The Effect of Three Months of Resistance Training on TCF7L2 Expression in Pancreas Tissues of Type 2 Diabetic Rats
author: Mojtaba Eizadi, Department of Exercise Physiology, College of
Physical Education and Sport Sciences, University of Tehran, Tehran, IR
Iran. Email: firstname.lastname@example.org
exercise is recommended as a useful therapeutic tool for the treatment
of type 2 diabetes (T2D); however, the frequency of studies is
inadequate to establish the precise mechanisms of any association
this study, we aimed to assess the effect of three months of resistance
training on TCF7L2 expression in pancreatic tissues, serum insulin and
Materials and Methods: For
this purpose, type 2 diabetes (T2D) was induced by intraperitoneal
streptozotocin-nicotinamide in eighteen male Wistar rats aged 10 weeks
(220 ± 30 g). Then, the rats were randomly divided into exercise and
control groups. The exercise rats completed a three-month resistance
training intervention that included climbing on a stepladder for 5 days
weekly. The control group did not participate in exercise intervention.
Fasting glucose and insulin were measured before and after injection (7
days) and after intervention. TCF7L2 gene expression of pancreatic
tissues was measured in both groups after the exercise treatment, and
the ratio between the two groups was calculated.
glucose increased and serum insulin decreased significantly by T2D
induction in the two groups at baseline. Resistance training resulted in
a decrease in fasting glucose and an increase in insulin in exercise
rats. Data also showed that TCF7L2 gene expression decreased after
resistance training compared with the control group.
on these data, increased serum insulin can be attributed to a decrease
in TCF7L2 gene expression of pancreatic cells by resistance training in
Keywords: Type II Diabetes; TCF7L2 Gene Expression; Resistance Training
Diabetes mellitus type 2 (T2D) is the most common metabolic disorder of the present century (1).
It is well known that in addition to reduced insulin sensitivity,
impaired beta cell function has a key role in the pathogenesis of T2D,
which is expected to affect more than 300 million people by 2025 (2).
However, the exact mechanisms by which beta cell function is reduced in
these patients are still not fully understood. Among the factors
contributing to this disorder, the role of insulin receptors in the
regulation of beta cell function (3) and beta cell mass (4)
can be mentioned. Thus, longitudinal studies have always emphasized the
importance of the damage progression of beta cell function in the
prevalence and severity of T2D.
Although T2D is a multifactorial
disease, obesity is one of the leading risk factors for its incidence.
The crucial role of obesity in T2D is supported by many recent and past
On the other hand, the question arises why all obese people do not
develop T2D or why some T2D patients have normal weight. Hence, it seems
that apart from obesity, other important factors play major roles in
this disease, which has recently been the focus of many researchers. In
this context, recent genetic studies, particularly from 2007 onward, on
diabetics or pre-diabetics indicated that some recently discovered genes
(CDKAL1, CDKN2A/B, IGF2BP2, HHEX, HNF1B, KCNJ11, PPARG, TCF7L2,
SLC30A8, WFS1, ADAMTS9, CDC123, CAMK1D, JAZF1, NOTCH2, THADA, TSPAN8,
and LGR5) set the stage for T2D, even in the absence of obesity (6). Interestingly, some of these genes do not affect body weight or obesity but alter beta cell function and insulin secretion (7-10).
the meantime, it has been recently shown that Transcription Factor
7-Like 2 (TCF7L2) polymorphisms are associated with diabetes (11), and its increased expression increases the risk of developing T2D by 1.46 times (12).
TCF7L2 is a T cell transcription factor that plays an important role in
cellular signaling pathways of Wnt as the main components of the
regulation of cell proliferation and differentiation (13).
Although Kovacs et al. (2008) reported no significant difference in
TCF7L2 gene expression in visceral and subcutaneous adipose tissue
between diabetics and non-diabetics as well as between obese and
non-obese people (14),
some recent studies reported a 5-fold increase in its expression in
pancreatic cells of T2D patients compared with healthy people, which was
also associated with decreased insulin secretion (9).
