AN ORAL PRESENTATION ON HOW THE HORMONES RESPONSIBLE FOR GLUCOSE METABOLISM FUNCTIONS.

1. BABCOCK UNIVERSITY
COLLEGE OF HEALTH AND MEDICAL SCIENCES
BENJAMIN S. CARSON (SNR) SCHOOL OF MEDICINE
DEPARTMENT OF BIOCHEMISTRY
2014/2015 ORAL SEMINAR PRESENTATION (BCHM
433)
HORMONAL CONTROL OF INTERMEDIARY
METABOLISM OF GLUCOSE AND CONTROL IN
DIABETES.
BY
OLUTOLA, MICHAEL OLAJIDE
BIOCHEMISTRY, 400 LEVEL (11/2913)
9th,October 2014.
SUPERVISED BY MR OMENKA.

2. Introduction
What is intermediary metabolism?
 It refers to the intracellular process by which
nutritive material is converted into cellular
components-can also be called
intermediate metabolism
(Merriam-webster dictionary, 2014).
 The sum of all metabolic reactions between
uptake of nutrient and formation of its excretory
products (Great soviet encyclopedia,1979).
 Intermediary metabolism of glucose begins with
the uptake by glucose transporters located on the
surface of the cell membrane (Bell et al.,1990).

3. Glucose Transporters (Glut)
 Glucose transporters are integral membrane
proteins that facilitate the transport of glucose
across a plasma membrane (oka et al.,1990)
 Each glucose transporter isoform plays a
specific role in glucose metabolism determined
by its pattern of tissue expression, substrate
specificity, and regulated expression in
different physiological conditions (Thorens,
1996).

4. table 1: Table showing glucose
transporters, location and function.
(Burant et al., 1991)

5. UTILIZATION OF GLUCOSE
INTRACELLULARLY
 Glucose is utilized based on the current requirement of the cell
and state of the body system.
 Once its actively transported into the cell, its is immediately
phosphorylated to Glucose 6-phosphate by the enzyme
hexokinase or its isozyme depending on the tissue.
 Glucose 6-phosphate can be further metabolized in the
glycolytic pathway to pyruvate which in turn can be converted
to lactate or alanine or oxidized to acetyl-CoA.
 Alternatively, glucose 6-phosphate can be converted to
glucose 1-phosphate for glycogen synthesis or metabolized in
the pentose phosphate pathway to generate the ribose 5-
phosphate needed for nucleotide/nucleic acid synthesis and
the NADPH. (Nelson and Cox, 2008).

6. Insulin, Glucose metabolism and
Diabetes.
 Insulin is a small protein (5.7 kD) with two polypeptide
chains, A and B containing 51 amino acids, joined by
two disulfide bonds.
 It is synthesized in the pancreas as an inactive single-chain
precursor; preproinsulin with an amino-terminal
“signal sequence” that directs its passage into
secretory vesicles. Proteolytic removal of the signal
sequence and formation of three disulfide bonds
produces proinsulin, which is later cleaved (Nelson and
Cox, 2008).
 After cleavage of the C peptide, mature insulin is
formed in the β-granules and is stored in the form of
zinc-containing hexamers until secretion (Koolman and
Roehm, 2005).

7. Figure 1: Insulin (Koolman and Roehm,2005).

8. Functions of insulin.
Insulin is the only hormone that reduces blood glucose
levels, and it does this by activating the glucose transport
mechanisms and glucose-utilizing metabolic pathways in
different tissues of the body. Insulin also downregulates
glucose forming pathways. The effects of insulin are given
below:
1. Stimulates the uptake of glucose by muscle and
adipose tissue;
2. Stimulates glycolysis;
3. Stimulates glycogenesis;
4. Stimulates protein synthesis
5. Inhibits gluconeogenesis;
6. Inhibits lipolysis;
(Kahn, 2007).

