AMERICAN RESEARCH THOUGHTS
ISSN: 2392 – 876X
Volume 1 │ Issue 1 │ November 2014
Available online at: www.researchthoughts.us
DIABETES, A CHALLENGE FOR MODERN
RESEARCH
Khaista Rahman1, Ghulam Nabi2, Sana Ullah2*and Muhammad Jamal
Khan3
Department of Biotechnology, Quaid-i-Azam University Islamabad Pakistan
Department of Animal Sciences, Quaid-i-Azam University Islamabad, Pakistan
3Department of Biotechnology, University of Malakand Lower Dir, Khyber Pakhtunkhwa
Pakistan
1
2
Abstract: Since time unmemorable human beings are facing a number of problems. Diseases and
epidemics being on front lines. Human beings have faced a number of disorders such as cancer,
malaria, poliomyelitis and diabetes etc. Some of these menaces have been eradicated successfully, yet
some remains a mystery to be solved such a diabetes. Scientists have successfully discovered insulin
for treating diabetes. Despite being this advancement in biomedical sciences, diabetes is still a
challenge for modern research, because its frequency is on increasing trend regularly. This article
briefly reviews diabetes, its history, clinical symptoms, clinical diagnosis, risk factors, prevalence and
its current status.
Key words: diabetes, modern research, clinical symptoms, clinical diagnosis, risk factors
INTRODUCTION
Diabetes was initially identified by the Egyptians around 1500 BC, it was
defined as a clinical condition with extensive urination and weight loss
experienced by affected individuals. Later on, Aretaeus (80 to 138 AD) a
Greek physician used the term diabetes mellitus for the first time. He
*
Corresponding author: [email protected]
217
Khaista Rahman, Ghulam Nabi, Sana Ullah, Muhammad Jamal Khan- DIABETES, A CHALLENGE FOR
MODERN RESEARCH
observed that the affected individuals had elevated level of sugar in the
urine. In 1776, the urinary sugar was measured by Matthew Dobson who
found it to be present only in the urine of diabetic patients. In 1812 New
England Journal of Medicine and Surgery recognized diabetes as a clinical
entity, however, not enough information about the disease was available at
that time [Clarke and Foste, 2012].
In 1889, the first evidence regarding the role of pancreas in
controlling the glucose concentration was obtained by Mering and
Minkowski. They surgically removed pancreas of the animals to study the
onset of diabetes. In 1910 Sir Edward Albert Sharpey-Schafer used the term
insulin, derived from the Latin word insula (meaning Island) to define the
hormone involved in glucose homeostasis, he also identified the pancreatic
islet cells of Langerhans as the source of this hormone, he hypothesized
that the deficiency of this hormone results in diabetes. In 1921, this
hypothesis was tested in diabetic animal models in whom extracts of the
pancreatic islet cells were used to reverse diabetes; this resulted in the
isolation of insulin by Frederick Banting and Charles Best. James Collip
and John Macleod also showed how diabetic patients can be effectively
treated by insulin. They were able to purify insulin from bovine
pancreases, which resulted in the first ever biological discovery being
industrialized. Shortly afterwards in the mid-19th century, Claude Bernard
demonstrated the critical role of the liver in manufacturing glucose from
non-glucose precursors and absorption of dietary carbohydrate in
regulating blood glucose levels; this provided the basis for the discovery of
other biomolecules involved in the glucose metabolic pathway [Holt, 2009].
Multifaceted research in diabetes resulted in a number of landmark
discoveries including in 1958, the method of amino acid sequencing, which
was developed by Frederick Sanger who used it to sequence insulin.
Subsequently Dorothy Hodgkin determined the three-dimensional crystal
218
AMERICAN RESEARCH THOUGHTS- Volume 1 │ Issue 1 │ 2014
Khaista Rahman, Ghulam Nabi, Sana Ullah, Muhammad Jamal Khan- DIABETES, A CHALLENGE FOR
MODERN RESEARCH
structure of Insulin. In 1967 Donald Steiner’s demonstrated how insulin
polypeptide molecule is derived from proinsulin. All this work clarified the
biochemistry of insulin as well as to highlight the role of other polypeptide
hormones. The discovery of insulin also resulted in the emergence of new
fields of research such as recombinant DNA technology, which was used to
produce insulin by cloning. Various studies on diabetes and its pathways
that participate in glucose metabolism generated such landmark research
that 10 scientists were awarded the Nobel Prize for their work [Polonsky,
2012].