Recent clinical studies have indicated that the decreased TCF7L2
expression in beta cells results not only in reduced blood glucose
levels, but also in improved glucose tolerance (15).
Given the role of TCF7L2 and its variants on the prevalence of T2D reported in recent studies on the Iranian population (16, 17),
it is of utmost importance to answer the question whether changes in
the expression of this gene or its variants due to extrinsic
interventions is associated with changes in insulin and blood glucose
levels as the determinants of T2D. In this context, some studies have
examined the combined effect of exercise training and diet on TCF7L2
expression. It was found in a recent study that in response to changes
in lifestyle (exercise + diet), changes in rs7903146 of the TCF7L2 gene
has a negative correlation with insulin secretion and insulin
However, in the meantime, no study was found regarding the direct
effect of resistance exercises on TCF7L2 expression in pancreatic cells
Hence, the present study
was carried out to evaluate the effect of 12 weeks of resistance
exercises on pancreas TCF7L2 expression and insulin and glucose fasting
levels in male Wistar rats with T2D.
3. Materials and Methods
3.1. Experimental Animals
Eighteen 10-week-old male Wistar rats (220 ± 30 g), procured from
the institutional animal house facility, were used for all the
experiments. Animals were provided with a standard pellet diet and water
ad libitum, and they were maintained under standardized conditions
(12-hours light/dark cycle, 25 ± 2˚C and humidity 45% - 55%). The rats
were left for 1 week for acclimatization prior to the commencement of
the experiment. The study was approved by the department of exercise
physiology at Tehran university, Iran, and carried out in accordance
with guidelines from the committee for the purpose of control and
supervision of experiments on animals (CPCSEA).
3.2. Induction of Type 2 Diabetes
After 1 week of acclimation, the Wistar rats were randomized and
divided into two groups: the exercise diabetes group (ED) and the
control diabetes group (CD). T2D was induced by a single intraperitoneal
(i.p.) injection of 60 mg/kg streptozotocin (dissolved in citrate
buffer, pH 4.5), 15 min after the i.p. administration of 95 mg/kg of
nicotinamide (dissolved in normal saline) (19).
Hyperglycemia was confirmed by elevated blood glucose levels on day 7
after injection, and only animals with fasting blood glucose levels
between 150 and 400 mg/dL were selected to serve as T2D rats and used in
the study. The animal experimental protocols were approved by the
animal ethics committee of Tehran university.
3.3. Training Protocol
At this phase, 7 days after the induction of diabetes, the rats
in the exercise group climbed on a stepladder without any resistance for
6 times in 3 training sessions in order to learn how to exercise. Then,
they participated in a 12-week course of resistance training for 5 days
per week in the format of climbing a 26-step, 1 meter vertical ladder
with a gradient of 80%. Each session of resistance training was
performed in the form of 3 courses with 6 repetitions on each course,
and resistance was increased through attaching a weight to each rat’s
tail. The attached weights were proportional to the body weight of the
rats during exercise. Breaks between courses and between repetitions
were 3 minutes and 45 seconds, respectively. The only method used to
stimulate the rats to climb the ladder was touching and rubbing the
tail. To warm up and cool down before and after the workout, the rats
climbed and descended the ladder 2 times without any resistance.
resistance was increased gradually during exercise as follows;
repetitions with 10% of body weight in the first week, 20% of body
weight in the second week, 40% of body weight in the fourth and fifth
weeks, 60% of body weight in the sixth and seventh weeks, 80% of body
weight in the eighth and ninth weeks, and 100% of body weight in the
tenth, eleventh, and twelfth weeks ((20, 21):
justified). Finally, all rats were dissected 48 hours after the last
training session following 10 to 12 hours of overnight fasting. It
should be noted that the diabetic control rats were not included in the
training program during this period.
