Download 52. Akram INSULIN_et al

Journal of Cell and Animal Biology Vol. 6(8), pp. 123-128, 30 April, 2012
Available online at http://www.academicjournals.org/JCAB
DOI: xxx
ISSN 1996-0867 ©2012 Academic Journals
Review
Insulin: A review
M. Akram*, Khan Usmanghani, H. M. Asif
Department of Basic Medical Sciences, Faculty of Eastern Medicine, Hamdard University, Karachi, Madinat-al-Hikmah,
Muhammad Bin Qasim Avenue, Karachi, Pakistan-74600, Pakistan.
Accepted 25 April, 2012
Insulin is anabolic hormone that is secreted from beta cells of pancreas and is involved in various
cellular functions of body insulin is a polypeptide hormone produced by the beta cells of islets of
langerhans of pancreas. It has profound influence on the metabolism of carbohydrate, fat and protein.
Insulin is considered as anabolic hormone, as it promotes the synthesis of glycogen, triacylglycerols
and proteins. This hormone has been implicated in the development of diabetes mellitus. Insulin
occupies a special place in the history of biochemistry as well as medicine. Insulin was the first
hormone to be isolated, purified and synthesized; first hormone to be sequenced; first hormone to be
produced by recombinant DNA technology. Its deficiency results in diabetes mellitus.
Key words: Insulin, effect of insulin on body organ, insulin related metabolic disorders.
INTRODUCTION
Insulin plays a key role in the regulation of carbohydrates,
lipid and protein metabolism. Insulin exerts anabolic and
anticatabolic influences on the body metabolism. In a
normal individual, about half of the individual glucose is
utilized to meet the energy needs of the body (mainly
through glycolysis). The other half is converted to fat
(40%) and glycogen (10%). Insulin is required for the
uptake of glucose by muscle (skeletal, cardiac and
smooth), adipose tissue, leucocytes and mammary
glands (Kahn, 1994). Insulin increases glucose utilization
in muscle and liver. The net effect of insulin on lipid
metabolism is to reduce the release of fatty acids from
the stored fat and decrease the production of ketone
bodies. Insulin favors the synthesis of triacylglycerols
from glucose by providing more glycerol 3 – phosphate
(from glycolysis) and NADP (from HMP shunt). Insulin
decreases the activity of hormone – sensitive lipase and
thus reduces the release of fatty acids from stored fat in
adipose tissue. The mobilization of fatty acids from liver is
also decreased by insulin. Insulin reduces ketogenesis by
decreasing the activity of HMG Co-A synthetase. Further,
*Corresponding
author.
E-mail:
[email protected]. Tel: 92-021-6440083. Fax:
92-021-6440079.
insulin promotes the utilization of acetyl Co-A for
oxidation (Krebs cycle). Insulin promotes cell growth and
replication. It increases protein synthesis. Xi et al. (2005)
has studied that Crocetin prevents dexamethasoneinduced insulin resistance in rats.
STRUCTURE OF INSULIN
Human insulin (mol. Wt. 5,734) contains 51 amino acids
arranged in two polypeptides chains. The chain A
contains 21 amino acids while B has 30 amino acids.
Both are held together by two interchain disulfide bridges,
connecting A7 to B7 and A20 to B19. In addition, there is an
intercahain disulfide link in chain A between the amino
acids 6 and 11(Bell et al., 1980).
BIOSYNTHESIS OF INSULIN
Insulin is produced by the beta cells of the islets of
langerhans of pancreas. The gene for this protein
synthesis is located on chromosome 11. The synthesis of
insulin involves two precursors, namely preproinsulin with
108 amino acids (mol. Wt. 11,500) and proinsulin with 86
amino acids (mol. Wt. 9, 000). They are sequentially
degraded to form the active hormone insulin and a
connecting peptide (C-peptide). Insulin and C-peptide are
produced in equimolar concentration. C-peptide has no
biological activity; however, its estimation in the plasma
serves as a useful index for the endogenous production
of insulin. In the beta cells, insulin and also (proinsulin)
combines with zinc to form complexes. In this form,
insulin is stored in the granules of the cytosole which is
released in response to various stimuli by exocytosis
(Froguel et al., 1994).
REGULATION OF INSULIN SECRETION
About 40-50 units of insulin are secreted daily by human
pancreas. The normal insulin concentration in plasma is
20-30µU/ml(Gartner et al., 2007).
This short life permits rapid metabolic changes in
accordance to the alteration in the circulating levels of
insulin. This is advantageous for the therapeutic
purposes. A protease enzyme, namely insulinase (mainly
found in liver and kidney), degrades insulin (Bowerman,
2007).
Metabolic effects of insulin
Insulin plays an important role in regulating the
metabolism of carbohydrates, lipid and proteins. Insulin
has anabolic effects on body metabolism (Madi son et
al ., 1960).
Insulin receptors
GLUCOSE
Glucose is the most important stimulus for insulin
release. The effect is more pronounced when glucose is
administered orally (either direct or through a
carbohydrate rich meal). A rise in blood glucose level is a
signal for insulin secretion (Alberti et al., 1998).
It is found on target tissue for insulin. It is a tetramer of
two alpha and two beta subunit. The beta subunits span
the cell membrane and have tyrosine kinase activity. The
phosphorylated receptor then phosphorylates intracellular
proteins. The insulin receptor complexes enter the target
cells. Insulin down regulates its own receptors in target
tissues (Abbasi et al., 2002).
AMINO ACIDS
Effects on carbohydrate metabolism
Amino acids induce the secretion of insulin. This is
particularly observed after the ingestion of protein rich
meal that causes transient rise in plasma amino acid
concentration. Among the amino acids, arginine and
leucine are potent stimulators of insulin release (John et
al., 1966).
