p85α regulatory subunit of the phosphatidylinositol 3-

kinase which is a logical candidate gene for involvement

in causing of Type 2 diabetes owing to its role in insulin

signal transduction. An intronic variant, SNP42, was

associated with increased disease risk under two genetic

models (OR 1.41, p = 0.0090 for the allele 2 dominant

and OR1.34, p = 0.0088 for the additive model (Barroso

et al., 2003). According to QT study, Barroso et al.

(2003) revealed that SNP42 was significantly associated

with increased BMI and showed a borderline

significance with increased fasting insulin (measure of

insulin resistance) under a dominant model for allele 2.

Obesity is a major risk factor for insulin resistance, and

the observed increase in BMI coupled with increased

insulin resistance in carriers of allele G at SNP42

suggests that variation at this gene may be increasing

Type 2 diabetes risk through impaired insulin action.

One study did describe an association with disease status

and with QTs underlying Type 2 diabetes (Baier et al.,

1998). Finally Barroso et al. (2003) suggested about their

research data that variation in this gene is a risk factor for

the development of Type 2 diabetes. The gene SOS1 (son

of sevenless homolog 1 in Drosophila) encodes a guanine

nucleotide exchange factor that performs in the

transduction of signals that control cell growth and

differentiation. Barroso et al. (2003) analysed two SNPs

for association with disease status, a nonsynonymous

SNP (N1011S) and an intronic variant (SNP8). While the

nonsynonymous S1011 variant, which was very rare

(minor allele, 0.003), did not associate with disease

status, the intronic SNP was highly significantly

associated with decreased disease risk (OR 0.58, p =

0.0032). After their study, Barroso et al. (2003) noted

that this was the first investigation into the role of SOS1

in Type 2 diabetes risk.

Environmental factor: Arsenic: Arsenic can be found

naturally in drinking water. Studies of people exposed to

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high levels of arsenic from Taiwan, Bangladesh,

Mexico, and Sweden have found that arsenic may

contribute to the development of diabetes (Coronado-

Gonzalez, 2007). Arsenic could influence type 1 diabetes

development by mechanisms involving oxidative stress,

inflammation, or programmed cell death (apoptosis)

(Navas-Acien et al., 2006). Rat pancreatic beta cells

treated with arsenic showed impaired insulin secretion

and function (Díaz-Villaseñor et al., 2006). A recent

study published in the Journal of the American Medical

Association (JAMA) revealed that even at lower levels,

arsenic exposure was associated with increased

prevalence of diabetes in U.S. adults (Navas-Acien et al.,

2008). A study from Korea did find an association

between arsenic exposure and diabetes in people exposed

to normal, background exposure levels of arsenic,

especially women (Kim and Lee, 2011). Another newer

study found that in people from rural communities in the

US with high rates of diabetes, arsenic was associated

with poorer diabetes control (a higher HbA1c) in people

with. A study from parts of Mexico with historically high

levels of arsenic exposure noticed that people who had

certain genes are more likely to develop diabetes when

exposed to arsenic (Drobna et al., 2012).

Pesticides

Pesticides include a number of substances,

including herbicides and insecticides. The women who

reported agricultural exposure during pregnancy, the risk

of diabetes was associated with the use of four herbicides

(2,4,5-T; 2,4,5-TP; atrazine; butylate) and three

insecticides (diazinon; phorate; carbofuran) (Saldana

et al., 2007). Some pesticides can interfere with beta cell

function in ways that may promote diabetes

development. For an example, atrazine was found to

induce obesity and insulin resistance in rats by impairing

the function of mitochondria (Lim et al., 2009).

Mitochondria dysfunction may be involved in the

development of both type 1 and type 2 diabetes

(Szabadkai and Duchen, 2009). A study of the staff of an

Australian insecticide application program found higher

mortality rates for diabetes (probably type 2), as

compared with the general Australian population (Beard

et al., 2003). The widely-used organophosphate

pesticides (including malathion, diazinon, parathion, and

chlorpyrifos) have been found to be toxic to the immune

system in animals and sometimes humans (Galloway and

Handy, 2003). Early life exposure to these pesticides also

causes metabolic dysfunction resembling pre-diabetes in

animals, especially when adults eat a high-fat diet

(Slotkin, 2011). If animals exposed to malathion develop

high blood sugar levels, and their carbohydrate

metabolism is affected in ways that could increase

insulin resistance (Rezg et al., 2010).

Selenium

Selenium is an essential trace element, but it can

also be toxic at high doses. Selenium has bioaccumulated

to four times the toxic level in the food chain, a level that

can cause harm in fish and birds. Groundwater wells are

also affected, and state advisories are in effect for

consumption of fish due to high selenium levels (Palmer

et al., 2010). Selenium has been found to associate with

type 2 diabetes in some studies of people in the U.S.

Laclaustra et al. (2009) revealed that in U.S. adults

exposed to background selenium levels, the prevalence

of diabetes raised with raising levels of selenium. Fasting

glucose levels and hemoglobin A1C

levels increased with increasing selenium levels as

well. Another study using the same dataset but from an

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earlier time period also found selenium levels to be

associated with diabetes (Bleys et al., 2007). The dataset

used in these studies does not differentiate between type

1 and type 2 diabetes, although most participants would

have had type 2.