3.4. Sample Collection and Biochemical Assays
Finally, 48 hours after the last training session, the fasting
rats in both groups (with 10 to 12 hours of no food overnight) were
anesthetized through intraperitoneal injection of 10% ketamine at a dose
of 50 mg/kg along with 2% xylosine at a dose of 10 mg/kg, after which
they were underwent dissection. After the rats were anesthetized, blood
samples were collected through cardiac puncture. Then, pancreatic tissue
was removed and immersed in RNA until biochemical analysis was
performed later to determine TCF7L2 expression. The blood samples were
used to analyze blood glucose and serum insulin levels. The serum was
separated by centrifugation (5 minutes, 3,000 rpm) and was analyzed for
glucose using a Cobas 6000 analyzer (Roche, Germany). Glucose was
determined by the oxidase method (Pars Azmoon kit, Tehran). The
remaining serum samples were then stored at -20˚C until the insulin
determination was made by the ELISA method (Demeditec, Germany). The
intra-assay and inter-assay coefficients of variation of the method were
2.6% and 2.88, respectively.
3.5. RNA Extraction/Real-Time PCR
To purify RNA, 20 milligrams of tissue were ground using a mortar
and pestle, and extraction was then performed employing the RNeasy
Protect Mini Kit (manufactured by Qiagen Inc. in Germany) according to
the manufacturer’s protocol.
In this stage, the One Step SYBR
Prime Script RT-PCR Kit (manufactured by the Takara Bio, Inc., in Japan)
was employed according to the manufacturer’s protocol to prepare the
reaction product. The thermal cycle program used for the Rotor-Gene Q
instrument was as follows: 42˚C for 20 minutes, 95˚C for two minutes,
and 40 cycles at 94˚C for 10 seconds and 60˚C for 40 seconds.
Temperatures from 50 to 99˚C were used for the melting curve after the
PCR to study the characteristics of the primers. The comparative ΔΔCT
method was used to quantify the TCF mRNA expression. We used RNA
polymerase II as a normalizer.
3.6. Statistical Analysis
All the data are expressed as mean ± SD. Data were analyzed by
computer using the statistical package for social sciences (SPSS) for
Windows, version 15.0. At baseline, comparisons of parameters between
the two groups were made by unpaired student’s t-test. Student’s t-tests
for paired samples were performed to determine whether there were
signiﬁcant within-group changes in the outcomes. Differences were
considered to be statistically significant when P < 0.05.
Based on statistical
data, no significant differences were observed in fasting insulin
between groups (P > 0.05). In control and exercise diabetes groups,
fasting glucose increased significantly after the
streptozotocin-nicotinamide injection (P < 0.05). Fasting glucose
decreased by resistance training in exercise diabetes subjects (P =
0.000) while no significant change was observed in the control diabetes
group (Table 2).
Mean and Standard Deviation of Fasting Glucose in Studied Groups
shows the changes in serum insulin in the 2 groups. Similar to fasting
glucose, there were no statistically significant differences between
exercise and control diabetic rats with regard to serum insulin at
baseline (P > 0.05). Compared to baseline, fasting insulin
concentration decreased significantly by streptozotocin-nicotinamide
injection in both diabetes groups (P < 0.05). Insulin levels were
significantly increased in exercise rats when compared with pre-training
values (P < 0.05).
Mean and Standard Deviation of Serum Insulin in Studied Groups
All changes in TCF7L2 expression in the exercise group with
respect to the control group are standard. TCF7L2 expression decreased
significantly with exercise training. On the other hand, 3 months of
resistance training for 5 sessions per week led to a significant
decrease in TCF7L2 expression in exercise diabetic rats compared to
control diabetic rats. TCF7L2 expression in pancreas tissue decreased
72% in the resistance training group compared to the control group (Figure 1).