CLINICAL SYMPTOMS
Diabetes is recognized as a collection of metabolic abnormalities. The
person suffering from diabetes experiences hyperglycemia, in which the
body is unable to synthesize an adequate amount of insulin because the
cells don’t respond to the amount of insulin produced. Classical symptoms
are observed due to the above described condition, like frequent desire to
urinate accompanied by increased hunger and thirst. Diabetes Mellitus
(DM) commonly referred to as diabetes causes the excretion of excessive
sweet urine or glycosuria. The most common condition of DM is diabetes
insipidus, which results in frequent urination [Jyothi and Rajasekhar, 2011].
CLINICAL DIAGNOSIS
For decades, plasma glucose levels were used as standard for the diagnosis
of diabetes, either Fasting sugar (FG) or the 2-h levels in 75grams Glucose
Tolerance Test (GTT) was used [ADA, 2012]. In 2009, an international
experts committee including representatives from International Diabetes
Federation (IDF), American Diabetes Association (ADA), and European
219
AMERICAN RESEARCH THOUGHTS- Volume 1 │ Issue 1 │ 2014
Khaista Rahman, Ghulam Nabi, Sana Ullah, Muhammad Jamal Khan- DIABETES, A CHALLENGE FOR
MODERN RESEARCH
Association for the Study of Diabetes (EASD) agreed on using glycated
hemoglobin test (HbA1C) for diagnosing diabetes [IEC, 2009]. While the
ADA adopted this criterion for diagnosis of DM in 2010 [ADA, 2012]. It
was shown that the HbA1C levels are influenced by factors such as race
and ethnicity of the patients. Some investigators also observed differences
in glycation in African Americans [Kumar et al., 2010; Zeimer et al., 2010].
The routine diagnostic test is usually performed using a method that has
been certified by the National Glycohemoglobin Standardization Program
(NGSP), which is based upon the Diabetes Control and Complications Trial
(DCCT)
reference
assay.
Epidemiologic
analysis
show
a
similar
relationship between HbA1C and risk of retinopathy as has been shown for
the corresponding Fasting Plasma Glucose [FPG] and 2hour Plasma
Glucose levels. The diagnostic test for diabetes have to follow certain
standards, for example HbA1C tests should be conducted in a proper lab
environment recommended by NGSP certified method and DCCT assay
standards, while for FPG during the fasting period there should be no
caloric intake for 8hrs at least, while for OGTT 75gm glucose mixed in
water should be given [IEC, 2009].
PREVALENCE OF DIABETES
Diabetes is prevalent throughout the world, in the developed countries
type 2 diabetes mellitus (T2DM) is the most prevalent which is projected to
have the greatest increase in prevalence in the regions of Asia and Africa
till 2030 [Antonetti et al., 2012]. The increased incidence of DM in
developing countries is due to urbanization and changes in lifestyle
primarily to western-style diet by a mechanism which is not completely
understood [ADA, 2007].
220
AMERICAN RESEARCH THOUGHTS- Volume 1 │ Issue 1 │ 2014
Khaista Rahman, Ghulam Nabi, Sana Ullah, Muhammad Jamal Khan- DIABETES, A CHALLENGE FOR
MODERN RESEARCH
In the year 2030, worldwide increase in diabetic population will be 429
million, this increase is thought to be due to obesity, increased duration of
life and improved disease [Al-Rubeaan, 2010; Wild et al., 2004]. In 2010,
estimates of diabetes prevalence among the adults aged between 20-79was
shown to be 6.4% (285 million adults). It has been estimated that between
the year 2010 and 2030, there will be a 69% and 20% increase in the number
of individuals with diabetes in the developed and developing countries,
respectively. Currently Pakistan is 7th among the top ten countries of
patients with diabetes, with an estimate of 7.1 million adults suffering from
the disease and by 2030 it will be 4th in the world with 13.8 million adults
with diabetes [Shaw et al., 2010]. In India there was an estimated patient
population of 32 million with diabetes till the year 2000 and this number is
predicted to increase to 79 million by 2030. In the absence of any preventive
measures approximately 0.7 million people in India are likely to develop
proliferative diabetic retinopathy (PDR) and 1.8 million will be having
macular edema [Rema et al., 2005]. Improved diagnostic and treatment
procedures have reduced the incidence of the disease in Caucasians
including Denmark, Sweden and the United States. It is still unclear
whether unhealthy lifestyle due to urbanization in developing countries
will jeopardize the preventive measures, which are being taken nowadays
[Antonetti, 2012].