Bisphenol A

It is found that plastic such as water bottles, metal

can linings, dental sealants, toys, and other products, and

can leach out of these products, especially when exposed

to heat or acidity (Welshons et al., 2006). Worldwide,

over 6 billion pounds of BPA are produced each year,

and over 100 tons are released into the air annually

(Vandenberg et al., 2009).A human study has found an

association between BPA exposure and increased insulin

resistance, general obesity, and abdominal obesity in

Chinese adults (Wang et al., 20112). Nadal et al. (2009)

expressed how BPA targets the insulin-producing beta

cells in the pancreas, and creates insulin resistance in

animals. By doing so, it may contribute to beta cell

exhaustion. More recent study revealed from the same

laboratory confirms these effects, in human beta cells as

well as mouse beta cells (Soriano et al., 2012). A further

study finds that BPA slows down whole-body

metabolism in mice and ingulences insulin resistance

throughout their bodies (Batista et al., 2012).

Phthalates

Phthalates are widely used chemicals that soften

PVC plastic, and are also used in cosmetics, perfumes,

and industrial paints and solvents. Phthalates activate

certain hormone receptors called PPARs. PPARs are

known to influence blood glucose levels, via insulin

resistance, insulin secretion, and fat formation. When

pregnant and lactating rats were given DEHP, their

offspring formed abnormal beta cells, and alternations of

the genes controlling beta cell function at the time of

weaning. These results propose that developmental

exposure to phthalates can lead to beta cell dysfunction

and glucose abnormalities, and is a potential risk factor

for diabetes development (Lin et al., 2011). In New York

City children, certain phthalate exposures measured at

age 6-8 were associated with a higher body mass index

and waist circumference one year later (Teitelbaum et al.,

2012). Another study on Swedish women, the phthalate

MiBP was related to increased abdominal body fat two

years later (Lind et al., 2012).

Gut microbiota

Gut microbiota may be involved in the development

of obesity and type 2 diabetes as well (Cani and

Delzenne, 2010). Animal studies find that gut microbiota

can affect the formation of obesity, insulin resistance,

and diabetes through a variety of mechanisms. A

Western diet can raise microbiota that promotes obesity,

as could overuse of antibiotics (Musso et al., 2010). In a

study of rats, the animals given probiotics had a lower

body weight and more diverse intestinal biota than the

controls and those who received E coli (a harmful

microorganism) (Karlsson et al., 2011). It is especially

curious that gastric bypass surgery often leads to

lessening of type 2 diabetes without causing any weight

loss (Pournaras et al., 2010).

Prevention from type 2 diabetes

Exercise

Exercise is very important in the control of type 2

diabetes. Obesity is associated with hepatic and

peripheral insulin resistance and may have a deleterious

influence on the regulation of glucose homeostasis

(Coker et al., 2009). Weight gain, especially with central

fat accumulation, as indicated by a high waist

Hossain et al., 2014

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circumference is associated with impaired glucose

tolerance (IGT) and type 2 diabetes. Obesity in persons

with diabetes is also associated with poorer control of

blood glucose levels, blood pressure and cholesterol

(Anderson et al., 2003). Increased physical activity and

improved diet can delay or even prevent the progression

of insulin insensitivity from IGT to overt type 2

diabetes. Insulin resistance is an important pre-cursor to

type 2 diabetes, and in its early stages is reversible by

weight loss and an increase in physical activity (Ross

et al., 2000). The metabolic abnormalities of established

type 2 diabetes, including hyperglycaemia,

hyperinsulinaema and dyslipidaemia can be improved by

an increase in physical activity. Regular taking of

exercise reduce the risk of obesity and thereby minimize

the incidence of causing of diabetes types diseases. By

losing of weight and increasing physical activity can

neutralize the powerful effect of insulin resistance on

progression to diabetes (Hossain and Khatun, 2013). A

person who takes regular physical exercise appears to:

firstly reduce the activity of the pancreatic β-cells and

makes cellular tissues more sensitive to insulin, secondly

increase the rate at which glucose is taken into the

muscles, independent of the activity of insulin and finally

improve cardiovascular health and aids weight

management (Goodyear and Kahn, 1998).

Keep way from smoking

Smoking has been shown to increase insulin

resistance and diminish insulin secretion, both of which

are connected with the onset type 1 diabetes. There is a

growing body of evidence to show that smoking is a risk

factor for Type 2 Diabetes (Yeh et al., 2010). Smoking

has been identified as a possible risk factor for insulin

resistance, a precursor for diabetes. Smoking has also

been shown to deteriorate glucose metabolism which

may lead to the onset of type 2 diabetes (Fagard and

Nilsson, 2009). In 2010, Yeh et al. conducted a

community-based study of 15 792 middle-aged adults, to

test the hypothesis that although smoking is an

independent predictor of incident type 2 diabetes,

smoking cessation increases diabetes risk in the short

term, possibly because of cessation-related weight gain.

There is also some evidence which suggests that smoking

increases diabetes risk through a body mass index

independent mechanism. Smoking has been connected

with a risk of chronic pancreatitis and pancreatic cancer,

suggesting that tobacco smoke may be toxic to the

pancreas. A systematic review of 25 studies found that

all but one revealed an association between active

smoking and an increased risk of diabetes (Willi et al.,

2007). On the basis of this review, it is estimated that

12% of all type 2 diabetes in the United States may be

attributable to smoking (Ding and Hu, 2007). If the same

proportion is applied to the UK, smoking may account

for as many as 360,000 cases of diabetes. So, keep way

from smoking, is the best away to prevent from type 2

diabetes.

Conclusion

Type 2 diabetes risk is mainly depending upon a

genetic susceptibility and environmental factor that make

the insulin resistance. Some researches have suggested

that taking proper physical exercise to reduce over body

weight and maintain proper nutritional diet may also

contribute to prevent diabetes. Though the genetic

therapy are not well established yet we hope, in the near

future scientist can know the roles of these causative

genes and their molecular pathways that are related to the

risk of T2D and may potentially lead to targeted therapies

Hossain et al., 2014

www.currentsciencejournal.info

for type 2 diabetes patient for treating or preventing

diabetes.

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