The Changes in TCF7L2 Expression of Pancreas Tissue by Resistance Training in T2D Rats
The major finding of the
present study was the decreased TCF7L2 expression in response to 3
months of resistance training in T2D rats. The training course, on the
other hand, decreased fasting blood glucose levels and increased serum
insulin in diabetic rats with resistance training compared to those
without resistance training. However, the answer to the question whether
the increase in serum insulin levels occurred in response to reduced
TCF7L2 expression seems a little difficult. Type 2 diabetes is a result
of complex interactions between genetic and environmental factors
playing a role in the metabolism of fat and glucose, such as
malfunctioning of hepatic and muscular insulin and defects in insulin
secretion, adipose tissue metabolism, whole body lipolysis, and possibly
metabolic defects in other organs of the body; nevertheless, the main
cause of the disease, especially in its severe form, is the lack of
sufficient insulin secretion from pancreatic beta cells to compensate
for insulin resistance (21).
In fact, although an increase in insulin resistance results in an
increased mass of beta cells to secrete more insulin to compensate for
insulin resistance (22-24),
severe long-lasting insulin resistance is associated with reduced
proliferation of beta cells. As a result, in response to long-term
insulin resistance, levels of beta cell mass are not maintained for
adequate secretion of insulin (25).
If the capacity of insulin secretion is sufficient to compensate for
insulin resistance, people with insulin resistance will not develop
Previous studies have noted that increased expression of TCF7L2 is
associated with decreased insulin secretion from pancreatic beta cells.
Common genetic variations in TCF7L2 reveal the strongest association
with type 2 diabetes known to date (26).
The importance of genetic variations in TCF7L2 for type 2 diabetes has
been reported in numerous studies in populations of diverse ethical
backgrounds, although the physiopathological mechanisms underlying these
associations are largely unknown. On the other hand, the exact location
of the genetic variations associated with the disease is different in
cohorts of Asian descent (27).
studies on Asian populations have revealed that during increased
insulin resistance after high-calorie or high-fat diets, secretion of
insulin is insufficient to compensate for insulin resistance (28-30).
In addition, a Korean study showed that a significant proportion of
patients with type 2 diabetes are not obese and their insulin levels are
normal or below normal (30).
These studies point out in general that the non-obese Asians secrete
insufficient amounts of insulin during insulin resistance, leading
ultimately to type 2 diabetes (25, 28).
In recent years, researchers have found 70 genetic variants with the
risk for diabetes, but TCF7L2 is still identified as the most important
diabetes susceptibility gene, so that the gene has carriers and variants
with the greatest risk of type 2 diabetes (21, 29).
TCF7L2 is a member of a transcription factors family and plays an
important role in cellular signaling pathways of Wnt through regulation
of cell proliferation and differentiation (30). The TCF7L2 gene is located on chromosome 10q25, where it has a strong linkage with diabetes type 2 (31, 32).
It is known that Wnt signals affect secretion of glucagon-like
peptide-1 (GLP-1) through nuclear receptors of TCF7L2 that trigger the
release of insulin from beta cells of the small intestine (13).
Phenotypic changes in TCF7L2 indicate that type 2 diabetes exacerbates through or due to malfunctioning of beta cells (33-35).
Changes in TCF7L2 expression and its variants are associated with
impaired insulin secretion that reduces the capacity of insulin
secretion in response to insulin sensitivity. Among variants of TCF7L2,
rs7903146 T-allele is one of the most important genetic risk factors for
T2D (36) and has been reported to have a strong direct relationship with T2D in different populations (12).
This relationship is associated with defects in insulin production, and
it is represented by reducing the release of insulin from pancreatic
beta cells (37, 38). Other studies have reported the association between rs7903146 T-allele with impaired glucose tolerance (34, 38, 39), increased birth weight (40), and increased anthropometric indices which show the role of the TCF7L2 phenotype in several tissues (33).
It seems that the diabetic effect of TCF7L2 rs7903146 or TCF7L2-related
variants is presented as reduced insulin secretion or defects in
insulin function, reduced effect of glucagon-like peptide-1 (GLP-1), and
increased hepatic glucose production (37, 41, 42).
Wegner et al. (2008) have recently shown that the TCF7L2 rs7903146
T-allele is associated with impaired insulin secretion in elderly twins (43).