CLINICAL CHARACTERIZATION
Clinically diabetes is subdivided into two major categories Type 1 diabetes
mellitus (T1DM) which occurs due to destruction of β-cells, usually leading
to absolute insulin deficiency and T2DM, which is a result of
desensitization of the target cells. Other peculiar type of DM are due to
different causes, e.g. genetic abnormality in β-cell function, insulin action,
221
AMERICAN RESEARCH THOUGHTS- Volume 1 │ Issue 1 │ 2014
Khaista Rahman, Ghulam Nabi, Sana Ullah, Muhammad Jamal Khan- DIABETES, A CHALLENGE FOR
MODERN RESEARCH
the abnormalities of exocrine pancreas , drug induced diabetes due to
organ transplantation or treatment of HIV/AIDS and diabetes induced as a
result of pregnancy, known as Gestational diabetes mellitus (GDM). In rare
cases it is difficult to classify T1DM or T2DM, although both types of DM
show different clinical symptoms and disease progression, sometimes the
latter can result in ketoacidosis. However, there are certain cases in which
it is difficult to diagnose diabetes since the patient might have late onset of
T1DM, or slow rate of progression and due to autoimmune diseases. In
different age groups it is difficult to diagnose DM e.g. in adults,
adolescents and children; however, in future the implementation of proper
diagnosis might become possible [Diabetes Care, 2012].
RISK FACTORS
Recently in both type of diabetes (T1DM and T2DM) besides the above
stated risk factors other factors have been observed to be involved in the
disease like Genetic susceptibility (Human Leukocyte Antigen-HLA),
autoimmunity, some viruses (Coxsackie B4) and intra-uterine environment,
which have been shown to enhance T1DM [Atkinson et al., 1994; Dahlquist
et al., 1999; Nakayama et al., 2005]. In addition inheritable T1DM is also
dependent on environmental triggering factors [Jyothi and Rajasekhar,
2011]. As opposed to this T2DM is often considered life-style mediated and
has been linked with obesity, high serum levels of low density lipoprotein,
though the role of genetic susceptibility and problems in intra uterine
development can also not be denied [Defronzo and Ferrannini, 1991; Dycke
et al., 2001; Hofman et al., 2004; Rich-Edwards et al., 1999; Sullivan et al.,
2005]. T2DM related obesity in the population is caused by increased fat
and caloric diets and less active lifestyle, which are most common factors
linked with the high prevalence of T2DM. This type of disease is mostly
222
AMERICAN RESEARCH THOUGHTS- Volume 1 │ Issue 1 │ 2014
Khaista Rahman, Ghulam Nabi, Sana Ullah, Muhammad Jamal Khan- DIABETES, A CHALLENGE FOR
MODERN RESEARCH
present in elderly individuals but the age of onset has decreased in recent
years and at this rate its prevalence will increase in teen-agers and young
adults [Polonsky, 2012].
GENETIC FACTORS
For T1DM, genes present on the HLA locus, at the “p” arm of 6th
chromosome have been shown to be involved in up to 50% of the cases of
familial
inheritance
[Nerup
et
al,
1974;
Ounissi-Benkalha
and
Polychronakos, 2008].
For T2DM genetic analysis have reported more than 40 genetic
variants, which enhance the risk for T2DM, however, the overall effect of
these variants explains only 10% of the heritable forms of the disorder
[Ahlqvist et al., 2011; Stoleman and Florez, 2009].
