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Biotechnology and Society---Part IV
Genetic Diseases---Diabetes
You see things that are and say, how? But I see things that never were and say, why not?
-----George Bernard Shaw (1856-1950)
“kAlaththin vidhi madhiyaik kadandhidumO” enREn
“kAlamE madhiyinukkOr karuviyAm” enRAL
-----Mahakavi Subramanya Bharathi (1882-1921)
We discussed haemophilia, its
reputation as a ‘royal disease’, and the currently available treatment for
it in the previous article. Let us examine another genetic disorder, which is
not so royal, but affects a lot of commoners. It is said Fate does not
discriminate between the prince and the pauper. Recall that our Brahma
dhandam is impartial and blind (figuratively-speaking, that is).
However, as Bharathi observed in the quote above, time, in conjunction
with knowledge, can be used as an opportunity (instrument) through appropriate
application to overcome adversity.
Diabetes: Diabetes is
a metabolic disorder manifested by an abnormality in the way the body uses
glucose generated from food. It is a rather complex, “multi-factorial”
disease which when left unmanaged can lead quickly to heart attack, stroke,
blindness, kidney failure and a whole host of problems. It is classified as
either Type-I, wherein there is no insulin production (by the
body’s endocrine gland pancreas), a hormone required for glucose uptake by
the cells needed for their function, or Type-II, which is characterised
by resistance of the body tissues to the action of insulin. Of the total
diabetic population, only ~10% belong to Type-I and the rest to Type-II. The
cause of either type is not known for sure, but it is related to history of
diabetes in the family.
Without the insulin (or its
effective function) binding to cells, glucose cannot enter the cells and the
cells starve for glucose while all the glucose keeps circulating in the blood.
Poverty in the midst of plenty!! Interestingly, the brain has been considered
“insulin-insensitive” because of its ability to use glucose without the
aid of insulin. Thus, while the body is suffering, the brain is still active
(a blessing amid a curse, perhaps!).
A connection has been
observed between the X chromosome and Type-I diabetes. In contrast to
haemophilia patients being predominantly male, diabetes affects both male and
female populations. European countries have a higher male:female ratio of
Type-I diabetic patients, while Asian and African countries have a low
male:female ratio. Fortunately, the body tissues respond to insulin (delivered
by injection) in all these patients.
Heredity plays an important
role in Type-II diabetes too. Patients whose mothers had diabetes are twice as
likely to get the disease as those whose fathers had it. It is known that over
a number of generations, the Type-II disease has been transmitted along the
maternal line. One reason for such transmission lies in the role of maternally
inherited genetic elements such as the mitochondrial DNA, which is outside the
nucleus (the nucleus contains all the chromosomes). Any defects in the
mitochondrial DNA will be passed along only through the mother.
Type-II diabetes is very
relevant to countries like India where the recent relative affluence has
exacerbated the condition in both native population as well as the Indian
diaspora throughout the world1. Although Type-II diabetes is often linked to
obesity, not every obese person gets Type-II diabetes. Correspondingly, even
non-obese people get Type-II, an indication that some are more genetically
susceptible than others.
Type-II diabetes can,
however, be managed by a variety of approaches, including diet, exercise and
oral medications, in addition to insulin (in some cases). Most of the oral
drugs used by Type-II patients are small molecules designed either to suppress
glucose production by the liver, or enable greater insulin secretion by the
pancreas, or even make insulin work better. Type-II diabetes is generally more
manageable than Type-I (which requires insulin injections constantly).
However, Type-II diabetes is capable of causing severe complications if left
uncontrolled.
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Insulin,
which is made in the pancreas (in cells called beta islet cells) first as a
precursor (predecessor) in the form of proinsulin which is later converted to
insulin by an enzyme in the pancreas, was discovered in 1921 and subsequently
its structure was determined and its mechanism of action was delineated.
Before insulin was discovered and utilised for diabetic condition, the disease
was usually fatal. In the early days, insulin was isolated from human
cadavers. That supply having proved inadequate, animal insulin from pigs and
cows was used pretty effectively. This required virtually the entire available
stock of beef and pork pancreas from the slaughterhouses. However, it was
found that the animal insulin, while functionally effective, differed slightly
in composition from the human analog thereby generating an immune response
when administered to humans. An effective alternative had to be found to
circumvent this problem.
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Arrives
on the scene recombinant DNA technology to the rescue! The human gene for
insulin was isolated and packaged into a plasmid (a circular piece of
DNA normally found in several bacteria) and introduced into a bacterium, a la
Trojan horse by Genentech, a biotechnology company in California. Eli
Lilly, a multinational pharmaceutical company, manufactured insulin in a
cousin of the common intestinal bacterium E.coli. Once the gene was inserted
in E.coli and the bacteria grown in a fermenter, the microorganism started
making insulin. The product was processed, and purified through an elaborate
procedure, rigorous clinical trials were conducted and an FDA (Food & Drug
Administration) licence was obtained in 1982. It was the first biotechnology
drug to gain market approval. The product called Humulin® is marketed
now all over the world. Other analogs of Humulin®, such as Humalog®,
have also been made with different properties needed under different
conditions. These recombinant products have been quite a blessing for all
Type-I diabetics (and some Type-II) who can use them with utmost confidence
from the safety and efficacy points of view. In recent years, other companies
such as Aventis, Novo Nordisk and Hoechst have also introduced
recombinant insulin products.
Genomic
researchers have their work cut out for them. It appears that there are
several diabetes-susceptible genes in humans with Type-II diabetes. Several
are being identified which could provide good targets for anti-diabetic drugs.
Some drugs like thiazolidinediones are already in the market. Unlike Type-I,
Type-II cannot be treated by insulin (in most cases) since the insulin
resistance is not the result of insulin deficiency alone, but a combination of
several deficiencies including the protein that transports the glucose from
the blood across into the cell, and further processing of glucose all of which
are due to mutated or non-functional genes. Research in molecular biology can
open the doors for further understanding and thus the amelioration of the
disease condition.
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We shall examine a couple of other prominent genetic diseases in the next two
articles to give us a perspective on the diversity of recombinant DNA
technology in addressing the health issues of a variety of populations.
1 It is advisable, for all
Indians, to check their body mass index with their physicians and their
susceptibility for Type-II diabetes. They can also check it themselves. Body
mass index (BMI) is defined as follows: In metric system, BMI= weight in
kilograms/ (height in meters)2 In the US, BMI= {(weight in pounds)
x 705} / (height in inches)2 In general, a BMI value of = or <
24 should be a target to aim. Consult your doctor.
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