It is known that each TCF7L2 rs7903146 T-allele increases the risk of
type 2 diabetes, even in the presence of a weight loss of 1.37-fold (11, 33, 34, 44).
Several studies have also indicated that rs7903146 affects insulin
production in type 2 diabetes through reducing the conversion of
proinsulin to insulin. These studies in fact support the close
relationship between rs7903146 and damaged conversion of proinsulin to
insulin (37, 45).
Genetic variations of rs7903146 are located in the non-coding region,
and similar to other type 2 diabetes-related variants, it seems that
their impact on the disease occurs through changes in gene expression.
one cannot be certain about the mechanisms of resistance training
leading to reduced fasting blood glucose levels in diabetic rats in this
study, according to previous evidence, it seems that reduced TCF7L2
expression following exercise is of great importance in improvement of
blood glucose. Most previous studies in this area have introduced
increased TCF7L2 expression in pancreatic cells as the most important
genetic factor contributing to decreased insulin secretion. Thus, it
appears that the mentioned resistance training protocol has led to
increased secretion of insulin from beta cells through reducing the
expression of TCF7L2 in the pancreas. In this context, some studies have
noted that both diet and physical activity increase insulin secretion,
while functional mechanisms are independent of each other. Diet
increases beta cell mass through hypertrophy to overcome insulin
resistance, while exercise training increases beta cell mass through
hyperplasia, which is displayed as increased beta cell proliferation and
reduced apoptosis (25).
In addition, some studies have reported that exercise reduces symptoms
of hepatic insulin through reducing hepatic glucose release in
hyperinsulinemic conditions (46, 47).
Nevertheless, some studies have shown that exercise training improves
the mass and function of beta cells in type 2 diabetic patients.
existing evidence supports increased expression of the TCF7L2 gene in
the presence of type 2 diabetes, and the decline in insulin secretion in
these patients has, in a way, been attributed to this higher gene
expression. In this research, three months of resistance training
significantly increased serum insulin levels accompanied by reduced
fasting blood glucose levels in rats with type 2 diabetes that had been
manipulated to develop defective insulin secretion. Moreover, this
training program was accompanied by reduced levels of TCF7L2 expression
in pancreatic tissue. Based on this evidence, higher insulin secretion
in the studied rats probably can be attributed to lower TCF7L2 gene
expression resulting from resistance training.
We thank the research deputy of the college of
physical education and sport sciences, Tehran, for the college’s
financial support and cooperation in implementing this project.
S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes:
estimates for the year 2000 and projections for 2030. Diabetes Care. 2004;27(5):1047-53. [PubMed]
Adeghate E, Schattner P, Dunn E. An update on the etiology and
epidemiology of diabetes mellitus. Ann N Y Acad Sci. 2006;1084:1-29. [DOI] [PubMed]
Silva Xavier G, Qian Q, Cullen PJ, Rutter GA. Distinct roles for insulin
and insulin-like growth factor-1 receptors in pancreatic beta-cell
glucose sensing revealed by RNA silencing. Biochem J. 2004;377(Pt 1):149-58. [DOI] [PubMed]
Ogino J, Sakurai K, Yoshiwara K, Suzuki Y, Ishizuka N, Seki N, et al.
Insulin resistance and increased pancreatic beta-cell proliferation in
mice expressing a mutant insulin receptor (P1195L). J Endocrinol. 2006;190(3):739-47. [DOI] [PubMed]
Lazar MA. How obesity causes diabetes: not a tall tale. Science. 2005;307(5708):373-5. [DOI] [PubMed]
Ruchat SM, Rankinen T, Weisnagel SJ, Rice T, Rao DC, Bergman RN, et al.
Improvements in glucose homeostasis in response to regular exercise are
influenced by the PPARG Pro12Ala variant: results from the HERITAGE
Family Study. Diabetologia. 2010;53(4):679-89. [DOI] [PubMed]
Samson S. Role of Wnt signaling and TCF7L2 for beta cell function and
regeneration in mouse models of diabetes. Houston,Texas: Baylor College
of Medicine; 2011.
