EDITORIAL

Type 2 Diabetes Mellitus and its Complications: From the Mo-

lecular Biology to the Clinical Practice

Maciej T. Malecki

Department of Metabolic Diseases, Medical College, Jagiellonian University, 15 Kopernika Street, 31-501 Krakow, Poland,
e-mail: [email protected].

Introduction netic background also influences the complications of

type 2 diabetes mellitus [6-8].

P robably the most urgent problem in the field of

diabetology, and one of the most important in
XXI. century medicine, is an epidemic of type 2
diabetes mellitus. It is estimated that the number of
Genetics of type 2 diabetes
A long time before molecular biology bloomed as it
people with diabetes worldwide exceeds 200 million [1, does today, scientists were able to provide evidence
2]. Most of them are patients with type 2 diabetes. In that genetic factors influenced susceptibility to type 2
the societies of the industrialized world the prevalence diabetes mellitus. The disease clustered in families, the
of this disease has reached a few percent of the entire concordance rate in monozygotic twins was higher
population and is still growing [1, 2]. For many dec- than in dizygotic ones, and in addition there were
ades type 2 diabetes, formerly referred to as non- populations, for example Pima Indians, with such a
insulin-dependent, has been regarded a less dangerous high prevalence of type 2 diabetes mellitus that could
type of disease by both the patients and their doctors. only be explained by genetic predisposition [5, 9, 10].
Just recall, latent diabetes, biochemical diabetes, In the last decade substantial progress has been made
diabetes of old age. Wrong!!! The scientists, physi- in the genetic methods enabling the identification of
cians, patients, politicians and entire societies must the actual sequence differences responsible for the
now realize that type 2 diabetes is a leading cause of occurrence of the disease. So far, mutations in about
premature death, mainly due to cardiovascular causes, ten genes have been linked to the development of
and of occurrence of complications that can lead to monogenic, for example autosomal dominant (MODY
blindness, amputations, and renal insufficiency. The - maturity onset diabetes of the young) or maternally
life expectancy of millions of patients is shortened due inherited, forms of type 2 diabetes mellitus [11-13]. All
to the diagnosis of type 2 diabetes [3]. The disease of these forms are relatively rare and were found to be
imposes huge human and economic costs on patients, responsible for a few percent of all type 2 diabetes
their families, local communities, health care systems, cases. Monogenic diabetes is usually characterized by
and societies [4]. Type 2 diabetes is characterized by high phenotypic penetrance and severe impairment in
two major defects: impaired insulin secretion and a insulin secretion [11, 13]. Less effective were efforts
decrease in its peripheral action [5]. Both of them have aiming to identify genes responsible for the more
roots in the interaction of genetic and environmental common, polygenic form of the disease. This diabetes
factors. Moreover, there is growing evidence that ge- usually develops in the middle and later years of life