DIABETES INDUCED COMPLICATIONS
Some of the acute complications induced by DM are Diabetic ketoacidosis,
Hypoglycemia and hyperosmolar coma, while severe chronic effects are
cardiovascular diseases, retinal and renal abnormalities. Therefore proper
treatment and management of DM is recommended early in the course of
the disease along with proper management of blood pressure, cessation of
smoking and maintaining proper body weight [Diabetes Care, 1997].
Diabetes causes chronic disorders and constant hyperglycemia damages
the complex networks of blood vessels i.e. both micro vessels and macro
vessels. This can result in blindness and visual impairment, non-injury
amputation, and end stage kidney disease in adults. In addition these
vascular complications threaten the vision in patients with DM and can
223
AMERICAN RESEARCH THOUGHTS- Volume 1 │ Issue 1 │ 2014
Khaista Rahman, Ghulam Nabi, Sana Ullah, Muhammad Jamal Khan- DIABETES, A CHALLENGE FOR
MODERN RESEARCH
result in cataract if it occurs at an earlier age, as well as doubling the
susceptibility to develop glaucoma [Sharma et al., 2005].
CONCLUSION
Diabetes is poly symptomatic and multifactorial disease. Although the
genetic factor with different complications is the most prevalent all over
the world. From the beginning of 19th century scientists have focused upon
the findings and treatment of diabetes. Till now many discoveries and
trends have been incorporated in the treatment and the control of the
diabetes, but still the cases are increasing day by day.
REFERENCES
1. ADA (American Diabetes Association). (2007). Standards of Medical
Care in Diabetes—2007. Diabetes Care, 30, S4-S41.
2. ADA (American Diabetes
Association). (2012). Available
at:
http://www.diabetes.org/
3. Ahlqvist, E., Ahluwalia T.S. and Groop, L. (2011). Genetics of type 2
diabetes. Clin Chem., 57, 241-254.
4. Al-Rubeaan, K. (2010). Type 2 diabetes mellitus red zone. International
Journal of Diabetes Mellitus, 2, 1-2.
5. Antonetti, D.A., Klein, R. and Gardner, T.W. (2012). Diabetic
retinopathy. N Engl J Med., 366, 1227-1239.
6. Atkinson, M.A. and Maclaren, N.K. (1994). The pathogenesis of
insulin-dependent diabetes mellitus. N Engl J Med., 331, 1428-1436.
224
AMERICAN RESEARCH THOUGHTS- Volume 1 │ Issue 1 │ 2014
Khaista Rahman, Ghulam Nabi, Sana Ullah, Muhammad Jamal Khan- DIABETES, A CHALLENGE FOR
MODERN RESEARCH
7. Clarke, S.F. and Foste, J.R. (2012). A History of blood glucose meters
and their role in self-monitoring of diabetes mellitus. British Journal of
Biomedical Science, 69(2).
8. Dahlquist, G.G., Patterson C. and Oltesz, G.S. (1999). Perinatal risk
factors for childhood type 1 diabetes in Europe. The EURODIAB
Substudy 2 Study Group. Diabetes Care, 22, 1698-1702.
9. Defronzo, R.A., and Ferrannini, E. (1991). Insulin resistance. A
multifaceted
syndrome
responsible
for
NIDDM,
obesity,
hypertension, dyslipidemia, and atherosclerotic cardiovascular
disease. Diabetes Care, 14, 173-194.
10.Diabetes Care, 1997. Available at: http://www.diabetes.org/
11.Diabetes Care, 2012. Available at: http://www.diabetes.org/
12.Dyck, R.F., Klomp, H. and Tan, L. (2001). From "thrifty genotype" to
"hefty fetal phenotype": the relationship between high birth weight
and diabetes in Saskatchewan Registered Indians. Can J Public Health,
92, 340-344.
13.Hofman, P.L., Regan, F., Jackson, W.E., Jefferies, C., Knight, D.B. et al.
(2004). Premature birth and later insulin resistance. N Engl J Med.,
351, 2179-2186.