Melzer D, Murray A, Hurst AJ, Weedon MN, Bandinelli S, Corsi AM, et al.
Effects of the diabetes linked TCF7L2 polymorphism in a representative
older population. BMC Med. 2006;4:34. [DOI] [PubMed]
Lyssenko V, Lupi R, Marchetti P, Del Guerra S, Orho-Melander M, Almgren
P, et al. Mechanisms by which common variants in the TCF7L2 gene
increase risk of type 2 diabetes. J Clin Invest. 2007;117(8):2155-63. [DOI] [PubMed]
Villareal DT, Robertson H, Bell GI, Patterson BW, Tran H, Wice B, et al.
TCF7L2 variant rs7903146 affects the risk of type 2 diabetes by
modulating incretin action. Diabetes. 2010;59(2):479-85. [DOI] [PubMed]
Grant SF, Thorleifsson G, Reynisdottir I, Benediktsson R, Manolescu A,
Sainz J, et al. Variant of transcription factor 7-like 2 (TCF7L2) gene
confers risk of type 2 diabetes. Nat Genet. 2006;38(3):320-3. [DOI] [PubMed]
Cauchi S, El Achhab Y, Choquet H, Dina C, Krempler F, Weitgasser R, et
al. TCF7L2 is reproducibly associated with type 2 diabetes in various
ethnic groups: a global meta-analysis. J Mol Med (Berl). 2007;85(7):777-82. [DOI] [PubMed]
F, Brubaker PL, Jin T. TCF-4 mediates cell type-specific regulation of
proglucagon gene expression by beta-catenin and glycogen synthase
kinase-3beta. J Biol Chem. 2005;280(2):1457-64. [DOI] [PubMed]
Kovacs P, Berndt J, Ruschke K, Kloting N, Schon MR, Korner A, et al.
TCF7L2 gene expression in human visceral and subcutaneous adipose tissue
is differentially regulated but not associated with type 2 diabetes
mellitus. Metabolism. 2008;57(9):1227-31. [DOI] [PubMed]
Hansson O, Zhou Y, Renstrom E, Osmark P. Molecular function of TCF7L2:
Consequences of TCF7L2 splicing for molecular function and risk for type
2 diabetes. Curr Diab Rep. 2010;10(6):444-51. [DOI] [PubMed]
Palizban A, Nikpour M, Salehi R, Maracy MR. Association of a common
variant in TCF7L2 gene with type 2 diabetes mellitus in a Persian
population. Clin Exp Med. 2012;12(2):115-9. [DOI] [PubMed]
Amoli MM, Amiri P, Tavakkoly-Bazzaz J, Charmchi E, Hafeziyeh J,
Keramatipour M, et al. Replication of TCF7L2 rs7903146 association with
type 2 diabetes in an Iranian population. Genet Mol Biol. 2010;33(3):449-51. [DOI] [PubMed]
McCaffery JM, Jablonski KA, Franks PW, Dagogo-Jack S, Wing RR, Knowler
WC, et al. TCF7L2 polymorphism, weight loss and proinsulin:insulin ratio
in the diabetes prevention program. PLoS One. 2011;6(7):ee21518 [DOI] [PubMed]
Shirwaikar A, Rajendran K, Dinesh Kumar C, Bodla R. Antidiabetic
activity of aqueous leaf extract of Annona squamosa in
streptozotocin-nicotinamide type 2 diabetic rats. J Ethnopharmacol. 2004;91(1):171-5. [DOI] [PubMed]
Molanouri Shamsi M, Hassan ZM, Mahdavi M, Gharakhanlou R, Azadmanesh K,
Baghersad L, et al. Influence of Resistance Training on IL-15 mRNA
Expression and the Protein Content in Slow and Fast Twitch Muscles of
Diabetic Rats. Iranian J Endocrinol Metab. 2012;14(2):185-92.