DOI 10.1900/RDS.2004.1.5 5 www.The-RDS.org

6 The Review of Diabetic Studies Type 2 Diabetes and its Complications
Vol. 1, No. 1, 2004

and occurs with both: impaired insulin secretion and plex etiology of all diabetic complications that are the
insulin resistance. The clinical picture is created by the result of interaction between plural genetic and clinical
interaction of the environment and genetic factors, factors. Nevertheless, it should be pointed out that
such as frequent polymorphisms of many genes, not some studies produced promising results and have
just one. Those polymorphisms may be localized in the been replicated in other populations. One should men-
coding or regulatory parts of the genes and are present, tion the aldose reductase, a gene from the polyol
although with different frequencies, in diabetes pa- pathway, associated with diabetic nephropathy and
tients as well as in healthy populations [14]. Sequence retinopathy in type 1 and type 2 diabetes in several
differences in two genes have been associated so far studies [33-36]. Another good example is haptoglobin,
with the complex form of type 2 diabetes: calpain 10 a candidate gene from the group of antioxidant pro-
and PPAR [15, 16]. Polymorphisms in those genes teins, that was linked to cardiovascular complications
mainly affect sensitivity to insulin in humans [17, 18]. in different populations [37-39].
In addition, some evidence exists that genes, such as
adiponectin [19], sulfonylurea receptor 1 (SUR1) [20], From the molecular background to the clini-
HFE hemochromatosis gene [21], and insulin [22] may cal practice
also influence susceptibility to this disease acting
There is little doubt that the coming years will bring
through different mechanisms. Efforts are being made
new fascinating discoveries in the field of genetic sus-
to verify the hypothesis that frequent polymorphisms
ceptibility to type 2 diabetes mellitus and its complica-
in the MODY genes may contribute to the develop-
tions. The important question is how to use this
ment of the more common forms of late onset type 2
knowledge of molecular background in clinical practice
diabetes [23-26].
for the benefit of individual patients as well as entire
societies. We should notice, however, that genetic
Genetic factors of diabetic complications research in type 2 diabetes already has not only scien-
Not only diabetes, both type 1 and type 2, but also tific, but also prognostic and prophylactic significance,
their complications seem to be influenced by genetic moreover it sometimes determines therapeutic deci-
factors. The strongest evidence from epidemiological sions. For example, the molecular diagnosis of MODY
observations and family studies for the role of molecu- that in some countries has become clinical reality is not
lar background has been found for diabetic nephropa- just the domain of the scientific research [40]. It influ-
thy. The majority of data come from studies per- ences the mode of treatment of diabetes patients in the
formed in type 1 [27, 28], but some studies were car- family, since it is generally accepted that the sulfony-
ried out in type 2 diabetes [7, 29, 30]. Unlike for neph- lurea are the agents of choice in this form of diabetes
ropathy the epidemiological studies do not provide [41]. This diagnosis also defines the risk of diabetes,
strong support for the role of genes in diabetic reti- since on average 50% of individuals in each generation
nopathy [31], however some clinical observations and develop the disease [11]. Molecular genetic testing can
genetic analyses in type 2 diabetes mellitus [30, 32] specifically indicate the carriers of the mutations, i.e.
suggest that genetic influences are also present in this who are very likely to develop diabetes, but it can also
microvascular complication. In addition to the mi- provide relief for those who did not inherit the disease
crovasculature, it is important to define the role of variant. While the prophylaxis of diabetes does not
genes in the occurrence of macrovascular complica- work in MODY and the penetrance rate is very high, it
tions, mainly coronary artery disease, in patients with should be very effective for diabetes complications,
diabetes. In this context one should emphasize that the since frequent glucose level examination of susceptible
UKPDS study showed significant ethnic differences in individuals can lead to early diagnosis and introduction
the incidence of cardiovascular diseases in type 2 dia- to treatment. This is particularly important for the
betes patients, that were very likely the result of the women from MODY families planning pregnancy.
heterogeneity of their genetic background [8]. Hun- The results of genetic studies of the complex form of
dreds of loci have been studied so far in order to ex- type 2 diabetes mellitus and its complications had
plain genetic susceptibility to diabetic complications. much less influence on clinical practice than in the case
However, associations described for specific polymor- of monogenic disease. However, one may imagine that
phisms in different studies seem to be rather weak and in future the identification of the carriers of certain
inconsistent. The major reason is probably the com- sequence differences predisposing to type 2 diabetes

Rev Diabetic Stud (2004) 1:5-8 Copyright by The SBDR

Malecki The Review of Diabetic Studies 7
Vol. 1, No. 1, 2004

mellitus will allow the introduction of specifically in- tion would be the consideration of early use of medica-
tensive behavioral and pharmacological intervention in tions that can protect the patient from the develop-
this group. Moreover, the type of specific pharmacol- ment of vascular complications, such as ACE inhibi-
ogical intervention may depend on the genetic back- tors or antioxidants. Their nature may also depend on
ground of the individual. Similarly, the identification of the genetic factors inherited by the patient. Finally,
the carriers of susceptibility alleles for chronic diabetic gene therapy completes the scenario for future ap-
complications may lead to the introduction of clinical proaches to type 2 diabetes mellitus and chronic com-
measures in this group that aim to maintain the dia- plications of the disease [42].
betic compensation as well as possible. A further op-

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Rev Diabetic Stud (2004) 1:5-8 Copyright by The SBDR