9. Figure 2: Mobilization of Glut 4 by insulin (Nelson and Cox,2008)

10. Functions of insulin cont.
 Insulin stimulates glycolysis by translocating
Glucokinase through the action of Glucokinase
regulatory protein (GKRP) to and fro the nucleus in
hepatocytes based on glucose concentration
(Schaftingen, 1994; Veiga da Cunha et al., 2004).
 In subject to diabetes it is either:
 Insulin production is absent because of autoimmune
pancreatic β-cell destruction. OR
 Insulin secretion is inadequate because the body has
developed resistance to insulin.
(Preeti, 2014).

11. Figure 3: Insulin signal transduction (Koolman and Roehm,2005).

12. Amylin, Glucose metabolism and
Diabetes.
 Amylin also called Islet Amloid polypeptide (IAPP),
is a 37 – residue peptide hormone weighing 7404
Dalton.
 It is co-secreted with insulin from the pancreatic
(beta) cells in the ratio of approximately 1:100.
 Proislet Amyloid Polypeptide (pro IAPP, Proamylin,
Proislet protein) is produced in the pancreatic
(beta) cells as 67- amino acid.
 it undergoes a post-translational modifications
including protease cleavage to produce amylin
(Sanke et al., 1988).

13. Amylin, Glucose metabolism and
Diabetes cont.
 Amylin exerts it actions primarily through the central
nervous system.
 Animal studies have identified specific calcitonin-like
receptor sites for amylin in regions of the brain,
predominantly in the Area Postrema (Ratner et al.,
2004).
 The Area Postrema is a part of the dorsal vagal
complex of the brain stem.
 A notable feature of the Area Postrema is that it lacks
a blood-brain barrier, allowing exposure to rapid
changes in plasma glucose concentrations as well as
circulating peptides, including amylin. (Wimalawansa
et al., 1997).

14. Functions of Amylin.
 Amylin plays a role in glycemic regulation by slowing
gastric emptying and promoting satiety, thereby
preventing post-prandial spikes in blood glucose
levels.
 Amylin’s metabolic function is well-characterized as an
inhibitor of the appearance of nutrient [especially
glucose] in the plasma. (Pittner et al., 1994)
 it functions as a synergistic partner of insulin, with
which it is cosecreted from pancreatic (beta) cells in
response to meals. The overall effect is to slow the
rate of appearance (Ra) of glucose in the blood after
eating.
 this is accomplished via coordinate slowing down
gastric emptying, inhibition of digestive secretion
[gastric acid, pancreatic enzymes, and bile ejection],
and a resulting reduction in food intake.

15. Functions of Amylin cont.
 amylin works to regulate the rate of glucose
appearances from both endogenous (liver-derived)
and exogenous (meal-derived) sources, and insulin
regulates the rate of glucose disappearance. (Buse
et al., 2002).
In subject with diabetes:
 Amylin is deficient in type 1 and impaired in type 2
(Kruger et al., 1999).

16. Glucagon, Epinephrine, Glucose
metabolism and Diabetes.
 The pancreatic hormone glucagon is a 29-amino acid
peptide that is synthesized by the Alpha-cells at the
periphery of the islets of Langerhans and released
primarily in response to low blood glucose levels
(hypoglycemia). (Miller et al., 2003)
 Glucagon is synthesized as proglucagon and
proteolytically processed to yield glucagon within
alpha cells of the pancreatic islets. Proglucagon is also
expressed within the intestinal tract, where it is
processed not into glucagon, but to a family of
glucagon-like peptides (enteroglucagon)
(Bowen,1999).

17. Glucagon, Epinephrine, Glucose metabolism and
Diabetes.
 Epinephrine (also known as adrenaline, or β,3,4-trihydroxy-N-methylphenethylamine)
is a hormone and a neurotransmitter.
 Epinephrine is synthesized in the medulla of the adrenal gland
in an enzymatic pathway that converts the amino acid tyrosine
into a series of intermediates and, ultimately, adrenaline.
 Tyrosine is first oxidized to L-DOPA, which is subsequently
decarboxylated to give dopamine. Oxidation gives
norepinephrine and the methylation of the primary amine of
norepinephrine gives epinephrine. This reaction is catalyzed by
the enzyme phenylethanolamine N-methyltransferase (PNMT)
 This enzyme utilizes S-adenosylmethionine (SAMe) as the
methyl donor.
(Koolman and Roehm, 2008).