Alibegovic AC, Sonne MP, Hojbjerre L, Hansen T, Pedersen O, van Hall G,
et al. The T-allele of TCF7L2 rs7903146 associates with a reduced
compensation of insulin secretion for insulin resistance induced by 9
days of bed rest. Diabetes. 2010;59(4):836-43. [DOI] [PubMed]
Jetton TL, Lausier J, LaRock K, Trotman WE, Larmie B, Habibovic A, et
al. Mechanisms of compensatory beta-cell growth in insulin-resistant
rats: roles of Akt kinase. Diabetes. 2005;54(8):2294-304. [PubMed]
Rooman I, Lardon J, Bouwens L. Gastrin stimulates beta-cell neogenesis
and increases islet mass from transdifferentiated but not from normal
exocrine pancreas tissue. Diabetes. 2002;51(3):686-90. [PubMed]
GC, Bonner-Weir S. Five stages of evolving beta-cell dysfunction during
progression to diabetes. Diabetes. 2004;53(Supplement 3):S16-21. [DOI]
S, Hong SM, Lee JE, Sung SR. Exercise improves glucose homeostasis that
has been impaired by a high-fat diet by potentiating pancreatic
beta-cell function and mass through IRS2 in diabetic rats. J Appl Physiol (1985). 2007;103(5):1764-71. [DOI] [PubMed]
Renstrom E. Impact of transcription factor 7-like 2 (TCF7L2) on
pancreatic islet function and morphology in mice and men. Diabetologia. 2012;55(10):2559-61. [DOI] [PubMed]
WL, Zheng HC, Bukuru J, De Kimpe N. Natural medicines used in the
traditional Chinese medical system for therapy of diabetes mellitus. J Ethnopharmacol. 2004;92(1):1-21. [DOI] [PubMed]
Cockram CS. The epidemiology of diabetes mellitus in the Asia-Pacific
region. Hong Kong Med J. 2000;6(1):43-52. [PubMed]
Anders R, Ola H. Mechanisms whereby genetic variation in the TCF7L2 gene
causes diabetes: novel targets for anti-diabetic therapy? . Sweden :
Lund University Diabetes Centre; 2013.
SE, Hemati N, Longo KA, Bennett CN, Lucas PC, Erickson RL, et al.
Inhibition of adipogenesis by Wnt signaling. Science. 2000;289(5481):950-3.
Wiltshire S, Hattersley AT, Hitman GA, Walker M, Levy JC, Sampson M, et
al. A genomewide scan for loci predisposing to type 2 diabetes in a U.K.
population (the Diabetes UK Warren 2 Repository): analysis of 573
pedigrees provides independent replication of a susceptibility locus on
chromosome 1q. Am J Hum Genet. 2001;69(3):553-69. [PubMed]
Reynisdottir I, Thorleifsson G, Benediktsson R, Sigurdsson G, Emilsson
V, Einarsdottir AS, et al. Localization of a susceptibility gene for
type 2 diabetes to chromosome 5q34-q35.2. Am J Hum Genet. 2003;73(2):323-35. [DOI] [PubMed]
Cauchi S, Meyre D, Dina C, Choquet H, Samson C, Gallina S, et al.
