insulin and glucagon hormones

1. Insulin and Glucagon Hormones
Faculty of Medicine
Department of Biochemistry

2. Overview
• Four major organs play a
dominant role in fuel
metabolism: liver, adipose
tissue, muscle and brain.
• Communication between
tissues is mediated by the
nervous system, by the
availability of circulating
substrates and by variation
in the levels of plasma
hormones.

3. • Changes in the circulating levels of these hormones
allow the body to:
a) Store energy when food is available in abundance,
b) Make stored energy available, for example, during
severe injury, and “fight-or-flight” situations.
• The integration of energy metabolism is controlled
primarily by the actions of two peptide hormones:
insulin and glucagon, with the catecholamines;
(epinephrine & norepinephrine); have a supporting
role.
Overview

4. INSULIN HORMONE
• Insulin is a polypeptide hormone produced by the
β cells of islets of Langerhans.
• The islets of Langerhans are about 1-2% of the
total cells of the pancreas.
• Insulin is the most important hormone
coordinating the use of fuels by tissues.
• Its metabolic effects are anabolic, i.e., favoring
synthesis of glycogen, TAGs and proteins.

5. • Insulin is composed of 51 amino
acids arranged in two
polypeptide chains, A and B,
which are linked together by two
disulfide bridges.
• Insulin molecule contains also
one intra-molecular disulfide
bridge between amino acid
residues of the A chain.
Structure Of Insulin

6. Synthesis of Insulin:
The biosynthesis involves two inactive precursors, pre-
pro-insulin and pro-insulin, which are sequentially
cleaved to form the active hormone “ insulin” and the
connecting or the C-peptide.

7. • The C-peptide is essential for proper insulin folding.
• The C-peptide has a long half-life in the plasma, so, it
is a good indicator of insulin production and
secretion in early diabetes.
• Insulin is stored in the cytosol in granules. Proper
stimulus of these granules causes release of insulin by
exocytosis.
• Insulin is degraded by insulinase enzyme which is
present in liver and to a lesser extent in the kidneys.
• Insulin has a plasma half-life of approximately 6 minutes.

8. Regulation of Insulin Secretion
1- Stimulation of Insulin Secretion
l Insulin secretion by the β-cells of the pancreas is
closely coordinated with the release of glucagon
by α-cells of islets of Langerhans.
l The relative amounts of insulin and glucagon
released by the pancreas are regulated so that the
rate of hepatic glucose production is kept equal
to the use of glucose by peripheral tissues.

9. Changes in blood levels of glucose, insulin, and
glucagon after ingestion of a carbohydrate-rich meal

10. A - Glucose:
• Glucose is the most important stimulus for insulin
secretion.
• β-cells are the most important glucose-sensing cells in
the body. Like the liver, β-cells contain GLUT-2 and have
glucokinase activity.
• So, they can uptake and phosphorylate glucose in
amounts proportional to its actual concentration in the
blood.
• Ingestion of glucose or a carbohydrate-rich meal leads
to a rise in blood glucose level, which is a signal for
increased insulin secretion and a decreased glucagon
synthesis and release.

11. Plasma glucose transporters

12. SGLT: sodium-glucose linked transporter
• SGLT are a family of glucose transporter found in
the intestinal mucosa (enterocytes), (SGLT1) and
the proximal tubule of the nephron (SGLT2 in S1
and S2 segments of PCT and SGLT1 in S3 segment
of PCT).
• They contribute to renal glucose reabsorption.
• In the kidneys, 100% of the filtered glucose in
the glomerulus is reabsorbed along the nephron
(98% in PCT, via SGLT2).

13. SGLT: sodium-glucose linked transporter
• In case of too high plasma glucose concentration
(hyperglycemia), glucose is excreted in urine
(glucosuria); because SGLT are saturated with
the filtered glucose
• Glucose is never secreted by the nephron.

14. B - Amino acids:
• Ingestion of protein causes a transient rise in
plasma amino acid levels, which in turn, induces
the immediate secretion of insulin.
• Elevated plasma arginine is a particularly potent
stimulus for insulin synthesis and secretion.
Stimulation of Insulin Secretion

15. C - Gastrointestinal hormones:
• Most gastrointestinal hormones favor insulin release.
• The intestinal peptides Cholecystokinin and Gastric-
Inhibitory Polypeptide increase insulin secretion in
response to oral glucose.
• This may explain why the same amount of glucose
given orally induces a much greater secretion of
insulin than if it is given intravenously.
Stimulation of Insulin Secretion

16. • The synthesis and release of insulin are decreased
when there is a decrease of dietary fuels and also
during periods of stress (for example: fever,
infection ......etc)
• These effects are mediated primarily by
epinephrine, which is secreted by the adrenal
medulla in response to stress, trauma or extreme
muscular exercise.
Inhibition of Insulin Secretion

17. • In these conditions, epinephrine is largely
controlled by the nervous system.
• Epinephrine has a direct effect on energy
metabolism, causing a rapid mobilization of
energy-yielding fuels, including glucose from the
liver ( by glycogenolysis or gluconeogenesis) and
fatty acids from adipose tissue.
Inhibition of Insulin Secretion

18. • In addition, epinephrine can override the normal glucose
- stimulated release of insulin.
• Thus, in emergency situations, the CNS (sympathetic
nervous system) largely replaces the plasma glucose
concentration as the controlling influence over β - cell
secretion.

