This document summarizes the regulation of blood glucose levels. It discusses how blood glucose levels fluctuate after meals and during fasting states. The pancreas plays a key role by secreting hormones like insulin and glucagon that work to maintain normal blood glucose levels. Insulin promotes glucose uptake by cells to lower blood glucose, while glucagon has the opposite effect of raising blood glucose levels. The body uses negative feedback loops and other hormones to precisely control blood glucose levels through processes like glycogenesis and glycogenolysis in the liver.

1. Regulation of blood glucose
Radhakrishna G Pillai
Department of Life Sciences
University of Calicut

2. Regulation of blood glucose
• Blood-glucose levels fluctuate as a person’s intake of food varies over a
24-hour period
• After meals, the blood-glucose levels rise although this is buffered by
glucose storage in the liver
When the body is in a post-absorptive
state and, as the body’s cells use
glucose to make energy, blood-
glucose levels fall
Despite these fluctuations, the body
needs to maintain blood-glucose
levels within certain limits

3. Normal glucose levels
• Post-absorptive, fasting-state glucose levels are
more reliable and are generally used by health
care professionals when testing blood glucose
• Typical fasting levels of blood glucose lie
between 3.3 and 6.1mmol/L
• Results outside this range could indicate a
dysfunction in glucose regulation such as that
which occurs in patients with diabetes mellitus

4. The role of the pancreas
• The pancreas is unusual in having both an exocrine and endocrine function
• As an exocrine gland it produces several digestive enzymes that are
secreted into the duodenum via the pancreatic duct
• Over 90 per cent of the pancreas is devoted to its exocrine, digestive
function
As an endocrine gland, the
pancreas secretes a variety of
hormones that are concerned
with the regulation of blood
glucose, including insulin,
glucagon, and somatostatin

5. Hormones from pancreas
• These hormones are produced by groups of cells -
appear as small clusters, or islands
• They were discovered by the German anatomist Paul
Langerhans- hence called Islets of Langerhans or
• simply pancreatic islets.
• Response to an increase in blood glucose, an increase
in blood glucose is detected by the beta cells of the
pancreatic islets, causing them to increase the
release of insulin into the blood
• Insulin stimulates cells, especially adipose and muscle
cells, to take up glucose from the blood

6. Insulin and the transport of glucose into
cells
• To enter cells, glucose requires trans-membrane transporters and
there is a family of these called GLUT (GLUcose Transporter)
• The most numerous is GLUT4, which is found on muscle and fat
cells
• When insulin binds to insulin receptors on the cell membrane,
cells are stimulated to increase the number of glucose
transporters.
• The more transporters are produced, the more glucose is
transported into cells – with a corresponding drop in blood glucose
• The precise mechanism whereby insulin binds to receptors causing
translocation is still to be determined (Sanger Institute, see
‘websites’).
• Not all tissues require insulin to take up glucose, for example brain
and liver cells use GLUT transporters that are not dependent on
insulin

7. Further effects of insulin
• The hormone has other effects on the body’s cells
• All of which contribute to an increase in glucose usage and
storage and
• Result a reduction in blood glucose
• These include:
– The promotion of glycolysis -breaks down glucose for cellular
energy
– The promotion of glycogenesis-a process that converts glucose
into glycogen for storage
– The inhibition of lipolysis, a process that breaks down lipids to
release energy
– These effects of insulin actively shift the metabolism away from
fat and towards glucose
– Insulin drives the body to utilise carbohydrates as a source of
energy and to spare its fat reserves

8. Response to a decrease in blood glucose
• Insulin levels fall along with blood glucose and this results in the hormone
glucagon being released by the alpha cells of the pancreas
• Glucagon has the opposite effect to insulin -it increases blood-glucose
levels and
• Promotes processes that spare glucose utilisation
• Glucagon works primarily on the hepatocytes in the liver to:
– Convert stored glycogen into glucose and release it into the blood
– Promote gluconeogenesis, the manufacture of new glucose from lactic acid
and other metabolites
– Glucagon binds to glucagon receptors, which are part of the G-protein-
coupled receptor family.
– This stimulates a series of linked enzyme reactions, resulting in the activation
of
– glycogen phosphorylase the enzyme responsible for the mobilisation of
glycogen reserves into free glucose
– the creation of glucose from amino acids
– Glucagon release is inhibited by both insulin and somatostatin

9. Homeostatic control
The control of blood glucose is an
excellent example of homeostatic
control via negative feedback
This is where the corrective response,
triggered by a deviation from normal
levels, is turned off by a return to
normal levels
For example, low blood glucose
results in the production of glucagon
and this raises blood glucose
Consequently, as glucose levels rise,
the stimulation to produce glucagon
is turned off