Transcription factor TCF7L2 genetic study in the French population:
expression in human beta-cells and adipose tissue and strong association
with type 2 diabetes. Diabetes. 2006;55(10):2903-8. [DOI] [PubMed]
Cauchi S, Meyre D, Choquet H, Dina C, Born C, Marre M, et al. TCF7L2
variation predicts hyperglycemia incidence in a French general
population: the data from an epidemiological study on the Insulin
Resistance Syndrome (DESIR) study. Diabetes. 2006;55(11):3189-92. [DOI] [PubMed]
Saxena R, Gianniny L, Burtt NP, Lyssenko V, Giuducci C, Sjogren M, et
al. Common single nucleotide polymorphisms in TCF7L2 are reproducibly
associated with type 2 diabetes and reduce the insulin response to
glucose in nondiabetic individuals. Diabetes. 2006;55(10):2890-5. [DOI] [PubMed]
Helgason A, Palsson S, Thorleifsson G, Grant SF, Emilsson V,
Gunnarsdottir S, et al. Refining the impact of TCF7L2 gene variants on
type 2 diabetes and adaptive evolution. Nat Genet. 2007;39(2):218-25. [DOI] [PubMed]
Kirchhoff K, Machicao F, Haupt A, Schafer SA, Tschritter O, Staiger H,
et al. Polymorphisms in the TCF7L2, CDKAL1 and SLC30A8 genes are
associated with impaired proinsulin conversion. Diabetologia. 2008;51(4):597-601. [DOI] [PubMed]
Raitakari OT, Ronnemaa T, Huupponen R, Viikari L, Fan M, Marniemi J, et
al. Variation of the transcription factor 7-like 2 (TCF7L2) gene
predicts impaired fasting glucose in healthy young adults: the
Cardiovascular Risk in Young Finns Study. Diabetes Care. 2007;30(9):2299-301. [DOI] [PubMed]
J, Kuusisto J, Vanttinen M, Kuulasmaa T, Lindstrom J, Tuomilehto J, et
al. Variants of transcription factor 7-like 2 (TCF7L2) gene predict
conversion to type 2 diabetes in the Finnish Diabetes Prevention Study
and are associated with impaired glucose regulation and impaired insulin
secretion. Diabetologia. 2007;50(6):1192-200. [DOI] [PubMed]
Freathy RM, Weedon MN, Bennett A, Hypponen E, Relton CL, Knight B, et
al. Type 2 diabetes TCF7L2 risk genotypes alter birth weight: a study of
24,053 individuals. Am J Hum Genet. 2007;80(6):1150-61. [DOI] [PubMed]
RJ, Franks PW, Francis RW, Barroso I, Gribble FM, Savage DB, et al.
TCF7L2 polymorphisms modulate proinsulin levels and beta-cell function
in a British Europid population. Diabetes. 2007;56(7):1943-7. [DOI] [PubMed]
Stolerman ES, Manning AK, McAteer JB, Fox CS, Dupuis J, Meigs JB, et al.
TCF7L2 variants are associated with increased proinsulin/insulin ratios
but not obesity traits in the Framingham Heart Study. Diabetologia. 2009;52(4):614-20. [DOI] [PubMed]
Wegner L, Hussain MS, Pilgaard K, Hansen T, Pedersen O, Vaag A, et al.
Impact of TCF7L2 rs7903146 on insulin secretion and action in young and
elderly Danish twins. J Clin Endocrinol Metab. 2008;93(10):4013-9. [DOI] [PubMed]
Sladek R, Rocheleau G, Rung J, Dina C, Shen L, Serre D, et al. A
genome-wide association study identifies novel risk loci for type 2
diabetes. Nature. 2007;445(7130):881-5. [DOI] [PubMed]
Gonzalez-Sanchez JL, Martinez-Larrad MT, Zabena C, Perez-Barba M,
Serrano-Rios M. Association of variants of the TCF7L2 gene with
increases in the risk of type 2 diabetes and the proinsulin:insulin
ratio in the Spanish population. Diabetologia. 2008;51(11):1993-7. [DOI] [PubMed]
Heled Y, Shapiro Y, Shani Y, Moran DS, Langzam L, Barash V, et al.
Physical exercise enhances hepatic insulin signaling and inhibits
phosphoenolpyruvate carboxykinase activity in diabetes-prone Psammomys
obesus. Metabolism. 2004;53(7):836-41. [PubMed]
Perseghin G, Lattuada G, De Cobelli F, Ragogna F, Ntali G, Esposito A,
et al. Habitual physical activity is associated with intrahepatic fat
content in humans. Diabetes Care. 2007;30(3):683-8. [DOI] [PubMed]