19. Insulin Receptor

20. Biologic Effects of Insulin

21. Metabolic effects of Insulin
Effects on metabolism:
The effects of insulin on glucose metabolism:
• Promote its storage and are most prominent in
three tissues: liver, muscle and adipose tissue”.
• Increase glucose uptake
• Increase glycogen synthesis.
• Increase protein synthesis.
• Increase Lipid synthesis.
• Inhibition of glycogenolysis and gluconeogenesis.

22. Mechanism of Insulin Action

23. Characteristics of glucose transport in various tissues

24. Receptor regulation:
• Binding of insulin is followed by internalization
of the hormone–receptor complex. Once inside
the cell, insulin is degraded in the lysosomes.
• The receptors may be degraded but most are
recycled to the cell surface.
• Elevated levels of insulin promote the
degradation of receptors, thus decreasing the
number of surface receptors.
• This is one type of “down-regulation.”

25. Glucagon Hormone
• Glucagon is a polypeptide hormone secreted by
the α cells of the islets of Langerhans of the
pancreas.
• Glucagon, along with epinephrine, cortisol and
growth hormone oppose many of the actions of
insulin.
• Glucagon acts to maintain blood glucose levels at
normal values between meals by the activation
of hepatic glycogenolysis and gluconeogenesis.

26. Regulation of Glucagon Release
“from pancreatic α cells"

27. Glucagon Receptor

28. Stimulation of Glucagon Secretion
1- Low blood glucose:
During an overnight or prolonged fast, elevated
glucagon levels prevent hypoglycemia.
2- Amino acids:
A meal containing proteins stimulates the release of
both glucagon and insulin.
Glucagon effectively prevents hypoglycemia that
would otherwise occurs as a result of increased
insulin secretion that occurs after a protein meal.

29. 3- Epinephrine:
• Elevated levels of circulating epinephrine produced by
the adrenal medulla, or norepinephrine produced by
sympathetic nervous system of the pancreas, or both,
stimulate the release of glucagon.
• Thus, during periods of stress, trauma, or severe
exercise, in these situations—regardless of the
concentration of blood glucose, glucagon levels are
elevated in anticipation of increased glucose use.
• In contrast, insulin levels are depressed.
Stimulation of Glucagon Secretion

30. Metabolic effects of glucagon
Effects on carbohydrate metabolism:
• Increase in the breakdown of liver (not muscle)
glycogen and an increase in gluconeogenesis.
Effects on lipid metabolism:
• Activates lipolysis in adipose tissue.
Effects on protein metabolism:
• Increases uptake of amino acids by the liver,
resulting in increased availability of carbon
skeletons for gluconeogenesis. So, plasma levels
of amino acids are decreased.

31. Opposing actions of insulin by
glucagon plus epinephrine

32. Diabetes Mellitus (DM)
• Normal plasma glucose 70-110 mg/dL.
• Type 1 diabetes: or insulin dependent diabetes is a
chronic condition in which the pancreas produces little or
no insulin. Usually diagnosed in children & young adults.
• Type 2 diabetes: characterized by high blood sugar,
insulin resistance and relative lack of insulin.
• About 90% of cases of diabetes.
• Caused by a combination of lifestyle & genetic factors.
• Gestational diabetes: is a rare disorder that happens
in pregnancy, usually in the third trimester.
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33. Diagnosis of Diabetes Mellitus (DM)
ØThe American Diabetes Association defines the
normal glucose reference ranges as below:
- Fasting plasma glucose 70-99 (≤ 110) mg/dL .
- Two-hour postprandial plasma glucose levels: Give
the patient a 75 g glucose orally and after 2hrs
measure plasma glucose; level ≤ 140mg/dL.
- Random plasma glucose level of ≤ 140 mg/dL.
- HbA1c level: normal range less than 6%.
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34. WHO Diabetes Diagnostic Criteria
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Condition
2 hour
glucose
Fasting
glucose
HbA1c
Unit mg/dl mg/dl %
Normal <140 <110 <6.0
Impaired fasting
glycaemia
<140 ≥110 & <126 6.0–6.4
Impaired glucose
tolerance
≥140 <126 6.0–6.4
Diabetes mellitus ≥200 ≥126 ≥6.5
!

35. Diagnosis of Diabetes Mellitus (DM)
HbA1c
Ø According to the American Diabetes Association (ADA)
guidelines regarding to the HbA1c level:
a) HbA1c <7.5% = well controlled DM.
b) HbA1c 7.5% & ≤ 9% = fairly controlled DM.
c) HbA1c >9% = poorly controlled DM.
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