18. Glucagon and Epinephrine works in synergy.
 Catabolism of tissue glycogen is triggered by the actions of the
hormones epinephrine and glucagon . In response to decreased
blood glucose, glucagon is released from the cells in pancreatic
islets of Langerhans.(Glucagon is active in liver and adipose
tissue, but not in other tissues).
 Similarly, signals from the central nervous system cause release
of epinephrine from the adrenal glands into the bloodstream.
Epinephrine acts on liver and muscles. When the hormone binds
to its receptor on the outside surface of the cell membrane, a
cascade is initiated that activates glycogen phosphorylase and
inhibits glycogen synthase (Voet and Voet, 2004).
 Although the role of glucagon in the regulation of blood glucose
is well documented, its potential to cause target organ damage in
type 2 diabetes remains poorly understood.(Miller et al.,2003)
 In the kidney, glucagon induces glomerular hyperfiltration, a
characteristic of early type 2 diabetic glomerular injury.(Tolins,
2004)

19. Figure 4: Biosignaling
cascade of Epinephrine in
myocyte and Glucagon in
hepatocyte (Nelson and
Cox, 2008).

20. Tissue Specificity.
 The Liver is the major organ targeted by glucagon
which inhibits glucose utilizing pathways like
(glycolysis, glycogenesis , hexose monophosphate
shunt etc.) and promote glucose producing pathways
such as (gluconeogenesis, glycogenolysis) to supply or
replenish glucose into circulation. The kidney is also
targeted by glucagon to replenish glucose into
circulation.
 These are the only tissues (liver and kidney) capable
of replenishing blood glucose due to the possession of
glucose 6-phosphatase, other tissues in the body
system aren't capable of this due to absence of this
enzyme.
(Garrett and Grisham,)

21. Cortisol, Glucose metabolism and
Diabetes.
 Cortisol is a steroid hormone, more specifically
a glucocorticoid, produced by the zona
fasciculata of the adrenal cortex (Scott, 2011).
 It is released in response to stress and a low
level of blood glucose.
 Its primary functions are to increase blood
sugar through gluconeogenesis, and aid the
metabolism of fat, protein, and carbohydrate
(Hoehn and Marieb, 2010).

22. Cortisol, Glucose metabolism and
Diabetes cont.
 Cortisol is a primary stress hormone secreted by the
adrenal glands in response to inflammation from
infection,injury,reactive substances like allergens or
toxins, and certain digestive disturbances (Nelson and
Cox, 2008).
 High level of cortisol decreases metabolism of glucose
and increases mobilization and metabolism of fats.
 Decreased metabolism of glucose contributes to
increased blood glucose levels, and increased blood
fat levels contribute to insulin resistance.
 Increased levels of blood glucose and blood fats are
classic symptoms of diabetes. When blood cortisol
levels are too high, insulin will not lower blood sugar
(Cartwell, 2006).

23. Somogyi Effect and Dawn
phenomenon
 Somogyi Effect: nocturnal hypoglycemia
(from fasting) leads to a surge of
counterregulatory hormones (glucagon
and epinephrine) that produce
hyperglycemia at around 7AM.
 Dawn Phenomenon: reduced tissue
sensitivity to insulin between 5 and 8
AM.

24. Conclusion
Hormones are responsible for the control and
modulation of enzymes through complex cascade
biosignaling pathways that functions majorly via the
generation or activation of second messengers
located in a biological cell.
In general the imbalance between insulin and
glucagon results into Diabetes mellitus.

25. References
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sensing and stimulus response coupling in insulin release by pancreatic beta-cells”.
Pathogenesis of Non-Insulin-Dependent Diabetes Mellitus”. pp. 61-78.
 Matschinsky, F., Liang, Y., Kesavan, P. (1993). “Glucokinase as pancreatic beta cell
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 Matthaei S, Stumvoll M, Kellerer M, Haring H-U. “Pathophysiology and
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