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Diabetes Pathophysiology and Genetics
Table 1: Overview of Genetic Variants Associated obesity. However, these variants are generally not the causal
with Type 2 Diabetes and Their Putative Role in
variants. The ORs of the causal variants should be higher and will
Disease Pathogenesis
presumably explain a larger percentage of the genetic susceptibility
to these two conditions. In addition, it is likely that many more
Marker Chr Closest Gene(s) Putative Mechanism in T2D
genes contribute a similar or smaller effect.
rs7578597 2 THADA Apoptosis of β cells
rs10010131 4 WFS1 Apoptosis of β cells
rs10923931 1
Functions of Type 2 Diabetes and
NOTCH2 β-cell growth and
development
Obesity Genes
rs4402960 3
The susceptibility loci for obesity and type 2 diabetes can provide
IGF2BP2 β-cell growth and
development
insight into the aetiology of the traits, yet it is difficult to link genetic
rs10946398 6 associations to biological mechanisms. It is important to keep inCDKAL1 β-cell growth and
development mind that most of the observed associations are located in non-
rs1111875 10 HHEX-IDE β-cell growth and
coding regions of the genome and that the presented type 2
development
diabetes and obesity genes are mostly genes near the associated
rs7901695 10 TCF7L2 β-cell growth and
markers. We assume that at least some of these nearby genes are
development
truly involved in the traits as we discuss the function of these genes
rs4430796 17 TCF2 β- cell growth and
to gain more insight into the disease pathology.
development
Cell cycle
rs864745 7
Type 2 Diabetes
JAZF1 Cell cycle
rs10811661 9
The main feature of type 2 diabetes is the inability of an individual
CDKN2A-2B Cell cycle
rs12779790 10
to maintain proper blood glucose levels. The key player in this
CDC123-CAMK1D Cell cycle
rs13266634 8 homeostasis is the peptide hormone insulin, which is produced inSLC30A8 Insulin secretion
rs2237892 11 KCNQ1 Insulin secretion the β cells of the pancreas. After a meal this hormone is released
rs5215 11 KCNJ11 Insulin secretion
into the bloodstream and transported to its several target tissues,
rs10830963 11 MTNR1B Insulin secretion
where it diminishes hepatic glucose output and triggers glucose
rs17036101 3 SYNC, PPARG Unknown
uptake and storage as either fat or glycogen. Type 2 diabetes starts
rs4607103 3 ADAMTS9 Unknown
rs1153188 12 DCD Unknown
rs7961581 12 TSPAN8 Unknown
Chr = chromosome, T2D = type 2 diabetes.
The susceptibility loci for obesity
Table 2: Overview of Genetic Variants Associated with
and type 2 diabetes can provide insight
Obesity and Their Putative Role in Pathogenesis
into the aetiology of the traits, yet it is
Marker Chr Closest Gene(s) Putative Mechanism in Obesity
difficult to link genetic associations
rs4074134 11 BDNF Energy homeostasis
to biological mechanisms.
rs7498665 16 SH2B1 Energy homeostasis
rs9939609 16 FTO Energy homeostasis
rs17782313 18 MC4R Energy homeostasis
rs1805081 18 with the failure of several tissues, such as adipose tissue andNPC1 Lipid transport
rs2815752 1 NEGR1 Neural development muscle, to respond to the stimulus of insulin (this is often referred
rs6548238 2 TMEM18 Neural development
to as insulin resistance). As a result, insulin levels rise and it is
rs10838738 11 MTCH2 Satiation signalling
presumed that, after a certain time, β cells are not able to keep up
rs10913469 1 SEC16B Unknown
with the growing demands for insulin release. At this point a
rs7647305 3 ETV5 Unknown
(second) vicious cycle of higher blood glucose levels and a higher
rs10938397 4 GNPDA2 Unknown
demand for insulin is entered, which increases the strain on the
rs2844479 6 NCR3 Unknown
rs4712652 6
β cells and leads to β-cell apoptosis and, ultimately, a complete
PRL Unknown
rs10508503 10
inability to produce insulin.
15
PTER Unknown
rs7138803 12 BCDIN3D Unknown
rs1424233 16
The type 2 diabetes risk variants currently pinpointed appear to
MAF Unknown
rs11084753 19 act through interference with β-cell insulin secretion rather thanKCTD15 Unknown
through insulin sensitivity of insulin target tissues. This indicates
Chr = chromosome.
that disturbances in β-cell function are ultimately decisive for the
ranging from 0.26 for TCF7L2 to 0.85 for PPARG in the European actual development of type 2 diabetes. The known type 2 diabetes
population, and have a low effect size with odds ratios (ORs) genes can be classified into subgroups for their potential role in
ranging from 1.10 (confidence interval [CI] 1.07–1.14) for TCF2 to β-cell function based on what is known about their molecular
1.37 (CI 1.31–1.43) for TCF7L2. For obesity, each of the associated function.
15
It has been proposed that KCNJ11, KCNQ1, MTNR1B and
variants has a very modest effect, ranging from 0.06kg/m
2
for SLC30A8 are involved in insulin secretion; CDKAL1, IGF2BP2, HHEX-
KCTD15 to 0.33kg/m
2
for FTO per allele change in body mass index IDE, NOTCH2, JAZF1, TCF7L2 and TCF2 in β-cell growth and
(BMI). All these variants together can explain only a small development; TCF2, CDKN2A-2B, CDC123 and JAZF1 in the cell
percentage of the genetic susceptibly of type 2 diabetes and cycle; and THADA and WFS1 in the apoptosis of β cells.
28 EUROPEAN ENDOCRINOLOGY
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