14.Holt, P. (2009). Diabetes in Hospital: A Practical Approach for Healthcare
Professionals. John Wiley & Sons, Ltd.
15.IEC (International Expert Committee). 2009. International Expert
Committee report on the role of the A1C assay in the diagnosis of
diabetes. Diabetes Care, 32, 1327-1334.
16.Jyothi, K.G.A. and Rajasekhar. (2011). A Review on diabetic
retinopathy. International Journal of Pharmacology Research, 1, 1-10.
17.Kumar, P.R., Bhansali, A., Ravikiran, M., Bhansali, S., Dutta, P. et al.
(2010). Utility of glycated hemoglobin in diagnosing type 2 diabetes
225
AMERICAN RESEARCH THOUGHTS- Volume 1 │ Issue 1 │ 2014
Khaista Rahman, Ghulam Nabi, Sana Ullah, Muhammad Jamal Khan- DIABETES, A CHALLENGE FOR
MODERN RESEARCH
mellitus: a community-based study. J Clin Endocrinol Metab., 95, 28322835.
18.Nakayama, M., Abiru, N., Moriyama, H., Babaya, N., Liu, E. et al.
(2005). Prime role for an insulin epitope in the development of type 1
diabetes in NOD mice. Nature, 435, 220-223.
19.Nerup, J., Platz, P., Andersen, O.O., Christy, M., Lyngsoe, J. et al.
(1974). HL-A antigens and diabetes mellitus. Lancet, 2, 864-866.
20.Ounissi-Benkalha, H., and Polychronakos, C. (2008). The molecular
genetics of type 1 diabetes: new genes and emerging mechanisms.
Trends Mol Med., 14, 268-275.
21.Polonsky, K.S. (2012). The past 200 years in diabetes. N Engl J Med.,
367, 1332-1340.
22.Rema, M., Premkumar, S., Anitha, B., Deepa, R., Pradeepa R. et al.
(2005). Prevalence of diabetic retinopathy in urban India: the Chennai
Urban Rural Epidemiology Study (CURES) eye study. I. Invest
Ophthalmol Vis Sci., 46, 2328-2333.
23.Rich-Edwards, J.W., Colditz, G.A., Stampfer, M.J., Willett, W.C.,
Gillman, M.W. et al. (1999). Birthweight and the risk for type 2
diabetes mellitus in adult women. Ann Intern Med., 130, 278-284.
24.Sharma, S., Oliver-Fernandez, A., Liu, W., Buchholz, P. and Walt, J.
(2005). The impact of diabetic retinopathy on health-related quality of
life. Curr Opin Ophthalmol., 16, 155-159.
25.Shaw, J.E., Sicree, R.A. and Zimmet, P.Z. (2010). Global estimates of
the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract.,
87, 4-14.
26.Stolerman, E. S., and Florez, J.C. (2009). Genomics of type 2 diabetes
mellitus: implications for the clinician. Nat Rev Endocrinol., 5, 429-436.
27.Sullivan, P.W., Morrato, E.H., Ghushchyan, V., Wyatt H.R. and Hill,
J.O. (2005). Obesity, inactivity, and the prevalence of diabetes and
226
AMERICAN RESEARCH THOUGHTS- Volume 1 │ Issue 1 │ 2014
Khaista Rahman, Ghulam Nabi, Sana Ullah, Muhammad Jamal Khan- DIABETES, A CHALLENGE FOR
MODERN RESEARCH
diabetes-related cardiovascular comorbidities in the U.S., 2000-2002.
Diabetes Care, 28, 1599-1603.
28.Wild, S., Roglic, G., Green, A., Sicree, R. and King, H. (2004). Global
prevalence of diabetes: estimates for the year 2000 and projections for
2030. Diabetes Care, 27, 1047-1053.
29.Ziemer, D.C., Kolm, P., Weintraub, W.S., Vaccarino, V., Rhee, M.K. et
al.
(2010).
Glucose-independent,
black-white
differences
in
hemoglobin A1c levels: a cross-sectional analysis of 2 studies. Ann
Intern Med., 152, 770-777.
227
AMERICAN RESEARCH THOUGHTS- Volume 1 │ Issue 1 │ 2014