10. Other hormones involved in the
regulation of blood glucose
• The regulation of blood glucose is complex and there are many other
hormones beside insulin and glucagon that play an important function
• Somatostatin is released by the delta cells located in the pancreatic islets
in response to a post-prandial increase in blood glucose and amino acids
• It reduces gut motility and the further absorption of nutrients as well as
inhibiting pancreatic exocrine secretions
• The function of gastrin and cholecystokinin
• The gastrointestinal tract also releases hormones such as gastrin and
cholecystokinin that stimulate the pancreas to secrete insulin in
anticipation of the absorption of nutrients
• During stress, neuro-endocrine mechanisms cause the release of stress
hormones such as adrenaline (epinephrine)
• These increase blood-glucose levels by mobilising glycogen and
suppressing the release of insulin
• Other hormones such as amylin and pancreatic polypeptide (PP) are
involved in glucose regulation but their roles are less well understood

11. Neuroregulation of blood glucose
• The autonomic division of the nervous system
modulates the release of insulin and glucagon
• The sympathetic stimulation that occurs with
exercise stimulates glucagon production
• This maintains blood-glucose levels
• BG fall as muscles use glucose for their energy
• During the body is at rest;
– parasympathetic activity stimulates digestion and
– release insulin to deal with the expected rise in blood
glucose.

12. Glycogenesis
• The process of glycogen synthesis, in
which glucose molecules are added to chains of
glycogen for storage
• This process is activated during rest periods
following the Cori cycle, in the liver, and
• also activated by insulin in response to high
glucose levels, for example after
a carbohydrate-containing meal

13. The Cori cycle
• Also known as the Lactic acid cycle, named after its discoverers, Carl
Ferdinand Cori and Gerty Cori,
• Refers to the metabolic pathway in which lactate produced by
anaerobic glycolysis in the muscles moves to the liver and is converted to
glucose
• which then returns to the muscles and is metabolized back to lactate

14. Glycogenesis
• Glucose is converted into glucose-6-phosphate by the
action of glucokinase or hexokinase.
• Glucose-6-phosphate is converted into glucose-1-
phosphate by the action of phosphoglucomutase, passing
through the obligatory intermediate glucose-1,6-
bisphosphate.
• Glucose-1-phosphate is converted into UDP-glucose by the
action of the enzyme UDP-glucose phosphorylase
• Pyrophosphate is formed, which is later hydrolysed by
pyrophosphatase into two phosphate molecules
• Glycogenin, a homodimer, has a tyrosine residue on each
subunit that serves as the anchor for the reducing end of
glycogen

15. Glycogenesis
• Initially, about eight UDP-glucose molecules are added
to each tyrosine residue by glycogenin, forming α(1→4)
bonds
• Once a chain of eight glucose monomers is
formed, glycogen synthase binds to the growing
glycogen chain and adds UDP-glucose
• to the 4-hydroxyl group of the glucosyl residue on the
non-reducing end of the glycogen chain, forming more
α(1→4) bonds in the process
• Branches are made by glycogen branching enzyme
• which transfers the end of the chain onto an earlier part
via α-1:6 glycosidic bond
• forming branches, which further grow by addition of
more α-1:4 glycosidic units

16. Glycogenolysis
• breakdown of glycogen to glucose-6-
phosphate and glycogen
• Glycogen branches are catabolised by the sequential
removal of glucose monomers via phosphorolysis, by
the enzyme glycogen phosphorylase
• Here, glycogen phosphorylase cleaves the bond
linking a terminal glucose residue to a glycogen
branch by substitution of a phosphoryl group for the
α[1→4] linkage
• Glucose-1-phosphate is converted to glucose-6-
phosphate by the enzyme phosphoglucomutase
• Glucose residues are phosphorolysed from branches
of glycogen until four residues before a glucose that is
branched with a α[1→6] linkage.

17. Glycogenolysis
• Glycogen debranching enzyme then transfers three
of the remaining four glucose units to the end of
another glycogen branch
• This exposes the α[1→6] branching point, which
is hydrolysed by α[1→6] glucosidase, removing the
final glucose residue of the branch as a molecule of
glucose and eliminating the branch
• This is the only case in which a glycogen metabolite
is not glucose-1-phosphate
• The glucose is subsequently phosphorylated to
glucose-6-phosphate by hexokinase

18. Gluconeogenesis
• Metabolic pathway that results in the generation of glucose from
certain non-carbohydrate carbon substrates
• From breakdown of proteins, these substrates include glucogenic
amino acids (not ketogenic amino acids);
• From breakdown of lipids (such as triglycerides), they include
glycerol (although not fatty acids) and
• From products of other steps in metabolism – pyruvate and
lactate
• The process occurs during periods of fasting, starvation, low-
carbohydrate diets, or intense exercise
• The process is highly endergonic until it is coupled to the
hydrolysis of ATP or GTP, effectively making the
process exergonic