Insulin influences glucose metabolism in many ways. The
net effect is that insulin lowers blood glucose level
(hypoglycemic effect) by promoting its utilization and
storage and by inhibiting its production (Hanson et al.,
2000).
GASTROINTESTINAL HORMONES
Effect on glucose uptake by tissues
Gastrointestinal hormones (secretin, gastrin, and
pancreozymin) enhance the secretion of insulin. The GIT
hormones are released after the ingestion of food
(Capella, 1995).
Insulin is necessary for the absorption of glucose by
muscle (skeletal, cardiac and smooth), adipose tissue,
white blood cells and mammary glands. Surprisingly,
80% of glucose uptake in the body is not dependent on
insulin (Ohkubo et al., 1995). Regarding the liver, the
entry of glucose into hepatocytes does not require insulin.
However, insulin stimulates utilization of glucose in the
liver and therefore indirectly promotes uptake (Atkin et
al., 1994).
FACTORS AFFECTING INSULIN SECRETION
Epinephrine is the most potent inhibitor of insulin release.
In emergency situations like stress, extreme exercise and
trauma in the nervous system stimulates adrenal medulla
to release epinephrine. Epinephrine suppresses insulin
release and promotes energy metabolism by mobilizing
energy yielding compounds –glucose from liver and fatty
acids from adipose tissue (Bach, 1994).
Degradation of insulin
In the plasma, insulin has a normal half life of 4-5 min.
Effect on glucose utilization
Insulin increases glucose utilization in muscle and liver.
The activation and the quantities of certain key enzymes
of glycolysis that is, glucokinase (not hexokinae)
phosphofructokinase and pyruvate kinase are increased
by insulin, increasing the activity of glycogen synthetase
(Cherri ngt on et al ., 1978).
Effect on glucose production
Insulin decreases gluconeogenesis by suppressing
enzymes pyruvate carboxylase, phosphoenolpyruvate
carboxykinase and glucose 6 phosphatase. Insulin also
inhibits glycogenolysis by glycogen phosphorylase
inactivation (Edgert on et al. , 2001).
iii) Increased glycerol phosphate synthesis
iv) Increased triglyceride deposition
v) Activation of lipoprotein lipase
vi) Inhibition of hormone-sensitive lipase
vii) Increased K+ uptake (Si ndel ar et al ., 1997).
Muscle
Effect on lipid metabolism
The net effect of insulin on lipid metabolism is to reduce
the release of fatty acids from the stored fat and reduce
the production of ketone bodies. Among the tissues,
adipose tissue is more sensitive to insulin (Gosch et al.,
1996).
i) Increased glucose entry
ii) Increased glycogen synthesis
iii) Increased amino acid uptake
iv) Increased protein synthesis in ribosomes
v) Decreased protein catabolism
vi) Decreased release of gluconeogenic amino acids
vii) Increased ketone uptake
viii) Increased K+ uptake
Effect on lipogenesis
Liver
Insulin promotes the synthesis of triglycerides from
glucose through more glycerol -3- phosphate (from
glycolysis) and NADP (from HMP shunt). Insulin
increases the activity of acetyl Co-A carboxylase, a key
enzyme in synthesis of fatty acids (Rosdahl et a l .,
1998).
i) Decreased ketogenesis
ii) Increased protein synthesis
iii) Increased lipid synthesis
iv) Decreased glucose output due to decreased
gluconeogenesis, increased glycogen synthesis, and
increased glycolysis.
Effect on lipolysis
General
Insulin decreases the activity of the hormone - sensitive
lipase and thus reduces the release of fatty acids from fat
stored in adipose tissue. The mobilization of fatty acids
by the liver is also decreased by insulin (Choudhury et
al., 2004).
Increased cell growth.
Insulinoma
Insulin reduces ketogenesis by reducing the activity of
HMG Co-A synthetase. Furthermore, insulin promotes
the utilization of acetyl Co-A for oxidation (Krebs cycle).
Insulinoma must be considered as one possible cause of
spontaneous hypoglycemia. This is arbitrarily defined as
a blood-glucose concentration below 2.2 mmo1/1 (40
mg/100 ml). It may be many years before it is realized
that the patient, commonly in the care of the neurologist
or psychiatrist, has this rare condition (Iskra et al., 2011).
Effects on protein metabolism
RESEARCH STUDY
Insulin causes the entry of amino acids into cells. Insulin
promotes cell growth and replication. It also increases
protein synthesis.
Effect of Zingiber officinale on insulin and diabetic
patient
Effect on ketogenesis
Effects of insulin on various tissues
Adipose tissue
i) Increased glucose entry
ii) Increased fatty acid synthesis
Z. officinale produces a significant increase in insulin
levels and a decrease in fasting glucose levels in diabetic
rats. In an oral glucose tolerance test, treatment with Z.
officinale was found to decrease significantly the area
under the curve of glucose and to increase the area
under the curve of insulin in STZ-diabetic rats. Z.
officinale
is
effective
in
hypercholestrolemia,
hypertriglyceridemia and blood blood pressure in diabetic
rats. This study suggest a potential antidiabetic activity of
the juice of Z. officinale in type I diabetic rats, possibly
involving 5-HT receptors (Sanjay et al., 2004).
CONCLUSION
Insulin is secreted by the beta cells of pancreas. Insulin
deficiency results in diabetes mellitus. Insulin is involved
in metabolism of carbohydrate, protein and lipids. Insulin
is in widely used to treat diabetes
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